ViroPharma Incorporated (Nasdaq: VPHM) announced that it has completed enrollment in its Phase 2 study evaluating subcutaneous delivery of Cinryze™ (C1esterase inhibitor [human]). This multi-center, open-label, multi-dose Phase 2 study is designed to evaluate the safety, pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous administration of Cinryze in adolescent and adult subjects with hereditary angioedema (HAE). The company expects to have preliminary data from this study by the end of this year, which will help inform the next steps of development for this mode of administration.
"The rapid enrollment into this study is indicative of the interest in, and also the potential for, prophylaxis with a subcutaneous form of Cinryze," commented Judy Johnson, ViroPharma's vice president of clinical pharmacology and nonclinical development. "We look forward to completing this important study which will inform our path forward, including the Phase 3 study design. We are excited by the potential of a subcutaneous option for patients who choose prevention of their HAE attacks."
Cinryze was approved by the U.S. Food and Drug Administration in October 2008 for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE.
Clinical Study Design
This is a multi-center, open-label multiple dose study in 24 adolescent and adult HAE patients in the US. All eligible subjects have been randomized into one of two treatment groups: Patients received Cinryze via IV infusion two times per week for two weeks. Then, following a 14-day washout period, subjects received Cinryze via subcutaneous administration at one of two dose levels (either 1000U or 2000U) two times per week for two weeks. Safety and PK/PD assessments are being evaluated throughout each treatment period.
About Cinryze™ (C1 esterase inhibitor [human])
Cinryze is a highly purified, pasteurized and nanofiltered plasma-derived C1 esterase inhibitor product that has been approved by FDA for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE. C1 inhibitor therapy has been used acutely for more than 35 years in Europe to treat patients with C1 inhibitor deficiency. Cinryze is not currently approved in the European Union or any of its member states.
The most common adverse reactions observed have been upper respiratory infection, sinusitis, rash and headache. No drug-related serious adverse events (SAEs) have been observed in clinical trials. Severe hypersensitivity reactions may occur. Thrombotic events have occurred in patients receiving high dose off-label C1 inhibitor therapy well above the approved treatment dosage regimen. Monitor patients with known risk factors for thrombotic events. With any blood or plasma derived product, there may be a risk of transmission of infectious agents, e.g. viruses and, theoretically, the CJD agent. The risk has been reduced by screening plasma donors for prior exposure to certain virus infections and by manufacturing steps to reduce the risk of viral transmission including pasteurization and nanofiltration.
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Cinryze is for intravenous use only. A dose of 1000 Units of Cinryze can be administered every 3 or 4 days for routine prophylaxis against angioedema attacks in HAE patients. Cinryze is administered at an injection rate of 1 mL per minute.
About Hereditary Angioedema (HAE)
HAE is a rare, severely debilitating, life-threatening genetic disorder caused by a deficiency of C1 inhibitor, a human plasma protein. This condition is the result of a defect in the gene controlling the synthesis of C1 inhibitor. C1 inhibitor maintains the natural regulation of the contact, complement, and fibrinolytic systems, that when left unregulated, can initiate or perpetuate an attack by consuming the already low levels of endogenous C1 inhibitor in HAE patients. Patients with C1 inhibitor deficiency experience recurrent, unpredictable, debilitating, and potentially life threatening attacks of inflammation affecting the larynx, abdomen, face, extremities and urogenital tract. Patients with HAE experience approximately 20 to 100 days of incapacitation per year. There are estimated to be at least 6,000 people with HAE in the United States.
Forward Looking Statements
Certain statements in this press release contain forward-looking statements that involve a number of risks and uncertainties. Forward-looking statements provide our current expectations or forecasts of future events, including the therapeutic indication and use, safety, efficacy, tolerability and potential of Cinryze and our focus, goals, strategy, research and development programs, and ability to develop pharmaceutical products, commercialize pharmaceutical products, and execute on our plans including clinical development activities with Cinryze related to subcutaneous administration. There can be no assurance that that our phase 2 clinical program with Cinryze utilizing subcutaneous administration will yield positive results or support further development of Cinryze for subcutaneous administration. The FDA or EMA may view the data regarding subcutaneous administration of Cinryze as insufficient or inconclusive, request additional data, require additional clinical studies, delay any decision past the time frames anticipated by us, limit any approved indications, or deny the approval of Cinryze for subcutaneous administration. These factors, and other factors, including, but not limited to those described in our annual report on Form 10-K for the year ended December 31, 2009 filed with the Securities and Exchange Commission, could cause future results to differ materially from the expectations expressed in this press release. The forward-looking statements contained in this press release are made as of the date hereof and may become outdated over time. ViroPharma does not assume any responsibility for updating any forward-looking statements. These forward looking statements should not be relied upon as representing our assessments as of any date subsequent to the date of this press release.
Source: ViroPharma Incorporated.
Tuesday, 2 November 2010
Saturday, 5 June 2010
Research Laid Out At ASCO By Foremost Physicians And Investigators From The John Theurer Cancer Center
The John Theurer Cancer Center at Hackensack University Medical Center has announced that its physicians and researchers will present 16 abstracts on treatment and diagnostic progress in many different areas of oncology during the Annual Meeting of American Society of Clinical Oncology (ASCO) in Chicago, IL from June 4-8.
"At the John Theurer Cancer Center, we're dedicated to providing extraordinary cancer care to our patients, which includes conducting high-quality cancer research and cutting-edge clinical trials," said Andrew L. Pecora, M.D., F.A.C.P., C.P.E., Chairman and Executive Administrative Director, the John Theurer Cancer Center. "We're pleased to add to an important body of research at this premier oncology conference."
Abstracts from the John Theurer Cancer Center research that are scheduled to be presented include:
* Phase I study of combined vorinostat (V), lenalidomide (L), and dexamethasone (D) in patients (pts) with relapsed or refractory multiple myeloma (MM). (8031) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* Phase II study of denileukindiftitox with CHOP chemotherapy in newly-diagnosed PTCL: CONCEPT trial. (8045) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* Response of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) with nongerminal center B-cell phenotype to lenalidomide (L) alone or in combination with rituximab (R). (8038) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* The association between the Mantle Cell Lymphoma International Prognostic Index (MIPI) and survival in patients treated with rituximab-HCVAD (RHCVAD) alternating with rituximab-methotrexate-AraC (R-MTX-AraC). (8092) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Effect of front-line therapy with either high-dose therapy and autologous stem cell rescue (HDT/ASCR) or dose-intensive therapy (R-Hypercvad) on outcome in mantle cell lymphoma (MCL). (8067) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Impact of high-risk classification by FISH on overall survival in myeloma: An Eastern Cooperative Oncology Group (ECOG) study E4A03. (10546) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Interim results of phase II trial of pegylated liposomal doxorubicin (PLD) followed by bexarotene in advanced cutaneous T-cell lymphoma (CTCL). (8053) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Neurotoxic and peripheral neuropathic effects in preclinical and clinical studies of carfilzomib (CFZ), a novel proteasome inhibitor (PI). (8135) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) for patients with relapsed indolent B-cell lymphoma (RIL). (8078) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Treatment patterns and outcome among patients with multiple myeloma relapsing and or refractory to bortezomib and immunomodulatory drugs: A multicenter International Myeloma Working Group study. (8125) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Update on vantage program to assess combined vorinostat (V) and bortezomib (B) in patients (pts) with relapsed and/or refractory (RR) multiple myeloma (MM). (8133) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Effect of early chemotherapy intensification with BEACOPP in high-risk, interim-PET positive, advanced-stage Hodgkin lymphoma on overall treatment outcome of ABVD. (8006) (Oral Abstract Session) - Saturday, June 5 from 1:00 p.m. - 4:00 p.m. in E354a
* Elotuzumab in combination with bortezomib in patients with relapsed/refractory multiple myeloma: A phase I study. (8003) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a
* Phase Ib study of oral panobinostat (LBH589) plus intravenous bortezomib in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM). (8001) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a
* Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). (8000) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a
Source:
Amy Leahing
John Theurer Cancer Center
"At the John Theurer Cancer Center, we're dedicated to providing extraordinary cancer care to our patients, which includes conducting high-quality cancer research and cutting-edge clinical trials," said Andrew L. Pecora, M.D., F.A.C.P., C.P.E., Chairman and Executive Administrative Director, the John Theurer Cancer Center. "We're pleased to add to an important body of research at this premier oncology conference."
Abstracts from the John Theurer Cancer Center research that are scheduled to be presented include:
* Phase I study of combined vorinostat (V), lenalidomide (L), and dexamethasone (D) in patients (pts) with relapsed or refractory multiple myeloma (MM). (8031) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* Phase II study of denileukindiftitox with CHOP chemotherapy in newly-diagnosed PTCL: CONCEPT trial. (8045) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* Response of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) with nongerminal center B-cell phenotype to lenalidomide (L) alone or in combination with rituximab (R). (8038) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* The association between the Mantle Cell Lymphoma International Prognostic Index (MIPI) and survival in patients treated with rituximab-HCVAD (RHCVAD) alternating with rituximab-methotrexate-AraC (R-MTX-AraC). (8092) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Effect of front-line therapy with either high-dose therapy and autologous stem cell rescue (HDT/ASCR) or dose-intensive therapy (R-Hypercvad) on outcome in mantle cell lymphoma (MCL). (8067) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Impact of high-risk classification by FISH on overall survival in myeloma: An Eastern Cooperative Oncology Group (ECOG) study E4A03. (10546) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Interim results of phase II trial of pegylated liposomal doxorubicin (PLD) followed by bexarotene in advanced cutaneous T-cell lymphoma (CTCL). (8053) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Neurotoxic and peripheral neuropathic effects in preclinical and clinical studies of carfilzomib (CFZ), a novel proteasome inhibitor (PI). (8135) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) for patients with relapsed indolent B-cell lymphoma (RIL). (8078) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Treatment patterns and outcome among patients with multiple myeloma relapsing and or refractory to bortezomib and immunomodulatory drugs: A multicenter International Myeloma Working Group study. (8125) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Update on vantage program to assess combined vorinostat (V) and bortezomib (B) in patients (pts) with relapsed and/or refractory (RR) multiple myeloma (MM). (8133) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Effect of early chemotherapy intensification with BEACOPP in high-risk, interim-PET positive, advanced-stage Hodgkin lymphoma on overall treatment outcome of ABVD. (8006) (Oral Abstract Session) - Saturday, June 5 from 1:00 p.m. - 4:00 p.m. in E354a
* Elotuzumab in combination with bortezomib in patients with relapsed/refractory multiple myeloma: A phase I study. (8003) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a
* Phase Ib study of oral panobinostat (LBH589) plus intravenous bortezomib in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM). (8001) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a
* Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). (8000) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a
Source:
Amy Leahing
John Theurer Cancer Center
Wednesday, 19 May 2010
Update On Lymphoma Drug Trial: Potential Breakthrough For T- Cell Lymphoma Patients With Drug That Mimics A Vitamin
Final results of a pivotal Phase 2 clinical trial of pralatrexate (PDX) for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) were reported by the study's principal investigator, Dr. Owen A. O'Connor of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital/Columbia. T-cell lymphoma (PTCL) is a biologically diverse group of blood cancers that account for as many as 15 percent of non-Hodgkin's lymphoma (NHL) cases in the United States.
Data from the PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial show that pralatrexate, a drug that partially works by mimicking the vitamin folic acid, has an estimated median duration of response of 287 days, or 9.4 months. As previously reported, 29 of 109 evaluable patients, or 27 percent, showed a complete or partial response.
"Until now, these patients could only expect to survive several weeks. This study shows that it may be possible to extend this to many months - a result that is nothing short of spectacular and may likely represent a breakthrough in the development of new drugs for T-cell lymphoma," said Dr. O'Connor, director of the Lymphoid Development and Malignancy Program and chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, and associate professor of medicine at Columbia University College of Physicians and Surgeons. "Based on these promising data, pralatrexate has the potential to play a clinically meaningful role in the treatment of patients with relapsed or refractory PTCL."
Pralatrexate, designed to look like the natural vitamin folic acid, disrupts DNA synthesis in tumor cells. The drug is designed to selectively accumulate in tumor cells, after which it then induces programmed cell death, or apoptosis, in the cancer cell.
There are currently no pharmaceutical agents approved for use in the treatment of either first-line or relapsed or refractory PTCL, and overall five-year survival is approximately 25 percent after first-line therapy. In addition to those PTCL patients who do not respond to first-line treatment, a significant number of first-line multi-agent chemotherapy responders relapse or become refractory after treatment.
The PROPEL trial is organized by Allos Therapeutics Inc., the maker of the drug. The company expects to submit a New Drug Application to the U.S. Food and Drug Administration for marketing approval of pralatrexate sometime in the first half of 2009. The results of the trial will be submitted for presentation at an upcoming scientific meeting and for publication in a peer-reviewed journal.
Pralatrexate was developed by a team of researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Southern Research Institute, including Dr. O'Connor, while at MSKCC. Dr. O'Connor and his colleagues identified the unique activity of pralatrexate in patients with lymphoma. Dr. O'Connor has continued to study pralatrexate at NewYork-Presbyterian/Columbia, now focusing on determining how the drug works in T-cell lymphoma, and on how best to combine it with other drugs to improve the treatment of patient with hematologic cancers.
The critical PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial - an international, multicenter, open-label, single-arm study - enrolled a total of 115 patients with relapsed or refractory PTCL, 109 of whom are considered evaluable for response according to the trial protocol. It is believed that PROPEL is the largest prospectively designed single-agent trial conducted to date for this patient population.
To be eligible for the trial, patients' disease must have progressed after at least one prior treatment. Patients were considered evaluable if they received at least one dose of pralatrexate and their diagnosis of PTCL was confirmed by independent pathology review. Patients received 30 mg/m2 of pralatrexate intravenously once every week for six weeks followed by one week of rest per cycle of treatment. Patients also received vitamin B12 and folic acid supplementation. The primary endpoint of the trial is objective response rate, as assessed by central, independent oncology review using International Workshop Criteria (IWC). Duration of response is the key secondary endpoint.
Of the 29 patients who achieved a response according to central independent oncology review, 7 patients had a complete response (CR), 2 patients had a complete response unconfirmed (CRu) and 20 patients had a partial response (PR). According to the PROPEL investigators, 42 of 109 evaluable patients, or 39 percent, achieved a response. Of these, 15 patients had a CR, 4 patients had a CRu and 23 patients had a PR. PROPEL patients received a median of three prior systemic treatment regimens (range of 1 to 12), including 18 patients, or 16 percent, who had previously undergone an autologous stem cell transplant. In the trial, 66 percent of the patients who responded did so after cycle one of therapy. Patients will continue to be followed for long-term survival.
Peripheral T-Cell Lymphoma
According to the American Cancer Society, approximately 66,000 patients are expected to be diagnosed with non-Hodgkin's lymphoma in the United States in 2009. Annual prevalence is estimated to be approximately 9,500 patients. In addition to the 30 percent to 50 percent of PTCL patients that do not respond to first-line treatment, a significant number of first-line, multi-agent chemotherapy responders relapse or become refractory after treatment.
NewYork-Presbyterian Hospital
NewYork-Presbyterian Hospital, based in New York City, is the nation's largest not-for-profit, non-sectarian hospital, with 2,242 beds. The Hospital has nearly 2 million inpatient and outpatient visits in a year, including more than 230,000 visits to its emergency departments - more than any other area hospital. NewYork-Presbyterian provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/The Allen Pavilion and NewYork-Presbyterian Hospital/Westchester Division. One of the largest and most comprehensive health care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. It ranks sixth in U.S.News & World Report's guide to "America's Best Hospitals," ranks first on New York magazine's "Best Hospitals" survey, has the greatest number of physicians listed in New York magazine's "Best Doctors" issue, and is included among Solucient's top 15 major teaching hospitals. The Hospital's mortality rates are among the lowest for heart attack and heart failure in the country, according to a 2007 U.S. Department of Health and Human Services (HHS) report card. The Hospital has academic affiliations with two of the nation's leading medical colleges: Weill Cornell Medical College and Columbia University College of Physicians and Surgeons. For more information, visit www.nyp.org.
Columbia University Medical Center
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The Medical Center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States.
Source: NewYork-Presbyterian Hospital
Data from the PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial show that pralatrexate, a drug that partially works by mimicking the vitamin folic acid, has an estimated median duration of response of 287 days, or 9.4 months. As previously reported, 29 of 109 evaluable patients, or 27 percent, showed a complete or partial response.
"Until now, these patients could only expect to survive several weeks. This study shows that it may be possible to extend this to many months - a result that is nothing short of spectacular and may likely represent a breakthrough in the development of new drugs for T-cell lymphoma," said Dr. O'Connor, director of the Lymphoid Development and Malignancy Program and chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, and associate professor of medicine at Columbia University College of Physicians and Surgeons. "Based on these promising data, pralatrexate has the potential to play a clinically meaningful role in the treatment of patients with relapsed or refractory PTCL."
Pralatrexate, designed to look like the natural vitamin folic acid, disrupts DNA synthesis in tumor cells. The drug is designed to selectively accumulate in tumor cells, after which it then induces programmed cell death, or apoptosis, in the cancer cell.
There are currently no pharmaceutical agents approved for use in the treatment of either first-line or relapsed or refractory PTCL, and overall five-year survival is approximately 25 percent after first-line therapy. In addition to those PTCL patients who do not respond to first-line treatment, a significant number of first-line multi-agent chemotherapy responders relapse or become refractory after treatment.
The PROPEL trial is organized by Allos Therapeutics Inc., the maker of the drug. The company expects to submit a New Drug Application to the U.S. Food and Drug Administration for marketing approval of pralatrexate sometime in the first half of 2009. The results of the trial will be submitted for presentation at an upcoming scientific meeting and for publication in a peer-reviewed journal.
Pralatrexate was developed by a team of researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Southern Research Institute, including Dr. O'Connor, while at MSKCC. Dr. O'Connor and his colleagues identified the unique activity of pralatrexate in patients with lymphoma. Dr. O'Connor has continued to study pralatrexate at NewYork-Presbyterian/Columbia, now focusing on determining how the drug works in T-cell lymphoma, and on how best to combine it with other drugs to improve the treatment of patient with hematologic cancers.
The critical PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial - an international, multicenter, open-label, single-arm study - enrolled a total of 115 patients with relapsed or refractory PTCL, 109 of whom are considered evaluable for response according to the trial protocol. It is believed that PROPEL is the largest prospectively designed single-agent trial conducted to date for this patient population.
To be eligible for the trial, patients' disease must have progressed after at least one prior treatment. Patients were considered evaluable if they received at least one dose of pralatrexate and their diagnosis of PTCL was confirmed by independent pathology review. Patients received 30 mg/m2 of pralatrexate intravenously once every week for six weeks followed by one week of rest per cycle of treatment. Patients also received vitamin B12 and folic acid supplementation. The primary endpoint of the trial is objective response rate, as assessed by central, independent oncology review using International Workshop Criteria (IWC). Duration of response is the key secondary endpoint.
Of the 29 patients who achieved a response according to central independent oncology review, 7 patients had a complete response (CR), 2 patients had a complete response unconfirmed (CRu) and 20 patients had a partial response (PR). According to the PROPEL investigators, 42 of 109 evaluable patients, or 39 percent, achieved a response. Of these, 15 patients had a CR, 4 patients had a CRu and 23 patients had a PR. PROPEL patients received a median of three prior systemic treatment regimens (range of 1 to 12), including 18 patients, or 16 percent, who had previously undergone an autologous stem cell transplant. In the trial, 66 percent of the patients who responded did so after cycle one of therapy. Patients will continue to be followed for long-term survival.
Peripheral T-Cell Lymphoma
According to the American Cancer Society, approximately 66,000 patients are expected to be diagnosed with non-Hodgkin's lymphoma in the United States in 2009. Annual prevalence is estimated to be approximately 9,500 patients. In addition to the 30 percent to 50 percent of PTCL patients that do not respond to first-line treatment, a significant number of first-line, multi-agent chemotherapy responders relapse or become refractory after treatment.
NewYork-Presbyterian Hospital
NewYork-Presbyterian Hospital, based in New York City, is the nation's largest not-for-profit, non-sectarian hospital, with 2,242 beds. The Hospital has nearly 2 million inpatient and outpatient visits in a year, including more than 230,000 visits to its emergency departments - more than any other area hospital. NewYork-Presbyterian provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/The Allen Pavilion and NewYork-Presbyterian Hospital/Westchester Division. One of the largest and most comprehensive health care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. It ranks sixth in U.S.News & World Report's guide to "America's Best Hospitals," ranks first on New York magazine's "Best Hospitals" survey, has the greatest number of physicians listed in New York magazine's "Best Doctors" issue, and is included among Solucient's top 15 major teaching hospitals. The Hospital's mortality rates are among the lowest for heart attack and heart failure in the country, according to a 2007 U.S. Department of Health and Human Services (HHS) report card. The Hospital has academic affiliations with two of the nation's leading medical colleges: Weill Cornell Medical College and Columbia University College of Physicians and Surgeons. For more information, visit www.nyp.org.
Columbia University Medical Center
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The Medical Center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States.
Source: NewYork-Presbyterian Hospital
Tuesday, 4 May 2010
A Century-Old Puzzle Comes Together, Scientists ID Potential Protein Trigger In Lung Disease Sarcoidosis
Lung researchers at Johns Hopkins have identified a possible protein trigger responsible for sarcoidosis, a potentially fatal inflammatory disease marked by tiny clumps of inflammatory cells that each year leave deep, grainy scars on the lungs, lymph nodes, skin and almost all major organs in hundreds of thousands of Americans.
The disorder, whose cause has been a persistent mystery for nearly a century, strikes mostly young adults and disproportionately affects African Americans.
The link between sarcoidosis and overproduction of the suspected protein trigger, called serum amyloid A, was revealed after a six-year investigation encompassing more than two dozen laboratory experiments, including some on diseased lung tissue samples from 86 patients in the Baltimore area.
"The increase in production of serum amyloid A explains for the first time how inflammation can persist in the lungs without being triggered by an active infection," says study senior investigator and pulmonologist David Moller, M.D., a professor at the Johns Hopkins University School of Medicine. Moller is also director of the sarcoidosis clinic at The Johns Hopkins Hospital.
Study lead investigator Edward Chen, M.D., says the new findings also clear the path for developing drug treatments or vaccines that can block serum amyloid A from binding to cell receptors and kicking off inflammation.
In the short term, however, Moller says his team has plans to use the study results to create diagnostic tests that could better predict which people with the disease are likely to heal on their own or are more likely to suffer persistent inflammation, which can lead to scarring, difficulty breathing, and heart failure that can only be fixed by lung transplantation.
In a report published in February in the American Journal of Respiratory and Critical Care Medicine, the Johns Hopkins scientists described their research on what was behind the microscopic clusters of inflamed tissue and white blood cells, or granulomas, which are a defining feature of sarcoidosis.
Such lung lesions are not unique to sarcoidosis and can be triggered by infections, such as in tuberculosis, which is often confused with sarcoidosis. But unlike tuberculosis, sarcoidosis is not an infectious disease, does not yield to antibiotics, and is not limited to any particular organ, occurring as well in the eyes, skin, brain, heart and liver.
Of particular interest to researchers was the role played by so-called amyloids, a set of proteins known to cause other persistent inflammatory conditions, such as amyloidosis. Indeed, a different kind of amyloid has been tied to plaques in the brain tissue of people with Alzheimer's disease.
Key among the researchers' findings in sarcoidosis patients was that serum amyloid A stood out because it was heavily concentrated within the granulomas in diseased and scarred lung tissue. Researchers found the protein a hundred to a thousand times more widespread in sarcoidosis tissue samples than in samples from people with tuberculosis, another granuloma-forming lung disease. Similarly elevated amyloid levels were seen in comparison tests with tissue samples from people with lung cancer and Crohn's disease.
Further tests in patients' lung cell cultures showed that adding serum amyloid A spiked production of at least a half-dozen key inflammatory chemicals known to be involved in damaging tissue.
In another series of experiments in mice, the team discovered that granuloma formation in the lungs sped up when the mice were given injections of synthetic serum amyloid A. Mice had previously been injected with specially coated plastic beads designed to trigger sarcoidosis-like lesions. Adding the synthetic protein led to the same biochemical reactions in the mice as observed in humans, suggesting to the researchers that serum amyloid A played a key role in triggering sarcoidosis.
To better understand how serum amyloid A might be driving granuloma formation, the team used special antibodies to block various cell surface receptor sites where the protein would bind to the white blood cells and spur inflammation. Tests in human lung cells showed that blocking one particular receptor, toll-like receptor-2 (TLR2), inhibited the sustained inflammatory reaction typically associated with sarcoidosis. But when left to bind on its own, without an antibody blocking TLR2, the open receptor could attach to serum amyloid A, and raised production of inflammatory chemicals would ensue.
"Not only have we shown that serum amyloid A is a key protein trigger in sarcoidosis, but we also have evidence that the resulting inflammation is dependent on binding the protein at toll-like receptor-2, which opens up a host of possibilities that drugs blocking this binding site could prove an effective treatment for this disease," says Chen, an assistant professor at Johns Hopkins.
Funding support for the report and research was provided by the National Institutes of Health, the American Thoracic Society, the Foundation for Sarcoidosis Research, the Life and Breath Foundation, and the Hospital for the Consumptives of Maryland (Eudowood.)
Source: Johns Hopkins Medicine
The disorder, whose cause has been a persistent mystery for nearly a century, strikes mostly young adults and disproportionately affects African Americans.
The link between sarcoidosis and overproduction of the suspected protein trigger, called serum amyloid A, was revealed after a six-year investigation encompassing more than two dozen laboratory experiments, including some on diseased lung tissue samples from 86 patients in the Baltimore area.
"The increase in production of serum amyloid A explains for the first time how inflammation can persist in the lungs without being triggered by an active infection," says study senior investigator and pulmonologist David Moller, M.D., a professor at the Johns Hopkins University School of Medicine. Moller is also director of the sarcoidosis clinic at The Johns Hopkins Hospital.
Study lead investigator Edward Chen, M.D., says the new findings also clear the path for developing drug treatments or vaccines that can block serum amyloid A from binding to cell receptors and kicking off inflammation.
In the short term, however, Moller says his team has plans to use the study results to create diagnostic tests that could better predict which people with the disease are likely to heal on their own or are more likely to suffer persistent inflammation, which can lead to scarring, difficulty breathing, and heart failure that can only be fixed by lung transplantation.
In a report published in February in the American Journal of Respiratory and Critical Care Medicine, the Johns Hopkins scientists described their research on what was behind the microscopic clusters of inflamed tissue and white blood cells, or granulomas, which are a defining feature of sarcoidosis.
Such lung lesions are not unique to sarcoidosis and can be triggered by infections, such as in tuberculosis, which is often confused with sarcoidosis. But unlike tuberculosis, sarcoidosis is not an infectious disease, does not yield to antibiotics, and is not limited to any particular organ, occurring as well in the eyes, skin, brain, heart and liver.
Of particular interest to researchers was the role played by so-called amyloids, a set of proteins known to cause other persistent inflammatory conditions, such as amyloidosis. Indeed, a different kind of amyloid has been tied to plaques in the brain tissue of people with Alzheimer's disease.
Key among the researchers' findings in sarcoidosis patients was that serum amyloid A stood out because it was heavily concentrated within the granulomas in diseased and scarred lung tissue. Researchers found the protein a hundred to a thousand times more widespread in sarcoidosis tissue samples than in samples from people with tuberculosis, another granuloma-forming lung disease. Similarly elevated amyloid levels were seen in comparison tests with tissue samples from people with lung cancer and Crohn's disease.
Further tests in patients' lung cell cultures showed that adding serum amyloid A spiked production of at least a half-dozen key inflammatory chemicals known to be involved in damaging tissue.
In another series of experiments in mice, the team discovered that granuloma formation in the lungs sped up when the mice were given injections of synthetic serum amyloid A. Mice had previously been injected with specially coated plastic beads designed to trigger sarcoidosis-like lesions. Adding the synthetic protein led to the same biochemical reactions in the mice as observed in humans, suggesting to the researchers that serum amyloid A played a key role in triggering sarcoidosis.
To better understand how serum amyloid A might be driving granuloma formation, the team used special antibodies to block various cell surface receptor sites where the protein would bind to the white blood cells and spur inflammation. Tests in human lung cells showed that blocking one particular receptor, toll-like receptor-2 (TLR2), inhibited the sustained inflammatory reaction typically associated with sarcoidosis. But when left to bind on its own, without an antibody blocking TLR2, the open receptor could attach to serum amyloid A, and raised production of inflammatory chemicals would ensue.
"Not only have we shown that serum amyloid A is a key protein trigger in sarcoidosis, but we also have evidence that the resulting inflammation is dependent on binding the protein at toll-like receptor-2, which opens up a host of possibilities that drugs blocking this binding site could prove an effective treatment for this disease," says Chen, an assistant professor at Johns Hopkins.
Funding support for the report and research was provided by the National Institutes of Health, the American Thoracic Society, the Foundation for Sarcoidosis Research, the Life and Breath Foundation, and the Hospital for the Consumptives of Maryland (Eudowood.)
Source: Johns Hopkins Medicine
Monday, 3 May 2010
Tumors Hide Out From The Immune System By Mimicking Lymph Nodes
A new mechanism explaining how tumors escape the body's natural immune surveillance has recently been discovered at EPFL (Ecole Polytechnique Fédérale de Lausanne) in Switzerland. The study shows how tumors can create a tolerant microenviroment and avoid attack by the immune system by mimicking key features of lymph nodes. The discovery, published in Science and in Science Express, online March 25, 2010, underscores the role of the lymphatic system in cancer and may open up new possibilities for cancer treatment.
"The tumor tricks the body into thinking it is healthy tissue," says lead author Melody Swartz, head of the Laboratory of Lymphatic and Cancer Bioengineering (LLCB) and EPFL professor. Swartz and her team set out to understand how immune tolerance is induced by tumors, allowing them to progress and spread. The researchers from EPFL concentrated their efforts on a certain protein that is normally present in healthy lymph nodes to attract T cells and program them to perform vital immune functions. They found that some tumors can secrete this protein to transform the outer layer of the tumor into lymphoid-like tissue. This outer layer then attracts and effectively re-programs the T cells to recognize the tumor as friend not foe, resulting in a tumor that goes undetected by the immune system.
Since most tumors progress only if they have escaped the immune system, this new understanding of one mechanism by which the tumor can bypasses or hides from immune defenses is an important step towards future cancer therapies. "The finding that tumors can attract naïve and regulatory T cells and educate them has important implications for tumor immunotherapy," says Jacqui Shields, from LLCB. The study also opens up potential novel areas of research focusing on the relationship between lymphatic systems and cancer research. According to Shields, the concept that tumors mimic lymphoid tissue to alter the host's immune response represents a new understanding of tumors' interactions with the lymphatic system.
The laboratory is affiliated with the EPFL's Institute of Bioengineering and the Swiss Institute for Experimental Cancer Research.
Source: Ecole Polytechnique Federale de Lausanne (EPFL)
"The tumor tricks the body into thinking it is healthy tissue," says lead author Melody Swartz, head of the Laboratory of Lymphatic and Cancer Bioengineering (LLCB) and EPFL professor. Swartz and her team set out to understand how immune tolerance is induced by tumors, allowing them to progress and spread. The researchers from EPFL concentrated their efforts on a certain protein that is normally present in healthy lymph nodes to attract T cells and program them to perform vital immune functions. They found that some tumors can secrete this protein to transform the outer layer of the tumor into lymphoid-like tissue. This outer layer then attracts and effectively re-programs the T cells to recognize the tumor as friend not foe, resulting in a tumor that goes undetected by the immune system.
Since most tumors progress only if they have escaped the immune system, this new understanding of one mechanism by which the tumor can bypasses or hides from immune defenses is an important step towards future cancer therapies. "The finding that tumors can attract naïve and regulatory T cells and educate them has important implications for tumor immunotherapy," says Jacqui Shields, from LLCB. The study also opens up potential novel areas of research focusing on the relationship between lymphatic systems and cancer research. According to Shields, the concept that tumors mimic lymphoid tissue to alter the host's immune response represents a new understanding of tumors' interactions with the lymphatic system.
The laboratory is affiliated with the EPFL's Institute of Bioengineering and the Swiss Institute for Experimental Cancer Research.
Source: Ecole Polytechnique Federale de Lausanne (EPFL)
Friday, 30 April 2010
Shire Presents Positive Data For Patients With Type 1 Gaucher Disease Who Switched To VPRIV(TM)
Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, presented positive data from a Phase III clinical trial (TKT-034) designed to evaluate the safety of switching to VPRIV (velaglucerase alfa for injection), from imiglucerase, as well as an interim analysis of safety data from an ongoing multicenter open-label treatment protocol (HGT-GCB-058) implemented to provide VPRIV to patients affected by the continuing shortage of imiglucerase. A post-hoc analysis of Phase I/II data on therapeutic goal attainment was also presented at the 2010 American College of Medical Genetics Annual Clinical Genetics Meeting in Albuquerque, New Mexico. These data add to the growing body of clinical evidence which support the use of VPRIV in patients both transitioning from imiglucerase or who are treatment naive.
Adult and pediatric patients with Type 1 Gaucher disease were switched from imiglucerase (15-60 U/kg every other week) to the same number of units of VPRIV in the Phase III switch study (40 patients) and the ongoing US treatment protocol (>150 patients). In study TKT-034, no patients developed IgG antibodies to VPRIV, including 3 patients who tested positive for anti-imiglucerase antibodies at screening. In addition, hemoglobin concentration, platelet counts, and liver and spleen volumes remained stable over the course of the one year study, demonstrating safety and maintenance of efficacy over this time frame. One patient in the Phase III trial discontinued due to a serious hypersensitivity reaction and the most common side effects reported in the two studies were infusion-related reactions.
"Results from the Phase III study provide important information regarding the safety and sustained efficacy of VPRIV for patients with Type 1 Gaucher disease who were previously on imiglucerase and should help inform treatment decisions during and after the imiglucerase supply shortage," said Dr. Gregory Grabowski, Director of the Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Principal Investigator of the 034 study. "These data confirm what many physicians have experienced."
A post hoc analysis from a third study, TKT-025EXT, designed to examine attainment of long-term therapeutic goals in 8 patients with Type 1 Gaucher disease treated with velaglucerase alfa, was also presented at the meeting. The initial dose of 60 U/kg was lowered to 30 U/kg after patients achieved at least 2 of 4 predefined therapeutic goals following 1 year of treatment. Clinically meaningful achievement of long-term therapeutic goals for hemoglobin concentration, platelet counts, and liver and spleen volumes was observed within 4 years of initiation of treatment.
Shire also reported important findings that suggested substantial antigenic differences when antibody response to treatment with VPRIV and imiglucerase were compared. Among the 99 patients who enrolled in the Phase III studies the seroconversion rate was 1% (1 of 82) against VPRIV versus 23% (4 of 17) against imiglucerase.
Velaglucerase alfa is manufactured in Shire's facility in Cambridge MA, which was inspected and approved by the FDA for the commercial production of VPRIV.
Study Results and Design for TKT-034, HGT-GBC-058 and TKT-025EXT
TKT-034
In this global, open-label, multicenter study, patients were enrolled in the US (11 sites), Europe (3 sites) and Israel (1 site), and of the 41 patients enrolled, 40 received study drug. One patient discontinued due to a serious hypersensitivity reaction and one patient discontinued at week 31 due to a perceived lack of improvement. At the time of discontinuation, this patient's clinical parameters were stable and consistent with those of the entire group of patients in the study.
Hemoglobin concentration, platelet counts, and spleen and liver volume were sustained at therapeutic levels through one year of treatment with VPRIV, as demonstrated by pre-specified efficacy criteria for clinically significant change:
-- Hemoglobin concentration: the mean change from baseline was -0.1 g/dL, with a 90 percent confidence interval of -0.3 to 0.1 g/dL, within the predefined efficacy criterion of plus or minus 1 g/dL.
-- Platelet counts: the percent change from baseline was +7.0%, with a 90 percent confidence interval of 0.5 to 13.5%, within the predefined efficacy criterion of plus or minus 20%.
-- Spleen volume: the percent change from baseline was -5.6%, with a 90 percent confidence interval of -10.8 to -0.4% within the predefined efficacy criterion of plus or minus 15%.
-- Liver volume: the percent change from baseline was -0.0%, with a 90 percent confidence interval of -2.6 to 2.6% within the predefined efficacy criterion of plus or minus 15%.
Study design
The primary objective of TKT-034 was to evaluate the safety of VPRIV in patients with Type 1 Gaucher disease who transitioned from imiglucerase to VPRIV. The secondary objectives were to evaluate changes from baseline in hemoglobin concentration, platelet counts, and spleen and liver volumes by Magnetic Resource Imaging (MRI) after every other week dosing of VPRIV.
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Patients over the age of two years and receiving imiglucerase at a dose between 15 and 60 U/kg every other week for at least 30 months with no dose change in the last 6 months were eligible, provided they had demonstrated stable hemoglobin concentration and platelet counts. Patients were infused in one hour with the same number of units of VPRIV as their prior imiglucerase dose.
HGT-GCB-058
This ongoing multicenter, open-label treatment protocol was initiated at the request of the Food and Drug Administration (FDA) to provide VPRIV to patients who otherwise have limited or no access to imiglucerase due to a continuing supply shortage.
Between September 1, 2009 and January 31, 2010, more than 150 patients in the US enrolled into HGT-GCB-058 and received at least one infusion of VPRIV. Of these, 3 were treatment naive and the rest were previously treated with imiglucerase. Following the administration of the first three infusions of VPRIV at the clinical site, patients who experienced no treatment-related serious adverse events or infusion-related adverse events were eligible to transition to home therapy at the discretion of the investigator. Patients were required to return to the clinic site quarterly for observation.
An interim safety analysis of the more than 150 patients on the treatment protocol was conducted. Among those patients previously treated with imiglucerase, a total of 18% experienced a treatment emergent adverse event that was possibly or probably related to the study drug. The most commonly observed treatment emergent adverse events among switch patients included at least one infusion-related reaction, nasopharyngitis, nausea, fatigue, headache, dizziness and influenza. Approximately 1% of patients experienced a severe adverse event that was considered to be possibly or probably related to the study drug.
TKT-025EXT: Study Results and Design of Therapeutic Goal Analysis
This post-hoc analysis of data from the Phase I/II and extension trial of velaglucerase alfa showed that clinically meaningful long-term therapeutic goals were achieved within 4 years of initiation of velaglucerase alfa treatment.
The efficacy parameters were evaluated against the therapeutic goals described by Pastores et al (Seminars in Hematology, 2004) aand included absolute and percent changes in hemoglobin levels, platelet counts, and spleen and liver volumes as measured by MRI. Evaluation in this study was limited to those patients who were exposed to velaglucerase alfa for a minimum of 48 months and for whom a complete clinical data set corresponding to the study endoints was available at baseline and annually through 48 months (8 patients, 4 male, 4 female). Patients were evaluated for the achievement of each individual therapeutic goal. The percentage of patients achieving each specific goal over time was determined. In addition the percentage of patients with a complete response (achieved all 4 therapeutic goals) over time was also evaluated.
At baseline, no patient was at goal for all 4 clinical parameters: 4 of 8 patients were at goal for hemoglobin concentration, 0 of 8 for platelet count, 4 of 8 for liver volume, and 0 of 8 for spleen volume. After 1 year of treatment, all patients achieved at least 2 therapeutic goals, and all patients maintained clinical parameters for goals that were already at the recommended targets when treatment began. All 8 patients were eligible for and began step-wise dose reduction to velaglucerase alfa 30 U/kg EOW starting between 12 and 18 months. By year 4 of treatment, all patients met goals for all 4 clinical parameters; therefore, 100% achievement was observed for each of the 4 long-term, therapeutic goals.
More about VPRIV
VPRIV (velaglucerase alfa for injection) was approved by the US FDA as a long-term enzyme replacement therapy for adult and pediatric patients with Type 1 Gaucher disease on February 26, 2010. A marketing application for VPRIV has also been granted accelerated assessment by the European Medicines Agency in the European Union (EU). Shire expects to launch VPRIV in the EU by the end of 2010 and in other countries beginning in 2011.
VPRIV is for patients who are treatment naive as well as patients who have been treated with imiglucerase. The most serious adverse reactions seen with VPRIV were hypersensitivity reactions. Infusion-related reactions were the most commonly observed adverse reactions in patients treated with VPRIV in clinical studies. The most commonly observed symptoms of infusion-related reactions were: headache, dizziness, low or high blood pressure, nausea, tiredness and weakness, and fever. Generally the infusion-related reactions were mild and, in treatment-naive patients, onset occurred mostly during the first 6 months of treatment and tended to occur less frequently with time. Adverse reactions more commonly seen in pediatric patients compared to those observed in adult patients (>10% difference) include rash, upper respiratory tract infection, prolonged activated partial thromboplastin time, and fever.
As with all therapeutic proteins, there is a potential for immunogenicity. In the clinical studies 1 of 54 treatment-naive patients treated with VPRIV developed IgG class antibodies. It is unknown if the presence of IgG antibodies to VPRIV is associated with a higher risk of infusion reactions.
SHIRE PLC
Shire's strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.
"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995
Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company's Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company's products; the Company's ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company's products; the Company's ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company's ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company's filings with the Securities and Exchange Commission.
Source: Shire plc
Adult and pediatric patients with Type 1 Gaucher disease were switched from imiglucerase (15-60 U/kg every other week) to the same number of units of VPRIV in the Phase III switch study (40 patients) and the ongoing US treatment protocol (>150 patients). In study TKT-034, no patients developed IgG antibodies to VPRIV, including 3 patients who tested positive for anti-imiglucerase antibodies at screening. In addition, hemoglobin concentration, platelet counts, and liver and spleen volumes remained stable over the course of the one year study, demonstrating safety and maintenance of efficacy over this time frame. One patient in the Phase III trial discontinued due to a serious hypersensitivity reaction and the most common side effects reported in the two studies were infusion-related reactions.
"Results from the Phase III study provide important information regarding the safety and sustained efficacy of VPRIV for patients with Type 1 Gaucher disease who were previously on imiglucerase and should help inform treatment decisions during and after the imiglucerase supply shortage," said Dr. Gregory Grabowski, Director of the Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Principal Investigator of the 034 study. "These data confirm what many physicians have experienced."
A post hoc analysis from a third study, TKT-025EXT, designed to examine attainment of long-term therapeutic goals in 8 patients with Type 1 Gaucher disease treated with velaglucerase alfa, was also presented at the meeting. The initial dose of 60 U/kg was lowered to 30 U/kg after patients achieved at least 2 of 4 predefined therapeutic goals following 1 year of treatment. Clinically meaningful achievement of long-term therapeutic goals for hemoglobin concentration, platelet counts, and liver and spleen volumes was observed within 4 years of initiation of treatment.
Shire also reported important findings that suggested substantial antigenic differences when antibody response to treatment with VPRIV and imiglucerase were compared. Among the 99 patients who enrolled in the Phase III studies the seroconversion rate was 1% (1 of 82) against VPRIV versus 23% (4 of 17) against imiglucerase.
Velaglucerase alfa is manufactured in Shire's facility in Cambridge MA, which was inspected and approved by the FDA for the commercial production of VPRIV.
Study Results and Design for TKT-034, HGT-GBC-058 and TKT-025EXT
TKT-034
In this global, open-label, multicenter study, patients were enrolled in the US (11 sites), Europe (3 sites) and Israel (1 site), and of the 41 patients enrolled, 40 received study drug. One patient discontinued due to a serious hypersensitivity reaction and one patient discontinued at week 31 due to a perceived lack of improvement. At the time of discontinuation, this patient's clinical parameters were stable and consistent with those of the entire group of patients in the study.
Hemoglobin concentration, platelet counts, and spleen and liver volume were sustained at therapeutic levels through one year of treatment with VPRIV, as demonstrated by pre-specified efficacy criteria for clinically significant change:
-- Hemoglobin concentration: the mean change from baseline was -0.1 g/dL, with a 90 percent confidence interval of -0.3 to 0.1 g/dL, within the predefined efficacy criterion of plus or minus 1 g/dL.
-- Platelet counts: the percent change from baseline was +7.0%, with a 90 percent confidence interval of 0.5 to 13.5%, within the predefined efficacy criterion of plus or minus 20%.
-- Spleen volume: the percent change from baseline was -5.6%, with a 90 percent confidence interval of -10.8 to -0.4% within the predefined efficacy criterion of plus or minus 15%.
-- Liver volume: the percent change from baseline was -0.0%, with a 90 percent confidence interval of -2.6 to 2.6% within the predefined efficacy criterion of plus or minus 15%.
Study design
The primary objective of TKT-034 was to evaluate the safety of VPRIV in patients with Type 1 Gaucher disease who transitioned from imiglucerase to VPRIV. The secondary objectives were to evaluate changes from baseline in hemoglobin concentration, platelet counts, and spleen and liver volumes by Magnetic Resource Imaging (MRI) after every other week dosing of VPRIV.
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Patients over the age of two years and receiving imiglucerase at a dose between 15 and 60 U/kg every other week for at least 30 months with no dose change in the last 6 months were eligible, provided they had demonstrated stable hemoglobin concentration and platelet counts. Patients were infused in one hour with the same number of units of VPRIV as their prior imiglucerase dose.
HGT-GCB-058
This ongoing multicenter, open-label treatment protocol was initiated at the request of the Food and Drug Administration (FDA) to provide VPRIV to patients who otherwise have limited or no access to imiglucerase due to a continuing supply shortage.
Between September 1, 2009 and January 31, 2010, more than 150 patients in the US enrolled into HGT-GCB-058 and received at least one infusion of VPRIV. Of these, 3 were treatment naive and the rest were previously treated with imiglucerase. Following the administration of the first three infusions of VPRIV at the clinical site, patients who experienced no treatment-related serious adverse events or infusion-related adverse events were eligible to transition to home therapy at the discretion of the investigator. Patients were required to return to the clinic site quarterly for observation.
An interim safety analysis of the more than 150 patients on the treatment protocol was conducted. Among those patients previously treated with imiglucerase, a total of 18% experienced a treatment emergent adverse event that was possibly or probably related to the study drug. The most commonly observed treatment emergent adverse events among switch patients included at least one infusion-related reaction, nasopharyngitis, nausea, fatigue, headache, dizziness and influenza. Approximately 1% of patients experienced a severe adverse event that was considered to be possibly or probably related to the study drug.
TKT-025EXT: Study Results and Design of Therapeutic Goal Analysis
This post-hoc analysis of data from the Phase I/II and extension trial of velaglucerase alfa showed that clinically meaningful long-term therapeutic goals were achieved within 4 years of initiation of velaglucerase alfa treatment.
The efficacy parameters were evaluated against the therapeutic goals described by Pastores et al (Seminars in Hematology, 2004) aand included absolute and percent changes in hemoglobin levels, platelet counts, and spleen and liver volumes as measured by MRI. Evaluation in this study was limited to those patients who were exposed to velaglucerase alfa for a minimum of 48 months and for whom a complete clinical data set corresponding to the study endoints was available at baseline and annually through 48 months (8 patients, 4 male, 4 female). Patients were evaluated for the achievement of each individual therapeutic goal. The percentage of patients achieving each specific goal over time was determined. In addition the percentage of patients with a complete response (achieved all 4 therapeutic goals) over time was also evaluated.
At baseline, no patient was at goal for all 4 clinical parameters: 4 of 8 patients were at goal for hemoglobin concentration, 0 of 8 for platelet count, 4 of 8 for liver volume, and 0 of 8 for spleen volume. After 1 year of treatment, all patients achieved at least 2 therapeutic goals, and all patients maintained clinical parameters for goals that were already at the recommended targets when treatment began. All 8 patients were eligible for and began step-wise dose reduction to velaglucerase alfa 30 U/kg EOW starting between 12 and 18 months. By year 4 of treatment, all patients met goals for all 4 clinical parameters; therefore, 100% achievement was observed for each of the 4 long-term, therapeutic goals.
More about VPRIV
VPRIV (velaglucerase alfa for injection) was approved by the US FDA as a long-term enzyme replacement therapy for adult and pediatric patients with Type 1 Gaucher disease on February 26, 2010. A marketing application for VPRIV has also been granted accelerated assessment by the European Medicines Agency in the European Union (EU). Shire expects to launch VPRIV in the EU by the end of 2010 and in other countries beginning in 2011.
VPRIV is for patients who are treatment naive as well as patients who have been treated with imiglucerase. The most serious adverse reactions seen with VPRIV were hypersensitivity reactions. Infusion-related reactions were the most commonly observed adverse reactions in patients treated with VPRIV in clinical studies. The most commonly observed symptoms of infusion-related reactions were: headache, dizziness, low or high blood pressure, nausea, tiredness and weakness, and fever. Generally the infusion-related reactions were mild and, in treatment-naive patients, onset occurred mostly during the first 6 months of treatment and tended to occur less frequently with time. Adverse reactions more commonly seen in pediatric patients compared to those observed in adult patients (>10% difference) include rash, upper respiratory tract infection, prolonged activated partial thromboplastin time, and fever.
As with all therapeutic proteins, there is a potential for immunogenicity. In the clinical studies 1 of 54 treatment-naive patients treated with VPRIV developed IgG class antibodies. It is unknown if the presence of IgG antibodies to VPRIV is associated with a higher risk of infusion reactions.
SHIRE PLC
Shire's strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.
"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995
Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company's Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company's products; the Company's ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company's products; the Company's ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company's ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company's filings with the Securities and Exchange Commission.
Source: Shire plc
More News From The Journal Of Clinical Investigation: April 1, 2010
One thing that predisposes individuals who are obese to type 2 diabetes is the persistent, low-level inflammation that results, in part, from dysregulation of the function of white fat tissue in the abdominal cavity between the internal organs (visceral white fat tissue). New insight into the signaling pathways that contribute to visceral white fat tissue dysregulation has now been provided by Philippe Lefebvre and colleagues, at INSERM, UMR1011, France, who determined that the PPAR-gamma signaling pathway operates differently in the visceral white fat tissue of lean and obese mice and humans. Specifically, it shows increased sensitivity to activation by the anti-diabetic drug rosiglitazone in obese mice and humans. These data therefore provide a mechanistic explanation why rosiglitazone acts differently in lean and obese patients.
TITLE: Proteasomal degradation of retinoid X receptor-alpha reprograms transcriptional activity of PPAR-gamma in obese mice and humans
GASTROENTEROLOGY: Enteroendocrine cells in the gut needed for optimal postnatal survival
Enteroendocrine cells are cells found in the wall of the gut that secrete hormones that regulate numerous processes in the body, including controlling glucose levels, food intake, and stomach emptying. There are at least ten types of enteroendocrine cell and it has been hard to determine the exact role of each cell type and hormone they secrete because many of the hormones have partially overlapping functions. However, a team of researchers, led by Georg Mellitzer and Gérard Gradwohl, at INSERM U964, Université de Strasbourg, France, has now generated mice lacking all enteroendocrine cells and hormones by deleting the gene Ngn3 and found that a lack of these cells leads to a high chance of dying during the first week of life. Surviving mice were smaller than normal littermates, had soft stool, and were impaired in their ability to absorb fat in the intestines. The clinical relevance of these data are highlighted by the recent identification of several patients with NGN3 gene mutations who show an almost complete lack of all enteroendocrine cells and suffer, from the first days of life, from malabsorptive chronic diarrhea.
TITLE: Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival
LYMPHATIC SYSTEM: Regulator of lymph vessel growth uncovered
In addition to our network of blood vessels, humans have a network of vessels known as lymphatic vessels. These vessels have a role in many processes in the body, including regulating fluid levels in tissues and immune surveillance. Although dysfunction in the lymphatic system contributes to human diseases such as the spread of cancer to other sites and lymphademas (localized fluid retention and tissue swelling), little is known about the molecules that regulate the formation of new lymphatic vessels, a process known as lymphangiogenesis. However, a team of researchers, led by Sophia Tsai and Ming-Jer Tsai, at Baylor College of Medicine, Houston, has now identified a role for the gene regulatory protein COUP-TFII in lymphangiogenesis in mouse embryonic development and tumor lymphangiogenesis in adult mice. The authors therefore suggest that COUP-TFII might be an effective molecular target in pro-lymphangiogenic treatment of lymphedemas or in antilymphangiogenic therapy targeting tumor spreading via the lymphatic vessels.
Source:
Karen Honey
Journal of Clinical Investigation
TITLE: Proteasomal degradation of retinoid X receptor-alpha reprograms transcriptional activity of PPAR-gamma in obese mice and humans
GASTROENTEROLOGY: Enteroendocrine cells in the gut needed for optimal postnatal survival
Enteroendocrine cells are cells found in the wall of the gut that secrete hormones that regulate numerous processes in the body, including controlling glucose levels, food intake, and stomach emptying. There are at least ten types of enteroendocrine cell and it has been hard to determine the exact role of each cell type and hormone they secrete because many of the hormones have partially overlapping functions. However, a team of researchers, led by Georg Mellitzer and Gérard Gradwohl, at INSERM U964, Université de Strasbourg, France, has now generated mice lacking all enteroendocrine cells and hormones by deleting the gene Ngn3 and found that a lack of these cells leads to a high chance of dying during the first week of life. Surviving mice were smaller than normal littermates, had soft stool, and were impaired in their ability to absorb fat in the intestines. The clinical relevance of these data are highlighted by the recent identification of several patients with NGN3 gene mutations who show an almost complete lack of all enteroendocrine cells and suffer, from the first days of life, from malabsorptive chronic diarrhea.
TITLE: Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival
LYMPHATIC SYSTEM: Regulator of lymph vessel growth uncovered
In addition to our network of blood vessels, humans have a network of vessels known as lymphatic vessels. These vessels have a role in many processes in the body, including regulating fluid levels in tissues and immune surveillance. Although dysfunction in the lymphatic system contributes to human diseases such as the spread of cancer to other sites and lymphademas (localized fluid retention and tissue swelling), little is known about the molecules that regulate the formation of new lymphatic vessels, a process known as lymphangiogenesis. However, a team of researchers, led by Sophia Tsai and Ming-Jer Tsai, at Baylor College of Medicine, Houston, has now identified a role for the gene regulatory protein COUP-TFII in lymphangiogenesis in mouse embryonic development and tumor lymphangiogenesis in adult mice. The authors therefore suggest that COUP-TFII might be an effective molecular target in pro-lymphangiogenic treatment of lymphedemas or in antilymphangiogenic therapy targeting tumor spreading via the lymphatic vessels.
Source:
Karen Honey
Journal of Clinical Investigation
Thursday, 29 April 2010
Study Offers First Clinical Evidence Of Anti-Cancer Drug Triggering Viral Infection
Important advances in the fight against cancer have come as researchers proved that viruses and cancers interact in ways that were previously unknown to scientists.
A new study led by UNC scientists shows that a common cancer drug can activate a viral infection that, paradoxically, can help anti-viral medications eradicate virus-associated cancer.
The cooperative study, conducted by a team of UNC School of Medicine scientists and the UNC Project in Malawi, demonstrated for the first time in humans that a common drug used to treat Burkitt lymphoma can activate infection by the Epstein-Barr virus (EBV), a virus which typically lies latent inside the tumor cells of affected patients. The finding paves the way for a future study using both a cancer drug and an antiviral agent to eradicate both the active virus infection and the tumor. The findings are reported in the April 1 issue of the journal Clinical Cancer Research.
Margaret Gulley, MD, professor of pathology and laboratory medicine, said, "What we have learned from this work is a potential means of capitalizing on presence of viral genomes within tumor cells to alter those tumor cells in a way that makes them more susceptible to treatment. Our findings have implications for other EBV- related malignancies that, overall, are among the most common cancers worldwide." Gulley is a member of UNC Lineberger Comprehensive Cancer Center.
EBV infects more than 90 percent of the world's population and is associated with diseases ranging from infectious mononucleosis to lymphomas, gastric cancer and cancer of the nose and throat.
Burkitt lymphoma, which is associated with EBV, is rare in most parts of the world, but is endemic in sub-Saharan Africa. Burkitt lymphoma is an aggressive, fast-growing type of non-Hodgkin lymphoma that often occurs in children. The disease may affect the jaw, bowel, lymph nodes, or other organs.
The study demonstrated that initiating treatment with the anti-cancer drug cyclophosphamide in children with Burkitt lymphoma simultaneously triggered an active EBV infection. The increased replication of EBV in cancer tissue makes these cells more susceptible to the antiviral drugs that kill cells containing replicating virus. Antiviral agents such as ganciclovir and valacyclovir are already in routine clinical use for treating active viral infections.
Researchers enrolled 21 patients with a confirmed diagnosis of EBV-related Burkitt lymphoma. The patients ranged in age from 5-15 and were under treatment with cyclophosphamide for their cancer. Through laboratory analysis of biopsy samples, researchers found that cyclophosphamide seems to induce the phase of viral infection most susceptible to antiviral therapy.
"The next step," explains Gulley," is to design a clinical trial using both cytoxan and an antiviral agent simultaneously." Plans for such a trial are already underway under the leadership of Carol Shores, MD, PhD, associate professor of surgery in UNC's Department of Otolaryngology/Head and Neck Surgery and senior author of the study.
Other UNC scientists involved in the study are members of the departments of pathology, otolaryngology, and medicine/infectious disease division. Additional collaborators are affiliated with Kamuzu Central Hospital and the UNC Malawi Project, and Dr. Shannon Kenney who was Sarah Graham Kenan professor at UNC before joining the departments of medicine and oncology at the University of Wisconsin in Madison.
Source: University of North Carolina at Chapel Hill School of Medicine
A new study led by UNC scientists shows that a common cancer drug can activate a viral infection that, paradoxically, can help anti-viral medications eradicate virus-associated cancer.
The cooperative study, conducted by a team of UNC School of Medicine scientists and the UNC Project in Malawi, demonstrated for the first time in humans that a common drug used to treat Burkitt lymphoma can activate infection by the Epstein-Barr virus (EBV), a virus which typically lies latent inside the tumor cells of affected patients. The finding paves the way for a future study using both a cancer drug and an antiviral agent to eradicate both the active virus infection and the tumor. The findings are reported in the April 1 issue of the journal Clinical Cancer Research.
Margaret Gulley, MD, professor of pathology and laboratory medicine, said, "What we have learned from this work is a potential means of capitalizing on presence of viral genomes within tumor cells to alter those tumor cells in a way that makes them more susceptible to treatment. Our findings have implications for other EBV- related malignancies that, overall, are among the most common cancers worldwide." Gulley is a member of UNC Lineberger Comprehensive Cancer Center.
EBV infects more than 90 percent of the world's population and is associated with diseases ranging from infectious mononucleosis to lymphomas, gastric cancer and cancer of the nose and throat.
Burkitt lymphoma, which is associated with EBV, is rare in most parts of the world, but is endemic in sub-Saharan Africa. Burkitt lymphoma is an aggressive, fast-growing type of non-Hodgkin lymphoma that often occurs in children. The disease may affect the jaw, bowel, lymph nodes, or other organs.
The study demonstrated that initiating treatment with the anti-cancer drug cyclophosphamide in children with Burkitt lymphoma simultaneously triggered an active EBV infection. The increased replication of EBV in cancer tissue makes these cells more susceptible to the antiviral drugs that kill cells containing replicating virus. Antiviral agents such as ganciclovir and valacyclovir are already in routine clinical use for treating active viral infections.
Researchers enrolled 21 patients with a confirmed diagnosis of EBV-related Burkitt lymphoma. The patients ranged in age from 5-15 and were under treatment with cyclophosphamide for their cancer. Through laboratory analysis of biopsy samples, researchers found that cyclophosphamide seems to induce the phase of viral infection most susceptible to antiviral therapy.
"The next step," explains Gulley," is to design a clinical trial using both cytoxan and an antiviral agent simultaneously." Plans for such a trial are already underway under the leadership of Carol Shores, MD, PhD, associate professor of surgery in UNC's Department of Otolaryngology/Head and Neck Surgery and senior author of the study.
Other UNC scientists involved in the study are members of the departments of pathology, otolaryngology, and medicine/infectious disease division. Additional collaborators are affiliated with Kamuzu Central Hospital and the UNC Malawi Project, and Dr. Shannon Kenney who was Sarah Graham Kenan professor at UNC before joining the departments of medicine and oncology at the University of Wisconsin in Madison.
Source: University of North Carolina at Chapel Hill School of Medicine
MU Researchers Collaborate To Develop Standard Of Care For Breast Cancer Survivors With Lymphedema
Lymphedema, a chronic swelling condition that can appear after breast cancer surgery, is a risk for 1.3 million breast cancer survivors. Although lymphedema can cause lifelong swelling in the arms, back, neck and chest, there is no national standard of diagnosis or care. Now, University of Missouri researchers are leading the American Lymphedema Framework Project (ALFP), a national, multi-disciplinary collaboration to develop comprehensive guidelines for the assessment, treatment, and management of lymphedema.
"We can't cure lymphedema today - we can only manage it," said Jane Armer, MU nursing professor and director of the project at the MU Ellis Fischel Cancer Center. "Lymphedema is a complex, chronic condition. Currently, there are inconsistent approaches to care for lymphedema, and often the most common form of self-management is to not treat it at all."
The ALFP, established in 2008, has two main goals: establish a best practices document with evidence-based lymphedema treatment guidelines for health practitioners, and create a minimum data set of all available lymphedema research and clinical data. The ALFP researchers plan to publish the best practices document in 2011.
"Part of why there isn't a standard of care is the lack of reliance on current evidence by health practitioners and third party payers, which in turn causes problems with reimbursement from health insurance companies. Many people with lymphedema have to pay out-of-pocket for care," Armer said. "There isn't a clear, national consensus for how to diagnose lymphedema and when to start treating it. The ALFP collaborators aim to document a standard of care reflecting a consensus on best practices that will help solve these problems."
Researchers, including those at MU, have found that the most effective method of care for lymphedema is complete decongestive physiotherapy, in which therapists use specialized lymphatic massage techniques to reduce protein-rich fluid buildup. Bandages and compression garments also help to reduce swelling.
One of Armer's innovations at MU is measuring patients' arms with a perometer, a machine that was first used to fit garments for swollen limbs. First implemented in a research setting at MU, the machine has a large optoelectric frame that glides over a patient's arm, scans its image and records an estimated limb volume reading. Perometer measurement is as, or more, accurate than several previous methods to measure arm circumference and volume. The machine is now used in about 20 sites across the country.
Highlights of MU Sinclair School of Nursing research from the past 10 years reveal that there is a 40 percent higher risk of developing lymphedema in women with a body mass index (BMI) classified as overweight or obese compared to normal-weight women. The researchers also found that younger patients may have less occurrence of the condition but tend to report more symptoms, which could be a result of psychological and aging-related factors.
"In addition to our previous findings, we're currently studying whether there are any genetic factors that increase the risk of lymphedema," Armer said. "A pilot study now underway and a proposed multi-site research study will look at the possibility of genetic predisposition for secondary lymphedema. The results could be applied to cancer treatment in which surgery and radiation affect the lymphatic system."
In recognition of the leadership in lymphedema research at MU, the ALFP is housed at the MU Ellis Fischel Cancer Center. Armer's research is funded by the National Institutes of Health and is published in several journals, including the Journal of Lymphoedema; Lymphology; Lymphatic Research and Biology; and the Journal of Cancer Survivorship, and presented at conferences throughout the world. The activities of the ALFP have been funded by industry partnerships and grants from the American Cancer Society through The Longaberger Company, a direct-selling company offering home products, and the Longaberger Horizon of Hope Campaign, which provided a grant for breast cancer research and education.
Source:
Emily Martin
University of Missouri-Columbia
"We can't cure lymphedema today - we can only manage it," said Jane Armer, MU nursing professor and director of the project at the MU Ellis Fischel Cancer Center. "Lymphedema is a complex, chronic condition. Currently, there are inconsistent approaches to care for lymphedema, and often the most common form of self-management is to not treat it at all."
The ALFP, established in 2008, has two main goals: establish a best practices document with evidence-based lymphedema treatment guidelines for health practitioners, and create a minimum data set of all available lymphedema research and clinical data. The ALFP researchers plan to publish the best practices document in 2011.
"Part of why there isn't a standard of care is the lack of reliance on current evidence by health practitioners and third party payers, which in turn causes problems with reimbursement from health insurance companies. Many people with lymphedema have to pay out-of-pocket for care," Armer said. "There isn't a clear, national consensus for how to diagnose lymphedema and when to start treating it. The ALFP collaborators aim to document a standard of care reflecting a consensus on best practices that will help solve these problems."
Researchers, including those at MU, have found that the most effective method of care for lymphedema is complete decongestive physiotherapy, in which therapists use specialized lymphatic massage techniques to reduce protein-rich fluid buildup. Bandages and compression garments also help to reduce swelling.
One of Armer's innovations at MU is measuring patients' arms with a perometer, a machine that was first used to fit garments for swollen limbs. First implemented in a research setting at MU, the machine has a large optoelectric frame that glides over a patient's arm, scans its image and records an estimated limb volume reading. Perometer measurement is as, or more, accurate than several previous methods to measure arm circumference and volume. The machine is now used in about 20 sites across the country.
Highlights of MU Sinclair School of Nursing research from the past 10 years reveal that there is a 40 percent higher risk of developing lymphedema in women with a body mass index (BMI) classified as overweight or obese compared to normal-weight women. The researchers also found that younger patients may have less occurrence of the condition but tend to report more symptoms, which could be a result of psychological and aging-related factors.
"In addition to our previous findings, we're currently studying whether there are any genetic factors that increase the risk of lymphedema," Armer said. "A pilot study now underway and a proposed multi-site research study will look at the possibility of genetic predisposition for secondary lymphedema. The results could be applied to cancer treatment in which surgery and radiation affect the lymphatic system."
In recognition of the leadership in lymphedema research at MU, the ALFP is housed at the MU Ellis Fischel Cancer Center. Armer's research is funded by the National Institutes of Health and is published in several journals, including the Journal of Lymphoedema; Lymphology; Lymphatic Research and Biology; and the Journal of Cancer Survivorship, and presented at conferences throughout the world. The activities of the ALFP have been funded by industry partnerships and grants from the American Cancer Society through The Longaberger Company, a direct-selling company offering home products, and the Longaberger Horizon of Hope Campaign, which provided a grant for breast cancer research and education.
Source:
Emily Martin
University of Missouri-Columbia
Wednesday, 28 April 2010
Lymphedema: Risk Reduction And Management Strategies
There are no scientific studies showing that lymphedema can be prevented, but there are ways to lower your risk of developing this treatment side effect. During the 10th Annual Conference for Young Women Affected by Breast Cancer, we will explore the myths and recent scientific evidence about lymphedema, learn about risk reduction techniques and discuss approaches to lymphedema management, including exercise, physical therapy, lymphatic drainage, massage and other treatment methods.
The 10th Annual Conference for Young Women Affected by Breast Cancer is the only international conference dedicated to the critical issues of young breast cancer survivors and those who care about them. Nearly 1,000 young breast cancer survivors, caregivers and medical professionals from around the world are expected to attend the Conference, to be held Friday, Feb. 26-Sunday, Feb. 28 at the Sheraton Atlanta Hotel in Atlanta, Ga.
The Lymphedema: Risk Reduction and Management Strategies workshop will take place from 3:30 - 5:00 p.m. on Friday, Feb. 26 , and will be led by physical therapist Jill Binkley, PT, MSc, FAAOMPT, executive director of TurningPoint Women's Healthcare in Alpharetta, Ga.
To learn more about the Conference and for a complete list of workshops, visit http://www.youngsurvivorsconference.org.
Source
Living Beyond Breast Cancer (LBBC)
The Young Survival Coalition (YSC)
The 10th Annual Conference for Young Women Affected by Breast Cancer is the only international conference dedicated to the critical issues of young breast cancer survivors and those who care about them. Nearly 1,000 young breast cancer survivors, caregivers and medical professionals from around the world are expected to attend the Conference, to be held Friday, Feb. 26-Sunday, Feb. 28 at the Sheraton Atlanta Hotel in Atlanta, Ga.
The Lymphedema: Risk Reduction and Management Strategies workshop will take place from 3:30 - 5:00 p.m. on Friday, Feb. 26 , and will be led by physical therapist Jill Binkley, PT, MSc, FAAOMPT, executive director of TurningPoint Women's Healthcare in Alpharetta, Ga.
To learn more about the Conference and for a complete list of workshops, visit http://www.youngsurvivorsconference.org.
Source
Living Beyond Breast Cancer (LBBC)
The Young Survival Coalition (YSC)
Monday, 19 April 2010
HIV interrupts resistant cell migration to avert detection
The HIV protein Nef sparked intensive research after observations that patients with a rare strain of HIV lacking Nef took a very long time to develop AIDS symptoms. Nef has been linked to molecules involved in cell signaling pathways and may use them for its own ends.
But how Nef does this has not been clear. Now Jacek Skowronski and his colleagues at Cold Spring Harbor Laboratory in New York have identified a mechanism involving Nef, by which HIV-infected T cells are kept from traveling to sites within lymphatic tissues where they can become activated.
Skowronski's lab found that Nef associates with two proteins, DOCK2 and ELMO1. DOCK2 regulates enzymes (Rac1 and Rac2) that are required for normal lymphocyte migration and antigen-specific responses. ELMO1 has also been shown to help DOCK2 activate Rac.
Because DOCK2 activates Rac as part of two different signaling pathways--one activated by the T cell receptor, which mediates T cell activation, and one by a chemokine receptor, which controls T cell migration--the researchers investigated whether Nef could affect these important pathways by modulating Rac activity.
They found that Nef in fact activates Rac by binding to the DOCK2ELMO1 complex. And they went on to show that HIV uses these components of the chemokine receptor pathway to disrupt T cell migration.
To generate an effective immune response, it is crucial that T cells travel to sites within lymphatic tissues where they interact with other lymphocytes. By inhibiting T cell migration, the researchers propose, Nef prevents these critical interactions, thereby providing a mechanism for stifling the immune response.
These results, the authors argue, provide the biochemical evidence that Nef targets a protein 'switch' that can interfere with important aspects of T cell function.
In this way, Nef subverts the immune response pathways controlled by receptors on the surface of T cells to effectively disarm the immune system and turn T cells into viral replication factories.
Understanding how Nef interacts with these proteins to spread infection could lay the foundation for valuable new therapies aimed at inhibiting and arresting HIV infection by blocking Nef-mediated effects.
Source: plosbiology
But how Nef does this has not been clear. Now Jacek Skowronski and his colleagues at Cold Spring Harbor Laboratory in New York have identified a mechanism involving Nef, by which HIV-infected T cells are kept from traveling to sites within lymphatic tissues where they can become activated.
Skowronski's lab found that Nef associates with two proteins, DOCK2 and ELMO1. DOCK2 regulates enzymes (Rac1 and Rac2) that are required for normal lymphocyte migration and antigen-specific responses. ELMO1 has also been shown to help DOCK2 activate Rac.
Because DOCK2 activates Rac as part of two different signaling pathways--one activated by the T cell receptor, which mediates T cell activation, and one by a chemokine receptor, which controls T cell migration--the researchers investigated whether Nef could affect these important pathways by modulating Rac activity.
They found that Nef in fact activates Rac by binding to the DOCK2ELMO1 complex. And they went on to show that HIV uses these components of the chemokine receptor pathway to disrupt T cell migration.
To generate an effective immune response, it is crucial that T cells travel to sites within lymphatic tissues where they interact with other lymphocytes. By inhibiting T cell migration, the researchers propose, Nef prevents these critical interactions, thereby providing a mechanism for stifling the immune response.
These results, the authors argue, provide the biochemical evidence that Nef targets a protein 'switch' that can interfere with important aspects of T cell function.
In this way, Nef subverts the immune response pathways controlled by receptors on the surface of T cells to effectively disarm the immune system and turn T cells into viral replication factories.
Understanding how Nef interacts with these proteins to spread infection could lay the foundation for valuable new therapies aimed at inhibiting and arresting HIV infection by blocking Nef-mediated effects.
Source: plosbiology
Study Gives Initial Clinical Proof Of Anti-Cancer Drug Activating Viral Infection
Important advances in the fight against cancer have come as researchers proved that viruses and cancers interact in ways that were previously unknown to scientists.
A new study led by UNC scientists shows that a common cancer drug can activate a viral infection that, paradoxically, can help anti-viral medications eradicate virus-associated cancer.
The cooperative study, conducted by a team of UNC School of Medicine scientists and the UNC Project in Malawi, demonstrated for the first time in humans that a common drug used to treat Burkitt lymphoma can activate infection by the Epstein-Barr virus (EBV), a virus which typically lies latent inside the tumor cells of affected patients. The finding paves the way for a future study using both a cancer drug and an antiviral agent to eradicate both the active virus infection and the tumor. The findings are reported in the April 1 issue of the journal Clinical Cancer Research.
Margaret Gulley, MD, professor of pathology and laboratory medicine, said, "What we have learned from this work is a potential means of capitalizing on presence of viral genomes within tumor cells to alter those tumor cells in a way that makes them more susceptible to treatment. Our findings have implications for other EBV- related malignancies that, overall, are among the most common cancers worldwide." Gulley is a member of UNC Lineberger Comprehensive Cancer Center.
EBV infects more than 90 percent of the world's population and is associated with diseases ranging from infectious mononucleosis to lymphomas, gastric cancer and cancer of the nose and throat.
Burkitt lymphoma, which is associated with EBV, is rare in most parts of the world, but is endemic in sub-Saharan Africa. Burkitt lymphoma is an aggressive, fast-growing type of non-Hodgkin lymphoma that often occurs in children. The disease may affect the jaw, bowel, lymph nodes, or other organs.
The study demonstrated that initiating treatment with the anti-cancer drug cyclophosphamide in children with Burkitt lymphoma simultaneously triggered an active EBV infection. The increased replication of EBV in cancer tissue makes these cells more susceptible to the antiviral drugs that kill cells containing replicating virus. Antiviral agents such as ganciclovir and valacyclovir are already in routine clinical use for treating active viral infections.
Researchers enrolled 21 patients with a confirmed diagnosis of EBV-related Burkitt lymphoma. The patients ranged in age from 5-15 and were under treatment with cyclophosphamide for their cancer. Through laboratory analysis of biopsy samples, researchers found that cyclophosphamide seems to induce the phase of viral infection most susceptible to antiviral therapy.
"The next step," explains Gulley," is to design a clinical trial using both cytoxan and an antiviral agent simultaneously." Plans for such a trial are already underway under the leadership of Carol Shores, MD, PhD, associate professor of surgery in UNC's Department of Otolaryngology/Head and Neck Surgery and senior author of the study.
Other UNC scientists involved in the study are members of the departments of pathology, otolaryngology, and medicine/infectious disease division. Additional collaborators are affiliated with Kamuzu Central Hospital and the UNC Malawi Project, and Dr. Shannon Kenney who was Sarah Graham Kenan professor at UNC before joining the departments of medicine and oncology at the University of Wisconsin in Madison.
Source: University of North Carolina at Chapel Hill School of Medicine
A new study led by UNC scientists shows that a common cancer drug can activate a viral infection that, paradoxically, can help anti-viral medications eradicate virus-associated cancer.
The cooperative study, conducted by a team of UNC School of Medicine scientists and the UNC Project in Malawi, demonstrated for the first time in humans that a common drug used to treat Burkitt lymphoma can activate infection by the Epstein-Barr virus (EBV), a virus which typically lies latent inside the tumor cells of affected patients. The finding paves the way for a future study using both a cancer drug and an antiviral agent to eradicate both the active virus infection and the tumor. The findings are reported in the April 1 issue of the journal Clinical Cancer Research.
Margaret Gulley, MD, professor of pathology and laboratory medicine, said, "What we have learned from this work is a potential means of capitalizing on presence of viral genomes within tumor cells to alter those tumor cells in a way that makes them more susceptible to treatment. Our findings have implications for other EBV- related malignancies that, overall, are among the most common cancers worldwide." Gulley is a member of UNC Lineberger Comprehensive Cancer Center.
EBV infects more than 90 percent of the world's population and is associated with diseases ranging from infectious mononucleosis to lymphomas, gastric cancer and cancer of the nose and throat.
Burkitt lymphoma, which is associated with EBV, is rare in most parts of the world, but is endemic in sub-Saharan Africa. Burkitt lymphoma is an aggressive, fast-growing type of non-Hodgkin lymphoma that often occurs in children. The disease may affect the jaw, bowel, lymph nodes, or other organs.
The study demonstrated that initiating treatment with the anti-cancer drug cyclophosphamide in children with Burkitt lymphoma simultaneously triggered an active EBV infection. The increased replication of EBV in cancer tissue makes these cells more susceptible to the antiviral drugs that kill cells containing replicating virus. Antiviral agents such as ganciclovir and valacyclovir are already in routine clinical use for treating active viral infections.
Researchers enrolled 21 patients with a confirmed diagnosis of EBV-related Burkitt lymphoma. The patients ranged in age from 5-15 and were under treatment with cyclophosphamide for their cancer. Through laboratory analysis of biopsy samples, researchers found that cyclophosphamide seems to induce the phase of viral infection most susceptible to antiviral therapy.
"The next step," explains Gulley," is to design a clinical trial using both cytoxan and an antiviral agent simultaneously." Plans for such a trial are already underway under the leadership of Carol Shores, MD, PhD, associate professor of surgery in UNC's Department of Otolaryngology/Head and Neck Surgery and senior author of the study.
Other UNC scientists involved in the study are members of the departments of pathology, otolaryngology, and medicine/infectious disease division. Additional collaborators are affiliated with Kamuzu Central Hospital and the UNC Malawi Project, and Dr. Shannon Kenney who was Sarah Graham Kenan professor at UNC before joining the departments of medicine and oncology at the University of Wisconsin in Madison.
Source: University of North Carolina at Chapel Hill School of Medicine
Saturday, 10 April 2010
Fresh way of analysing lymph tissue discovers concealed melanoma
Afresh report shows that molecular analytic thinking of a very little tissue sample can discover obscured melanoma metastases in lymph nodes. The comportment of melanoma in the lymph nodes is the exclusive most crucial factor in checking a patient's prospect and is a central factor in checking a patient's class of treatment.
Released in the October 1 issue of the Journal of Clinical Oncology, the field is the inaugural to use such a slim section of archival paraffin-embedded tissue and demonstrate that a particular set of molecular features signals the presence of melanoma in the lymph nodes - even amid patients whose lymph nodes seem cancer-free applying stock formulas.
By applying a small tissue part, diagnosticians bare additional of the whole specimen, which is demanded for further pathology trials.
'Our determinations indicate that by executing molecular analysis on a really little patch of tissue, we can rapidly and precisely discover previously indiscernible metastases, and leave a more exact forecast for patients,' said Dr. Dave S.B. Hoon, manager of the Department of Molecular Oncology at the John Wayne Cancer Institute in Santa Monica, California, and elder writer of the study.
'Allowing a more exact prospect can inform conclusions on when and how to care for patients, and could ultimately improve our power to treat patients with melanoma.'
Dr. Hoon and his squad made a molecular test to discover the comportment of 4 melanoma-associated proteins, or 'marks,' in lymph node tissue. They found filed away tissue samplings from seventy-seven patients.
Stock trials uncovered that thirty-seven of the samplings held melanoma, showing a hapless medical prognosis.
Even so, applying the fresh molecular psychoanalysis, investigators bore witness that the lymph nodes of twenty-five pct of the forty patients whose nodes were believed to be cancer-free really bore 2 or additional of the melanoma-associated markers.
Released in the October 1 issue of the Journal of Clinical Oncology, the field is the inaugural to use such a slim section of archival paraffin-embedded tissue and demonstrate that a particular set of molecular features signals the presence of melanoma in the lymph nodes - even amid patients whose lymph nodes seem cancer-free applying stock formulas.
By applying a small tissue part, diagnosticians bare additional of the whole specimen, which is demanded for further pathology trials.
'Our determinations indicate that by executing molecular analysis on a really little patch of tissue, we can rapidly and precisely discover previously indiscernible metastases, and leave a more exact forecast for patients,' said Dr. Dave S.B. Hoon, manager of the Department of Molecular Oncology at the John Wayne Cancer Institute in Santa Monica, California, and elder writer of the study.
'Allowing a more exact prospect can inform conclusions on when and how to care for patients, and could ultimately improve our power to treat patients with melanoma.'
Dr. Hoon and his squad made a molecular test to discover the comportment of 4 melanoma-associated proteins, or 'marks,' in lymph node tissue. They found filed away tissue samplings from seventy-seven patients.
Stock trials uncovered that thirty-seven of the samplings held melanoma, showing a hapless medical prognosis.
Even so, applying the fresh molecular psychoanalysis, investigators bore witness that the lymph nodes of twenty-five pct of the forty patients whose nodes were believed to be cancer-free really bore 2 or additional of the melanoma-associated markers.
80 million people now treated to forestall elephantiasis
One of world's most disfiguring diseases could be eliminated in 20 years.
Simple treatment costs only pennies per person.
London and Philadelphia - In only four years, a massive World Health Organization-led global program to eliminate one of the world's most disfiguring and disabling tropical diseases, lymphatic filariasis (LF), has already provided remarkable benefits for the populations of at least 37 endemic countries.
A simple 2-drug, once-yearly treatment of all 'at risk' individuals using very safe and effective medicines (albendazole plus either ivermectin or DEC) has been responsible for the fastest ramp up of a global public health program in history.
The World Health Organization (WHO) reports that today nearly 80 million people -- 30 million of whom are children -- have begun to be protected from LF by stopping transmission of the disease, which can lead to the huge enlargement and disfigurement of the arms, legs and genital organs known as elephantiasis.
Two of these drugs are being donated by their manufacturers - albendazole by GlaxoSmithKline and MectizanTM (ivermectin) by Merck & Co., Inc.
'Our company has already donated 250 million treatments of albendazole to this program, and we will continue to donate as much of the drug as is needed,' says J.P. Garnier, CEO of GlaxoSmithKline. 'We estimate that it will take about 20 years to break the cycle of the disease globally. But we have the proof now that it is practical to eliminate this ghastly disease completely, within our lifetimes.'
Some one billion people in 80 tropical countries are at risk from LF, and 120 million people actually carry the infection, which is spread by a microscopic, parasitic worm that invades the human lymphatic system. The disease is spread by parasite-carrying mosquitoes, which act as vectors for the disease when they bite multiple people.
In many endemic regions, the infection is found in as much as 25 percent of children 4-6 years old. However, early damage is hidden and no immediate signs of LF are visible. LF generally begins to be recognized only in the victim's teen years. The disease often leads to profound psychological disability as a very understandable consequence of the severe physical disfigurements.
Efforts to eliminate the carrier of the parasite, the mosquito, are rarely sufficient to stop the spread of infection. Medical studies of the 1990s showed that the best opportunity for eliminating lymphatic filariasis is through medicines-combinations of the inexpensively purchased diethylcarbamazine (DEC) and the donated albendazole and Mectizan (ivermectin).
The principal goal of treating affected communities is to eliminate the microfilariae from the blood of infected individuals so that transmission of infection by the mosquito can be interrupted.
The crucial research of the 1990s demonstrated that a single dose of two drugs administered concurrently (albendazole with either DEC or ivermectin) could be 99 percent effective in killing microfilariae from the blood for a full year after treatment. It is this level of treatment effectiveness that has made feasible the new global efforts to eliminate lymphatic filariasis.
But everyone living in areas at risk for the disease must be targeted for drug treatment. In Yemen and Sub-Saharan African countries where river blindness (treated with Mectizan) and LF co-exist, the two donated drugs - albendazole and Mectizan (ivermectin) - are used against the disease. Elsewhere in the world the combination of DEC and albendazole is used.
The cost-benefit ratio of LF treatment is also astounding, according to The Global Alliance for the Elimination of Lymphatic Filariasis (GAELF), a global partnership of 80 health ministries, GlaxoSmithKline, Merck, WHO, UNICEF, World Bank and others.
Administration of LF treatment costs between US$0.10 and US$2.00 per person for the full five-year course. GlaxoSmithKline and Merck provide all necessary quantities of albendazole and Mectizan - at no cost - to assist the Global Programme in achieving its goals.
Data gathered by the WHO have revealed that LF is endemic in 32 of the 38 least developed countries (referred to in the Report of the WHO-established Commission on Macroeconomics and Health) and more than 80 percent of the LF endemic population live in these countries.
Considering the close link between poverty and LF, elimination of the disease will also provide an opportunity to reduce poverty and inequality.
The strong community participation and capacity-building components of the Global Programme that have been developed are highly-effective means of producing skilled personnel and reliable information systems and of ultimately strengthening the health system.
The elimination of LF is expected to provide tremendous economic advantages in affected areas. Economists estimate that people protected from the effects of LF could be expected to contribute billions more dollars to the economies of endemic regions throughout their lifetimes than they would have had they been stricken by the disease.
In India alone, the economic losses resulting from decreased productivity and lost work days are estimated to be in the order of US$1 billion annually.
'The fight against LF is absolutely winnable,' says Dr. Garnier. 'What's required is the continuous commitment of the major players involved in the effort - governments, non-governmental organizations, international institutions, pharmaceutical companies and the communities themselves.'
GlaxoSmithKline expects to donate more than US$1 billion worth of medicine and cash donations over the projected 20 -year program.
And while early support for the Global Alliance has also come from the Ministries of Health of the endemic countries and a number of international organizations, including the Bill & Melinda Gates Foundation, Arab Fund for Economic and Social Development, US Centers for Disease Control and Prevention, US Agency for International Development, UK Department for International Development and the Japan International Cooperation Agency, there is a need for additional donors to join the campaign.
'The main problem is that LF disease (elephantiasis and genital damage) is mostly unknown in the West, because travelers and tourists rarely become infected, since multiple mosquito bites over a long period are usually necessary before a victim begins to show symptoms. So LF has been ignored by policymakers in many developed countries,' says David Molyneux, PhD, a tropical disease expert from the Liverpool School of Tropical Medicine. 'This is a disease that affects the poorest of the poor.'
'In diseases like tuberculosis, HIV and malaria where parasites, bacteria and viruses develop resistance, part of the medical challenge is to stay ahead of the mutations,' says Professor Molyneux. The LF worms, on the other hand, are slow growing and for a number of reasons are less likely to develop drug resistance. It makes the goal of ending the disease realistic.'
The disease elimination program involves very close collaboration with Ministries of Health of participating nations. WHO Headquarters, Regional Offices and Country Offices support mapping the extent of the diseases in endemic regions with a new test that can determine almost instantly whether a person, including a child, is infected.
In tropical and subtropical areas of Africa, Asia and the Americas where lymphatic filariasis is highly endemic, the prevalence of infection is continuing to increase. A primary cause of this increase is the rapid and unplanned growth of cities, which creates numerous breeding sites for the mosquitoes that transmit the disease.
Approximately one-third of people infected with the disease live in India; one third are in Africa and most of the remainder are in Southeast Asia, the Pacific and the Americas.
Background on disease
The thread-like, parasitic filarial worms Wuchereria bancrofti, Brugia malayi, and Brugia timori that cause lymphatic filariasis live almost exclusively in humans.
These worms lodge in the lymphatic system, the network of nodes and vessels that maintain the delicate fluid balance between the tissues and blood and that are an essential component for the body's immune defense system. They live for 4-6 years, producing millions of immature microfilariae, minute larvae that circulate in the blood.
The disease is transmitted by mosquitoes that bite infected humans, ingesting the microfilariae. In 7-14 days, the microfilariae mature and migrate to the mosquito's biting mouthparts, ready for inoculation into the bloodstream of the next unsuspecting individual, thus completing the infection cycle.
The appearance of the disease itself in humans is still something of an enigma to scientists. Though the infection is generally acquired early in childhood, the disease may take years to express itself. Indeed, many people never acquire the outward clinical manifestations of their infections.
An asymptomatic form of infection, characterized by the presence of millions of microfilariae in the blood and adult worms in the lymphatic system, may have no recognizable clinical manifestations at all. However, recent studies now show clearly that such victims, outwardly healthy, actually have hidden lymphatic pathology, kidney damage and defects in their immune responsiveness.
The worst symptoms of the chronic disease generally appear in adults, and in men more often than women. In endemic communities, some 10-50 percent of men suffer from genital damage, especially hydrocoele (fluid-filled balloon-like enlargement of the sacs around the testes) and elephantiasis of the penis and scrotum.
Elephantiasis of the entire leg, the entire arm, or the breast -- swelling up to three times normal size -- can affect up to 10 percent of men and women in these communities. The psychological and social stigmata associated with the disease are immense, including sexual dysfunction and social ostracism of men and women.
Young women and men often can never marry or are subsequently rejected.
Acute episodes of local inflammation involving skin, lymph nodes and lymphatic vessels often accompany the chronic lymphedema or elephantiasis.
Some of these are caused by the body's immune response to the parasite, but most are the result of the bacterial infection of skin where normal defenses have been partially lost due to underlying lymphatic damage.
Careful cleansing can be extremely helpful in healing the infected surface areas and in both slowing and, even more remarkably, reversing much of the overt damage that has occurred already.
In endemic areas, chronic and acute manifestations of filariasis tend to develop more often and sooner in refugees or newcomers than in local populations continually exposed to infection. Lymphedema may develop within six months and elephantiasis as quickly as a year after arrival. Once damaged, the lymphatic system never recovers.
The previous treatment regimen thought necessary for LF was a long, 2-week course of DEC. It is now recognized, however that when a single dose of either DEC or ivermectin is administered with albendazole, the results are even more effective than the old treatment regimen.
Unexpected Benefits of LF Campaign
The campaign to eliminate LF has also been found to have important ancillary benefits. 'Albendazole is highly effective not only against the LF parasites but also against the most serious intestinal parasites of children and childbearing women that inhibit mental development and stunt physical growth of hundreds of millions of newborns and young children yearly,' says Eric A. Ottesen, M.D., a professor at Emory University's Rollins School of Public Health and Director of the Emory LF Support Center.
The three most serious parasites are roundworms, which infect nearly a half billion children; whipworms, which infect 350 million children; and hookworms, which infect nearly 300 million children. In some regions, more than 90 percent of children are infected with one or more of these parasites.
Intestinal parasites take a severe toll on the nutritional status of infected children, resulting in poor physical growth, anemia and an inability to absorb vital nutrients.
Results from treating these infections have been dramatic in the developing countries where evaluations have been carried out. Examples include:
Growth and development - five months after being treated with albendazole and ivermectin, children gained over 0.5 kg more than children treated with placebo [Haiti];
Physical fitness - seven weeks after being treated with albendazole for intestinal worms, school children had improved resting heart rates and increased physical fitness [Kenya];
Physical activity - nine weeks after treatment with albendazole, school children showed demonstrable increases in spontaneous play and other measurable activities [Kenya];
School attendance - six months after treatment with albendazole, stunted children with whipworm infection showed improved school attendance [Jamaica].
'These results demonstrate convincingly that such drugs as albendazole can dramatically improve the health development of the poorest of the poor children throughout the world,' says Dr. Ottesen. 'What is more, this can be done with essentially no additional cost to them or to the healthcare systems responsible for them, since everyone living in areas where the Global Programme to Eliminate Lymphatic Filariasis is active - including the particularly vulnerable populations of children and women of childbearing age - will already be receiving these drugs.'
From Glaxo Smithkline
Simple treatment costs only pennies per person.
London and Philadelphia - In only four years, a massive World Health Organization-led global program to eliminate one of the world's most disfiguring and disabling tropical diseases, lymphatic filariasis (LF), has already provided remarkable benefits for the populations of at least 37 endemic countries.
A simple 2-drug, once-yearly treatment of all 'at risk' individuals using very safe and effective medicines (albendazole plus either ivermectin or DEC) has been responsible for the fastest ramp up of a global public health program in history.
The World Health Organization (WHO) reports that today nearly 80 million people -- 30 million of whom are children -- have begun to be protected from LF by stopping transmission of the disease, which can lead to the huge enlargement and disfigurement of the arms, legs and genital organs known as elephantiasis.
Two of these drugs are being donated by their manufacturers - albendazole by GlaxoSmithKline and MectizanTM (ivermectin) by Merck & Co., Inc.
'Our company has already donated 250 million treatments of albendazole to this program, and we will continue to donate as much of the drug as is needed,' says J.P. Garnier, CEO of GlaxoSmithKline. 'We estimate that it will take about 20 years to break the cycle of the disease globally. But we have the proof now that it is practical to eliminate this ghastly disease completely, within our lifetimes.'
Some one billion people in 80 tropical countries are at risk from LF, and 120 million people actually carry the infection, which is spread by a microscopic, parasitic worm that invades the human lymphatic system. The disease is spread by parasite-carrying mosquitoes, which act as vectors for the disease when they bite multiple people.
In many endemic regions, the infection is found in as much as 25 percent of children 4-6 years old. However, early damage is hidden and no immediate signs of LF are visible. LF generally begins to be recognized only in the victim's teen years. The disease often leads to profound psychological disability as a very understandable consequence of the severe physical disfigurements.
Efforts to eliminate the carrier of the parasite, the mosquito, are rarely sufficient to stop the spread of infection. Medical studies of the 1990s showed that the best opportunity for eliminating lymphatic filariasis is through medicines-combinations of the inexpensively purchased diethylcarbamazine (DEC) and the donated albendazole and Mectizan (ivermectin).
The principal goal of treating affected communities is to eliminate the microfilariae from the blood of infected individuals so that transmission of infection by the mosquito can be interrupted.
The crucial research of the 1990s demonstrated that a single dose of two drugs administered concurrently (albendazole with either DEC or ivermectin) could be 99 percent effective in killing microfilariae from the blood for a full year after treatment. It is this level of treatment effectiveness that has made feasible the new global efforts to eliminate lymphatic filariasis.
But everyone living in areas at risk for the disease must be targeted for drug treatment. In Yemen and Sub-Saharan African countries where river blindness (treated with Mectizan) and LF co-exist, the two donated drugs - albendazole and Mectizan (ivermectin) - are used against the disease. Elsewhere in the world the combination of DEC and albendazole is used.
The cost-benefit ratio of LF treatment is also astounding, according to The Global Alliance for the Elimination of Lymphatic Filariasis (GAELF), a global partnership of 80 health ministries, GlaxoSmithKline, Merck, WHO, UNICEF, World Bank and others.
Administration of LF treatment costs between US$0.10 and US$2.00 per person for the full five-year course. GlaxoSmithKline and Merck provide all necessary quantities of albendazole and Mectizan - at no cost - to assist the Global Programme in achieving its goals.
Data gathered by the WHO have revealed that LF is endemic in 32 of the 38 least developed countries (referred to in the Report of the WHO-established Commission on Macroeconomics and Health) and more than 80 percent of the LF endemic population live in these countries.
Considering the close link between poverty and LF, elimination of the disease will also provide an opportunity to reduce poverty and inequality.
The strong community participation and capacity-building components of the Global Programme that have been developed are highly-effective means of producing skilled personnel and reliable information systems and of ultimately strengthening the health system.
The elimination of LF is expected to provide tremendous economic advantages in affected areas. Economists estimate that people protected from the effects of LF could be expected to contribute billions more dollars to the economies of endemic regions throughout their lifetimes than they would have had they been stricken by the disease.
In India alone, the economic losses resulting from decreased productivity and lost work days are estimated to be in the order of US$1 billion annually.
'The fight against LF is absolutely winnable,' says Dr. Garnier. 'What's required is the continuous commitment of the major players involved in the effort - governments, non-governmental organizations, international institutions, pharmaceutical companies and the communities themselves.'
GlaxoSmithKline expects to donate more than US$1 billion worth of medicine and cash donations over the projected 20 -year program.
And while early support for the Global Alliance has also come from the Ministries of Health of the endemic countries and a number of international organizations, including the Bill & Melinda Gates Foundation, Arab Fund for Economic and Social Development, US Centers for Disease Control and Prevention, US Agency for International Development, UK Department for International Development and the Japan International Cooperation Agency, there is a need for additional donors to join the campaign.
'The main problem is that LF disease (elephantiasis and genital damage) is mostly unknown in the West, because travelers and tourists rarely become infected, since multiple mosquito bites over a long period are usually necessary before a victim begins to show symptoms. So LF has been ignored by policymakers in many developed countries,' says David Molyneux, PhD, a tropical disease expert from the Liverpool School of Tropical Medicine. 'This is a disease that affects the poorest of the poor.'
'In diseases like tuberculosis, HIV and malaria where parasites, bacteria and viruses develop resistance, part of the medical challenge is to stay ahead of the mutations,' says Professor Molyneux. The LF worms, on the other hand, are slow growing and for a number of reasons are less likely to develop drug resistance. It makes the goal of ending the disease realistic.'
The disease elimination program involves very close collaboration with Ministries of Health of participating nations. WHO Headquarters, Regional Offices and Country Offices support mapping the extent of the diseases in endemic regions with a new test that can determine almost instantly whether a person, including a child, is infected.
In tropical and subtropical areas of Africa, Asia and the Americas where lymphatic filariasis is highly endemic, the prevalence of infection is continuing to increase. A primary cause of this increase is the rapid and unplanned growth of cities, which creates numerous breeding sites for the mosquitoes that transmit the disease.
Approximately one-third of people infected with the disease live in India; one third are in Africa and most of the remainder are in Southeast Asia, the Pacific and the Americas.
Background on disease
The thread-like, parasitic filarial worms Wuchereria bancrofti, Brugia malayi, and Brugia timori that cause lymphatic filariasis live almost exclusively in humans.
These worms lodge in the lymphatic system, the network of nodes and vessels that maintain the delicate fluid balance between the tissues and blood and that are an essential component for the body's immune defense system. They live for 4-6 years, producing millions of immature microfilariae, minute larvae that circulate in the blood.
The disease is transmitted by mosquitoes that bite infected humans, ingesting the microfilariae. In 7-14 days, the microfilariae mature and migrate to the mosquito's biting mouthparts, ready for inoculation into the bloodstream of the next unsuspecting individual, thus completing the infection cycle.
The appearance of the disease itself in humans is still something of an enigma to scientists. Though the infection is generally acquired early in childhood, the disease may take years to express itself. Indeed, many people never acquire the outward clinical manifestations of their infections.
An asymptomatic form of infection, characterized by the presence of millions of microfilariae in the blood and adult worms in the lymphatic system, may have no recognizable clinical manifestations at all. However, recent studies now show clearly that such victims, outwardly healthy, actually have hidden lymphatic pathology, kidney damage and defects in their immune responsiveness.
The worst symptoms of the chronic disease generally appear in adults, and in men more often than women. In endemic communities, some 10-50 percent of men suffer from genital damage, especially hydrocoele (fluid-filled balloon-like enlargement of the sacs around the testes) and elephantiasis of the penis and scrotum.
Elephantiasis of the entire leg, the entire arm, or the breast -- swelling up to three times normal size -- can affect up to 10 percent of men and women in these communities. The psychological and social stigmata associated with the disease are immense, including sexual dysfunction and social ostracism of men and women.
Young women and men often can never marry or are subsequently rejected.
Acute episodes of local inflammation involving skin, lymph nodes and lymphatic vessels often accompany the chronic lymphedema or elephantiasis.
Some of these are caused by the body's immune response to the parasite, but most are the result of the bacterial infection of skin where normal defenses have been partially lost due to underlying lymphatic damage.
Careful cleansing can be extremely helpful in healing the infected surface areas and in both slowing and, even more remarkably, reversing much of the overt damage that has occurred already.
In endemic areas, chronic and acute manifestations of filariasis tend to develop more often and sooner in refugees or newcomers than in local populations continually exposed to infection. Lymphedema may develop within six months and elephantiasis as quickly as a year after arrival. Once damaged, the lymphatic system never recovers.
The previous treatment regimen thought necessary for LF was a long, 2-week course of DEC. It is now recognized, however that when a single dose of either DEC or ivermectin is administered with albendazole, the results are even more effective than the old treatment regimen.
Unexpected Benefits of LF Campaign
The campaign to eliminate LF has also been found to have important ancillary benefits. 'Albendazole is highly effective not only against the LF parasites but also against the most serious intestinal parasites of children and childbearing women that inhibit mental development and stunt physical growth of hundreds of millions of newborns and young children yearly,' says Eric A. Ottesen, M.D., a professor at Emory University's Rollins School of Public Health and Director of the Emory LF Support Center.
The three most serious parasites are roundworms, which infect nearly a half billion children; whipworms, which infect 350 million children; and hookworms, which infect nearly 300 million children. In some regions, more than 90 percent of children are infected with one or more of these parasites.
Intestinal parasites take a severe toll on the nutritional status of infected children, resulting in poor physical growth, anemia and an inability to absorb vital nutrients.
Results from treating these infections have been dramatic in the developing countries where evaluations have been carried out. Examples include:
Growth and development - five months after being treated with albendazole and ivermectin, children gained over 0.5 kg more than children treated with placebo [Haiti];
Physical fitness - seven weeks after being treated with albendazole for intestinal worms, school children had improved resting heart rates and increased physical fitness [Kenya];
Physical activity - nine weeks after treatment with albendazole, school children showed demonstrable increases in spontaneous play and other measurable activities [Kenya];
School attendance - six months after treatment with albendazole, stunted children with whipworm infection showed improved school attendance [Jamaica].
'These results demonstrate convincingly that such drugs as albendazole can dramatically improve the health development of the poorest of the poor children throughout the world,' says Dr. Ottesen. 'What is more, this can be done with essentially no additional cost to them or to the healthcare systems responsible for them, since everyone living in areas where the Global Programme to Eliminate Lymphatic Filariasis is active - including the particularly vulnerable populations of children and women of childbearing age - will already be receiving these drugs.'
From Glaxo Smithkline
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