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PegIntron plus Ribavirin study in African-Americans
 
 
  This paper was a Press Release from Schering Plough and forwarded to you for your information.
 
NEW STUDY CHALLENGES CURRENT THINKING ABOUT VARIED RESPONSETO HEPATITIS C TREATMENT IN DIFFERENT RACIAL GROUPS
 
STUDY REPORTS RESULTS IN AFRICAN AMERICAN PATIENTS AND NON-HISPANIC WHITES
 
"...it is vitally important for an infected individual to aggressively pursue, with their physician, evaluation for therapy..."
 
KENILWORTH, N.J., May 26, 2004 -- Results of a new study published in the current issue of the New England Journal of Medicine show that in patients who have chronic hepatitis C, genotype 1 -- the most common form of the disease and difficult to treat successfully -- non-Hispanic whites achieved one of the highest response rates reported to date, but response rates in African Americans were significantly lower. The findings challenge much of the current thinking about why African Americans respond less well to hepatitis C treatment and underscore the need for further clinical research.
 
In the large open-label study, non-Hispanic white patients achieved a sustained virologic response (SVR) rate of 52 percent, which was significantly higher than the 19 percent seen in African American patients (p < 0.001). SVR is the sustained undetectability of the hepatitis C virus for six months following therapy. Lower SVR rates in African Americans, as seen in this study, also have been seen in past studies using other forms of interferon therapy, ii, iii, iv, v including the newer peginterferon and ribavirin combination therapies. vi, vii
 
"The sustained virologic response rates achieved in this study in genotype 1 patients demonstrate that peginterferon alfa-2b and ribavirin combination therapy is effective," said lead investigator Andrew Muir, M.D., assistant professor of medicine, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina. He noted that the study was conducted in a "real-world" community setting, rather than in a more restrictive clinical trial. "However, the lower response rate in African Americans poses a critical challenge because even with the best therapies currently available, African American patients clearly have a lower response rate."
 
In the study, 100 African American and 100 non-Hispanic white patients with chronic hepatitis C, genotype 1, were treated with a regimen of peginterferon alfa-2b (1.5 mcg/kg/weekly) and 1,000 mg of ribavirin daily for the first 12 weeks and then 800 mg daily thereafter, for a total of 48 weeks. Growth factors were not used. The current U.S. label for peginterferon alfa-2b (1.5 mcg/kg/week) recommends that it be used in combination with 800 mg of ribavirin daily. The investigators analyzed a number of variables, including patients' socio-demographic and clinical characteristics, and found that only race was significantly associated with the difference in SVR rates.
 
The study demonstrated the safety and tolerability of peginterferon alfa-2b and ribavirin combination therapy in these patients, and showed that the rates and types of adverse events were similar in the African American and non-Hispanic white patient groups. Importantly, the rate of dose reduction of peginterferon alfa-2b because of neutropenia was similar in the two groups (13 vs. 14 percent, respectively) as was the rate of discontinuation due to neutropenia (4 vs. 3 percent, respectively). Neutropenia often is a concern when treating African Americans, as seen in previous clinical studies.6,
 
Challenging Current Thinking
 
Dr. Muir said the reasons for the different responses seen in the racial groups remains unknown, but the study results counter at least some previously held hypotheses. For example, some suggested the disparity could be due to a higher prevalence of hepatitis C, genotype 1, in African Americans, but in this study 98 percent of both racial groups had that form of the virus. Further analyses showed that other variables -- including age, sex, education, body weight, initial viral load, duration of HCV infection and other clinical factors -- had no significant effect on response. "Showing these other factors are not the reason for the difference in response rates adds to our understanding of the disease and is important in furthering research to identify what factors actually are responsible. We can speculate about what those causes might be, but we need additional clinical studies to get real answers," he said.
 
Importance of Treatment
 
"While we are concerned about these findings in African Americans, it is critical to point out that many of these patients do, in fact, respond to hepatitis C treatment, so it is vitally important for an infected individual to aggressively pursue, with their physician, evaluation for therapy," urged Jonathan McCone, M.D., director, Mount Vernon Endoscopy Center in Alexandria, Va., and a participating investigator in the study. He noted that hepatitis C, the most common blood-borne infection in America, affects approximately 4 million people, including a disproportionately high percentage of African Americans. Chronic hepatitis C infection substantially increases the risk of cirrhosis and liver cancer, and is the most frequent indication for liver transplantation among adults. "Timely therapy can help achieve a sustained virologic response," McCone said, "and patients can improve their chances of achieving an SVR by adhering to therapy." Dr. Muir concurred, noting that the study found a higher SVR rate (23 percent) among African Americans who completed the full course of therapy.
 
A Patient's Perspective
 
The importance of adhering to treatment is exemplified by Jackie Boykin, R.N., 41, an African American woman who contracted hepatitis C in the course of her work as a nurse. While not a participant in the study by Muir and his colleagues, she was treated at Duke University Medical Center. In 2002, Boykin received combination therapy with PEG-INTRON® (peginterferon alfa-2b) Powder for Injection and REBETOL® (ribavirin, USP) Capsules. She achieved an SVR and has been virus free for nearly one-and-a-half years. As a result of her experience, Boykin counsels many patients with hepatitis C to stay with the therapy "because compliance is so important to treating the disease," she said. "I found the Schering-Plough PEG-INTRON Web site very helpful, and the support I received from the nurses in the Be In Charge program helped me stay on therapy." Schering-Plough's Be In Charge hepatitis C patient-support program provides educational materials and telephone contact with registered nurse counselors skilled in the management of hepatitis C. "Support from family, the community and medical professionals is critical for hepatitis C patients," Boykin said. She continues to attend a hepatitis C patient support group at Duke University Medical Center.
 
Commitment to Hepatitis C Research
 
Schering-Plough, which supported the study by Muir and colleagues, is committed to improving outcomes of hepatitis C treatment in African Americans. The company's ongoing efforts include the WIN-R trial (Weight Based Dosing of PEG-INTRON and REBETOL), an investigator-initiated study supported by Schering-Plough that is the largest prospective clinical study in hepatitis C undertaken to date, involving approximately 4,900 patients from 250 centers throughout the United States. It includes the largest number of African American patients in any hepatitis C study to date. Results in African American study participants are expected to be reported in the near future.
 
To further illustrate the efficacy of individualized, weight-based PEG-INTRON therapy, Schering-Plough Research Institute is conducting comparative studies with the two approved forms of pegylated interferon. Foremost among these is the IDEAL Study (Individualized Dosing Efficacy vs. flat dosing to Assess optimaL pegylated interferon therapy), a major randomized clinical study involving 2,880 patients that is directly comparing the efficacy and safety of individualized weight-based dosing with PEG-INTRON and REBETOL versus PEGASYS (peginterferon alfa-2a), which is administered as a flat dose to all patients regardless of individual body weight, and COPEGUS (ribavirin, USP) dosed either at 1,000 mg or 1,200 mg, in U.S. patients with chronic hepatitis C, genotype 1. PEGASYS and COPEGUS are trademarks of Hoffmann-La Roche Inc.
 
Commitment to Hepatitis C Patients
 
In addition to its ongoing commitment to research and development, Schering-Plough is committed to supporting hepatitis C patients with education and service programs as well as to help locate reimbursement assistance for patients in need. The company's programs for patients in the United States are among the most comprehensive in the industry, providing support and guidance to patients, and ensuring that all eligible patients have access to the company's hepatitis C products.
 
Schering-Plough's Be In Charge hepatitis patient-support program has helped more than 100,000 people in the United States since its inception in 1997. This U.S. program is designed to support patients diagnosed with hepatitis C as well as patients treated with Schering-Plough's interferon-based therapies through the use of educational materials and telephone contact with registered nurse counselors who are available 24/7 and skilled in the management of hepatitis C.
 
The company's Commitment to Care program is designed to ensure that eligible U.S. patients have access to Schering-Plough's hepatitis products, either by assisting patients in obtaining the reimbursement or assistance for which they qualify, or by providing products free of charge to eligible patients. The market value of treatment provided to hepatitis C patients through this program in 2003 exceeded $150 million.
 
PEG-INTRON Combination Therapy
 
PEG-INTRON is the only peginterferon approved for dosing according to patient body weight. It is a longer-acting form of INTRON® A (interferon alfa-2b, recombinant) Injection that uses proprietary PEG technology developed by Enzon, Inc. (NASDAQ: ENZN) of Bridgewater, N.J. PEG-INTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy that is designed to achieve an effective balance between antiviral activity and elimination half-life. Schering-Plough holds an exclusive worldwide license to PEG-INTRON.
 
WARNING
 
  • REBETOL monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. (See WARNINGS.)

  • The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with REBETOL therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL. (See WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.)

  • Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking REBETOL therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month post-treatment follow-up period. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS-Information for Patients and Pregnancy Category X.)

  • Alpha interferons, including PEG-INTRON and INTRON A, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping therapy with PEG-INTRON or INTRON A. (See WARNINGS, ADVERSE REACTIONS.)


 
PEG-INTRON
 
There are no new adverse events specific to PEG-INTRON as compared to INTRON A, however, the incidence of some (e.g., injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEG-INTRON were "flu-like" symptoms, occurring in approximately 50% of patients, which may decrease in severity as treatment continues. Application site disorders were common (47%), but all were mild (44%) or moderate (4%) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation). Injection site pain was reported in 2% of patients receiving PEG-INTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEG-INTRON.
 
Psychiatric adverse events, which include insomnia, were common (57%) with PEG-INTRON, but similar to INTRON A (58%). Depression was most common at 29%. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1% of patients during or shortly after completing treatment with PEG-INTRON. PEG-INTRON is contraindicated in patients with autoimmune hepatitis and decompensated liver disease.
 
The following serious or clinically significant adverse events have been reported at a frequency <1% with PEG-INTRON or interferon alpha: Severe decreases in neutrophil or platelet counts, hypothyroidism, hyperglycemia, hypotension, arrhythmia, ulcerative and hemorrhagic colitis, development or exacerbation of autoimmune disorders including thyroiditis, RA, systemic lupus erythematosus, psoriasis, pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, some resulting in patient deaths), urticaria, angioedema, bronchoconstriction, anaphylaxis, retinal hemorrhages and cotton wool spots.
 
Renal failure patients should be closely monitored for signs and symptoms of interferon toxicity and PEG-INTRON should be used with caution in patients with creatinine clearance <50 mL/min. Patients on PEG-INTRON therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter.
 
INTRON A
 
All patients receiving INTRON A therapy experienced mild-to-moderate side effects. Some patients experienced more severe side effects, including neutropenia, fatigue, myalgia, headache, fever, chills and increased SGOT. Other frequently occurring side effects were nausea, vomiting, depression, alopecia, diarrhea and thrombocytopenia. DEPRESSION AND SUICIDAL BEHAVIOR, INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HAVE BEEN REPORTED IN ASSOCIATION WITH TREATMENT WITH ALFA INTERFERONS, INCLUDING INTRON A THERAPY. DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking" statements concerning PEG-INTRON, the market for drugs to treat hepatitis and Schering-Plough's products.
 
Forward-looking statements are subject to risks and uncertainties, which may cause actual results to differ materially. These risks and uncertainties include product availability, current and future branded, generic and OTC competition, the regulatory process for new products and new indications, market acceptance of new products and new indications, timing of trade buying, and patent positions. For further details and a discussion of these and other risks and uncertainties, see the company's past and future Securities and Exchange Commission filings, including the company's first quarter 2004 10-Q. Schering-Plough is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its more than 30,000 people around the world.
 
References:
 
  1. Muir AJ, Bornstein JD, Killenberg PG, for the Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in African Americans and Non-Hispanic Whites. N Engl J Med 2004; 350(22):27-33.
  2. Reddy KR, Hoofnagle JH, Tong MJ, Lee WM, Pockros P, Heathcote EJ, Albert D, Joh T. Racial differences in responses to therapy with interferon in chronic hepatitis C. Hepatology 1999; 30:787-93.
  3. Kinzie JL, Naylor PH, Nathani MG, Peleman RR, Ehrinpreis MN, Lybik M, Turner JR, Janisse JJ, Massanari M, Mutchnick MG. African Americans with genotype 1 treated with interferon for chronic hepatitis C have a lower end of treatment response than Caucasians. J Viral Hepat 2001;8:264-9.
  4. De Maria N. Colantoni A. Idilman R. Friedlander L. Harig J. Van Thiel DH. Impaired response to high-dose interferon treatment in African-Americans with chronic hepatitis C. Hepatogastroenterology 2002;49:788-92.
  5. McHutchison JG, Poynard T, Pianko S, Gordon SC, Reid AE, Dienstag J, Morgan T, Yao R, Albrecht J. The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. Gastroenterology 2000;119:1317-23.
  6. Howell CD, Jeffers LS, Hu S, Lopez-Talavera JC. Safety and adherence to peginterferon alfa-2a (40KD) plus ribavirin (RBV) in black Americans with chronic hepatitis C (CHC) HCV genotype 1. Poster presentation M1236 (Abstract No. 106885) at Digestive Disease Week, New Orleans, LA, May 15-20, 2004.
  7. Jeffers LJ, Cassidy W, Howell C, Reddy R, Sheridan S, Ho I, Khouri S, Harb G. Peginterferon alfa-2a (40kd) (Pegasys®) in combination with ribavirin in African American and Caucasian patients with chronic hepatitis C virus genotype 1: results of a multicenter study. Abstract 71, oral presentation at: 54th annual meeting of the American Association for the Study of Liver Diseases, Boston, MA, October 24-28, 2003.
  8. Howell C, Jeffers LJ, Cassidy W, Reddy R, Sheridan S, Ho I, Khouri S, Harb G. Peginterferon alfa-2a (40kd) (Pegasys®) in combination with ribavirin in African American and Caucasian patients with chronic hepatitis C HCV genotype 1: safety and tolerability. Abstract 332, poster presentation at: 54th annual meeting of the American Association for the Study of Liver Diseases, Boston, MA, October 24-28, 2003.

 
  
 
 
 
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