PR Newswire - 14 March 1996; 810 Seventh Avenue, New York, NY 10019.

Crixivan, a potent inhibitor of the HIV protease enzyme that is critical to replication of the virus that causes AIDS, can be taken in combination with other anti-HIV therapies or alone. Crixivan was reviewed by FDA in 42 days; the New Drug Application for Crixivan was submitted by Merck on Jan. 31. Crixivan will be available by March 25, initially through a temporary special distribution system.

"Crixivan embodies our commitment to AIDS research and a decade of tireless work by scientists and others at Merck to discover and develop an effective AIDS medication," said Edward Scolnick, M.D., President of Merck Research Laboratories. "We believe protease inhibitors provide a significant advance in HIV therapy."

Crixivan is the first drug to emerge from Merck's AIDS research program, which began in 1986. Merck scientists have evaluated tens of thousands of compounds. Five investigational compounds reached human trials, and four of them failed in research. Merck's AIDS research program is one of the largest basic research programs in the company's history, and the company remains committed to research in HIV/AIDS.

Clinical Studies with Crixivan

In clinical trials, treatment with Crixivan caused substantial improvements in the surrogate markers for HIV disease -- CD4 cell counts and viral load, the indicators of disease status in people with HIV, on which the indication for Crixivan is based. Crixivan was also generally well tolerated. It produced increases in CD4 cell counts, an important measure of immune system function, and significant reductions in viral load, or levels of HIV in the bloodstream. However, the clinical relevance of changes in viral load induced by Crixivan has not been established. Crixivan is not a cure for AIDS, and its effect on the development of opportunistic infections and survival has not yet been shown, although such studies are under way.

Crixivan has been studied in more than 2,000 people in 14 studies to date, including several ongoing studies. One recent multicenter trial (035) studied Crixivan alone and in combination with two other antiviral drugs, zidovudine and lamivudine (Retrovir(R) and Epivir(R), Glaxo- Wellcome) in patients who had previously been treated with zidovudine. At 24 weeks in this "triple-therapy" trial, mean decreases observed in viral load were 1.77 log10(A) (98 percent) in 22 patients taking the triple combination of Crixivan with zidovudine and lamivudine, 0.95 log10(A) (89 percent) in 20 patients taking Crixivan alone, and 0.67 log10(A) (78 percent) in 19 patients taking zidovudine and lamivudine. The clinical relevance of changes in viral load effected by Crixivan has not been established.

At 24 weeks, 20 of 22 patients (91 percent) taking Crixivan with zidovudine and lamivudine had HIV levels in their blood (viral RNA copies) below the limit of detection of the test used (<500 copies/mL). In the same study, 7 of 20 patients (35 percent) taking Crixivan alone, and 0 of 19 (none) of the patients taking zidovudine and lamivudine had HIV levels below the limit of detection of the test used (<500 copies/mL). Patients receiving the triple combination and patients taking Crixivan alone had mean increases at 24 weeks of 100 cells/mm3(B), compared to mean increases of 33 cells/mm3(B) in patients taking zidovudine and lamivudine.

"The critical goal of therapy should be to reduce viral replication as much as possible, for as long as possible, and in as many people as possible, using the most potent and tolerable medications," said Roy Gulick, M.D., of The New York University School of Medicine, the study's lead investigator. "Although further study is needed, the ability of Crixivan to dramatically reduce viral levels demonstrates its potential usefulness in this approach and may indicate a new direction in the management of HIV disease."

Other research with Crixivan (two ongoing, pivotal Phase III trials, 028 and 033), studied the combination of Crixivan and zidovudine, Crixivan alone, and zidovudine alone in patients who had not previously been treated with zidovudine. Results from an interim analysis of one study (028) showed mean decreases in viral load up to 24 weeks of 0.99 log10(A) (90 percent) in 58 patients taking Crixivan with zidovudine, 0.75 log10(A) (82 percent) in 59 patients taking Crixivan alone and 0.26 log10(A) (45 percent) in 62 patients taking zidovudine alone. At 24 weeks, 21 of 58 patients (36 percent) taking Crixivan with zidovudine and 22 of 59 (37 percent) taking Crixivan alone had their virus levels reduced below the limit of detection of the test used (<500 copies/mL), compared to 4 of 62 (7 percent) of those taking zidovudine alone. The clinical relevance of changes in viral load affected by Crixivan has not been established.

Crixivan also caused substantial improvement in measures of immune system function. In this trial, at 24 weeks, Crixivan in combination with zidovudine resulted in mean increases in CD4 cell counts of 121 cells/mm3(B), Crixivan alone resulted in mean increases of 124 cells/mm3(B) and zidovudine caused mean increases of less than 20 cells/mm3(B).

In the other pivotal study (033) at 24 weeks, mean decreases observed in viral load were 1.04 log10(A) (91 percent) in 52 patients taking Crixivan with zidovudine, 0.94 log10(A) (89 percent) in 49 patients taking Crixivan alone, and 0.25 log10(A) (44 percent) in 53 patients taking zidovudine. At 24 weeks, 29 of 52 patients (56 percent) taking Crixivan with zidovudine and 18 of 49 (37 percent) taking Crixivan alone had their virus levels reduced below detection (<500 copies/mL), compared to 1 of 53 (2 percent) of those taking zidovudine alone. The clinical relevance of changes in viral load affected by Crixivan has not been established.

At 24 weeks in this trial, Crixivan in combination with zidovudine resulted in mean increases in CD4 cell counts of 94 cells/mm3(B), Crixivan alone resulted in mean increases of 109 cells/mm3(B), and zidovudine caused mean increases of less than 15 cells/mm3(B).

Crixivan has been generally well tolerated in clinical trials. Nephrolithiasis (defined as flank pain, blood in the urine or kidney stones) occurred in approximately 4 percent of patients. People who take Crixivan are encouraged to drink at least 48 ounces of water every day to maintain hydration and help avoid nephrolithiasis. In Phase II clinical studies, less than 6 percent of patients taking Crixivan alone discontinued therapy due to drug-related adverse experiences. Among the most common side effects of moderate or severe intensity reported in greater than or equal to 2 percent of patients on Crixivan alone in clinical trials are: nausea, abdominal pain, headache, diarrhea, vomiting, weakness/fatigue, insomnia, flank pain, taste changes, acid regurgitation and back pain. Crixivan is contraindicated in patients with clinically significant hypersensitivity to any of its components.

Asymptomatic hyperbilirubinemia (when a laboratory test of bilirubin indicates levels at or above 2.5 mg/dL) has occurred in approximately 10 percent of patients treated with Crixivan. In less than 1 percent of these patients, this was associated with elevations in serum transaminases.

Many studies were conducted with other medications commonly prescribed to people with HIV and AIDS. Clinically significant drug interactions shown to date were with rifabutin and ketoconazole. Merck recommends reducing the dose of rifabutin when taken with Crixivan, and reducing the dose of Crixivan when taken with ketoconazole.

Although not specifically studied, the prescribing information for Crixivan contains a warning against taking terfenadine, astemizole, cisapride, triazolam or midazolam with Crixivan because their use in combination may create the potential for serious and/or life threatening events (i.e., cardiac arrhythmias, prolonged sedation). In addition, Merck is currently studying interactions between Crixivan and rifampin and co-administration is not recommended at this time. In drug interaction studies, no clinically significant interactions were seen with Crixivan and zidovudine (zidovudine), d4T (stavudine), lamivudine (lamivudine), fluconazole, clarithromycin, trimethoprim/sulfamethoxazole, isoniazid, Ortho-Novum 1/35(R), cimetidine and quinidine.

Merck studies indicate that taking less than 2.4 grams of Crixivan a day can lead to the development of viruses that may be resistant to Crixivan. Skipping doses or taking "drug holidays" may also compromise the effectiveness and duration of response to treatment with Crixivan or other antiviral medications. Merck will support AIDS community efforts to educate people with HIV/AIDS about the importance of compliance with therapy as prescribed, and Merck is also planning to work with the FDA to develop a patient package insert for Crixivan.

How to Get Crixivan and Reimbursement Assistance

In keeping with its commitment to make Crixivan available to people with HIV disease as soon as possible, Merck is providing Crixivan six months before full-scale supplies are available from an extremely aggressive manufacturing and introduction timetable. Unprecedented efforts are under way to complete two new facilities where Crixivan will be manufactured starting later this year.

Because it is medically important for patients who start taking Crixivan to continue with uninterrupted therapy, Merck is establishing atemporary distribution program to keep an accurate count of the number of patients who receive Crixivan and assure ongoing availability of supply for their refill prescriptions. During the next few months, without this special program, it is possible that the number of prescriptions for Crixivan could exceed the initial supply.

Crixivan will be supplied for the first few months primarily through Stadtlanders Pharmacy, an independent nationwide pharmacy service specializing in HIV/AIDS therapies. Stadtlanders will track, count and send each prescription through a confidential and easy-to-use distribution program. The program will end as soon as it is determined that supplies are sufficient, which is expected to be later this year. At that time, Crixivan will be made widely available through retail pharmacies, wholesalers and other sources.

Stadtlanders will begin filling prescriptions by March 25, but patients and physicians can call 1-800-927-8888 beginning Monday, March 18, for information on receiving Crixivan.

Through this toll-free number, information will also be available regarding SUPPORT(TM), Merck's program to provide reimbursement assistance to patients. SUPPORT(TM) will help people who have been prescribed Crixivan identify third-party payor reimbursement for Crixivan and provide free medication to eligible patients until an alternate payment source can be identified.

Merck's catalog price for the recommended daily dose of 2.4 grams of Crixivan will be $12 per day or $4,380 annually.

Merck & Co., Inc. is a leading research-driven pharmaceutical products and services company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human animal health. Merck-Medco Managed Care Inc. manages pharmacy benefits for approximately 47 million Americans, encouraging the appropriate use of medicines and providing disease management programs.

NOTES: Full prescribing information for Crixivan to follow.

Crixivan is the Merck registered trademark for indinavir sulfate.

(A) The 10 in Log10 is a subscript.

(B) The 3 in cells/mm3 is a superscript.

CONTACT: Press, Michael Seggev, 215-652-6931, or Jan Weiner, 215-652-6462, or Investors, Jim Hinrichs, 908-423-6883, all of Merck & Co.

Copyright (c) 1996/PR NewsWire. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Permissions Desk, PR Newswire, 810 Seventh Avenue, New York, NY 10019.

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