New Studies Show Triple-Therapy with Crixivan (R) Drops HIV to Undetectable Levels in Patients in All Stages of HIV Disease [Conference on Retroviruses and Opportunistic Infections (4th: 1997: Washingoton, DC)]

JTAN-27-1'97 13: 43 FROrM MERCK 1334f_24979.021 O MERCK Embergoed until Sunday, January 26. 12 noon Contact: Michael Seggev (D.C.) Jan Weiner Stephen Hull 800-649-7317 (pager) 215/652-6462 908/423-3086 215-652-6931 (office) NEW STUDIES SHOW TRIPLE-THERAPY WITH CRIXIVAN arrow_forward ~ DROPS HIV TO UNDETECTABLE LEVELS IN PATIENTS AT ALL STAGES OF HIV DISEASE Benefits of Triple-Drug Therapy with arrow_back Crixivan arrow_forward Now Demonstrated in New Data from Advanced AIDS Patients and People Newly Infected With HIV WEST POINT, Pa., Jan. 26 -- In the first study of 320 patients with very advanced AIDS (s50 CD4 cells/mm 3) using triple therapy with Merck's potent protease inhibitor arrow_back Crixivan arrow_forward (indinavir sulfate), AZT (Retrovir~) and 3TC (Epivir~), 65 percent (55 of 85) had HIV in the bloodstream reduced to undetectable levels (:500 copies/mi) after 24 weeks. It is the first time such dramatic results have been seen in this advanced patient population. Researchers also reported results from a study of arrow_back Crixivan arrow_forward in people newly infected with HIV (within 3 months). At one of the study's sites, all (11 of 11) patients had undetectable virus levels (<100 copies/mi) after 4 to 9 months of triple therapy with arrow_back Crixivan arrow_forward , AZT and 3TC. At another site, all (5 of 5) patients taking the same triple combination had virus levels at or below 50 copies/mi after 6 months. The clinical significance of changes in serum viral RNA measurements during treatment with arrow_back Crixivan arrow_forward has not been established. SThese new studies were presented at the 4th Conference on Retroviruses and Opportunistic Infections in Washington, D.C. S_ "These studies demonstrate the potential value of treatment with arrow_back Crixivan arrow_forward in patients at all stages of HIV disease, from very advanced patients to those newly infected," said Dr. Emilio Emini, executive director of Antiviral Research at Merck Research Laboratories. "These new ___ results, in conjunction with the benefits shown in previous studies of arrow_back Crixivan arrow_forward combined with _--_ other anti-viral medications, indicate that this potent treatment can benefit a broad range of _people living with HIV/AIDS." At last year's conference, a study of triple therapy including arrow_back Crixivan arrow_forward (protocol 035) helped support the new treatment goal of anti-HtV therapy - undetectable virus levels in the blood - by reducing HIV below the limit of detebn (<500 copies/ml) in 85 percent of patients. Today, researchers updated the landmark results from protocol 035 and reported sustained C as the Merck-registeredforeCrixivan is the Merck-registered tradtnm!igh for indinavir sulfate

JFTN--27-:.?57 13:44 =OM MERC:K T'' T916199424979 P. 03.015 -2 -viral suppression up to 68 weeks in 86 percent (18/21) of patients whose virus in the bloodstream had been lowered below detection (<500 copies/ml) by triple therapy including arrow_back Crixivan arrow_forward . Using an experimental assay, 71 percent (10/14) were found to have virus levels below 50 copies/mi. Patients in this trial also had significant reductions (although not to undetectable) in virus levels in lymph nodes, which can harbor HIV even when it is no longer detectable in the bloodstream. In the United States, arrow_back Crixivan arrow_forward is indicated for the treatment of HIV infection in adults when antiretroviral therapy is warranted. This indication is based on analysis of surrogate endpoints in studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating the effect of therapy with arrow_back Crixivan arrow_forward on clinical progression of HIV infection, such as survival or the incidence of opportunistic infections. Dramatic New Results in Very Advanced Patients Preliminary data from the advanced AIDS study (protocol 039) included 320 patients with less than 50 CD4 cells/mm3 (an indication of advanced disease) who received either AZT and 3TC, arrow_back Crixivan arrow_forward alone, or arrow_back Crixivan arrow_forward in combination with AZT and 3TC. No (zero) patients taking AZT and 3TC, and 2 percent of those taking arrow_back Crixivan arrow_forward alone, had virus levels below detection (<500 copies/ml) after 24 weeks, compared to 65 percent of those taking arrow_back Crixivan arrow_forward , AZT and 3TC. These patients had previously taken AZT for at least 6 months, and had not taken 3TC or any protease inhibitor Patients had a median viral load of 89,500 copies/ml and a median of 15 CD4 (immune) cells/mm3 at baseline. "For so many patients with high viral loads and very low CD4 cell counts to have their virus lowered to undetectable is remarkable, demonstrating that even people with very advanced disease can benefit dramatically from triple therapy with indinavir, zidovudine and lamivudine," according to Dr. Martin Hirsch, Professor of Medicine, Harvard Medical School and the study's lead investigator. "Of course, it would be preferable to start therapy much earlier, before the virus has destroyed the capacity of patients' immune systems to regenerate." After 24 weeks, patients taking triple therapy including arrow_back Crixivan arrow_forward had median CD4 cell count increases of 84 cells/mm3 and median viral load reductions of 2.19 logio copies/mi (>99 percent). Patients taking arrow_back Crixivan arrow_forward alone had a median increase of 65 cells/mm3 and median

P-N-27-1: 9 13:44 cRM MERCK TO 91S19942497C ".004/35.3 -particularly considering the proportion with undetectable virus and CD4 count increases with triple therapy with arrow_back Crixivan arrow_forward in these patients," according to Dr. Jeff Chodakewitz, senior director of Clinical Research at Merck Research Laboratories. Promlsina Data n Newly Infected Patients Dr. Martin Markowitz of the Aaron Diamond AIDS Research Center presented data from a study in which 11 people received triple therapy with arrow_back Crixivan arrow_forward , AZT and 3TC, beginning within 3 months of contracting HIV. In this ongoing study, therapy has continued in these patients for 4 to 9 months, and all 11 patients had sustained suppression of viral levels below the level of detection (5100 copies/ml). Patients had a median viral load of 798,448 copies/mi at baseline. Dr. Luc Perrin of University Hospital in Geneva, Switzerland, presented data from 14 patients in the same study who have completed 3 months of triple therapy with arrow_back Crixivan arrow_forward , AZT and 3TC. After 3 months, 11 of 14 patients had HIV reduced below 500 copies/ml, dropping from baseline levels ranging from 5,000 to 5,000,000 copies/ml. Median CD4 cell counts in these patients increased by 111 cells/mm3 after 3 months from a median baseline of 460 cells/mm3. Among the 5 patients who have completed 6 months of therapy, viral levels measured with an experimental test with a lower limit of detection were undetectable (.20 copies/ml) in 2 patients, while the other 3 patients had virus levels of 50, 46 and 24 copies/mi. C04 cell count increases after 6 months are not yet available. Merck's Protease Inhibitor Widely Used arrow_back Crixivan arrow_forward is currently being used by more than 125,000 people with HIV/AIDS worldwide. Since becoming available last March, through December 1996, arrow_back Crixivan arrow_forward was the most commonly prescribed protease inhibitor in the U.S., with 75,000 people receiving the medication. arrow_back Crixivan arrow_forward is one of the most potent and highly specific compounds in a class of AIDS drugs called protease inhibitors. Unlike earlier AIDS therapies, arrow_back Crixivan arrow_forward attacks HIV at a different stage in its life-cycle. arrow_back Crixivan arrow_forward has been studied in more than 3,000 patients in 14 countries worldwide; Merck is continuing trials of arrow_back Crixivan arrow_forward . The recommended dosage of arrow_back Crixivan arrow_forward is 800 mg every 8 hours (2.4 g per day). Merck studies indicate that taking less than 2.4 grams of arrow_back Crixivan arrow_forward a day can lead to the development of viruses that may be resistant to arrow_back Crixivan arrow_forward . Skipping doses or taking "drug holidays" also may -4 -

JN-27'-1 99 13:45 FROM MERCK TO 916199424979 P.005/015 Median HIV Log Reductions not available

JliN1-27-1?99 13: 45 FROM NERCK STUDY-OVERVIEW: CRIXIVANO (indinLavir sly fate) 4h t Conference on Retroviruses and Opporunik 19et auN222 97, A A. m PROTOCOL 021 2-Year Impact of arrow_back CRIXIVAN arrow_forward Monotherapy on Viral Load and Immune System Recovery in Antiretroviral-experienced Patients Mý __ ___ __ __ __ L_ __ I_ ___ __ __ I _~_ I_ __ I_ Study SUmme r Objective: Design: Entry Criteria: Treatment Arms: To evaluate the maximal durability of long-term arrow_back CRIXIVAN arrow_forward (indinavir) therapy at varying dose levels. Randomized. Partially blind. 24 weeks + extension. 56 patients. CD4 cell counts between 150 and 500 cell/mm3. vRNA of a 20,000 copies/mi. arrow_back CRIXIVAN arrow_forward (800 mg q8) arrow_back CRIXIVAN arrow_forward (1000 mg q8) arrow_back CRIXIVAN arrow_forward (800 mg q6) Initial median CD4 count = 240 cells/mm3. Median vRNA= 39,070 copies/mi. D. Stein Exclusion Criteria: Baseline: Presenter; KevE Findinas * At almost 2 years (96 weeks) 30% (3/10) of patients taking arrow_back CRIXIVAN arrow_forward 800mg q8 achieved vRNA levels below detection (<500 copies/mi) and a median increase in CD4 count 140 cells/mm3 * 61.5% (8/13) of patients taking arrow_back CRIXIVAN arrow_forward 1000 mg q8 achieved vRNA levels below detection and a median increase of 230 CD4 cells/mmO at week 96. * 58.3% (7/12) of patients taking arrow_back CRIXIVAN arrow_forward 800mg q6 achieved vRNA levels below detection jqg3 a U BM Patients with IV low Lmit.of DetectionS<O coiest) PReimar # ts Weeapkm gIa --n p Is- rC0 P arrow_back CRIXIVAN arrow_forward 800 mg q8 arrow_back CRIXIVAN arrow_forward 1000 mg q8 arrow_back CRIXIVAN arrow_forward 800 mg q6 3/10 (30%) 8/13 (61.5%) 7/12 (58.3%) 96 96 84 Median MV Lo Reductins (Mediap baseline 39,070 cooiesmi) Renimp n ol-nn~ Weakek L33ag I Ilwtv VV lw I arrow_back CRIXIVAN arrow_forward 800 mg q8 arrow_back CRIXIVAN arrow_forward 1000 mg q8 arrow_back CRIXIVAN arrow_forward 800 mg q6 -1.34 -1.64 -1.85 96 96 84 Median Challaes from Baseline in CD4 Cell Counts Median baslie 240els/hm ------ --- --- ---- ---- --- c-- --- ---- ~-CI I c

S7137? 13:4 5 FROM MEPCK T3 Reirmen arrow_back CRIXIVAN arrow_forward 800 mg q8 arrow_back CRIXIVAN arrow_forward 1000 mg q8 arrow_back CRIXIVAN arrow_forward 800 mg q6 +cels/mm' +140 +230 [phone]

7F4N-)?-1S7 12:45 FROM MERCK 13: 4 55l ME- W '31i1S4I 4979 P3?412 STUDY OVERVIEW: arrow_back CRIXIVAN arrow_forward ~ (Indinavir sulfate) 4th Conference on Retroviruses eng Opportunistic Infections, January 22-26, 1997. PROTOCOL 035 arrow_back CRIXIVAN arrow_forward +AZT+3TC: Antiretroviral Activity at 68 Weeks and Lymph Node Results Study Sumary Objective: Design: experienced patients. Entry Criteria: Treatment Arms: Exclusion Criteria: Baseline: To evaluate the antiretroviral activity of arrow_back CRIXIVAN arrow_forward (indinavir)+AZT+3TC versus arrow_back CRIXIVAN arrow_forward monotherapy and AZT+3TC alone. Randomized. Double-blind. 52 weeks + extension. 97 AZLTAfter at least 24 weeks of blinded therapy (between 24 - 52 weeks), all patients were switched to open label. C04 count between 50 and 400 cells/mm3. VRNA 1 20,000 copies/mi. arrow_back CRIXIVAN arrow_forward (800 mg q8) + AZT (200 mg q8) + 3TC (150 mg q12) arrow_back CRIXIVAN arrow_forward (800 mg q8) AZT (200 mg q8) + 3TC (150 mg q12) Prior use of 3TC or protease inhibitor. Initial median CD4 count = 142 cells/mm3. Median vRNA = 43,190 copies/ml. - A- t i Key Findinus * During the double blind portion of the study (24-52 weeks), patients on triple combination therapy had median decreases in vRNA (log0o copies/mi) of at least -2.0 which was sustained through 52 weeks. * During the open label portion of the study, over 85% of patients on triple combination therapy experienced vRNA below detection (<500 copies/mi) at 68 weeks. * A subset of 9 patients (between weeks 36-52) were analyzed for VRNA presence in the blood and lymph nodes. Of the S patients in the subset who were on arrow_back CRIXIVAN arrow_forward +AZT+3TC. 2 of the patients had plasma vRNA levels < 20 copies/mi and negative PBMC and lymph node cultures. However, 50-100 copies of HIV RNAlmg of tissue were detectable in LN in these 2 patients. Of the patients in the subset who were on AZT+3TC (without arrow_back CRIXIVAN arrow_forward ), all had high virus levels in the plasma (19,000 -58,000 copies/mI); in the lymph nodes (3,800-230,000 =rPnni )Wmn= Summnarv Table Patients with HlV Below 500 oopiesmi JAMPLICOR assayv) and.Beflow 50 copies/ml (Ultrasgirect asEsa)

JAN-2?-199? 13:46 FPOM MERPCK 91619424973 r.?01315 Regimen #pts/24wks #pts/68wks arrow_back CRIXIVAN arrow_forward +AZT+3TC (<500 copies/mi) 27/30 (90%) (88%) arrow_back CRIXIVAN arrow_forward +AZT+3TC (<50 copies/mi) 20129 (69%) (71%) -dommow #pts/36wks #pts/S2wks 23/29 (79%) 23/28 (82%) 22/29 (76%) 21/27 (78%) 18/21 10/14 Median HIV Lo Reductions (Median baseine 43,190.copiesmi) Regimen -fIoI0 24wks -locIl3wVks -log(52wks arrow_back CRIXIVAN+AZT+3TC -2.2 -2.0 -2.3 Median C04 count not available -7 -