"Neither kinder nor gentler"

Observing the race between Roche and Schering for FDA approval of the two pegylated interferons (interferon as monotherapy as well as interferon in combination with ribavirin)—and a lion's share of the hepatitis C market—makes the race in the mid-1990s for FDA approval of the HIV protease inhibitors look like child's play. There is absolutely no love lost between the hep C clinical and marketing teams of the two companies. It's said that a Roche employee nearly had his lawyers file a cease and desist order against someone on the Schering team who continuously bad mouthed Pegasys at hepatology conferences. Michael Marco brings the laundry out for air.

The competitiveness with which the companies release data is like a carefully orchestrated fencing match. Hoffmann-La Roche filed a new drug application (NDA) with the FDA nineteen months ago for its pegylated interferon (Pegasys). During this time, hep C kingpin and marketing maven Schering-Plough sailed through the FDA approval process with its pegylated interferon (PEG-Intron), with not just a monotherapy indication, but also a recent combination therapy indication for use with its ribavirin. It is unfortunate that the FDA did not grant Roche's NDA a much-deserved "expedited" review (6 vs. 12 months) for use in treating HCV-positive cirrhotics.

Roche beat Schering with publishing its monotherapy study first—and in the New England Journal to boot—while Schering was reduced to Hepatology. But Schering then snuck by Roche with the publication of its combination therapy study in the Lancet—while Roche's data are still in abstract form.

Roche is planning on filing its NDA for Pegasys and ribavirin in the current quarter. The FDA granted Roche's Pegasys/ribavirin combination therapy NDA an "expedited" review. Roche will also be filing a separate NDA for approval of its own manufactured ribavirin. The goal is to have Pegasys and ribavirin available by the first half of 2002. Jesus Leal, Roche's HCV marketing director, said that Pegasys and ribavirin will be sold as separate products and no plans have been made to bundle them. Schering, in its usual arrogant and cagey way, will not commit to not bundling peginterferon and ribavirin (like it did with its standard interferon+ribavirin formulation, Rebetron) or making them individually so costly that one has no choice but to by the bundled product.

Roche has studied its pegylated interferon in over 1,000 HIV/HCV co-infected patients (compared to Schering with <200) and is currently conducting a Phase III trial in this population. Once they receive monotherapy approval, Roche plans to seek a supplemental NDA for the use of Pegasys in treating HIV/HCV co-infected patients.

Combination therapy data from Roche and Schering's Phase III registrational pegylated interferon plus ribavirin studies have recently been presented and published.

Schering conducted a 3-arm 1,500 patient study comparing two doses of peginterferon plus ribavirin against standard interferon+ribavirin for 48 weeks. According to the FDA's analysis—stricter than Schering's and thus differs from the Lancet piece—52% of individuals in the 1.5 mcg/kg arm achieved a sustained viral response compared to 47% and 46% of those in the low-dose peginterferon (0.5 mcg/kg) and interferon+ribavirin arms, respectively. When broken down according to genotype, 41% of the genotype 1 individuals in the high-dose peginterferon arm achieved a sustained viral response compared to 33% of the interferon+ribavirin ones. In genotype 2/3 individuals, there were no differences in response rates between the three arms with all achieving an &#tilde;80% sustained viral response.

As for side effects, in the Schering phase III (PEG-Intron) combination trial (which compared high-dose peginterferon+ribavirin vs. low-dose peginterferon+ribavirin vs. standard interferon+ribavirin) neutropenia occurred in 26% of the high-dose peginterferon+ribavirin study volunteers compared to 14% of those in the standard interferon+ribavirin arm. Anemia occurred in 12% and 17% of the volunteers, respectively. Approximately 60% of all study participants experienced fatigue and/or headaches, and more than 40% in all arms experienced depression of anxiety. Suicidal behavior was recorded in 2% of individuals, with three suicides occurring during the study: two in the high-dose peginterferon arm and one in the standard interferon arm. Virology data from the Roche combination therapy study look similar to that of Schering.

Presented at DDW last May, results from Roche's NV15801 study documented that 30% of the patients in the monotherapy arm achieved a sustained viral response compared to 45% in the interferon+ribavirin arm and 56% in the PEG-interferon+ribavirin arm for all comparisons). In genotype 1 patients, the sustained viral response rates were 21%, 37%, and 46%, respectively. And, in genotype 2/3 patients, the sustained viral response rates for the three arms were 45%, 61%, and 76%, respectively.

Results from the viral kinetics substudy have also become available. The study found that individuals who have either a 2 log drop in HCV RNA or become HCV RNA undetectable by week 12 have a 65% chance of remaining undetectable for 72 weeks (considered cured by some people). Conversely, for individuals who did not achieve a 2 log drop in HCV RNA or become HCV RNA undetectable after 12 weeks of treatment, there is a 97% chance that they never will. These kinetic data are similar to those presented by Schering in its Lancet paper. This indicates that checking one's HCV RNA at 12 weeks may help to determine if therapy should continue for a year or be discontinued.

Pegylated interferon, while markedly more convenient than and equally effective as standard interferon alone, is turning out to be neither kinder nor gentler. Nor is it more effective than standard interferon+ribavirin (Schering's Rebetron) for poor prognostic factor patients, individuals with a baseline HCV viral load >2 million copies/mL and an HCV genotype 1.

This, however, is not public knowledge. It appears nowhere in the Lancet paper. One has to look into the FDA label (page 6, section 2.0) in order to see that the response rates for individuals with poor prognostic factors were virtually indistinguishable between the two treatments: 30% for high-dose peginterferon+ribavirin and 29% for standard interferon+ribavirin in the Schering trial. This crucial piece of evidence means that while peginterferon is more convenient than standard interferon+ribavirin, it is not virologically superior in fully half the people with HCV.

Like Schering, Roche appears to be hush-hush about the comparative results in poor prognostic patients. The data were not presented at DDW and are not scheduled to be presented in a peer-reviewed oral or abstract presentation at the upcoming AASLD meeting. Sources say it's doubtful they will appear in the manuscript.

Officials at Hoffmann-La Roche recently notified the FDA that a serious adverse event (hepatic decompensation) has occurred in seven HCV/HIV co-infected individuals enrolled in its NR15961 study. Five of these cases occurred among study participants in the PEG-Intron+ribavirin study group, and two of the cases occurred in those receiving standard interferon (Intron) plus ribavirin. Five of these study volunteers didn't recover. According to the Roche letter:

All seven of these patients had cirrhosis and were receiving concomitant HAART therapy. 5 of 7 were on stavudine, 4 of these 5 patients were also on didanosine. All seven of these cases of hepatic decompensation occurred during the first 4 months of therapy. In five of the seven cases, the patients subsequently died while off study drug. Among the seven patients, three patients were enrolled by investigators even though they violated the protocol entry criteria; two patients had Child's class B and one had previous splenectomy...All three of these patients who violated entry criteria had further progression of hepatic decompensation and later died. The other four patients fulfilled all protocol entry criteria and had no evidence of pre-existing hepatic decompensation. Two of these patients died.

Roche says that "a thorough evaluation of the safety data from all other on-going trials with patients co-infected with HCV/HIV has not identified any additional cases of hepatic decompensation." The study will continue, but Roche has requested all investigators ensure that:

• Study personnel should be educated on the importance of careful assessment for evidence of hepatic decompensation in co-infected patients with cirrhosis who are being treated with antiretroviral therapy, especially at baseline, but also throughout therapy, particularly within the first 16 weeks.
• Patients with evidence of hepatic decompensation should be withdrawn from therapy immediately and carefully followed until they recover completely.

It will take some time to understand why these patents decompensated so quickly after study entry. It may be a combination of several things, including: 1) the natural history of HIV/HCV co-infection in patients with cirrhosis; 2) HAART hepatotoxicity; and/or 3) interferon-based therapy in late-stage cirrhotics. To determine if this deleterious interaction between HAART and interferon in cirrhotic patients has occurred before, the FDA must gain access to Schering and Amgen's databases of co-infected patients—before Schering's marketing division figures out a way to use this as PR propaganda against Roche. ¤

"Weight of evidence"

On Tuesday, 3 October 2001 a panel assembled by the Antiviral Advisory Committee of the FDA convened to review Gilead's New Drug Application for its nucleotide reverse transcriptase inhibitor, tenofovir (trade name, Viread). Gilead is requesting accelerated approval for tenofovir, for use in combination with other antiretroviral agents in all HIV-infected adults. (Due to concerns about bone toxicity, tenofovir has not been studied in children.) The panel having voted in favor of Gilead's application, the FDA's Antiviral committee now takes the recommendation under advisement. A decision is expected early next month. Yvette Delph was there and prepared this summary.

Tenofovir, when added to a failing antiretroviral regimen in highly treatment experienced individuals, lowered plasma viral load an average of 0.6 logs. Tenofovir also has an encouraging resistance profile and has demonstrated efficacy against multi nucleoside-resistant HIV. Persons with resistance to AZT, 3TC, NNRTIs or PIs still saw their viral loads fall between 0.52 and 0.65 logs—at least during the 24 weeks of the study. The sole resistance mutation to date which seems to affect the efficacy of tenofovir is the K65R mutation, a relatively common nucleoside RTI substitution reported most frequently with prior use of ddC (Hivid). But even the presence of K65R results in only a 3-4 fold reduction in tenofovir sensitivity—and does not appear to be associated with virologic rebound.

Administered as one tablet once per day, tenofovir makes a substantial contribution to the simplification of antiretroviral regimens. TAG supports the accelerated approval of tenofovir.

Tenofovir also has a favorable side effect profile, In studies to date, the occurrence of clinical adverse events and laboratory abnormalities at a dose of 300 mg/day was similar to that observed in persons receiving placebo. The only adverse event that occurred in >5% of the study population was depression, which occurred after 48 weeks of study 902 in 6% of individuals in the tenofovir 300 mg daily arm. In study 907, during the first 24 weeks, no adverse event occurred in >2% of the population in either arm. There has been no evidence of mitochondrial toxicity due to tenofovir.

Tenofovir is excreted unchanged by the kidneys. Thus, there is potential for interaction with other drugs that are renally excreted and there is likely to be a need for dosage adjustment in individuals with renal impairment.

Additional concerns

1. Gilead is the first sponsor to respond to the calls from the community to study investigational agents in highly treatment-experienced individuals and should be congratulated, not penalized, for this.
2. TAG is concerned that a 48-week dose-finding study was conducted in individuals, virtually all of whom had HIV resistance to at least one class of antiretroviral agents and many who had resistance to more than one class. The FDA should require sponsors to determine the appropriate adult dose for antiretroviral agents before proceeding to large Phase III studies—especially in individuals with limited treatment options.
3. There is not yet enough evidence that tenofovir should be used only with nucleoside RT inhibitors. Until there is more evidence, tenofovir should be used in conjunction with at least one protease inhibitor or a non-nucleoside reverse transcriptase inhibitor and at least one NRTI.

Some have questioned whether broad approval for tenofovir should be granted when the data submitted to date focus on experienced individuals. Here are several reasons TAG would urge the FDA to grant accelerated approval for use of tenofovir, in combination with other antiretrovirals, in the treatment of adults with HIV infection.

Precedent
Since the 1995 approvals of 3TC and saquinavir, the FDA has used this language for approving new antiretroviral agents even though pivotal studies were not done in certain important HIV-infected populations. Although some thought these broad indications would let industry off the hook for post-marketing studies, both Glaxo and Roche continued developing 3TC and saquinavir (unlike what Roche had done with ddC after 1992). With the advent of HAART these indications proved useful.

Timing
Gilead did not have 24-week pivotal data on naïve individuals in May 2001 when it submitted the NDA. However, its pivotal study in treatment-naïve individuals fully accrued in January and so 24 week data is likely to be available within few months. Gilead could not, therefore, avoid doing the necessary study in naïve individuals.

Logic
Logic suggests that if the drug reduces HIV RNA by &#tilde;0.6 log in treatment-experienced individuals it will reduce RNA by even more in naïve individuals.

Safety
Safety data are available in both populations in real time; to date there has been no serious safety problem in either population. In fact, tenofovir has a very favorable safety profile in the treatment-experienced—the population for which safety data have been analyzed.

Weight of Evidence
Cumulatively, the drug has good potency, a favorable resistance and safety profile, is easy to take and generally well tolerated.

Consistency
For years, the community has been asking industry to study new drugs in experienced as well as in naïve individuals. Unlike Abbott, a giant pharmaceutical company with lots of resources, which could therefore submit a NDA for lopinavir/r containing pivotal data on naïve and experienced individuals, Gilead is a relatively small company with fewer resources. We might wish Gilead had studied both populations in parallel, but they had just had a setback with adefovir and had been required to get 48-week safety data in tenofovir for renal and bone toxicity. We should not penalize them for going sequentially.

Overview of the data
Safety
The two pivotal studies of the safety and efficacy of tenofovir, studies 902 and 907, were conducted in individuals with 4.6 and 5.4 years, respectively, of prior antiretroviral therapy. Study 902 enrolled 189 HIV-infected individuals with viral loads of 400-100,000 copies/mL on stable antiretroviral therapy consisting of <4 drugs for >8 weeks. They were randomized to receive one of three daily doses of tenofovir (75 mg, 150 mg or 300 mg) or placebo in addition to their existing antiretroviral treatment regimen for 48 weeks. At week 24, all individuals receiving placebo were switched the tenofovir 300 mg daily arm. After the end of the 48-week blinded study, 135 participants rolled over into an open-label extension phase and received 300 mg of tenofovir daily.

Study 907 enrolled 552 individuals with viral loads of 400-10,000 copies/mL on stable antiretroviral therapy for at least eight weeks prior to entering the study. Study volunteers were randomized to receive tenofovir 300 mg once daily, or placebo, in addition to their existing antiretroviral therapy. After 24 weeks, all study participants had the option of receiving tenofovir for the remainder of the 48-week study period; 170 individuals who received placebo rolled over to receive treatment with tenofovir.

For the first 24 weeks of study 907, rates of drug discontinuation, of serious adverse events, and of grade 3 or 4 laboratory abnormalities in the 368 volunteers who received tenofovir 300 mg daily were all comparable to those for placebo. Two serious adverse events in study 902 were considered by the investigator to be possibly related to tenofovir: liver failure in one subject in the tenofovir 75 mg group and acute pancreatitis in a subject in the tenofovir 300 mg group. During this study, there was also one suicide, which was judged by the investigator not to be related to tenofovir.

As of September 28, 2001, over 4,900 individuals worldwide have enrolled in the tenofovir expanded access program which opened to accrual in March 2001. Globally, serious adverse events have been reported in 122 (2%) enrollees and all individual events were reported in <1% of participants.

Since osteomalacia (softening of the bones due to demineralization) was observed in rats and dogs dosed at doses equivalent to 6- to 10-fold greater than human exposure and in juvenile monkeys at 12 to 50-fold greater than human exposure, close monitoring for bone toxicity in humans was done in studies 902 and 907. There was no evidence of bone abnormalities.

Because of the nephrotoxicity of adefovir, another nucleotide RTI, and because there was evidence of nephrotoxicity in newborn and juvenile monkeys dosed with tenofovir equivalent to 12- to 50-fold greater than human therapeutic doses, individuals with renal impairment were excluded from studies 902 and 907. In addition, participants were closely monitored for evidence of renal toxicity. No nephrotoxicity was seen and changes in serum creatinine and phosphate were similar to those seen in the placebo arm.

Efficacy
The primary efficacy endpoint for both studies was the average change in viral load between 0 and 24 weeks.

Viral load change at week 24 by intent-to-treat analysis among the 54 individuals treated with tenofovir 300 mg in study 902 was -0.58 log copies/mL while for placebo it was +0.02 log. For study 907, it was -0.59 log copies/mL for the tenofovir arm and -0.01 log in the placebo group In study 907, 45% (155/346) of individuals treated with tenofovir achieved viral load reductions to <400 copies/mL at 24 weeks, compared with 13% (23/172) in the placebo group. Reduction in viral load to <50 copies/mL was achieved by 22% (76/346) of individuals in the tenofovir group compared to 1% (2/172) in the placebo group. Average viral load change at week 24 for both non-Caucasians (35% study population) and women (15%) was -0.6 log by intent-to-treat analysis of 907. Average viral load changes at week 48 for study volunteers who received tenofovir 300 mg in study 902 was -0.62 log copies/mL.

Tenofovir has demonstrated good efficacy against drug resistant HIV. Participants in study 902 with virus resistant to AZT, NNRTIs, or PIs experienced an average viral load change at week 24 of -0.52 to -0.61 log copies/mL. Individuals with HIV exhibiting >10-fold change in susceptibility to AZT had an average viral load change at week 24 of -0.58 log copies/mL. Average viral load change at week 24 for individuals in 907 with and without the M184V mutation on tenofovir 300 mg were was -0.65 and -0.48 log cells/mL, respectively, compared to -0.20 and +0.28 log for those on placebo.

In the tenofovir arm of study 907, the average viral load change at week 24 for CD4 cells was an increase of 12.6 cells/mL compared with a decrease of 10.6 cells/mL in the placebo arm.

Pharmacokinetics and Drug-Drug Interactions
Tenofovir is only about 6% bio-available when administered orally. To get around this obstacle, it is administered as tenofovir disoproxil fumarate which is then converted to tenofovir by esterases in the intestinal lumen and plasma. Tenofovir disoproxil fumarate (TDF) is 20-40% orally bioavailable. Food enhances the absorption of TDF and oral bio-availability with a high fat meal is 40%. Gilead therefore recommends that tenofovir be taken with food.

Drug interactions between tenofovir and agents from all three licensed classes of antiretrovirals have been conducted. Among the NRTIs, interactions with 3TC and ddI, which are both excreted primarily by the kidneys, were studied. The NNRTI, efavirenz, and the protease inhibitors, indinavir and lopinavir/r, were also studied.

The pharmacokinetic of tenofovir 300 mg once daily was not affected by administration with efavirenz 600 mg once daily. Neither was the PK of efavirenz affected by administration with tenofovir. There was no clinically relevant effect of 3TC (150 mg twice daily) on the pharmacokinetics of tenofovir (300 mg once daily); nor was there any significant change in 3TC exposure when administered with tenofovir. When ddI is taken one hour prior to tenofovir, there is also no clinically relevant effect on tenofovir drug levels. Drug levels of ddI, however, are increased 44%.

As for the protease inhibitors, there is no significant effect for either of the drugs when tenofovir is used in combination with indinavir. The combination of tenofovir with lopinavir/r, however, was found to raise drug levels of tenofovir approximately 30%.

Further Studies Planned or in Progress

Study 903: To evaluate the potential role of tenofovir in treatment-naïve individuals, Gilead initiated a randomized, double-blind, multi-center, Phase III clinical trial in June 2000. This trial is designed to compare the safety and tolerability of two treatment regimens, tenofovir, efavirenz and lamivudine (3TC) versus stavudine (d4T), efavirenz and lamivudine. It was fully enrolled in January 2001 with 601 treatment-naïve individuals.

Study 910: Open-label rollover of studies 902 and 907. N=575.

Expanded Access Program: In January 2001, after protracted discussions with the community, Gilead initiated an expanded access program for individuals >18 years of age who required tenofovir to construct a viable treatment regimen and had failed treatment with at least two PIs or one PI and one NNRTI. Individuals were required to have a viral load of >10,000 copies/mL (by PCR) and CD4 count <100 cells/mL. Additionally, individuals with CD4 count between100 and 200 cells/mL, and documented evidence of an AIDS-defining opportunistic infection within the past 90 days were eligible. Individuals were also eligible for the expanded access program if they had completed a clinical trial including tenofovir and desired continued access to the medication.

In April 2001, after some start up difficulties, Gilead announced that the company had broadened the entry criteria for its U.S. expanded access program to provide tenofovir to individuals who had failed prior antiretroviral therapy, regardless of their CD4 cell count or viral load. To date, nearly 5,000 individuals have enrolled in tenofovir expanded access programs in the United States, Canada and Europe.

Pediatric Studies: A pediatric formulation of tenofovir is in development and Gilead has said that they expect it to be ready early in 2002. The study of tenofovir in infants and children was deferred pending the outcome of bone toxicology studies in animals.

Recommendations for Post-Marketing Studies
The FDA should require the sponsor to complete the following studies in the post-marketing period:

• A safety and efficacy study in individuals with viral loads >50,000 copies/mL
• A safety and efficacy study in treatment-naïve individuals—such a study (903) was fully enrolled in January 2001
• Safety, efficacy and pharmacokinetic studies in children
• Safety and pharmacokinetic studies in individuals with renal or hepatic impairment
• Studies to identify long-term toxicities of tenofovir
• Drug-drug interaction studies with drugs that inhibit renal tubular secretion such as trimethoprim (or cotrimoxazole) and probenecid; drugs that are excreted by the kidneys and are likely to be used concomitantly by some HIV-infected individuals, such as stavudine (d4T), certain antibiotics (including aminoglycosides, cephalosporins, and penicillins) narcotic analgesics (such as demerol and morphine) lithium and digoxin; and the studies which the sponsor has indicated that it plans to conduct with ddI EC, methadone, oral contraceptives and adefovir
• Correlation of the IC50 or IC90 with plasma levels of tenofovir

In the TAG press release issued on the eve of the FDA hearing, TAG's Antiviral Project Director Yvette Delph, M.D., said, "We salute Gilead Sciences for conducting its pivotal efficacy studies in heavily pre-treated individuals. This is something we have been asking industry to do for years. Over 50% of people taking antiretovirals are already resistant to many approved drugs, and they will need a potent drug with favorable toxicity and resistance profiles—such as tenofovir—to help them construct a potent new regimen." With vigilance and a little good fortune, we may be able to look forward to at least one or two additional Antiviral Advisory Committee hearings for new anti-HIV agents in the year ahead. ¤