Report of the FDA Hearings for approval of---azt/3tc, Saquinivir and D4T written by Jules Levin--November 10,1995

Transcription

1 National AIDS Treatment Advocacy Project Report of the FDA Hearings for approval of---azt/3tc, Saquinivir and D4T written by Jules Levin--November 10,1995 In keeping with tradition if not regulation, the FDA held its public hearing of the Antiviral Drugs Advisory Committee on November 6, 7 and 8, in Silver Springs, Md., for the consideration of approval for three AIDS antiviral therapies. The procedure is that at the end of the day, after consideration of the data, the Committee, in open hearing, offers to the FDA its recommendation to approve or not to approve. It also offers their recommendation for an indication of use for the treatment. The FDA is not bound to follow the committee's recommendation but they usually do. On each of the three days, a different application for approval was considered. Glaxo Wellcome had filed an application for Accelerated Approval for the combination of AZT/3TC, for both adults and pediatrics, on June 30, Their hearing was the first, scheduled for Monday, November 6th. The 2nd day- November 7th- was for consideration of Roche's application of Accelerated Aproval for Saquinivir, which they filed in September, November 8th, the third and last day, was for Bristol-Myers Squibb's application for full approval of D4T, as it had been previously granted Accelerated Approval. The first two meetings, Monday and Tuesday were very well attended; it seemed that 300 people or more were present. The press was well represented, as well as the drug industry and stock analysts; there were a lot of people with cellular phones. Representatives from Agouron, Merck and Abbott were present to observe and plan for their future hearings. By Wednesday the crowd was a little smaller. The big attraction seemed to be that the first protease inhibitor was about to be marketed. Protease inhibitor cross-resistance meeting Before reviewing the hearings, I'll briefly discuss a meeting that occurred on Sunday, November 4th, the day before the hearings began. A small gathering of community advocates including myself, arrived in Silver Springs early Sunday, in order to participate in a specially scheduled meeting with Roche and Merck to address the issues related to cross-resistance between their protease inhibitors. The meeting was pre-arranged by Project Inform and co-sponsored by GMHC. Since earlier in this year, there has been a significant difference of opinion between Roche and Merck regarding whether prior treatment with Roche's protease inhibitor Saquinivir can cause cross-resistance to Merck's protease inhibitor Crixivan or to other protease inhibitors. Of course, also up for discussion was the potential for crossresistance caused by prior treatment with Crixivan to other protease inhibitors; But, Merck freely admits that Crixivan can cause cross-resistance to other protease inhibitors, therefore this subject was not the main topic for discussion at this meeting. We were here,

2 in an attempt, to try and resolve the difference of opinion between Roche and Merck-- does prior treatment with Saquinivir facilitate the beginning of resistance to Crixivan (i.e, cross-resistance to Crixivan)?? Both Roche and Merck presented data and discussed research information about resistance and cross-resistance. We spent 5 hours in this meeting. Both companies faced off and the debate between them became heated a number of times. Noel Roberts handled the presentation for Roche while both Emilio Emini and Jon Condra spoke for Merck. Much of the information presented by the two companies had previously been presented. By the end of the day, both remained steadfast in their claims. Roche continued to claim that prior treatment with Saquinivir has minimal potential for cross-resistance to Crixivan and other protease inhibitors; Roche's data and opinions are based upon individuals from their trials with about 1 year's treatment exposure to Saquinivir. Merck maintains their claim that prior treatment with Saquinivir can cause some measure of cross-resistance to Crixivan. Dr. Doug Mayers, an AIDS researcher with the Division of Retrovirology at the Walter Reed Army Institute of Research, offered his theory as to why Roche may be mistaken. He claimed the manner in which Roche conducted the laboratory experiments to uncover the development of resistance and cross-resistance was no longer used and not reliable. Of course, Roche denied this and Merck supported it. It was again brought up at the Saquinivir hearing on Tuesday, but with no resolution. As of yet, there isn't enough information to adquately understand all the angles related to the development of crossresistance. A positive note was that this issue was addressed in the open hearing for Saquinivir on Tuesday; Dr. David Kessler, the FDA Commissioner, requested that the three protease inhibitor manufacturers -Abbott, Merck and Roche- cooperate with each other in trying to resolve the concerns about cross-resistance; and, representatives of the three companies stepped up to the microphone to agree to this cooperation. It was suggested that a "special resistance study" be conducted. That would be, to gather individuals who have been pretreated with Saquinivir for a prolonged period of time (possibly 1 year), who have developed the Saquinivir L90M mutation, and then switch their treatment to Crixivan. It is suggested they could study two groups--in addition to the one just mentioned where they would switch treatment from Saquinivir to Crixivan-- continue a group on Saquinivir and add Crixivan to the regimen. The Sunday meeting could be considered a noble attempt to discover who is telling the truth; but, the question was not resolved. We don't yet have enough information to understand the development of cross-resistance. Significantly, both Merck and Roche have followed up by continuing their dialogue started at this resistance meeting. It is expected that the "special resistance study" will be initiated in the very near future. It is incumbent upon advocates to keep the pressure on Merck and Roche to insure they conduct this study. AZT/3TC Glaxo Wellcome presented impressive and convincing data for the approval of this combination in adults. It was the most impressive data ever presented before this

3 committee up til this point. Of course, it could be surpassed, by the Abbott and Merck data expected to be presented before this committee by early 1996, for their protease inhibitors. Glaxo presented the results of 4 randomized controlled clinical studies of the combination. The two therapy-naive studies examined 495 therapy naive individuals with CD4 between 100 to 500. The other two trials examined 477 AZT-experienced individuals with CD4 between 100 and 400. The CD4 increases and viral load decreases, resulting from treatment with the AZT/3TC combination, were both well sustained for-- either 6 months or 1 year-- the amount of time for which data was presented, for a particular study. There were no significant safety concerns. However, the amount of study participants upon which the data was based at one year was vastly reduced from the baseline number. For example, in one study, at baseline the number of participants in the AZT/3TC-150 mg. arm was 88; by the time we arrived at one year there were 29 participants remaining in that arm. The only objection raised was regarding Glaxo's plan for comfirmatory trials. Glaxo was seeking approval of this combination for two uses in adults- (1) for use by individuals who are AZT experienced, and (2) for individuals who are AZT naive. The company presented data from studies of both of those groups. The benefits to AZT-naive individuals, in terms of both CD4 and viral load, were much superior to the benefits received by those who were AZT-experienced; but, the AZT-experienced individuals also received impressive benefits, as measured by both CD4 and viral load. Based on the data alone, it would be expected that these applications for approval should sail through the hearing before the committee and the FDA approval. However, an objection was raised by a vocal group of activists from TAG (Treatment Action Group). They wanted to prevent the committee from recommending approval for the AZT naive group in the higher CD4 range ( ). Their objection was based on -- - although Glaxo had already planned a clinical endpoint trial (following people to progression to AIDS and death) in the CD4 range below 250, they had not planned such a study for AZT-naive individuals above 250 CD4. They claimed good science and the regulations required such an undertaking. They would have liked a delay of approval for this population until Glaxo presented such a confirmatory or clinical endpoint study for this population-- AZT-naive (possibly to include AZT-experienced) and CD4 > 250. Their objections became very heated not only at the AZT/3TC hearing on Monday but also during the Saquinivir hearing on Tuesday. They feel (1) that a confirmatory trial in the AZT-naive, upper CD4 range poplulation is feasible ( unlike others who don't think such a trial is feasible), (2) that for varying populations (e.g.- lower CD4 range vs. upper CD4 range), efficacy responses to drugs are different and therefore each needs their own database, and (3) not requiring Glaxo to conduct this trial will open the floodgates for other drug companies to do the same. They relentlessly pursued the FDA on these points. Glaxo said they met with these activists to address the issue, but were unable to think of a feasible study design. After the hearing the other community activists, who supported full approval for AZT/3TC, said they would call the FDA after the hearing to ensure that the FDA follows the committee's recommendations for approval. The other community advocates at the hearing strongly disageed, with the objections to approval, and insisted the committee and the FDA support Glaxo's request of approval

4 for both groups--azt-experienced and AZT-naive above 250 CD4. The Committee strongly supported this position. Dr. David Feigal, the Director of the Anti-viral Drug Product Division of the FDA, also strongly supported this position. The body of arguments he and others stated that (1) there was in place a confirmatory trial from which we could extrapolate information to the higher CD4 range, (2) we have many new drugs coming to market in the near future--the Abbott, Merck, Roche, Agouron protease inhibitors-- as well as other expected HIV antiviral drugs; Dr. Feigal said, it will be extremely difficult, if not impossible, to conduct clinical endpoint trials for each and every one of those individual drugs in every population range, (3) the future for treatment of HIV and AIDS is going to be with multi-drug combinations and we will need to focus on conducting trials utilizing these combinations, (4) with the availability of these many new drugs it will be very difficult, if not impossible, to design trials that individuals will remain in-- a confirmatory trial in the CD4 range of would probably have to last 3 to 4 years; with the advent of 4 or 5 new protease inhibitors, study participants, over time, will want to start switching their treatment regimens; the more you allow study participants to switch treatments the more difficult it becomes to interpret results; (5) if we could design a trial that might be inclusive enough and big enough, it still may not yield the information we want; it is the opinion of many that by the time we would have the results from such a long trial, the results would no longer be very relevant, (6) many resources would have to be devoted to an undertaking that most researchers feel would not be successful, (7) the results recently released from ACTG 175 and Delta indicate survival can be prolonged when initiating treatment at an earlier stage of disease-- higher CD4 range; and lastly (8) forthcoming, in the near future, will be a multitude of studies examining and comparing different combinations for both safety and efficacy; Glaxo agreed to collaborate-- with other drug compnaies, the ACTG and the NIH-- to conduct these studies. The committee also felt that the AZT/3TC combination offered its most benefits, in terms of CD4 increases and viral load decreases, to the AZT-naive population; they felt it would be inappropriate to deny approval for that group and possibly deny access to that group; as discussed at the hearing, without explicit approval for that group, reimbursement could be denied by some insurers--private insurers, Medicaid in some states. Two noteworthy concerns discussed are (1) the possibility that prior treatment with 3TC, such as when used in combination with AZT/3TC, could cause some measure of crossresistance to DDI. Preliminary in vitro studies indicate that is a possibility. Further studies will need to be conducted to discern the measure of that problem; and, (2) TMP/SMX (used for PCP prophylaxis) decreases 3TC oral clearance by 29% (+/- 13%) and increases 3TC AUC by 44% (+/- 23%). AZT/3TC for pediatrics The new FDA rule is that a company can apply for approval for a pediatric use based on adequate and well controlled adult studies together with other supportive pediatric information (such as safety and pharamacokinetic data) when the course of disease and the effects of the drug are expected to be sufficiently similar in adults and children. This rule was put into effect to accelerate development of drugs for HIV treatment in

5 pediatrics. In other words, the presentation of convincing adult data along with pursauasive safety and pharmacokinetic data ought to be adequate for approval in the pediatric population. In this case, Glaxo used the adult efficacy data because although a pediatric clinical confirmatory trial is underway, there is a lack of adequate clinical controlled data for safety and efficacy in the pediatrics populations. Obviously, the adult efficacy data was adequate but pediatric data presented a safety concern. Pancreatitis occured at a higher rate in the two pediatric studies (15%) than in the adult trials overall (<0.5%). In spite of that concern, the Committee recommended approval to the FDA for this use. It was difficult to discern the actual cause for the occurrences of pancreatitis, because most of the children had advanced HIV disease and other risk factors for pancreatitis (including concomitant medications). There was some reluctance to recommend approval because of this concern, but the need for access to treatments for children was an important consideration. Saqunivir Roche presented the results from 5 contolled studies totalling 920 participants. They requested an unusual indication for approval. In addition to requesting approval for Saquinivir in the ways in which they studied it, in their controlled clinical trials-- Saquinivir monotherapy and in combination with either AZT alone or with the combination of AZT/DDC-- they also requested approval for Saqunivir to be used in combination with all other approved nucleoside analogues (that includes ddi, D4T and soon AZT/3TC). At the hearing, Roche presented that in their expanded access program some particpants (probably numbering up to 100 to 200 for each combination) were using these other un-studied combinations without reported safety concerns. The efficacy data presented by Roche was adequate as measured by CD4 and HIV RNA for the combinations of Saquinivir/AZT and Saquinivir/AZT/DDC. The Committee recommended approval for the combination therapy indication requested-- for the treatment of advanced HIV disease in adults, with approved nucleoside analogues. The committee denied recommending approval for monotherapy with Saquinivir. They didn't think the efficacy data provided was adequate to recommend monotherapy for Saquinivir. Another concern the committee had was approving monotherapy use for individuals with 50 or under CD4 as a last resort treatment option. The data was unconvincing. A noteworthy concern addressed at the hearing is the dosage for which Roche is requesting approval. Roche's application for approval is for a dose of 600 mg. three times daily for Saquinivir. At Stanford, Roche studied daily doses of 3,600 and 7,200 mg. of Saquinivir for 24 weeks. The CD4 increases and HIV RNA decreases were superior. In addition, Roche has developed a more potent (more bioavailable) formulation that is currently in a human trial; it might be available for approval by the Summer of An individual may want to wait until the enhanced formula (EOF) is available before using saquinivir; there is a concern that treatment with saquinavir at the currently recommended dose, 600 mg. 3 times daily, may cause some measure of resistance to the EOF, and thereby the EOF could be less effective for that individual; but some

6 individuals may not be able to wait or may not want to wait. Also, other protease inhibitors will be available by that time--merck's Crixivan and Abbott's ritonavir. The fact is that the individual responses to saquinavir, as with any drug, are variable; many individuals in their studies, at the 600 mg. 3 times daily dose, responded relatively well to combination treatment including saquinivir, as measured by CD4 and HIV RNA. In the Italian study, for those who were AZT-naive and taking AZT/saquinivir, Roche said 25% of the participants had a 2 log or greater suppression of HIV RNA at between 2 and 8 weeks; and, 75% maintained a.5 log or greater RNA reduction through week 16-- not a long time. Obviously, for an individual who is faced with making treatment decisions, this subject is very difficult to sort out. Saquinivir notes Saquinivir must be taken within 2 hours after a meal--bioavailability is improved by food. Drug interactions: (consult your doctor) -Ketoconazole increases blood levels of Saquinivir -Rifampin decreases Saquinivir blood levels -Rifabutin may decrease Saquinivir blood levels -other agents that affect the CYP3A4 isoenzyme of the Cytochrome P450 system (liver metabolism) can affect Saquinivir blood concentrations. Protease inhibitor future developments: Roche and Merck will colaborate in conducting a study of the combination of their 2 protease inhibitors; Roche and Abbott will conduct a similar study of their 2 protease inhibitors. Agouron will be starting their 3 U.S. phase III trials within a few months. Glaxo Wellcome is developing a protease inhibitor (Vx-478), for which preliminary in vitro studies have displayed minimal potential for cross-resistance with other protease inhibitors. As well, other protease inhibitors are in development. D4T - (Stavudine - Zerit) Bristol- Myers presented the results of their clinical confirmatory trial (#019), for the purpose of attaining full approval for D4T; they had previously received Accelerated Approval. Extracting a decision from the committee was more difficult in this case than for the other 2 hearings. The committee was very indecisive and unreluctant about granting approval of D4T; Dr. Feigal, of the FDA, had to coax a decision out of them. Some observers of the entire three days of hearings thought the committee may have been getting increasingly conservative. Maybe, the committee members were tired because three full days on this panel can be exhausting. D4T's indication for Accelerated Approval, granted in June of 1994, was for those individuals who were failing or intolerant to AZT. This confirmatory trial (#019) studied

7 individuals with a minimum of 6 months prior AZT experience, but actually the average prior AZT experience was about 1 1/2 years. Bristol, although not requesting a specific indication, is expecting the FDA to approve D4T for those-- who are failing or intolerant to AZT or have prior AZT experience of at least 6 months (since that was the criteria for the study). At the end of a confusing and picky discussion by the committee, they recommended by a 4-3 vote that D4T should receive full traditional approval for patients with (possibly prolonged) prior AZT experience. The committee was uncertain and seemed lost in trying to figure out the wording they wanted to recommend. Now, this goes to the FDA and they will sort this out and come up with a final wording. There were two issues that seemed to cause some reluctance on the part of committee members to grant the full approval: (1) the statistical significance of the study was not quite at the level they wanted to see, and (2) the data, although establishing that D4T had efficacy for AZT experienced individuals, was not overwhelming. Remember, for full approval, the issue is clinical endpoints-- not necessarily surrogate markers (CD4 and RNA). The 3 clinical endpoints used as parameters in the study were -- (1) time to first CD4 failure (a 50% reduction in CD4), (2) time to first AIDS-defining event, and (3) death. The data for the first endpoint-- CD4 failure-- was convincing; the data for the other two endpoints were not as convincing to the Committee members, although it seemed adequate. But, that was the point causing reluctance on the part of the committee members. It was mentioned at the hearing how many physicians are using D4T as first line therapy, instead of AZT. Bristol stressed the future use of D4T in combination with other drugs. The following drug combination studies utilizing D4T are ongoing: d4t + AZT d4t + ddi d4t + 3TC Both Merck and Agouron are utilizing d4t in their Phase III approval trials for their protease inhibitors. In the Abbott >100 CD4 study, some participants are probably using d4t because it is a standard of care option, i.e. participants can use any approved antiviral treatment. Of note is the d4t + ddi study that Bristol is currently conducting. Data from this study will be presented at the Antiretroviral Conference in January of Its a study of 85 to 90 AZT-naive individuals and preliminarily the data is attractive. The decreases in viral load were impressive; but, the only data available now is for a small number of people. Apparently, d4t is a useful tool in our arsenal in designing treatment alternatives; it should definitely be available to physicians and people with HIV or AIDS as an option in designing treatment regimens. Although the Committee had trouble sorting out the indication, the FDA should be granting full approval for d4t with an appropriate indication.

8 d4t- pediatrics Bristol has ongoing pediatric trials and we can expect an application for approval within a few months. The pediatric needs have been taking a back burner compared to drug development for adults. If they want to, drug companies can pursue pediatric development without delaying adult development. The problem, as I see it, is the companies don't feel the necessity because they haven't been sufficiently pressured by our community as they have been for adult development. However, myself and a few others at this hearing spoke openly in support of the need for a stronger commitment to pediatric drug development from the drug manufacturers.