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Aptivus® in the Hotseat

Excerpts From the FDA Hearings

May/June 2005

These are condensed excerpts from discussions by the FDA Antiviral Advisory Committee on the new drug application for Aptivus (tipranavir) 250 mg capsules indicated for treatment of patients with HIV.

May 19, 2005 -- During the first half of the daylong meeting, safety and efficacy data and analysis concerning tipranavir/ritonavir (TPV/r, brand name Aptivus) were presented, first by the sponsor, Boehringer Ingelheim (BI), and then by the FDA. After making clarifying querys to the sponsor and FDA, the members of the Committee discussed the formal questions posed to them by the FDA. The Committee also voted on the key question of whether TPV/r was safe and effective in the proposed population.

Janet Englund (Committee Chair): Welcome and turn off your Blackberries.

Englund: What is your risk/benefit assessment of TPV/r given the data provided for safety and efficacy in the treatment of "heavily pretreated" HIV-infected individuals?

Richard Haubrich: The evaluation of safety is in the context of need. The biggest need in the clinic today is for patients with multidrug-resistant HIV. This is who we clearly need new drugs for. The risk/benefit ratio is different for these patients. The bar would be much higher for treatment-naive patients. We are willing to tolerate more toxicity and complexity in these patients because we need new drugs. The promising drugs on the horizon won't be available in the clinic on Monday morning.

Douglas Fish: Most of the safety issues with tipranavir are reversible. While they are serious, they are manageable. But this is the reality of HIV care in 2005.

Maribel Rodriguez-Torres: I treat the complications. There is a need for a treatment for patients with resistance. Why not approve tipranavir in combination with Fuzeon? If not, then there should be a strong recommendation to use them together.

The prevalence of hepatitis C virus (HCV) is much higher in the clinic than in these studies. It is as high as 60 percent in our Baltimore patients. Simply measuring ALT does not tell enough about the severity of the disease. We need more biopsies. Did patients with elevated liver function tests (LFTs) also have lipid elevations?

I'm also concerned about so many drug interactions. How will garden-variety treaters sort this out? I'm concerned about interactions with methadone -- we need to know about this. Remember, it is usually a different doctor who is treating with methadone. How are we going to deal with women who may be treated with hormones by another doctor? We need to give some paradigms that primary treaters can follow.

Kenneth Sherman: I appreciate what Dr. Rodriguez-Torres said. From the viewpoint of the hepatologist, it is the patients with end-stage liver disease that are the problem. We see lots of patients dying of end-stage liver disease with undetectable viral load. This study has short-term HIV endpoints. We have seen nothing about prevention of opportunistic infections or long-term survival.

There was also a failure to address issues with early hepatic signals in these trials. A high proportion of patients had high liver enzymes but there was little attempt to get more biopsies to distinguish between those with different stages of liver disease.

Short term use of these drugs does not occur. This is the last drug for many people and it will be used for an extended period of time. The concern is not short term flares, but patients who cruise along with elevated LFTs for years. There is much more disease in coinfected patients. BI recommends more monitoring in coinfected patients. There is a poor understanding of liver injury in the community and there is poor monitoring. But once you have symptoms, the game is over. You have to worry about liver injury well before that point. While we are transplanting more people with HIV these days, these patients with advanced HIV disease are the least likely to be transplanted. Finally, drug-drug interactions that may lead to increased liver toxicity have not been well characterized to this point.

Lynda Dee: We have to look at the risks versus the benefits. Tipranavir may have a limited role in the clinic. We're talking about heavily pretreated patients. I think there has to be more education on what drugs can be taken with this.

Robert Munk: I think we can characterize the patient population, but what about the prescribing population? I don't think this can be turned loose on the market without education. I'm concerned the package insert won't cover all the issues. If I don't see a drug studied for interactions, I presume it is benign. But there are many potentially serious interactions with this drug that haven't been studied yet. I'm concerned about whether tipranavir is ready for prime time.

Lauren Wood: The patients who need this will also likely have high baseline LFTs. Clinicians will face situations with patients who need this drug who have LFTs above the upper limit of normal. What do they do? The company should generate data that tells us the magnitude of elevation over time. When you're talking about grade 3 and 4 LFT elevations sustained over months and years, that has much different implications for long term toxicity. We didn't discuss other parameters of liver function such as coagulation studies.

Scott McCallister (Boehringer Ingelheim): Patients had AST or ALT elevations. Coags were not elevated.

Victor DeGruttola: There appears to be a patient population that has a favorable risk/benefit ratio for this drug. But how well can we predict who will have liver toxicity and who will have virological response benefit? It would be useful to put analyses together to classify how well you can predict toxicity. Regression analysis doesn't do that.

Who will respond best? Doug Mayers made a crucial distinction between mutations that have a direct causal impact and those that are merely associated with mutations that have causal effect. If the mix of mutations does not change over time, that's fine, but that mix could change and the L90 could cease being associated with the causal mutations. What is the best classification for patients who are likely to respond?

Englund: I'm anxious to get drugs that will benefit my patients and I think I can follow and manage my patients. We should stress this drug's use by experienced HIV treaters, but that is hard to do.

Gene Morse: One of the concerns I have is that these patients may be on 8, 12, 15 drugs at a time. And many have coinfections. You can identify who is most likely to be safe, but beyond that how will those complex patients be managed? How will long-term toxicity be followed? We need studies.

Robert Grant: We've seen data that established that a sub-group that will benefit. I'd like to hear more about efficacy in the patients in the boosted PI study. The proposed language of the indication mentions salvage settings, but the people with the most resistance were excluded from the data presented.

Douglas Mayers (Boehringer Ingelheim): A small percentage got a durable drop, but most began to fail afterward. We've seen good anecdotal information on the Fuzeon-naive patient that combines Fuzeon with tipranavir.

Englund: Let's go around the table and vote. Do the data demonstrate that tipranavir/ritonavir (TPV/r) is safe and effective for the multi-drug resistant HIV-1 infected population?

Wood: Yes

DeGruttola: Yes

Rodriguez-Torres: No. Drug interaction studies are needed, as well as studies of histology and on the outcome of liver disease.

Munk: Yes

Sherman: No as a rapid approval pending long-term data and clinical outcomes.

John Gerber: Yes

Ronald Washburn: No. There is a need for long-term efficacy follow-up.

Grant: Yes

Veronica Miller: Yes

Frank Maldarelli: Yes

Morse: Yes

Edmund Capparelli: Yes

Stephen Hall: Yes

Englund: Yes

11 Yes; 3 No votes. All yes votes came with concerns and reservations.

Englund: Please discuss your highest degree concerns.

Hall: My concerns are with long-term outcomes and clinical management issues.

Capparelli: There needs to be a greater focus on use with other drugs. Few thymidine NRTIs were used and there was little variety in the background regimens.

Morse: My problem is that I can't tell my patient how well this will work.

Maldarelli: Efficacy is evident because new resistance mutations emerge, but the durability of the viral response remains uncertain.

Miller: I am concerned with long-term liver toxicity. It is too bad that 48-week data was not available. We need more information on rash, including its clinical management and the role of CD4 count in predicting rash. We should stress the need for physician expertise in using this drug.

Grant: I agree we should emphasize that the use of this drug in these patients should be restricted to experts. I'm concerned that the evidence is not yet sufficient to justify the risk/benefit ratio in women, particularly women on birth control pills.

Washburn: I remain unconvinced that the risk/benefit ratio is acceptable based on a summary of data from a short-term, unblinded trial.

Gerber: A drug proposed in this advanced population -- especially a drug with these interactions -- should have some clinical endpoint. We also need to see information on interactions with fibrates and lipid lowering drugs.

Sherman: If pretreatment status shows elevated LFTs, then patients should be thoroughly evaluated for stage of liver damage.

Munk: More drug-drug interaction studies are needed as are more studies of treatment in co-infected patients and in women. Better characterization of resistance is also needed.

Rodriguez-Torres: I agree with Dr. Sherman to fully workup patients for liver disease.

DeGruttola: It is very hard to interpret the surrogate endpoints here -- we need clinical endpoints. It is also important to make the best use of mutations at the start of treatment. A person with a 1.0 log drop, but still not undetectable, was counted as a success in this study. We need to know more about durability. We need to know how to classify those patients who are at most risk and those at low risk of toxicity.

Wood: It is also important to tell clinicians that there is no indication for this drug if a patient has susceptibility to other protease inhibitors and that this would be the only PI allowed in a regimen. Make that clear. It also needs to be reinforced that tipranavir needs to be accompanied by another active drug to gain the maximum benefit. Another priority focus for interaction studies are diabetes drugs. Also, look at additional oral contraceptives in women. That has to be at the front gate.

Dee: What authority does the agency have to recommend education to doctors?

Debra Birnkrant (FDA): We think there should be adequate educational materials. We never seem to learn whether these educational program work or not. We never get a testing of the materials in a large group. But we don't regulate this.

Fish: The short follow-up of 24 weeks is a casualty of accelerated approval.

Princy Kumar: I have a different take on this compared to my hepatologist colleagues. As a clinician looking at who was treated in these trials, I see an extremely treatment-experienced group of patients. Of course we worry about safety in these patients. But all the concerns should not deter from the fact that at the present time this is one of the few agents we have that can work in this group. As Dr. DeGruttola asked, which patients can we give this to safely? No single agent is going to be durable if it is the only active agent. What can be done to allow other, more potent drugs down the line to be added to this drug?

Haubrich: My comments are closely aligned with Dr. Kumar's. There is no way this study could show clinical benefit since it was designed to let people drop out if they were failing. Doing a study like that would be infeasible because you would have to keep people on a control arm. I hope people will stay away from that idea.

Janet Englund: My summary: We as a committee feel that the need for this drug is high, but the risks are present. We want to know about long-term durability. We need to know clinical incidence rates over the long term. We have questions as a group concerning management of toxicities; drug-drug interactions; about the lack of women in the trials. To hear that the ongoing studies are not preferentially set up to enroll women is troubling. We need much more information on hepatic function follow-up and on the prediction of toxicity and rash incidence. The full transcripts can be found at

Aptivus for the Rest of Us?

Janet Englund: The limited amount of data on females with HIV infection in the TPV program shows an increased incidence of rash in females. Please provide your recommendations for investigation of this safety signal in future studies with TPV.

Veronica Miller: I'd suggest that older women not on birth control also be studied, i.e., women on hormone replacement therapy.

Lauren Wood: It should be recommended in the label how to manage individuals with rash. It is encouraging that there is no evidence of Stevens Johnson Syndrome. But do you treat through if there is rash? Or discontinue and rechallenge? It would be a disservice to deny access of the drug to women.

Janet Englund: After so many years on this panel, I'm getting ready to recommend that a drug not be licensed if there is so little data on women.

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.