Labeling for Boehringer Ingelheim's HIV therapy Aptivus should note that tipranavir is most efficacious when used in combination with certain HIV therapies, particularly Fuzeon , members of FDA's Antiviral Drugs Advisory Committee said May 19.

"It really needs to be reinforced and made clear that tipranavir in a heavily treatment experienced population really does require another active drug - a drug with a high probability of activity," committee member Lauren Wood (Uniformed Services University of Health Sciences) said.

Wood said data on coadministration of Aptivus with Roche/Trimeris' fusion inhibitor Fuzeon (enfuvirtide) "was very strong and very consistent."

[Editor's Note: To ¹ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

In the Phase III RESIST-1 and RESIST-2 trials, 65% of tipranavir patients, boosted with ritonavir (Abbott's Norvir ) and receiving Fuzeon (also referred to as T-20), responded, compared to 40% of patients receiving boosted tipranavir alone. The difference was statistically significant.

"Why are you not considering this to be approved with T-20? That's the best efficacy numbers in all the data," committee member Maribel Rodriguez-Torres (Fundacion de Investigacion de Diego) said.

"If this is not approved to be used with T-20, at least that has to be very strongly recommended because it looks like it was superior," she said.

Relatively few patients currently receive Fuzeon due to the difficulty of preparation and administration, committee members said.

Enfuvirtide is provided to patients in a powder formulation and has to go through a reconstitution process in order to be administered subcutaneously (² Also see "Roche Fuzeon Phase IV Commitments Include Pneumonia Incidence Study" - Pink Sheet, 24 March, 2003., p. 37).

BI is seeking an indication for ritonavir-boosted tipranavir (TPV/r) for "combination antiretroviral treatment of HIV-1 infected patients who are protease inhibitor treatment experienced."

The panel voted 11 to 3 in favor of recommending accelerated approval for Aptivus.

The RESIST trials compared Aptivus to four protease inhibitors - lopinavir (Abbott's Kaletra ), amprenavir (GlaxoSmithKline's Agenerase ), saquinavir (Roche's Invirase ) or indinavir (Merck's Crixivan ) - in patients with between one and two PI genetic mutations. Physicians were able to select which PI comparator was appropriate for each patient.

In an analysis of 24-week data from RESIST-1, FDA found that 36% of tipranavir patients had a confirmed 1 log drop in HIV RNA vs. 16% for the protease inhibitor arm. RESIST-2 results were similar, with a 41% response rate for tipranavir vs. 14.9% for the comparator (p<0.001 for="">

While further efficacy and safety data is needed to guide clinical use of TPV/r, the lack of alternatives for protease inhibitor-resistant patients warrants accelerated approval, committee members said.

"The risk/benefit ratio for a drug that treats resistant patients is different than the risk/benefit ratio for treating patients that are naïve," committee member Richard Haubrich (University of California-San Diego) explained. Haubrich did not vote at the meeting due to a conflict of interest.

"In my opinion, the risk that we tolerate for a treatment for those patients is much higher," Haubrich said. "In the context of the toxicity, we are willing to tolerate more toxicity."

Committee members expressed particular concern about liver toxicity and rash in females.

In pooled safety data from the RESIST trials, 6% of tipranavir patients exhibited grade 3/4 elevations in ALT/ALS liver enzymes, compared to 2% of patients receiving active control.

FDA and the panel agreed that patients receiving Aptivus should be closely monitored for liver injury.

"The best monitoring and management strategy is unclear at this time, but ALT should probably be monitored early and often," Division of Antiviral Drug Products Medical Officer Andrea James said.

Committee member and hepatologist Kenneth Sherman (University of Cincinnati) suggested that guidelines for management of hepatotoxicity call for biopsy of patients with abnormal liver enzymes.

Doctors would then make a decision about initiation of tipranavir therapy "on an individual patient basis, based on the degree of fibrosis and the severity of their HIV disease in the setting of drug resistance," he said.

Co-infection with hepatitis B or C at the start of Aptivus treatment is also predictive of hepatotoxicity, James noted.

However, "having hepatitis B or C at baseline is not the only risk factor for developing hepatotoxicity," she noted, since patients with hepatitis accounted for only 20% of the patients exhibiting liver toxicity.

BI agreed that TPV/r patients should be monitored to detect liver abnormalities. The company said it is committed to studying the liver toxicity risk further.

Studying long-term liver toxicity should be a priority, committee members agreed.

"I clearly would urge the pharmaceutical sponsor, since we know that there is this persistent elevation in liver function studies, to generate data that lets us know the baggage with elevation over time," Wood said.

Further study of rash in women, especially in women receiving ethinyl estradiol, is also needed, committee members said.

In the overall RESIST population, rash appeared in 10% of patients, only slightly more than the comparator arm. However, rash appeared in 14% of women receiving TPV, compared to 9% of female PI patients; less than 15% of patients in the RESIST trials were female.

A Phase I drug interaction study with Johnson & Johnson's contraceptive Ortho Novum of 35 healthy female patients was halted early after 33% of participants developed rash.

Wood recommended that labeling include guidelines for managing rash.

The panel urged BI to conduct further study of rash and to enrich future trials with female patients. A fully-enrolled trial of tipranavir in treatment-naïve HIV patients includes more than 20% females and could provide more insight into the adverse event, BI said.

Committee members emphasized that further studies are required to guide the use of tipranavir.

"We as a committee have agreed that we feel that there is efficacy demonstrated, but the exact usefulness needs to be monitored in the future," committee chair Janet Englund (University of Washington) said.

The committee needs "guidance both from the company's future studies and from the FDA to be able to use the drug in the best possible way," Englund said.

FDA asked the panel what would be an appropriate indication for the antiviral, given available data.

An "escape clause" in the RESIST trials made it difficult to isolate which patients responded to therapy, FDA and committee members agreed. Patients in the comparator arm were given the option to switch to tipranavir after eight weeks of treatment if they experienced virologic failure.

Committee member Victor DeGruttola (Harvard University) said that the patients who are most likely to "benefit virologically" are "patients who have some degree of multi-drug resistance, but not very high level resistance to proteases."

Aptivus should be indicated for "PI-resistant," rather than "PI-experienced" patients because that was the population studied in the trial, the committee said.

Labeling should also include information on patient response rates according to genetic mutation, committee members agreed. Trial patients with 0-3 genetic mutations had a 38.9% response rate, compared to 18.9% for 4-10 and 0% for greater than ten.

For this reason, labeling should recommend phenotype or genotype testing pretreatment, panelists said. BI noted that it may be difficult for physicians to receive reimbursement for genetic testing pre-treatment.

Further genetic data on patients likely to respond to Aptivus would also be useful, members said.

BI is currently conducting an extended follow-up of the two pivotal trials, as well as a trial in pediatric patients, in addition to the trial in treatment-naïve patients.

Aptivus Labeling Should Note Added Efficacy With Fuzeon, Committee Says

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