Bristol Reyataz Gets Broad Label Vote Despite Concerns In Drug Experienced

Bristol-Myers Squibb's protease inhibitor Reyataz is on track for a June approval with a broad label recommendation following a positive advisory committee review May 13.

Reyataz (atazanavir) was unanimously recommended for approval by FDA's Antiviral Drugs Advisory Committee for the general indication "treatment of HIV infection" despite concerns about efficacy of the drug in HIV-infected patients who are treatment-experienced.

"Regarding atazanavir for the naïve population, there was a consensus that the drug was clearly active, that we saw convincing data compared to a tough comparator which was an efavirenz [Bristol's Sustiva ] based regimen," Committee Chair Roy Gulick, MD, Cornell University, said. However, "in terms of the experienced population, that presented much more of a quandary to us and the agency."

Bristol is seeking "a broad indication for the treatment of HIV infection based on two registrational trials," FDA noted in ¹ briefing documents. The agency "would like to hear comments from the committee regarding the proposed indication for atazanavir" due to mixed results from the two pivotal trials, the documents said.

FDA has wrestled over the breadth of indications in its recent approvals for HIV therapies. The agency's most recent antiretroviral approval limited the indication to only the population in which the agent showed a benefit in clinical trials.

Roche's Fuzeon (enfuvirtide) was approved for use in combination with other antiretrovirals for the treatment of HIV in treatment-experienced patients (² , p. 35). For Gilead's Viread (tenofovir) - the HIV agent approved immediately before Fuzeon - in 2001, the committee recommended an indication limited to treatment-experienced patients because of the scope of the trials. However, FDA approved the drug for use in all HIV patients (³ (Also see "Gilead Viread Virology Data Will Distinguish HIV Drug In Physician Promotions" - Pink Sheet, 5 Nov, 2001.), p. 21).

In the Reyataz trials reviewed by FDA, the drug showed equivalence or superiority to other HIV drugs in treatment-naïve patients, but failed to show non-inferiority to other drugs in treatment-experienced patients.

Evidence supporting use of atazanavir in treatment-naïve HIV patients included a double-blind, randomized, controlled pivotal trial (study 034) comparing atazanavir plus GlaxoSmithKline's Combivir (lamivudine/zidovudine) to Bristol's Sustiva (efavirenz) plus Combivir and two dose-finding studies (007 & 008) comparing atazanavir to Pfizer/Agouron's Viracept (nelfinavir) with background therapy.

In the atazanavir-efavirenz trial, HIV RNA levels were suppressed to below 400 copies/mL in 70% of patients receiving atazanavir 400 mg once daily vs. 64% of patients receiving efavirenz 600 mg once daily for 48 weeks.

In study 007, 62% of patients receiving atazanavir 400 mg qd had less than 400 copies/mL HIV RNA compared to 61% of patients receiving nelfinavir 750 mg three times daily with background therapy. In study 008, 68% of atazanavir 400 mg qd patients had less than 400 copies/mL compared to 59% of nelfinavir 1,250 mg twice daily.

The pivotal study (043) in treatment-experienced patients was a randomized, open-label trial comparing atazanavir 400 mg once daily to Abbott's Kaletra (400 mg lopinavir/100 mg ritonavir) twice daily, both in combination with two nucleoside therapies. Patients enrolled in the study had failed one protease inhibitor.

In the study, 65% of Kaletra patients achieved a viral load of less than 400 copies/mL HIV RNA compared to 47% of patients receiving atazanavir.

"With respect to percent below 400 copies at week 24, atazanavir is, with 95% confidence, directly observed to be between 7.9% and 30% worse than Kaletra," FDA Biometrics III Division Statistical Reviewer Thomas Hammerstrom, PhD, said.

Bristol presented further data at the meeting from a study (045) comparing atazanavir and Kaletra in highly treatment-experienced patients who had failed drugs in all three HIV drug classes.

At 24 weeks, 64% of patients receiving 300 mg atazanavir plus 100 mg ritonavir (Abbott's Norvir ) had less than 400 copies/mL HIV RNA compared to 62% of patients receiving Kaletra and 44% for atazanavir 400 mg/saquinavir (Roche's Invirase ) 1,200 mg. All of the patients also received tenofovir (Gilead's Viread ) and a nucleoside reverse transcriptase inhibitor.

FDA only recently received 24-week data from the study and will not have time to review it prior to the June 20 user fee deadline, the agency said. While 16-week data from study 045 were submitted with the original NDA submission in December, 16 weeks were not enough follow-up safety and efficacy, FDA added.

The disparity between the results of study 043 and 045 put the advisory committee "in a little bit of an awkward position," Gulick said. "We're shown evidence of activity" in study 043, "but it's not as good as the comparator arm. At the same time we saw preliminary activity" in study 045 "which hasn't been reviewed by the agency which seems to suggest similar biologic effects to a Kaletra based arm.

FDA Antiviral Drug Products Division Director Debra Birnkrant, MD, said the data is "also a dilemma for us as well to see snippets of data that look potentially promising." Noting the June 20 user fee date, she said, "between now and then there isn't that much time to review that additional data that came in late."

The committee asked FDA whether data from the atazanavir-boosted 045 study could be included in Reyataz labeling.

Committee member Princy Kumar, MD, Georgetown University, urged FDA to consider study 045 for labeling purposes, noting that the atazanavir-boosted dose "is going to be the dose that's most commonly used" in the treatment-experienced population.

"There is a possibility that perhaps some pharmacokinetic data could be placed into the label in the appropriate sections," Birnkrant said.

The inclusion of the 045 data is essential, committee member Courtney Fletcher, University of Colorado, maintained. "In my mind, it's the only data that really makes a case from a clinical trial for using the drug in a treatment-experienced patient. If you have to look at just a 400 once-a-day regimen versus Kaletra, it wasn't as good as other available agents."

Gulick pointed out that the data in study 045, which enrolled patients who had failed several drug therapies, may be more relevant than study 043, which enrolled early treatment failures, in assessing atazanavir efficacy in treatment-experienced patients.

"The 045 study looks at a more advanced group with more PI experience, and clearly that is the biggest need in the clinic right now - not so much the early failure people where you may have several options to choose from," Gulick said.

Gulick added that "043 really is not a study that we would do today because in a person that has failed on regimen, we would select the next regimen based on their resistance testing, which was not done in this study....So really it's difficult to apply that study to the optimal treatment of the experienced patient today."

The committee agreed that, despite atazanavir's failure to show a benefit equal to or better than Kaletra in the experienced population so far, Reyataz' convenient once-daily dosing and possibly advantageous lipid profile would benefit the salvage patients and thus may justify its use (see ⁴ (Also see "Reyataz Lipid Effect Offers Benefit But Not In Lipodystrophy, Cmte. Says" - Pink Sheet, 19 May, 2003.)).

Resistance data may argue for Reyataz as first-line treatment in naïve patients, but not necessarily in experienced patients, the committee noted.

Fifteen percent of 93 isolates from naïve patients with treatment failure were resistant to atazanavir. However, 80% of those isolates developed an I50L mutation and viruses that develop the I50L mutation remain susceptible to other protease inhibitors, FDA noted. Meanwhile, 51% of the 63 isolates from treatment-experienced failures were resistant to atazanavir, but the mutations that occurred were associated with cross-resistance to other protease inhibitors.

The committee recommended that resistance testing be included in Reyataz labeling. Gulick noted that the committee found the "signature mutation story intriguing, but we would like to see some clinical data to show that sequencing of these inhibitors really has clinical value."

Reyataz is expected to receive full approval by the June 20 user fee date. Although the NDA was originally submitted December 20, 2002 for accelerated approval, the 48-week data submitted by Bristol makes it eligible for full approval, FDA said.

Patient representatives expressed concern that FDA's consideration of Reyataz for full approval may enable Bristol to forgo Phase IV studies that are required under accelerated approval regulations.

"I am really concerned that if the drug gets full approval...that some of the follow-up studies will not be done," committee patient representative Matthew Sharp, Chicago, Ill., remarked.