Asunaprevir NDA Withdrawal Likely To Mean Daclatasvir Delay

Bristol pulls NDA for its second-generation protease inhibitor, which likely will alter the data needed for approval of its simultaneously filed NS5A inhibitor. Recent approval of daclatasvir in Europe may offer a glimpse at Bristol’s revised U.S. strategy in HCV.

Bristol-Myers Squibb Co.’s strategic decision to no longer seek FDA approval of a two-drug combination of its protease inhibitor asunaprevir and NS5A inhibitor daclatasvir for hepatitis C could mean a later approval for daclatasvir as a solo agent, but the firm is working with FDA on amending the application.

On Oct. 7, the Princeton, N.J., pharma announced that it had withdrawn an NDA for asunaprevir, a second-generation protease inhibitor intended to treat patients infected with genotype 1b of HCV, based on its assessment of the rapidly changing competitive landscape in HCV.

The separate NDA for daclatasvir, filed at the same time as asunaprevir, will go forward, but Bristol indicated that it would not be surprised if FDA needs to move back the Nov. 30 user fee goal date as both parties determine what additional data may be needed for approval.

Bristol is seeking approval of daclatasvir for use in combination therapy with other companies’ drugs and may still seek approval of a triple combination of daclatasvir with asunaprevir and its non-nucleoside polymerase inhibitor BMS-791325.

“With the consent of the FDA, we have withdrawn the asunaprevir NDA and maintained the daclatasvir [filing],” Doug Manion, Bristol’s head of specialty development, explained in an interview. “We’re in active discussions with FDA on supplementing that NDA … so that we can have a complete dataset for it to review,” he said.

“We’re literally in daily conversations with FDA to determine how best to do that, in terms of their regulatory frame but also to meet our aligned desires, which clearly is to see daclatasvir be made available to patients in the U.S. in an expeditious manner.”

The exec added that Bristol is “working under an assumption that [the action date] will change, but we don’t have confirmation from FDA on that one way or the other.” Pulling the asunaprevir NDA likely amounts to a major amendment, he explained, which could trigger a three-month user fee extension.

“If we’re not tracking to the pivotal trials that were in the initial submission and if we have to track to different pivotals, then the agency would have to deem that a major amendment,” Manion said. “Normally, a major amendment results in a clock-stop, but that has not been finalized yet.”

Although filed as separate NDAs for U.S. approval, Bristol’s intention with the initial submissions in late March was for the two direct-acting antivirals to be used as a two-drug combo, with or without a backbone of pegylated interferon and ribavirin, to treat patients with genotype 1b. The dual therapy already has been approved for that indication in Japan, with the brand names Dacluinza for the NS5A inhibitor and Sunvepra for the protease inhibitor (Also see "Japan Second Committee On Drugs Approves IFN-Free Hepatitis Drug" - Scrip, 30 Jun, 2014.).

Internally, Bristol made a decision that the pair’s 24-week regimen would not be competitive with other genotype 1b regimens available now or in late-stage development – deciding that daclatasvir would have better value as an independent agent for combination use.

In a same-day note, ISI Group analyst Mark Schoenebaum reported that revenue expectations were low for the combo “given the lower efficacy relative to other regimens from Gilead and AbbVie that are awaiting approval later this year.” Gilead Sciences Inc. is seeking approval of a two-drug pill combining Sovaldi (sofosbuvir) with ledipasvir, while AbbVie Inc. has a three-drug regimen under review at FDA.

EU Approval May Indicate U.S. Strategy

Daclatasvir (brand name Daklinza) obtained a positive opinion from Europe’s Committee for Medicinal Products for Human Use (CHMP) on June 27 to treat chronic HCV genotypes 1-4 in combination with other medicines (Also see "In Brief: Bristol’s Nivolumab Shows Survival, Boehringer Gains A Breakthrough & Sentinel Takes On Flu Vaccines, Plus CHMP Opinions" - Pink Sheet, 30 Jun, 2014.). This is basically the path forward Bristol now will seek for daclatasvir in the U.S., but Schoenebaum thinks a triple combination with asunaprevir and the non-nucleoside polymerase inhibitor BMS-791325 remains viable, as combo trials in the U.S. and Europe have been completed for the trio.

UBS Investment Research analyst Matthew Roden said in an Oct. 7 note that while the daclatasvir/asunaprevir combination is on the market in Japan, where genotype 1b is the predominant strain, its sustained virologic response rate of roughly 85%-90% would be less competitive in the U.S., where SVR rates above 95% with a 12-week treatment duration are becoming the standard.

“Key players are now pushing for four-to-six-week treatment duration,” Roden wrote. “We have spoken with the company and confirmed that Bristol is not exiting HCV, but will focus on the triple regimen or combinations with Sovaldi for the difficult-to-treat populations. It also remains open to adding strategic assets to its portfolio.”

Manion said the Phase IIb data that backed approval in Europe will now only be used to bolster the safety profile in the daclatasvir NDA. The firm’s Phase III trials studying daclatasvir with Sovaldi in three tough-to-treat HCV patient cohorts – people co-infected with HCV and HIV, patients awaiting liver transplant and patients with genotype 3 of the virus – will likely now be crucial to the daclatasvir filing. Bristol recently completed the ALLY 3 study in genotype 3 patients, while ALLY 1 and ALLY 2 for the other two subpopulations continue, Manion said.

Gilead’s Sovaldi is just one of several HCV therapies from other companies that Bristol has studied in tandem with daclatasvir. It has also studied its NS5A inhibitor with Merck & Co. Inc.’s second-generation protease inhibitor MK-5172, which has emerged as one of the more promising late-stage HCV candidates (Also see "Collaboration With Merck’s Protease Inhibitor The Fourth HCV Tie-Up For Bristol’s Daclatasvir" - Pink Sheet, 22 Apr, 2013.).

UBS’ Roden speculated that Bristol’s decision reflects an ongoing consolidation within the HCV competition, down from nine players currently to possibly three or four. Bristol may be elbowing with Johnson & Johnson to be the fourth player, alongside Gilead, AbbVie and Merck, he said. J&J increased its wager on the HCV space on Sept. 30 by purchasing Alios BioPharma Inc. to add nucleoside polymerase inhibitor candidates to its pipeline (Also see "Alios Purchase Boosts J&J Anti-Infectives Game, Especially Hep C" - Pink Sheet, 30 Sep, 2014.).