FDA's evolving regulation of biosimilars became a little clearer with the approval of the second product under the new 351(k) biologics license application pathway.

Inflectra (infliximab-dyyb), Celltrion Inc.'s biosimilar version of Johnson & Johnson's blockbuster tumor necrosis factor inhibitor Remicade (infliximab), cleared FDA on April 5. Pfizer Inc. holds US marketing rights and is maneuvering on the legal front to launch in 2016 (see related story, [A#00160411006]).

The biosimilar approval process had become something of a black hole following FDA's first biosimilar approval, for Sandoz Inc.'s Zarxio (filgrastim-sndz) in March 2015. User fee goals for 351(k) BLA applications for Inflectra and Apotex Inc.'s filgrastim and pegfilgrastim passed in 2015 with no news from the sponsors; in October, Pfizer Inc. disclosed a complete response letter for Retacrit, an epoetin alfa biosimilar, but declined to specify the issues involved.

FDA's approval letter for Inflectra indicates that a complete response letter was issued for the product on its original user fee goal date, June 8, 2015. The application was resubmitted on Oct. 5, 2015; the six-month review clock for Class II resubmissions would put the goal date on the April 5 approval date.

Inflectra Puts FDA's Draft Biosimilar Labeling Guidance Into Practice

Just one week before approving Inflectra, on March 31, FDA released a draft guidance on biosimilar labeling ([A#14160331004]).

Inflectra labeling shows the guidance's principles in action, including the directive to describe clinical efficacy and safety data for the reference product ([A#14160405006]). The clinical comparability data that 351(k) sponsors used to gain approval may be confusing to prescribers, FDA said in the draft guidance.

FDA approved Inflectra for what Pfizer called "all eligible indications" held by Remicade. J&J has built an extremely broad label for Remicade that encompasses Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. Orphan exclusivity kept Inflectra from a pediatric ulcerative colitis indication held by Remicade, but labeling nods to it with a statement that the biosimilar is "safe and effective in another pediatric indication" ([A#14160405005]).

Inflectra is not likely to be the only biosimilar anti-TNF biologic taking advantage of those broad and profitable immunology markets for long. FDA is reviewing Sandoz's biosimilar version of Amgen Inc.'s Enbrel (etanercept) and Amgen's ABP-501, a biosimilar of AbbVie Inc.'s Humira (adalimumab). Agency action is expected in June and September, respectively.

(Keep track of 351(k) applications with the Pending Biosimilars chart. Biosimilar goal dates and approvals are also followed on the comprehensive User Fee Goal Dates chart).

Descovy Approval Brings Gilead's TAF Portfolio To Three

Gilead Sciences Inc. has completed its trio of HIV products based on its successor to the nucleotide reverse transcriptase inhibitor Viread (tenofovir disoproxil fumarate), a targeted prodrug of Viread known as tenofovir alafenamide (TAF). Descovy, a fixed-dose combination of TAF and emtricitabine, was approved April 4, joining Odefsey (TAF, rilpivirine and emtricitabine) and Genvoya (TAF, elvitegravir, cobicistat, and emtricitabine) on the market.

Gilead's drive to replace TDF with its prodrug TAF comes as the older drug faces the loss of patent protection in 2018. The company has been emphasizing the newer product's safety advantages, which it predicts will become increasingly important as the HIV-infected population ages. "We have strong efficacy, improved bone and renal parameters, and we now know that we can treat patients with a lower kidney function than before," Gilead exec Paul Carter stressed at the recent Cowen conference, which he noted is an "important benefit, especially for patients who've been on therapy a long time" Also see "Investor Conference Business Updates, In Brief" - Pink Sheet, 14 March, 2016..

While it establishes the three TAF combination regimens on the HIV market, Gilead is turning its TAF development focus to hepatitis B virus infection. As a single agent, the prodrug is under review at FDA for treatment of adults with chronic HBV. The user fee goal for TAF in HBV likely falls in November 2016.

Movement In Opioid-Induced Constipation

High levels of prescription opioid use and misuse are one of the government's top public health priorities. A side effect of opioid use, constipation, also makes for an attractive market opportunity.

Shionogi Inc. is the latest company to make a play for the opioid-induced constipation (OIC) market. The company recently announced the submission of an NDA for naldemedine, a peripherally-acting mu-opioid receptor antagonist (PAMORA), for once-daily oral treatment OIC in chronic non-cancer pain patients. Naldemedine would be the second PAMORA on the market – FDA approved AstraZeneca PLC's Movantik (naloxegol) in 2014 – and can be expected to receive a standard review, which would put the likely user fee goal in March 2017.

Shionogi is backing naldemedine with seven studies in the global COMPOSE clinical trial program. The NDA is based on two Phase III trials, COMPOSE I and II; both are 12-week studies comparing naldemedine with placebo in around 550 patients with non-cancer pain.

Shionogi also announced submission of naldemedine in Japan on March 30 for a broader indication than in the US, treatment of OIC not limited to non-cancer pain. The company's COMPOSE IV trial, conducted in Japan, enrolled cancer patients with OIC.

Valeant Pharmaceuticals International Inc. and Progenics Pharmaceuticals Inc.'s Relistor (methylnaltrexone) has been available as a subcutaneous injection to treat OIC in adults with advanced illness and chronic non-cancer pain since 2008. The companies aim to grow the product with a more convenient oral formulation, but they will have to wait three months longer before they can expect to hear from FDA on the application. The user fee goal for oral Relistor was extended to July 19, 2016, so FDA can review Valeant's responses to information requests from the agency, the sponsors announced April 4.

Intercept Ocaliva Gets Advisory Committee Endorsement In PBC

The prospects for FDA approval of Intercept Pharmaceuticals Inc.'s Ocaliva (obeticholic acid) by the product's May 29 user fee goal for treatment of primary biliary cirrhosis are looking good after an FDA advisory committee meeting on April 7.

FDA's Gastrointestinal Drug Advisory Committee voted 17-0 that there is substantial evidence to support accelerated approval of obeticholic acid (OCA) for treatment of PBC in combination with ursodeoxycholic acid in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA, the only approved treatment for PBC.

The Ocaliva NDA is based on a single Phase III trial using a novel surrogate endpoint, reduction in alkaline phosphatase. The committee generally agreed that the surrogate endpoint is reasonably likely to predict clinical benefit, but suggested modifications to the ongoing confirmatory trial as well as additional post-marketing studies to address lingering uncertainties ([A#14160407004]).

(For more information on committee recommendations, see the Advisory Committee chart on the FDA Performance Tracker.)

FDA Adds Safety Warnings To AZ, Takeda Antidiabetic Labels

FDA's long evaluation of heart failure risk associated with dipeptidyl peptidase-4 (DPP-4) inhibitors from AstraZeneca (saxagliptin) and Takeda Pharmaceutical Co. Ltd. (alogliptin) has resulted in safety labeling changes for AstraZeneca' Onglyza (saxagliptin) and Kombiglyze XR (saxagliptin and metformin extended-release) and Takeda's Nesina (alogliptin), Kazano (alogliptin and metformin) and Oseni (alogliptin and pioglitazone).

The safety review has found that type 2 diabetes medicines containing saxagliptin and alogliptin may increase the risk of heart failure, particularly in patients who already have heart or kidney disease.

On April 5, the agency announced it was adding warnings of the increased risk of heart failure based on results of Takeda's EXAMINE and AstraZeneca's SAVOR cardiovascular outcomes trials (see related story, [A#00160411012]). The agency brought the issue to its Endocrinologic Drugs Advisory Committee in April 2015; the panel found that the risk could be handled in labeling rather than requiring withdrawal of the products.

Keeping Track: FDA Clears Celltrion's Biosimilar Inflectra; Review Activity In OIC Picks Up

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