Keeping Track: FDA Approves Briviact, Refuses To File Firdapse, Rejects Remune

FDA cleared its second new molecular entity of the year, UCB Pharma SA's Briviact, to cap a week otherwise dominated by news of novel products not receiving approval.

The agency refused to file an NDA for an orphan drug therapy with breakthrough therapy status and issued two complete response letters, one for a novel HIV therapy and one for a new cardiovascular outcomes claim for an old cholesterol-lowering drug.

UCB's Antiepileptic Briviact Clears FDA, Awaits DEA

UCB expects Briviact (brivaracetam) will be classified under the Drug Enforcement Agency's scheduling process within the next 90 days, clearing the way for launch, the company reported in announcing FDA's Feb. 19 approval of the antiepileptic drug as add-on therapy for partial onset seizures in epilepsy patients ages 16 years and older.

Briviact, like UCB's older AED Keppra (levetiracetam), has an affinity for synaptic vesicle protein 2A (SV2A) and could help to make up for Keppra sales lost to generic competition.

The timing of the approval – three months after the NDA's estimated November 2015 user fee goal – suggests that the goal date might have been extended by submission of a major amendment, which adds three months to the user fee timeline (Also see "UCB's Keppra Follow-On Briviact Gains FDA Nod For Epileptic Seizures" - Pink Sheet, 19 Feb, 2016.).

(The CDER Novel Approvals chart on the FDA Performance Tracker provides an annual listing of new molecular entity and novel therapeutic biologic approvals.)

Pfizer Ibrance Broadens Breast Cancer Label With Another Breakthrough Approval

FDA approved a second indication for Pfizer Inc.'s Ibrance (palbociclib) on Feb. 19, adding use in combination with fulvestrant (AstraZeneca PLC's Faslodex) to its approval for treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Ibrance, the only cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor on the US market, first cleared FDA in February 2015 for use in combination with letrozole (Novartis AG's Femara). Both Ibrance indications received breakthrough therapy designations from FDA.

The Ibrance/letrozole combination indication specifies use as initial endocrine-based therapy in postmenopausal women with HR-positive, HER2-negative breast cancer, while the Ibrance/fulvestrant claim is for "women with disease progression following endocrine therapy" for the same cancer.

The newly approved indication is based on data from the Phase III PALOMA-3 trial. AstraZeneca has also filed a supplemental NDA for Faslodex based on the findings (Also see "Keeping Track: Sarepta User Fee Extended; CTI/Baxalta Pull Pacritinib NDA" - Pink Sheet, 15 Feb, 2016.).

(See the Breakthrough Therapy Designations chart for detailed information on products receiving the expedited review designation.)

Catalyst Firdapse NDA Needs Additional Supporting Information, FDA Says

FDA's "refuse-to-file" letter for Catalyst Pharmaceutical Partners Inc.'s Firdapse (amifampridine phosphate) says the NDA was "not sufficiently complete, and requests additional supporting information," Catalyst said in a Feb. 17 statement. The NDA, submitted in December 2015, requested approval for two ultra-rare neuromuscular disorders: Lambert-Eaton myasthenic syndrome (LEMS) and Congenital myasthenic syndromes (CMS). Firdapse is designated a breakthrough therapy for LEMS.

Catalyst is working with FDA on a path for resubmitting the potassium channel blocker, which it licensed from BioMarin Pharmaceutical Inc. in 2012. BioMarin markets the drug in Europe for LEMS under exceptional circumstances, granted when evidence supporting use is incomplete because the disease is rare.

Firdapse has raised some controversy because amifampridine, also known as 3,4-diaminopyridine or 3,4-DAP, has been available via compounding and compassionate use. In an editorial published online in the journal Muscle and Nerve on Dec. 21, just after Catalyst finished its US filing of Firdapse, over 100 neurologists warned that approval of Firdapse could result in an “exorbitant” price increase for 3,4-diaminopyridine (Also see "Catalyst Stumbles With Filing Of Controversial 'Breakthrough Therapy' Firdapse" - Pink Sheet, 17 Feb, 2016.).

Immune Response Keeps Remune Momentum Going After CR Letter

Immune Response Biopharma has already "filed a response with the FDA with its intention to cure the deficiencies in its application" for approval of its therapeutic HIV vaccine Remune, the company reported in its Feb. 13 announcement of an FDA complete response letter.

The CR letter "was expected," Immune Response added in a Feb. 18 earnings release. The Remune application stumbled in its original filing, which earned a "refuse-to-file" letter from FDA in early March 2015. It took the company only a few weeks to address the agency's concerns, and FDA accepted the BLA resubmitted on March 27, 2015 for review.

In July, Immune Response disclosed its voluntary agreement to a boxed warning in labeling specifying that Remune must be taken in conjunction with highly active antiretroviral therapy (HAART) regimens (Also see "Keeping Track: Two New BLAs, Two Line Extensions And One Advisory Committee" - Pink Sheet, 13 Jul, 2015.).

At least some of the issues in FDA's CR letter may be related to manufacturing of the vaccine, which is based on inactivated HIV-1 virus particles from a Zairean strain of the virus. Immune Response "will request an extension of time to address the main issues of the CRL including sufficient time required for manufacturing of Remune to move the HIV vaccine towards approval," the company stated.

Is Zetia/Vytorin CR Letter A Sign Of Stricter FDA Stance On CV Outcomes Claims?

Merck announced Feb. 15 that FDA issued a complete response letter for supplemental new drug applications supporting a claim for its cholesterol absorption inhibitor Zetia (ezetimibe) and Vytorin, which combines Zetia with the statin simvastatin, in reducing cardiovascular events (CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or need for revascularization) in patients with coronary heart disease.

Merck said in a statement that it is “reviewing the letter and will determine next steps,” but declined to provide any further details about the content of the letter or its plans (Also see "FDA’s Zetia/Vytorin Rejection Leaves Cholesterol Drug Sponsors In Limbo" - Pink Sheet, 16 Feb, 2016.).

The commercial impact of the CRL on Merck is limited, given that Vytorin and Zetia are poised to face generic competition at the end of 2016 under a deal with Glenmark Pharmaceuticals Inc.

The CRL nonetheless suggests the importance of well-designed outcomes trials for future sponsors. FDA has traditionally approved hypercholesterolemia drugs on the basis of LDL cholesterol measurements as a surrogate for cardiovascular outcomes, but a series of trial failures has raised uncertainty in the field (Also see "LDL Hypothesis Brings Out Skeptics, Supporters At FDA Panel" - Pink Sheet, 25 Jan, 2016.).

Merck's sNDAs were based on data from the 18,000-patient IMPROVE-IT trial, where adding Zetia to statin therapy resulted in a statistically significant 6% reduction in risk. But the data did not hold up well to scrutiny. FDA's advisory committee, which voted against approval, questioned missing data, the modest benefit and differences in effects for various subgroups in the IMPROVE-IT study (Also see "IMPROVE-IT Study: Negative Panel Review Leaves FDA With Tough Choice" - Pink Sheet, 21 Dec, 2015.).

(The Complete Response Letters chart on the FDA Performance Tracker contains information on products receiving action letters from the agency.)

FDA Extends Gilead Harvoni Labeling In HCV Patients With Advanced Liver Disease

Gilead Sciences Inc.'s Harvoni (sofosbuvir/ledipasvir) earned a competitive edge over competing hepatitis C therapies from Merck and AbbVie Inc. with FDA's Feb. 16 approval of expanded labeling claims in patients with advanced liver disease.

The new language adds patients with genotype 1 HCV infections and Child-Pugh B or C disease (decompensated or later-stage cirrhosis) to the labeling for the fixed-dose combination pill. In addition, labeling now includes genotype 1 or 4 patients who have had a liver transplant and either are non-cirrhotic or have compensated (early-stage) cirrhosis, also known as Child-Pugh A disease. In both cases, the new language specifies a 12-week regimen of Harvoni combined with ribavirin (Also see "Harvoni Gains More Differentiation With Updated Labeling" - Pink Sheet, 16 Feb, 2016.).

Gilead noted that Harvoni now is the first HCV drug approved for genotype 1 liver transplant recipients with compensated cirrhosis. It also is the first endorsed for a 12-week course of therapy in genotype 4 liver-transplant recipients with compensated cirrhosis. More importantly, Harvoni is now explicitly approved to treat HCV-infected patients with decompensated cirrhosis, a population that is contraindicated for Merck's Zepatier and AbbVie's Viekira Pak.

FDA Clears The Way For Rosuvastatin Zinc

FDA granted tentative approval to a 505(b)(2) NDA for rosuvastatin zinc, an alternative salt version of the blockbuster statin Crestor, on Feb. 12, clearing the way for launch on May 2, 2016 under a settlement of patent litigation between Watson Laboratories Inc. (later Actavis, now Allergan PLC) and Crestor sponsor AstraZeneca. Crestor's patent exclusivity expires 67 days later, on July 8, 2016.

Watson filed the rosuvastatin zinc NDA on July 16, 2010. While FDA issued a tentative approval on Aug. 4, 2011, AstraZeneca filed a patent infringement suit arguing that the zinc salt formulation acts substantially the same way as the metal ions in the rosuvastatin salts claimed in the Crestor patent – litigation that was scuttled by the settlement in 2013 (Also see "Crestor Patent Settlement Allows Actavis Generic Entry In May 2016" - Pink Sheet, 25 Mar, 2013.).

FDA issued a complete response letter for the rosuvastatin zinc application on Nov. 13, 2013, which the sponsor responded to on August 13, 2015.

Allergan has agreed to sell its generic drug business, primarily made up of the former Watson and Actavis businesses, to Teva Pharmaceutical Industries Ltd. in a deal that the companies hope will close in April (Also see "Teva’s Allergan Generics Buy Progressing, Though Timeline Might Slip" - Pink Sheet, 11 Feb, 2016.).

(For more information on pending applications and recent approvals, see the User Fee Goal Dates chart on the FDA Performance Tracker.)