Catalyst Pharmaceutical Partners Inc.says it is working with FDA on a path for resubmitting its orphan disease drug Firdapse after receiving a “refuse-to-file” letter for an application submitted in December, and notes that there has been no judgment about the drug’s safety or efficacy.

The company announced on Feb. 17 it had received a refuse-to-file letter for the drug in two indications, both ultra-rare neuromuscular disorders: Lambert-Eaton myasthenic syndrome (LEMS) and Congenital myasthenic syndromes (CMS).

In the US, Firdapse (amifampridine phosphate) has orphan drug designation for treating LEMS, which is a rare autoimmune, neuromuscular disorder characterized by progressive muscle weakness of the limbs. Catalyst estimates some 3,000 people have LEMS in the US. In August 2013, FDA designated the drug as a breakthrough therapy for LEMS (see sidebar).

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The drug also has orphan drug status for CMS, a rare neuromuscular disorder with a spectrum of genetic defects, characterized by weakness of skeletal muscles. The size of the eligible patient population in the US with this condition ranges from 1,000 to 1,500, according to the company.

Catalyst started a rolling NDA for the drug in July 2015 and completed an NDA for both indications in December. The company had requested priority review, which would have meant a user fee date of Aug. 17 ([A#00151221015]).

Instead, the company announced the refuse-to-file (RTF) letter, news that sent the stock down by 37% to a close of $1.16 on Feb. 17.

FDA indicated the filing was not “sufficiently complete, and requests additional supporting information,” Catalyst explained in a statement.

“The letter does not provide comment on the acceptability of the submitted clinical data, and no judgment is made in the letter on the efficacy or safety of Firdapse,” the Coral Gables, Fla.-based biopharma said.

Catalyst declined to provide further comment.

A Controversial Compound

Amifampridine phosphate is a potassium channel blocker that increases the release of acetylcholine, in order to help muscle cells receive nerve signals.

Catalyst licensed North American rights to Firdapse in October 2012 from BioMarin Pharmaceutical Inc.[See Deal]. BioMarin had received clearance in 2010 to market the drug in Europe for LEMS under exceptional circumstances, meaning that there is incomplete evidence supporting use because the disease is rare Also see "BioMarin Launches Firdapse In Germany And The UK" - Pink Sheet, 22 April, 2010..

The drug has proven controversial given that amifampridine (3,4-diaminopyridine, or 3,4-Dap) had been around for decades, though in a different formulation, and not officially approved and marketed. Pricing proved controversial in some European markets and BioMarin reported only $11.6m in sales for the first nine months of 2015, down from $14m in 2014.

In the US, the drug reportedly has been available on a compassionate use basis for free since the 1990s from Princeton, N.J.-based Jacobus Pharmaceutical Also see "FDA To Facilitate 4-AP Compassionate Use INDs For MS, Axelrad Says" - Pink Sheet, 24 July, 2000..

The pharma industry as a whole has increasingly come under criticism for increasing the prices of old drugs for rare diseases, either by securing exclusivity through the Orphan Drug Act for a new FDA-approved formulation, as was the case with KV Pharma/Lumara Health Inc.’s Makena (hydroxyprogesterone), or by taking advantage of the lack of competition amongst generics on the market, as was the case with Turing Pharmaceuticals AG’s Daraprim (pyrimethamine) ([A#14151204002]).

In the case of amifampridine, the issue is exclusivity granted through the Orphan Drug Act.

The delay gives some time for critics to make their case about the risk for losing access to a well-established treatment.

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.

University of Virginia’s Ted Burns and colleagues noted that in Europe, the drug was priced at $60,000 a year, up from $1,600 a year, and that investor presentations with sales projections suggest an even higher price could be in store for the US.

The neurologists acknowledged that pricing of “some FDA-approved drugs under the ODA may be justified by the substantial investor risk and research and development costs incurred by the pharmaceutical company in preclinical and clinical development. However, 3,4-DAP is not a newly discovered molecule, nor is it expensive to manufacture; thus, it differs dramatically from some innovative drugs now in or coming to the market. It has been reported to be effective and safe since 1983,” they added.

A dramatic price increase could have a negative impact on patient access and adherence, the editorial stated.

The safety and efficacy of both a base formulation from Jacobus and a phosphate salt formulation from Catalyst have been demonstrated in prospective trials, the authors pointed out.

“We encourage the FDA to carefully evaluate the relative evidence for each formulation of 3,4-DAP and, if appropriate, to consider approving both for use in the US,” they urged.

Catalyst Stumbles With Filing Of Controversial 'Breakthrough Therapy' Firdapse

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