Shares of Catalyst Pharmaceuticals Inc. tumbled 37.3 percent Wednesday after the Coral Gables, Fla-based firm disclosed a refusal to file (RTF) letter from the FDA for its new drug application (NDA) for rare disease drug Firdapse (amifampridine phosphate). While RTFs are infrequent and usually only delay – rather than derail – regulatory approvals, the timing of Catalyst's letter is interesting for a couple of reasons.

For one, it comes late in the agency's administrative review. The FDA has 60 days following submission to accept or reject an application. Catalyst completed its rolling NDA in mid-December, seeking approval of Firdapse for Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS) and requesting priority review for the breakthrough-designated drug.

At "this stage in reviewing the NDA for acceptance, the most likely feedback is a request for additional supportive information or a technical issue with the application," said Piper Jaffray analyst Charles Duncan, who projected in a research note a six-month to 12-month delay.

Catalyst has not disclosed specifics from the RTF, stating that the agency deemed the submission insufficient and requested additional information, but noted that the letter provided no comment on the acceptability of the clinical data included in the NDA, "and no judgment is made in the letter on the safety or efficacy of Firdapse." Company executives declined to comment further but plan to request a meeting with the agency as soon as possible.

The RTF also comes at a time when the drug pricing debate has reached a fever pitch in the media and become a presidential campaign issue. Since acquiring North American rights from Biomarin Pharmaceutical Inc. in 2012, Catalyst has come under fire for its plans to seek premium orphan drug pricing for Firdapse, a modified version of a drug that has been available for two decades to patients for free under an FDA expanded access program.

Jacobus Pharmaceuticals Inc., a small, family-owned pharma manufacturer based in New Jersey, has been producing its formulation of 3,4-diaminopyridine – according to Catalyst, a less stable version compared to Firdapse that requires refrigeration – but has not sought FDA approval. Should Catalyst's drug clear the FDA, its orphan status would give it seven years of marketing exclusivity, potentially knocking the Jacobus drug out of the market.

Shareholders weren't thrilled, either, when they discovered the availability of Jacobus' drug. Catalyst agreed to pay $3.5 million in 2014 to settle a class action lawsuit alleging that the firm failed to disclose the existence of the biological equivalent to Firdapse that was free of charge through a compassionate use program.

Whether the pricing issue has anything to do with the RTF remains speculation for now, but Piper Jaffray's Duncan doesn't view it as all bad for Catalyst. He acknowledged that the "current political climate, with close public examination of orphan drug approvals and prices, may be contributing to a high level of scrutiny by the FDA, which is not a bad idea in the long run."

In fact, Duncan continued, "We'd actually argue that a rigorous FDA process could represent an eventual positive for Firdapse in terms of competitive dynamics and franchise value."

Catalyst – along with Biomarin, which already markets Firdapse in Europe – has pointed to the positive efficacy data for the drug, as well as data from a cardiac safety study requested by the FDA that showed Firdapse had no effect on heart rate or cardiac depolarization when given at and above therapeutic levels. (See BioWorld Today, Jan. 9, 2014.)

The company already has been investing in its commercial infrastructure. LEMS, a rare autoimmune disease is primarily characterized by debilitating muscle weakness, is estimated to affect about 3,000 people in the U.S. CMS, a rare neuromuscular disorder characterized by fatigable weakness of skeletal muscles, with onset usually shortly after birth or early childhood, is believed to affect between 1,000 and 1,500 patients in the U.S.

Catalyst has not yet released its fourth quarter financials. The firm ended the third quarter with about $63 million on its balance sheet, "which we believe is sufficient to fund Firdapse through approval, even with the anticipated delays," Duncan wrote.

Shares (NASDAQ:CPRX) closed Wednesday at $1.16, down 69 cents.

GAUGING THE DELAY

RTFs can refer to anything from an administrative or formatting problem in the application to missing information to a request for additional data, so trying to gauge what sort of delay Catalyst faces is tricky.

Some firms have managed to turn around resubmissions quickly. Gilead Sciences Inc., for instance, which received an RTF for its application for HIV combo drug Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) in January 2011, managed to refile a month later and gain approval in August of that year. And Acorda Pharmaceuticals Inc. won approval for multiple sclerosis drug Ampyra (dalfampridine) within about 10 months of receiving an RTF. (See BioWorld Today, April 1, 2009, Jan. 25, 2010, Jan. 26, 2011, and Aug. 12, 2011.)

Sanofi SA unit Genzyme earned an RTF in 2012 for Lemtrada (alemtuzumab), a drug it had previously sold as Campath for cancer but developed with new dosing for multiple sclerosis. While the letter did not ask for additional data or further studies, the resubmission for Lemtrada failed to sway the agency, which rejected the drug on first review in 2013 but finally granted approval in November 2014, more than two years after the RTF. (See BioWorld Today, Aug. 28, 2012, and Nov. 18, 2014.)

It was two and a half years from RTF to approval for partners Roche AG and Immunogen Inc., which received a surprising RTF in 2010 for breast cancer drug Kadcyla (trastuzumab emtansine), with the agency suddenly arguing the drug did not meet the standard for accelerated approval. Roche was forced to complete the phase III program before refiling. (See BioWorld Today, Aug. 30, 2010, and Feb. 25, 2013.)

And a few drugs never managed to make it over the regulatory hurdle. Pharmacyclics Inc. pushed for approval of cancer drug Xcytrin (motexafin gadolinium), despite the fact that it had failed two phase III trials. After an RTF, Pharmacyclics resubmitted its application by filing over the agency's protest, after which the FDA predictably delivered a not approvable letter on the drug. Xcytrin was later deprioritized in favor of other programs, namely BTK inhibitor Imbruvica (ibrutinib), which drew a $21 billion buyout bid from Abbvie Inc. last year. (See BioWorld Today, Feb. 22, 2007, and March 3, 2008.)

Gene therapy candidate Advexin also failed to progress. Developer Introgen Therapeutics Inc. never revealed the reasons for the 2008 RTF, and the firm filed for bankruptcy before it was able to address or appeal the FDA's decision. (See BioWorld Today, Sept. 3, 2008.)

Though it is approved in Europe, leukemia drug Ceplene (histamine dihydrochloride) has failed to win over U.S. regulators, with a 2010 RTF. That letter was unusual in that it actually required developer Epicept Corp. to conduct an additional pivotal study. Ceplene, however, might not be dead in the U.S. yet. Epicept later merged with Immune Pharmaceuticals Inc., which earlier this month filed a patent application for using drug in combination with immune checkpoint inhibitors to treat acute myeloid leukemia. (See BioWorld Today, Aug. 24, 2010.)

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