Catalyst Pharmaceuticals Inc. turned the commercial corner with FDA approval, on its PDUFA date, of Firdapse (amifampridine phosphate) 10-mg tablets as the first drug designated in the U.S. to treat adults with Lambert-Eaton myasthenic syndrome (LEMS).

The Coral Gables, Fla.-based company said Firdapse, a potassium channel inhibitor, will be launched in the first quarter. Catalyst scheduled a call for Dec. 13 to disclose pricing and commercialization plans, declining additional comment.

Details notwithstanding, H.C. Wainwright analyst Andrew Fein presumed the approval should "clear [the drug's] historical overhang," with the FDA's formal nod officially settling the race between Catalyst and privately held Jacobus Pharmaceutical Co. Inc. The latter's formulation of 3,4-diaminopyridine (3,4-DAP) for LEMS has been distributed under compassionate use investigational new drug applications for about five years, according to Cortellis Competitive Intelligence.

"With this approval, we think Firdapse should have a first-to-market, seven-year exclusivity period to prevent any compounding of the same drug by Jacobus, and the focus should shift to commercialization," Fein wrote in a first take.

Approval of Firdapse in LEMS, a rare autoimmune disease, is vindication of sorts for Catalyst, which in February 2016 faced an even rarer refuse to file (RTF) letter from the FDA late in the review cycle of the new drug application (NDA). The RTF also came at a time when noise around drug pricing was reaching a fever pitch in the run-up to the 2016 U.S. presidential campaign.

In 2012, Catalyst had acquired North American rights to Firdapse in all indications from Biomarin Pharmaceutical Inc. At the time, Biomarin, of Novato, Calif., agreed to invest $5 million in Catalyst while retaining rights to Firdapse in the rest of the world. Once Catalyst had North American rights to Firdapse, the company made no secret of its plans to seek premium orphan drug pricing for its modified version of a drug that had been freely available to patients for two decades under the FDA expanded access program. (See BioWorld Today, Feb. 18, 2016.)

Jacobus, a family-owned pharma manufacturer based in Princeton, N.J., had advanced its formulation of 3,4-DAP into phase II but never published data or sought FDA approval. Instead, the company continued to make the drug available to individuals with LEMS and congenital myasthenic syndrome (CMS) by way of expanded access. Catalyst shareholders demanded redress when they discovered the Jacobus drug was available free of charge through its compassionate use program. In 2014, Catalyst agreed to pay $3.5 million to settle a class action lawsuit alleging that it failed to disclose the existence of the biological equivalent to Firdapse.

With its orphan drug status, approval of Firdapse – which also garnered FDA breakthrough therapy designation and priority review – seemingly knocks the Jacobus candidate out of the market.

In the meantime, two months after the RTF, Catalyst disclosed that the FDA wanted to see positive results from an additional phase III study of Firdapse in individuals with LEMS before accepting the NDA, along with several short-term toxicology studies. (See BioWorld Today, April 27, 2016.)

Catalyst shares plunged, and in May 2016 the company slashed its work force by 30 percent to conserve cash.

By midyear, the company had reached agreement on the phase III design under a special protocol assessment with the FDA. The double-blind, placebo-controlled withdrawal trial, initiated in November 2016, enrolled 26 participants, with Quantitative Myasthenia Gravis (QMG) and Subject Global Impression (SGI) scores – the same as the initial phase III in LEMS – as co-primary endpoints. The FDA also allowed Catalyst to enroll patients from its expanded access program as participants in the second phase III, which was conducted in a parallel, rather than crossover, design.

Last year, Catalyst reported that the trial achieved statistical significance for both primary endpoints; the QMG achieved a "p" value of 0.0004 while the SGI achieved a "p" value of 0.0003, with a clinically significant difference of 6.4 points observed between the Firdapse and placebo groups for the QMG endpoint. A prospectively defined secondary endpoint of Physician's Clinical Global Impression of Improvement also achieved statistical significance (p=0.0020), as did several exploratory endpoints.

Together, the two phase III trials enrolled 64 adults across study drug or placebo. The most common (>10 percent) adverse events reported in trials were burning or prickling sensation, upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. The drug is contraindicated in individuals with a history of seizures.

Price could top $200,000 per year

Presumably, setbacks are now in the rearview window for Catalyst, where CEO Patrick McEnany issued a statement calling approval of Firdapse "a crowning achievement for our company and an important step forward in our transition into a premier neurological rare disease company."

During the company's third-quarter earnings call earlier this month, McEnany outlined steps that were underway to prepare for commercial launch of Firdapse in LEMS. They included the rollout of Catalyst Pathways, the company's patient assistance program, to assist individuals with LEMS and their physicians with disease education, clinical diagnosis and assistance in navigating the reimbursement landscape. The program is available to patients currently on Firdapse or 3,4-DAP therapy for LEMS, who will be "seamlessly transitioned to commercially available Firdapse," McEnany said.

In June, Catalyst picked up Dan Brennan as chief commercial officer. During six years at Lundbeck U.S., where he served as vice president and group general manager of the neurology division, Brennan oversaw the commercial launch of four drugs to treat rare neurological diseases. He subsequently hired former Lundbeck colleagues Jason James as senior vice president of operations and analytics at Catalyst and Jeff Del Carmen as the company's senior vice president of sales and marketing. On the earnings call, Brennan said Catalyst planned to hire a field force of 12 sales reps to cover the U.S. market plus a handful of patient access managers.

Catalyst also is accelerating studies of Firdapse to treat MuSK antibody-positive myasthenia gravis, CMS and spinal muscular atrophy type 3. To that end, in August the company hired Stanley Iyadurai, most recently global clinical program director for clinical R&D at CSL Behring, as vice president of clinical development.

In addition, Catalyst is moving to file for approval of Firdapse in Canada, and the company is working to develop a longer-acting formulation of the drug, which is dosed three to four times a day due to its short half-life.

The moves cheered Wainwright's Fein, who concluded they should "ready the company for commercialization."

On the third-quarter call, McEnany also ruminated on factors that Catalyst was weighing to set the price for Firdapse, which Fein speculated could top $200,000 per year. In doing so, McEnany clearly sought to put the specter of Jacobus to rest.

"We think that, obviously, one of the major keys is an FDA-approved therapy," giving "all patients affordable access to Firdapse, which is not the case today," he said. Based on company estimates and anecdotal information, only 250 to 300 patients currently have "what I'll call early access to Firdapse or 3,4-DAP therapy," he said, in the context of an addressable market of about 3,200 LEMS patients in the U.S., by Fein's yardstick.

The other 90 percent "don't have access because their doctor doesn't want to participate in an investigator IND program because of all of the required paperwork," McEnany said. "Patients don't want to have to travel to referral sites 300, 400, 500 miles to see a doctor to get drugs."

Approval would change that dynamic, he maintained, as physicians could simply write a script "and patients will have drug delivered to their house."

He acknowledged that reimbursement approval from payers could take 30 to 90 days following approval but said Catalyst Pathways would help ensure "that all patients have affordable access to the drug, minimal copays and minimal out-of-pocket expenses."

Catalyst also is banking on the clinical attributes of the drug, designed to provide dramatic improvement in quality of life and activities of daily living for individuals with LEMS, most often characterized by progressive limb muscle weakness. In approximately 50 percent of cases, LEMS is associated with an underlying malignancy, most often small-cell lung cancer, and is sometimes the first symptom of such malignancy.

"Those are sort of the cornerstones for which we use to build our value proposition, regardless of where we price this product," McEnany said.

With a small orphan market, and the expanded access program, Catalyst should be able to penetrate the market quickly – two to three years by the company's estimate, Fein noted.

"A label add-on of CMS could expand the addressable market to include another ~1,000-1,500 CMS patients in the U.S., and the approval of the MuSK indication could add another ~3,000-4,800 patients to Firdapse's market," he wrote. "Due to the similarity between [mechanism of action] for these neuromuscular diseases, we view the risk for these programs as reduced due to the recent LEMS win."

The consensus five-year sales forecast is approximately $434.1 million, according to Cortellis.

Perhaps awaiting more details, investors were less sanguine. On Thursday, Catalyst shares (NASDAQ:CRPX) retreated early and remained lower in heavy trading, finishing at $2.77 for a loss of 36 cents, or 11.5 percent. Volume of some 11.1 million shares was more than eight times the company's three-month moving average.

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