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FDA Approves a Second Orphan Drug for LEMS. Then It Is Promptly Sued by a Rival Drug's Maker

Article In Brief

Catalyst and Jacobus Pharmaceuticals have now had their drugs approved for LEMS—one for adults, another for children, respectively. But Catalyst is suing the Food and Drug Administration and other federal agencies for its decision to approve a rival drug in children.

First it was free, then it cost $375,000 per year, and now it's available for half that price. But how much the treatment for Lambert-Eaton myasthenic syndrome (LEMS), a rare neuromuscular disorder, will cost in the future may depend on the resolution of a lawsuit brought on June 12 against the Food and Drug Administration (FDA).

The FDA had approved amifampridine (Firdapse) for LEMS in adults in November of 2018. The manufacturer of that drug, Catalyst Pharmaceuticals, Inc., filed the lawsuit over the FDA's decision on May 6 to approve another drug for LEMS, a rare neuromuscular disorder, in children. The Catalyst suit charges that the FDA illegally approved the second drug in response to political pressure over the high price that Catalyst set for amifampridine.

For more than 25 years, the only medical treatment available for LEMS patients was 3,4-diaminopyridine (3,4-DAP), also known as amifampridine. Jacobus Pharmaceutical, a small, family-owned firm in New Jersey, manufactured the drug and distributed it to physicians, who had to obtain an Investigational New Drug waiver to prescribe it. With fewer than 300 patients receiving the drug, and the cost of making it relatively low, Jacobus chose to distribute it free rather than pursue the expensive process of obtaining FDA approval beyond its investigational status.

Then, in 2012, Catalyst obtained the US rights to amifampridine phosphate, the salt formulation of the drug, which was already being sold in Europe. After Catalyst began funding clinical trials of its drug in pursuit of full FDA approval, Jacobus launched a trial of its own free-base formulation of amifampridine (Ruzurgi).

Following the FDA approval last year, Catalyst began selling its drug in January this year at $171.40 per tablet, or $375,000 per year for a patient taking 60 mg per day. Soon after, Senator Bernie Sanders challenged the company to explain the high price of the drug, calling the price “not only a blatant fleecing of American taxpayers, but...also an immoral exploitation of patients who need this medication.”

On May 6, the FDA took the unusual step of approving the Jacobus drug for the same disorder. The Jacobus drug was not approved for adults, which would have violated Catalyst's exclusivity under the Orphan Drug Act rules; rather the FDA approved it for pediatric patients ages 6 to 17. Given that neurologists can prescribe the Jacobus drug off-label to adults, the move was widely seen as a way to allow a lower-priced alternative onto the market.

On June 11, Jacobus announced that it would price its drug at $80 per tablet, just under half the price of the Catalyst drug.

The next day, Catalyst filed its suit against the FDA.

The Lawsuit

The lawsuit by Catalyst names not only the FDA but also its Acting Commissioner, the US Department of Health and Human Services (HHS) as well as Alex Azar, Secretary of HHS. It notes that while 1,500 patients have been diagnosed with LEMS in insurance claims data, only 15 of those patients are known to be children under 17.

The Jacobus-supported clinical trials used to gain FDA approval for its formulation in children, the suit observes, included only adults.

Without a clinical trial involving children, the very population for which its use has been approved, “Jacobus also appears to lack sufficient clinical testing and other data for Ruzurgi to be lawfully approved under the full new drug approval process,” the suit alleges.

What's more, by making reference to clinical trials involving adults, the labeling for the Jacobus drug illegally encourages off-label use, Catalyst charges. “No drug approved only for adults can suggest or imply in its labeling that the drug is safe and effective for use in children, or vice versa,” the suit states.

Ultimately, Catalyst argued, “FDA's actions are, in fact, facilitating ‘off-label’ marketing by Jacobus.”

In an interview with Neurology Today, Patrick McEnany, the chief executive officer and co-founder of Catalyst, said he was shocked by the FDA's approval of the Jacobus drug after his firm spent the funds necessary—“over a hundred million dollars,” he said—to test and gain approval of its drug.

“We spent real money to get this to market,” he said. “We assumed that when we got approved that we would have our seven-year exclusivity, and it wasn't going to be diluted by an approval for a pediatric indication when the sponsor didn't even have clinical trial data to support that indication.”

Rather than serve only the LEMS patients to whom Jacobus is giving the drug free of charge, McEnany said his company's goal from the start was to greatly expand the market. “We concluded that Jacobus was providing drug to about 200 patients on a compassionate-use basis,” he said. “I'm proud to say that within the past four months, there are now 400 patients on [Firdapse], about a hundred of whom were totally naive to any form of 3,4-DAP.”

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“I think we have to be careful in how we criticize the pharmaceutical industry. The problem is really with the policymakers. Companies behave the way they do given the policies in place.”—DR. SAMI L. KHELLA

But according to Laura Jacobus, a co-owner and daughter of the company's founder, Jacobus was in fact giving the drug to “about 288” patients when it was forced to stop doing so at the end of December. And the company has provided the drug for free to about 300 patients with congenital myasthenic syndromes.

In a written response to questions from Neurology Today, she defended the evidence Jacobus provided to the FDA in its New Drug Application for its drug.

“Our NDA was supported by two double-blind placebo-controlled trials and 25-plus years of safety data from the compassionate distribution program,” she said. “In addition to providing our drug product to pediatric patients, we undertook a pharmacokinetic modeling study to support the pediatric indication. Given the small numbers of pediatric patients living with LEMS, the [pharmacokinetic] modeling afforded a robust methodology to ensure correct dosing strategies.”

The family-owned company, she said, was able to support its compassionate-use distribution of 3,4-DAP over the years by selling two other drugs: Dapsone 25 mg and 100 mg tablets, and PASER (aminosalicylic acid) granules.

“We have estimated that between the development costs [of 3,4-DAP] initiated in 1990, NDA and compassionate distribution, we have invested approximately $60 million dollars,” Jacobus stated. “We have between $15 and $20 million dollars in post-approval commitments. It was always our intention to seek FDA approval. It is important for us to charge for the product to sustain the company.”

Questions About LEMS Prevalence

Catalyst has estimated that there are between 1,500 to 3,000 LEMS patients in the United States, a figure that has come into question, given that Jacobus was giving the drug to just 288 patients.

According to McEnany: “We bought insurance claims data and saw that there were about 1,500 unique LEMS patients during a two-year time that doctors had treated.” What's more, he added, the true number of LEMS patients might be twice as high. “We do believe about half the population is misdiagnosed or totally undiagnosed,” he said.

In her written statement to Neurology Today, Jacobus gave a far lower estimate of the total number of LEMS patients in the United States. “We believe that there are less than 500 patients with LEMS,” she said.

An epidemiologic review of the US Veterans Affairs population, published in 2017, sheds light on the matter. The study found that on a single day in 2013—September 30—there were 15 confirmed and four probable cases of LEMS out of 5,724,096 VA patients, for a point prevalence of 2.6 per million adults. Applying that figure to the total adult population of the United States in 2013 would mean that about 700 people were being treated for LEMS on any given day in 2013. But if “probable” and “indeterminate” cases were included, the point prevalence reached 5.5 per million, or about 1,500 adults in the United States. And that is just for the one-day point prevalence. Over the four-year span of the study, between October 1, 1999 and September 30, 2013, a total of 48 patients were being treated for LEMS, about triple the number for the single-day prevalence.

The study also found that only 18 of those confirmed 48 cases of LEMS were being treated with 3,4-DAP. “Given that 3,4-DAP was not approved during the study period,” the study noted, “recipients had to receive the medication through either investigational new drug (IND) holders or compounding pharmacies. This at least partially explains why only a minority...of patients receive the drug despite its benefit.”

One other finding of the study was noteworthy, in light of the FDA's approval of Ruzurgi for a pediatric indication: The mean age of symptom onset in the VA population was 60 years old, with an age range from 43 to 80 years old.

Where Neurologists Stand

Back in 2016, more than a hundred neuromuscular specialists from 59 universities and medical systems across the United States published an editorial in the journal Muscle & Nerve expressing their concerns about the possible cost of the LEMS drug if it were approved by the FDA under the Orphan Drug Act (ODA).

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“To suggest they are serving patients while charging $375,000 per year for a product that was free up until the Firdapse approval defies belief. Unfortunately they are just the latest of a number of companies to take advantage of this loophole in the ODA.”—DR. A. GORDON SMITH

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“Over the years, when I would lecture medical students about LEMS, I would tell them that 3,4-DAP was being given free by the drug company, and that it was an exception to how drug companies usually operate. So I had this sort of bias toward Jacobus. In addition, I thought the study they did for the FDA was as good as you could possibly do in patients who had already been taking the drug for years.”—DR. DAVID RICHMAN

“What is particularly troubling to us,” the editorial stated, “is a ‘loophole’ in the ODA that allows companies to receive FDA market exclusivity under the ODA for older, existing drugs, such as 3,4-DAP.”

With the Catalyst drug then priced at $60,000 per year in parts of Europe, the editorial expressed concern that the company might sell it here for as much or more. “We encourage a revision of the ODA,” the editorial concluded, “to close the loophole that permits pharmaceutical companies to exploit market exclusivity of existing, inexpensive compounds for which they did not provide significant developmental investment.”

While all three of the neurologists who spoke with Neurology Today for this article were co-signers of the 2016 editorial, they expressed a range of views on Catalyst's pricing of the Catalyst drug.

“I think we have to be careful in how we criticize the pharmaceutical industry,” said Sami L. Khella, MD, FAAN, professor of clinical neurology and chief of the department of neurology at Penn Presbyterian. “The problem is really with the policymakers. Companies behave the way they do given the policies in place.”

Obtaining 3,4-DAPS from Jacobus under its compassionate-use program required any neurologist, including Dr. Khella, to obtain an IND from the FDA.

“The paperwork was onerous,” he said. “It's going to be much easier for physicians now to just write a script for the drug.” He also pointed out that the salt formulation of the drug, sold by Catalyst, is stable at room temperature, whereas the original formulation, sold by Jacobus, needed to be refrigerated.

Because he also treats patients with the muscle-specific kinase (MuSK) subtype of myasthenia gravis, for which 3,4-DAPS is being investigated, Dr. Khella is participating in a clinical trial using Firdapse.

Even so, he said, “What I think is going to happen is that people are going to use the Jacobus drug off-label to give it to adults with LEMS, or even to MuSK patients if the Catalyst trial turns out to be positive. People are going to use it off-label the way we use drugs off-label all the time.”

A. Gordon Smith, MD, FAAN, a neuromuscular specialist who is chair of neurology at the Virginia Commonwealth University School of Medicine, offered a contrasting view of Catalyst's entry into the LEMS market. “Catalyst did not go into this with patients' best interest in mind,” he said. “They clearly intended to monetize a nearly identical formulation of 3,4-DAP to that provided for free by Jacobus for decades. To suggest they are serving patients while charging $375,000 per year for a product that was free up until the Firdapse approval defies belief. Unfortunately they are just the latest of a number of companies to take advantage of this loophole in the ODA.”

David P. Richman, MD, FAAN, distinguished professor of neurology at the University of California, Davis, said he treats between five to ten LEMS patients, some of whom entered the randomized trial that led to the FDA's approval of Ruzurgi.

“Over the years,” Dr. Richman said, “when I would lecture medical students about LEMS, I would tell them that 3,4-DAP was being given free by the drug company, and that it was an exception to how drug companies usually operate. So I had this sort of bias toward Jacobus. In addition, I thought the study they did for the FDA was as good as you could possibly do in patients who had already been taking the drug for years.”

Disclosures

Dr. Richman has received funding for a sponsored research agreement with Cabeletta Bio, Inc. Dr. Khella owns stock in Catalyst. Dr. Smith has received consulting and speaking fees from Alexion Pharmaceuticals, Inc., consulting fees from Disarm Therapeutics, and chairs the data and safety and monitoring board for Regenesis Pharmaceutical Inc.

Link Up for More Information

• Shieh P, Sharma K, Kohrman B. Amifampridine phosphate (Firdapse) is effective in a confirmatory phase 3 clinical trial in LEMS https://journals.lww.com/jcnmd/fulltext/2019/03000/Amifampridine_Phosphate__Firdapse__Is_Effective_in.2.aspx. J Clin Neuromuscul Dis 2019; 20(3): 111–119.
    • Sanders DB, Juel VC, Harati Y, et al; for the DAPPER Study Team. 3,4-diaminopyridine base effectively treats the weakness of Lambert-Eaton myasthenia https://onlinelibrary.wiley.com/doi/full/10.1002/mus.26052. Muscle Nerve 2018; 57(4): 561–568.
      • Burns TM, Smith GA, Allen JA, et al. Editorial by concerned physicians: Unintended effect of the Orphan Drug Act on the potential cost of 3,4-diaminopyridine https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.25009. Muscle Nerve 2016; 53(2):165–168.
        • Abenroth DC, Smith AG, Greenlee JE, et al. Lambert-Eaton myasthenic syndrome: Epidemiology and therapeutic response in the national veterans affairs population https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.25520. Muscle Nerve 2017;56(3):421–426.