Duchenne Muscular Dystrophy Drug Sold Amid Controversy

Nancy A. Melville

March 22, 2017

Marathon Pharmaceuticals, facing intense criticism for putting what some lawmakers called an "obscenely high" $89,000-per-year price tag on deflazacort (Emflaza), recently approved for Duchenne muscular dystrophy (DMD), and additional controversy over the drug's approval, has announced the sale of all rights to the drug to PTC Therapeutics, of Southfield, New Jersey.

The announcement, made March 16, came a day after Sen. Bernie Sanders (I-VT) and Rep. Elijah Cummings (D-Md) filed a letter  with the US Food and Drug Administration (FDA), further blasting the price and demanding answers regarding the various "unusual circumstances" under which the drug was approved.

Families have been able to import the drug from overseas, where it is sold by Sanofi under the name Calcort, for approximately $1000 per year or less, but under the FDA's controversial orphan drug designation, Marathon was granted a monopoly on the drug for 7 years.

In an open letter posted on the company's website last month, Marathon CEO Jeffrey Aronin explained that the price reflected the investment in the clinical trials that were required for the FDA approval process, which was the same as for any new drug, despite its long being available outside the country, in addition to funding future research.

"The resources we invested were substantial and we don't expect to recoup our investment for several years and we have only seven years of market exclusivity," he writes.

But, as underscored in the lawmakers' letter to the FDA (and reported by Medscape Medical News), the phase 3 clinical trials that were used in the approval were in fact more than 20 years old — conducted in 1995, and not by Marathon.

"Is it standard practice for FDA to rely on 20-year-old efficacy data, and if so, how many times has this happened in the last 15 years?" Sen. Sanders and Rep. Cummings asked.

"If this is not a standard practice, is Emflaza'a approval an exception?"

They added that since the 1995 study was conducted, originally by the University of Rochester and funded by Marion Merrell Dow, there have been numerous mergers and acquisitions of companies overseeing the data.

"Given this lengthy chain, what evidence did Marathon present to FDA regarding the integrity of the decades-old efficacy trial data?" they asked.

The congressmen further take issue with the approval of the brand name, Emflaza, to a compound that no longer had patent protection or market exclusivity in the United States. "How many times has the FDA taken such a step in the last 15 years?" they asked.

The Orphan Drug Act was designed with the important mission of encouraging companies to invest in medications that are of high need in rare diseases that will likely involve only small numbers of patients.

But the case with deflazacort represents a troubling trend in companies taking advantage of the law, Daniel J. Berlau, PhD, an associate professor in the School of Pharmacy at Regis University, in Denver, Colorado, told Medscape Medical News.

"I believe the Orphan Drug Act has been successful, but companies are now learning how to 'game the system,' " he said. 

"Marathon invested a small fraction of (the $800 million typically required to develop a drug) in order to get deflazacort approved and now they have the ability to recoup costs that they never incurred.

"This is a company taking advantage of a loophole in the system, at the cost of the patient and their insurer."

Under the deal with PTC, Marathon is reportedly selling the drug for $140 million in cash and stock, with the stock sale expected to give Marathon up to a 15% to 20% stake in PTC.

Amid the storm of protest over the price hike, Marathon had delayed the drug's launch.

PTC Therapeutics has not yet announced how much the company plans to charge for the drug, but in a conference call to investors, the company's chief executive, Stuart Peltz, reportedly suggested a change is being considered.

"We're re-examining the current price of Emflaza.... We believe a change needs to be had, but...it's really too premature to speculate on the price level," Peltz told Reuters.

DMD, a rare and fatal genetic disorder estimated to occur in about 1 in every 3600 male infants worldwide, causes progressive muscle weakness beginning in early childhood, later resulting in heart and respiratory failure leading to premature death.

The clinical trials submitted for the deflazacort FDA approval showed improvements with deflazacort in muscle strength compared with placebo after 12 weeks, which was maintained at week 52. Patients also showed greater delays in the loss of the ability to walk compared with placebo.

Prednisone and other corticosteroids are also used in the treatment of DMD; however, the Marathon data for the FDA approval did not show comparisons with other corticosteroids.

Some research has shown increases in survival with deflazacort at 5 and 15 years' follow-up, and the drug is associated with significantly less weight gain compared with prednisone.

Deflazacort is the first FDA-approved steroid for DMD in patients aged 5 years and older.

PTC Therapeutics isn't new to DMD — outside of the United States,  the company sells the drug ataluren (Translarna), which treats a small subset of patients with nonsense mutations, making up about 13% of patients with DMD.

In a New Drug Application for ataluren with the FDA last year, however, PTC was told its application was not sufficiently complete for review. The company has since submitted another application.

Despite the rarity of DMD, deflazacort isn't even the only DMD drug approval causing controversy.

The first drug to be approved by the FDA for DMD, eteplirsen (Exondys 51, Sarepta Therapeutics), approved as recently as September 2016, also raised significant criticism, with many, even some within the FDA, questioning the strength and reliability of the evidence for the approval, as reported by Medscape Medical News.

Eteplirsen, like PTC's ataluren, also would treat only about 13% of patients with DMD: those with mutations of the dystrophin gene amenable to exon 51 skipping. Sarepta has announced that their drug will have an even heftier price tag than deflazacort — $300,000 per year.

Dr Berlau has disclosed nor relevant financial relationships.

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