Monday, September 19, 2016

Eteplirsen revisited

The US Food and Drug Administration (FDA) has granted accelerated approval to eteplirsen injection (Exondys 51, Sarepta Therapeutics), the first drug approved to treat patients with Duchenne muscular dystrophy (DMD).

Eteplirsen is specifically indicated for patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13% of the roughly 9000 to 12,000 people with DMD in the United States.

"Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval," Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, said in the statement.

The road to approval for eteplirsen has been rocky. In late April, as reported by Medscape Medical News, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee concluded that studies of eteplirsen failed to provide persuasive evidence that the drug is effective in DMD.

But the vote was close. Three panel members felt that substantial evidence was provided to support eteplirsen as effective for treating DMD, compared with 7 who didn't and 3 who abstained. Some panel members acknowledged that the public speakers — 52 of them during the day-long proceedings — were compelling and that there is a profound unmet need for boys with DMD. In late May, the FDA deferred a decision on eteplirsen.

DMD is a progressive, debilitating, and ultimately fatal inherited X-linked neuromuscular disease caused by mutations of the dystrophin gene that disrupts the mRNA reading frame, resulting in a lack of dystrophin. Eteplirsen was developed to cause "skipping" of exon 51 in mRNA, which could increase production of a truncated but partially functional dystrophin protein. 

The accelerated approval of eteplirsen is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some patients treated with the drug.

"The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping," the agency said.

A clinical benefit of eteplirsen, including improved motor function, has not been established, and Sarepta Therapeutics is required to do a clinical trial to confirm the drug's clinical benefit.

Specifically, the trial will assess whether eteplirsen improves motor function of patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug, the agency said. 
The most common side effects reported by patients taking eteplirsen in clinical trials to date were balance disorder and vomiting.



  1. Yesterday, the Food and Drug Administration made history, approving a drug to treat Duchenne muscular dystrophy that works by targeting the genetic mutation at the root of the disease.

    The decision was unique for reasons that were not just scientific. Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research, overruled the protests of her own staff to approve the drug. One of her division’s top officials appealed the ruling, and the agency’s chief scientist largely backed his conclusions, saying that “by any meaningful objective standard” the medicine is unlikely to improve patients. But the FDA’s commissioner, Robert Califf, decided not to overturn Woodcock’s decision, citing Woodcock’s long record of independence and arguing that her differences with other FDA scientists were a matter of honest scientific disagreement, and the decision was within Woodcock’s authority.

    The news is an unmitigated win for Sarepta Therapeutics, the biotechnology company that developed the drug, now known as Exondys 51 or, generically, eteplirsen. Sarepta shares increased 74% to almost $49, giving the company a market capitalization of $2.5 billion. Last night, on a conference call with investors, the company said that it expected to charge $300,000 per patient per year for Exondys 51, with the exact dosage being determined by weight. The company, which might have folded with a rejection, will now have money to fully test Exondys and other, similar drugs for Duchenne...

    “The moment I saw eteplirsen received approval, I broke down, I cried,” says Josh Argall, a network technician whose 15-year-old son has Duchenne caused by the gene Exondys 51 targets. “When my son was diagnosed 12 years ago a lot went through my mind that I wouldn’t be able to do with him. I felt as though some of our future was taken away. Today, it was given back and man, I couldn’t be more thankful.”

    But for the FDA, the decision represents a civil war that could have unknown reverberations. Ronald Farkas, the FDA reviewer charged with reviewing the Exondys new drug application, has already left the agency to take a job in industry. The contention between Woodcock and Ellis Unger, who is in charge of reviews of heart, kidney, neurology and psychiatric drugs, are sharp.

    And some outside experts are already arguing that Unger was right. Eric Topol, chief academic officer at Scripps Research Institute in La Jolla, Calif., says the decision is “compromising reasonable approval standards.” Walid Gellad, an associate professor of medicine at the University of Pittsburgh who frequently serves on FDA panels tweeted: “Let me summarize: a drug the FDA says has no clinical benefit will cost four times as much as a drug that cures hepatitis C.” (continued)

  2. (continued)From the start, the Sarepta story has been a strange case. It was incredibly expensive to make–in small batches probably costing $100,000 per patient, analysts say–and the company was strapped for cash. So it did a small study of 14 patients. Two of those patients were not evaluable, but in the rest something surprising seemed to happen: those that got Exondys 51 from the start of the study seemed to do much better than those who had a delayed start on the drug. More enticingly, the boys (because the genetic defect that causes Duchenne is on the X chromosome, it is a disease of boys) seemed to be showing marked increases in dystrophin, the protein that is missing in the disease.

    Based on these results, Sarepta filed with the FDA. It was likely the smallest pivotal study in FDA’s modern history. The FDA now says that it implored Sarepta to run a placebo-controlled study with more patients, but the company argued that it would be impossible to get Duchenne patients to enroll given the already positive results. But the FDA’s reviewers–in particular Farkas–did not believe the study results. They said the differences between boys who got the drug at the beginning of the trial and those that had to wait could be due to chance, as could what advocates said was the overall tendency of all the boys to do better than expected.

    Worse, the FDA had issues with the way Sarepta had tested dystrophin. After the FDA’s April advisory committee voted that the drug should not be approved, the FDA and Sarepta agreed to look at one more set of data points: Samples would be taken from patients to see if their dystrophin levels increased after 48 weeks of treatment. It was possible to get data from 12 of those patients. When the dystrophin data were produced the FDA would make a decision within four days, per an agreement made by Woodcock and agreed to by Unger.

    But when the data came in on June 27, they disappointed even Woodcock, according to a review of the facts presented by Luciana Borio, the FDA’s Acting Chief Scientist. The data showed an increase of only 0.28% of normal levels, which was, on average, a tripling of dystrophin levels for these boys. But Unger and the reviewers argued that, based on comparisons of different types of muscular dystrophy, an increase beyond 10% of normal would be needed to have a clinical impact on muscular dystrophy symptoms.

    Unger wanted to ask Sarepta to test the current dose of Exondys 51 against a much more frequent dose of the drug before approving the medicine. If the more frequent dose was more effective, the drug could then be approved. Woodcock, despite the disappointing data, wanted to grant accelerated approval right away.

    “By allowing the marketing of an ineffective drug, essentially a scientifically elegant placebo, thousands of patients and their families would be given false hope in exchange for hardship and risk,” Unger wrote in his protest. “I argue that this would be unethical and counterproductive. There could also be significant and unjustified financial costs–if not to patients, to society.”

  3. (continued)At the end of the day, Woodcock, Unger, Borio and Califf all wound up agreeing on many key points: that Sarepta’s studies were flawed and difficult to interpret; that early versions of the Sarepta data as released were misleading; that both the FDA and Sarepta stumbled at multiple points along the way; and that, at the end of the day, Sarepta’s drug showed only a minimal amount of dystrophin was produced. The disagreement is on one point: was this tiny increase in dystrophin enough to merit approving the drug, even on a conditional basis?

    Woodcock decided the answer was yes, and, for the first time in her eight-and-a-half-year term as director of the FDA’s drug division, overruled her scientists and decided to approve the drug, saying that she wanted to use “the greatest flexibility possible for FDA while remaining within its statutory framework.”

    Borio, the FDA’s Acting Chief Scientist, sided with Unger. “By any meaningful objective standard, however, the overall evidence derived from eteplirsen’s limited clinical development program does not support that the levels of dystrophin produced by eteplirsen at the doses studied are reasonably likely to provide a clinical benefit.”...

    Califf’s memo asserts that this decision should not be seen as precedent. But it will. Companies will spend more on lobbying, and more on supporting patient groups as a result. They will also try to push through drugs with minimal data. The decision also will demoralize FDA staff–imagine being told your boss could push you around even more. It would have been better if he had grappled with the data instead of throwing up his hands and standing on procedure...

    At least this decision sets up a clear path for testing whether Exondys works: A more frequent dose (the FDA suggests daily dosing) should clearly outperform the currently approved dose, or the FDA will yank the drug. The agency, after taking such a big risk, will have to follow through on yanking the drug if that trial, due in 2020, is not positive. That gives Sarepta, or whoever buys it, three years to marshal its evidence.

    Courtesy of Doximity

  4. The newly approved Sarepta Therapeutics drug for Duchenne muscular dystrophy will cost about $300,000 a year for the average patient in the United States, which is less than what some Wall Street analysts had expected.

    Sarepta CEO Dr. Edward Kaye said the pricing was “in the middle of the range” for rare disease drugs. “And given the sensitivity to pricing, we tried to be reasonable when looking at all the costs,” he said on a phone call Monday with securities analysts.

    Pricing is, indeed, a sensitive topic. The cost of prescription drugs is now a potent source of outrage across the country as Americans respond to companies that buy old medicines and jack up prices, take hefty price hikes each year, and set higher floors for the cost of new and innovative treatments.

    Rare disease drugs are defined as treatments for a disease with fewer than 200,000 patients in the US. The average annual cost per patient for such medications rose to $112,000 from $84,000 between 2010 and 2014, according to EvaluatePharma, a research firm.

    Kaye argued that Sarepta attempted to address pricing concerns while setting the cost for the drug, which will be called Exondys 51. He cited, for instance, the research and development costs the company has so far incurred, as well as future costs for additional trials, some of which are required by regulators.

    One advocate agreed. “Considering the cost of manufacturing, delivering, and supporting patients [with financial assistance programs], not to mention development costs over a decade, I don’t think it’s too much,” said Debra Miller of CureDuchenne, an advocacy group that also invests in drug makers.

    The cost is comparable to a cystic fibrosis treatment sold by Vertex Pharmaceuticals, suggesting the price is not out of line, according to Dr. Walid Gellad, the codirector of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.

    However, Gellad also noted that Food and Drug Administration reviewers found the Sarepta drug did not demonstrate a clinically meaningful benefit for patients.

    “Whether it’s $300,000 or $400,000, there are so few patients [with Duchenne] that payers will be able to pay,” he told us. “But what will they pay for?”

    Sarepta executives would not disclose further details surrounding pricing, but did say that the cost will vary a bit depending upon patient weight and that payer reimbursement is expected to start kicking in somewhere between 30 and 90 days.
    Courtesy of Doximity

  5. Miceli MC, Nelson SF. The case for eteplirsen: Paving the way for precision medicine. Mol Genet Metab. 2016 Jun;118(2):70-1.

    Eteplirsen (Sarepta Therapeutics), a phosphoramidite morpholino sequence complementary to a portion of exon 51, is designed to force the exclusion of exon 51 from the mature DMD mRNA. This drug is relevant for approximately 13% of the DMD population harboring specific DMD mutations. Similar drugs targeting other DMD exons are under development and could theoretically restore reading frame in up to 80% of patients. The fact that these drugs rely on specific sequence information and target the proximate cause of the disease make this one of the first examples of precision genetic medicine.

    The promise of personalized medicines is enormous, particularly for rare disease. However, their approval relies on the application of regulatory tools designed to specifically empower the FDA to use flexibility in approvals for severely debilitating rare disease with unmet need, like Duchenne. Thus, DMD exon skipping trials are drawing considerable attention from the drug industry, rare disease advocates, patients, physicians and scientists...

    The three year, and the now four year, data make a compelling case that there is substantive evidence of effectiveness, which seems in stark contrast to conclusions reached in the FDA Briefing Document. This has prompted a group of 36 leading Duchenne experts to provide written commentary to clarify several issues while the FDA deliberates on the approval of eteplirsen. This expert commentary, in the form of a letter, was sent to the Director of the Division of Neurology Products, CDER. The signatories include leaders in DMD biology, therapy development, patient care and natural history.

    In considering whether disease progression in the eteplirsen treated boys is substantially deviating from the expected disease course, the group of Duchenne experts comments “The collective signatories note that the group of 12 eteplirsen treated boys, even accounting for daily deflazacort usage or twice-weekly prednisone, is clearly performing better than our collective clinical experience and the published literature would predict. Collectively, a portion of us represent a group of physicians who have observed over 5,000 DMD patients in our practices over an average of more than 15 years. Published external natural history data and our clinical experience strongly support that the 12 boys treated for over 4 years show a milder clinical progression, likely due to a positive treatment effect of eteplirsen.”

    The group of Duchenne experts also considered whether the drug showed any convincing evidence of dystrophin protein induction. The letter states “In considering that eteplirsen promotes on average 0.93% of normal control levels of dystrophin (range 0%-2.47%), concentrated within an average of 16% “dystrophin positive” fibers (range 1.4%–33.5%), it is reasonable to expect that levels of dystrophin expressed in some positive fibers could be as high as 5–12% of normal; levels clearly predicted to impart some, albeit incomplete, protection of myofibers from contraction induced damage. We conclude that the findings of this trial are sufficiently robust to support the proposed mechanism of action of eteplirsen, to provide a plausible explanation for the relative gain in function observed within the treatment group, and serve to bolster confidence that there is a positive treatment effect.”

  6. Kesselheim AS, Avorn J. Approving a Problematic Muscular Dystrophy Drug: Implications for FDA Policy. JAMA. 2016 Oct 24. doi: 10.1001/jama.2016.16437. [Epub ahead of print]

    Despite this innovative mechanism, the development of eteplirsen was controversial, starting with its manufacturer-supported pivotal double-blind study, which involved only 12 patients: 8 were randomized to 2 different eteplirsen doses and 4 were randomized to placebo for 24 weeks. The latter were then switched to eteplirsen and all were to be followed for an additional 24 weeks. The sample size was substantially smaller than the study sample size in which a similar DMD drug, drisapersen, had been tested in 3 randomized trials that together enrolled 290 patients. The FDA declined to approve drisapersen in 2015 after these studies showed no clear benefit after 24 weeks in prespecified clinical end points, such as changes in a 6-minute walk test. Those trials also suggested the possibility of safety problems, including renal toxic effects and thrombocytopenia…

    In the eteplirsen study, by contrast, the primary trial end point was a surrogate measure: an increase in the presence of dystrophin in muscle biopsy specimens. Serial biopsies were performed at 12, 24, and 48 weeks, although biopsies were performed on only half the treated patients at each of the 12- and 24-week periods; all 12 patients were receiving drug treatment by week 48. The biopsy specimens were analyzed by scientists blinded to the patients’ group assignments but not blinded to the time receiving treatment. In a 2013 publication, the authors reported increases to about 50% of normal in dystrophin-containing fibers in the biopsy specimens, results that were met with enthusiasm by the DMD community.

    However, these results were based on an immunohistochemical assay that assessed only an increase of newly produced dystrophin compared with baseline values. Quantitative Western blot analysis of a fourth biopsy performed in 11 of the study patients after 3 to 3.5 years of continued open-label extension showed an actual increase to only a mean (SD) of 0.9% (0.8%) of normal dystrophin levels, far less than what might be expected to provide clinical benefit. A more rigorous, fully blinded reanalysis of the immunohistochemical assay organized by the FDA cast further doubt on the initial results. (continued)

  7. (continued)The trial also assessed clinical progression. At 24 and 48 weeks, there was no consistent advantage in the 6-minute walk test capacity of patients who received eteplirsen compared with those initially given placebo. However, new post hoc calculations excluded 2 eteplirsen-treated patients who deteriorated quickly while receiving therapy; these analyses suggested a statistically significant advantage for the remaining treated patients. These more selective post hoc analyses were highlighted in the figure displaying this finding in the 2013 article2 and in the manufacturer’s press release announcing the success of the trial. Subsequent evaluation of 6-minute walk test data over 3 to 3.5 years of open-label therapy appeared to be associated with slower rates of decline when compared with a historical cohort, but the problematic nature of historical controls complicated the interpretation…

    After the meeting, the FDA delayed its decision and requested additional data, including Western blot assays from biopsy specimens in 13 patients from another ongoing study at week 48. These data showed a mean increase in dystrophin to just 0.2% to 0.3% of normal. In September 2016, another reason for the delay was revealed—disagreement within the FDA about the approval decision. The main FDA scientific reviewers all opposed approval, but Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, overruled them, suggesting that the extremely small increase in dystrophin might conceivably translate to clinical benefit. She indicated that considering the life-threatening nature of the disease and the lack of reasonable alternative treatments, the FDA should exercise “the greatest flexibility possible” under its statutory authority in considering eteplirsen’s efficacy.

    The drug was thus approved, and the manufacturer was told to conduct a randomized trial to “verify [sic] the clinical benefit of eteplirsen,” with a deadline of May 2021 for submission of its results. A placebo group was not required (although it would be difficult to recruit patients to a placebo-controlled trial of an approved drug), and accordingly, without a true control, it is not clear how the results regarding drug efficacy will be assessed. Barring a major unexpected safety problem, it is unlikely that the new study could provide sufficient evidence leading to removing eteplirsen from the market.

    Eteplirsen represents another case in which the FDA used a surrogate measure (in this case muscle dystrophin levels) as the basis for approval. However, the accelerated approval pathway through which eteplirsen was authorized requires that a surrogate end point must be reasonably likely to predict clinical benefit of the drug,6 and this standard is challenged by the minimal changes seen in the dystrophin levels. Speeding drugs to market based on such biomarker outcomes can actually lead to a worse outcome for patients, even those with life-threatening diseases, if a product confers no meaningful benefit and carries a risk of adverse effects and a high cost. Immediately after approval, the manufacturer announced a price of $300 000 per year for eteplirsen. This approach also unfairly penalizes manufacturers that pursue a more rigorous course of development using more clinically relevant end points, while rewarding competitors that submit trials that have less evidence supporting efficacy.

    Courtesy of a colleague

  8. Sarepta Therapeutics, Inc. (NASDAQ: SRPT), a commercial stage developer of innovative RNA-targeted therapeutics, today announced it has entered a research agreement with Nationwide Children’s Hospital on their microdystrophin gene therapy program. Jerry Mendell, MD and Louise Rodino-Klapac, PhD, are the lead principal investigators of the program.

    “Given the complexities of Duchenne muscular dystrophy, we know it is going to it require multiple treatment approaches,” said Edward Kaye, Sarepta’s chief executive officer. “With that goal in mind, we are excited to support the trial for the Nationwide Children's gene therapy program with the goal to help all boys with DMD.”

    The initial trial, expected to go into Phase 1/2a trial in late 2017, will be conducted at Nationwide Children’s. Parent Project Muscular Dystrophy (PPMD) has committed 2.2 million dollars to the trial, with support from additional Duchenne foundations and families. Sarepta will also provide support to the trial through a separate research agreement with Nationwide Children’s, and will have an exclusive option to license the program. PPMD's grant provided incentive for Sarepta to help expand and accelerate this opportunity.

    “We are thrilled Sarepta has entered into this research agreement with Nationwide Children's Hospital. The additional resources will bolster Nationwide Children's ability to conduct an even more rigorous and robust trial,” said Pat Furlong, founding president and chief executive officer of Parent Project Muscular Dystrophy.