Friday, March 27, 2015

FDA Hard-Pressed to Approve Biomarin, But Not Sarepta Drug

When Biomarin late last year bought Prosensa for its experimental exon skipper drisapersen for the treatment of Duchenne Muscular Dystrophy (for $680M plus potential milestones), it exuded confidence about the likelihood of getting approval for the 2’-O-methyl phosphorothioate antisense molecule.  This, despite of the fact that drisapersen failed in a pivotal phase III trial of 186 patients which prompted the old partner GSK to dump the drug and walk away.

Tenuous early evidence for drisapersen in earlier trials

The confidence is largely based on some supposedly successful earlier trials, especially a multi-center, randomized, blinded 53-patient phase II study which had seen improvements in the 6 minute walk distance (6MWD) at week 25, the primary endpoint of the study (Voit et al. 2014).  

This, however was statistically significant only the case in the subgroup of patients that received drisapersen continuously (à treatment in 10 out of 10 weeks with 6mg/kg), but not in patients which were treated identically, except for the small difference in skipping the last week in a 10-week treatment cycle.

At week 49, the difference with placebo failed to reach statistical significance and Prosensa had to resort to pooling both subgroups to claim victory for that time point. Similarly, drisapersen failed in obtaining statistically significant outcomes for other muscle function endpoints.

Since the mechanism of action for the DMD exon skipping candidates is to change splicing of the mutated dystrophin transcript to a form in which the reading frame is restored with recovery of partial activity, it is important to understand the relationship between drug treatment and dystrophin production.

Here, too, the evidence was less than robust.  For example, even when applying the sensitive immunofluorescence technique, no increase or even a decrease in dystrophin was seen in almost half of treated subjects.  With the less sensitive Western blot, an increase in dystrophin was seen in only a third of treated subjects (0 for placebo).

Therefore, given the failed phase III trial and the less than robust earlier evidence in favor of the drug, I struggle to understand Biomarin’s confidence in obtaining approval in 2016.   

The importance of dystrophin as a surrogate endpoint

Part of the difficulty of obtaining statistically significant results for muscle function endpoints is most likely due to the small patient size (orphan disease affecting ~1 in 3500 male births) and the consequent need to pool boys at various stages of the disease together in a given trial.  It would thus not be surprising if say obtaining 10% levels of normal or Becker-type dystrophin will translate into very meaningful clinical benefit in some, but not other boys.

This will be an even more challenging problem for the DMD subgroups that are not amenable to exon 51-based exon skipping which is targeted by drisapersen.  Probably insurmountable for first-generation chemistries like drisapersen.

Accordingly, in both the drisapersen and the competitive PMO-based eteplirsen trials, it has not been possible to correlate dystrophin production with functional outcomes.

For that reason, I strongly support the importance of establishing reliable, quantitative methods to measure dystrophin in clinical trials (there was an FDA workshop related to this last week).  Dystrophin-dependent markers may also be acceptable if they can be measured by means that do not involve taking painful muscle biopsies.  For example, serum-based microRNAs as developed by Rosetta Genomics and Marina Biotech would be of interest here.

Eteplirsen before drisapersen

I thus find it difficult to grasp the notion of rejecting the current crop of exon skippers like drisapersen or eteplirsen should they be found to produce functional dystrophin with few side effects.  After all, it is the loss of dystrophin function that causes Duchenne Muscular Dystrophy and one has to wonder how generating additional dystrophin cannot be beneficial to patients, especially since the principle behind drisapersen and eteplirsen is strongly supported by human genetic evidence (à Becker’s Muscular Dystrophy).

In this world, it has got to be eteplirsen that should be first in line for regulatory approval.  This is because there is overwhelming evidence (e.g. Heemskerk et al., 2009; Sarepta's Barclays presentation March 12, 2015) that the PMO-based drug is much more potent than drisapersen which, let’s face it, is based on stone-age antisense chemistry (2’-O-methyl phosphorothioate).  Such chemistry is characterized by minimal efficacy and dose-limiting toxicities, especially renal in the case of drisapersen.

In a paper comparing 2’-O-methyl to PMO chemistry for DMD exon skipping conducted by researchers close to eteplirsen, it was found that at same doses in mice, PMO chemistry is moderately to vastly more potent than 2’-O-methyl phosphorothioate antisense compounds of a size comparable to drisapersen.  The extent of the difference depended on whether the human or mouse dystrophin were targeted and the target sequence.   Unsurprisingly given the acrimonious competition between the two parties, Sarepta has also picked up on this and continued along these lines by showing that in addition to chemistry, eteplirsen has the edge over drisapersen in terms of the targeted sequence:

Sure, there is the theoretical caveat that PMO and 2’-O-methyl scale differently from mice to humans and that what is the most potent target sequence for one chemistry does not necessarily have to be the most potent one for the other.  Intuitively, however, the differences are too big for these factors to compensate the preclinical evidence.  Also, keep in mind that in the clinic, eteplirsen is being given at 5 to almost 10-fold increased doses than drisapersen and, on top of that, is much safer and better tolerated than drisapersen.

Because of this and the competition, it is not surprising and disingenuous when Biomarin would now suddenly like to de-emphasize the importance of dystrophin as a surrogate biomarker (see last week's workshop).

Dear regulatory agency, if you approve drisapersen, you cannot deny eteplirsen.  Sure, drisapersen has been tested in more patients than eteplirsen and Sarepta has conducted a clinical trial in the worst possible manner and probably ‘embellished’/overstated some of their results, including the dystrophin evidence.  However, given that eteplirsen almost certainly generates more dystrophin than drisapersen, the highly favorable side effect profile of eteplirsen (also in comparison to drisapersen), and in light of the 6MWD issue that applies to both drug candidates, the question is whether the bureaucratic application of rules should trump scientific evidence and patient interests.

Disclosure: I am long SRPT based on the notion that Biomarin, with its orphan disease savvy, will turn out to be the biggest supporter of eteplirsen getting approval this time around.  Additionally, the agency is partly responsible for the long duration of the ongoing eteplirsen trial (close to 4 years soon) and the repeated taking of muscle biopsies, and after all this taking away hope from patients and their close ones is difficult to fathom.


Anonymous said...

Sarepta's 12 patient Phase II trial was not conducted in the worst possible manner. It was smartly designed in light of poor finances and small drug supply. Importantly, this trial was designed to inform the company, not achieve FDA approval.It has become crystal clear that the 30 NT MO is vastly superior to the 20 NT 2'-OM PT in every way you compare them. And FDA got it when they approved Sarepta's open label Ph III studies. Still there's risk left in the program, and your new-found love for SRPT may be tested by their uncertain executive and regulatory skills.

Anonymous said...

not going to happen. SRPT study too small and not controlled. they need to confirm results in a larger study. Hopefully they can do that by early 2016

Anonymous said...

Eteplirsen before drisapersen. The FDA needs to get their heads out of their butts and approve Eteplirsen. People should have the choice to take this medication without being told no when it does work If anyone at the FDA had family members with DMD they would've already approved it.

Anonymous said...

These are rare disease drugs so whoever is first on market has exclusivity, unless second drug has advantage in safety and/or efficacy. So FDA may approve both but better drug has to be approved second.

GB said...

"not going to happen. SRPT study too small and not controlled. they need to confirm results in a larger study. Hopefully they can do that by early 2016"

This response shows a clear lack of due diligence and understanding of the facts. The SRPT study most certainly had a control group. Those kids were switched over to taking Eteplirsen after 24 weeks but not before it was apparent that a STATISTICALLY SIGNIFICANT increase in dystrophin had been produced. This person should learn the facts before polluting with information that is patently false.

Anonymous said...

FDA panelist confirms conflict of interest following Sarepta drug discussions

Dr. Eric Hoffman, a member of the FDA panel, confirmed the disclosure oversight during in an email to the BBJ. Hoffman was one of several speakers at the all-day workshop, and he submitted a signed disclosure form saying he had no financial affiliation “in the past three years with any products or firms relevant to the discussions on the development of assays or therapeutics that involve dystrophin.”

Contacted by the Boston Business Journal this weekend, Hoffman acknowledged he is a co-founder of two firms that have developed a method of measuring dystrophin based on mass spectrometry. That approach is different from a competing method used by Sarepta, called immunofluorescence, over the past three years.

In an email to the Boston Business Journal, Hoffman acknowledged that he should have disclosed his association with those two firms — Hoffman is founder and vice-president of Agada Biosciences, a company whose technologies help measure dystrophin, and is CEO of ReveraGen, which is developing a drug to treat Duchenne — and attached a revised disclosure form which he says he sent the the FDA.

While Hoffman was one of 17 people who spoke at the workshop, he was one of just five who were on a panel toward the end to sum up take-aways for the day, according to the FDA’s webcast of the meeting. Indeed, at one point, he responded to a question from the FDA moderator about whether mass spectrometry measurement — the preferred measurement approach used by Hoffman's commercial interests — ought to be included in measuring dystrophin by saying, “maybe a next step would be to identify a couple labs in the country that were able to run (mass spectromety analysis) ... you still need a relatively good mass spec.”

Anonymous said...

Why we should care that an FDA panelist forgot to disclose conflicts of interest

The news that a participant at a recent Food and Drug Administration panel failed to disclose his financial conflicts of interest ahead of time has raised a slew of question over the past 24 hours. One of those is: Why should people care?

A brief synopsis: Yesterday, I broke the news that Eric Hoffman, a doctor at Children’s National Medical Center, failed to disclose his involvement in two companies prior to being in the workshop. The workshop itself addressed how best to measure a protein called dystrophin, and could play a big role in approval of a drug by Cambridge-based Sarepta Theraputics (Nasdaq: SRPT). It’s dystrophin which is lacking in patients with Duchenne muscular dystrophy, and all three of the drugs soon to come before the FDA seeking approval all work by “fixing” the gene mutation that causes the body not to produce dystrophin.

Hoffman told me that he simply forgot to disclose his financial interest in the two companies, and that he since sent in a revised disclosure form. One may ask, what’s the big deal? Hoffman was just one of several speakers at the all-day workshop on March 20. The panel didn’t even make any formal decisions regarding approval of Duchenne drugs, and the FDA allows experts with financial ties to participate in such forums as long as they disclose those ties. And in the end, the panel didn’t even mention any of the three companies that expect to file for approval this year (besides Sarepta, there is BioMarin (Nasdaq: BMRN) and PTC Therapeutics (Nasdaq: PTCT).).
But here’s why it matters: The FDA has yet to respond in any way other than to say it is “looking into the allegations.”

Anonymous said...

Wide gap in reactions of patients vs. investors over Sarepta CEO exit

The reaction from the families of patients affected by Duchenne muscular dystrophy, however, who saw Garabedian as their champion, has been very different. "It's a huge loss,” said Christine McSherry, head of the Kingston-based nonprofit Jett Foundation. She said the patient community still supports the company's efforts to get the drug approved as soon as possible, but blamed the FDA for “moving the goalposts” (i.e., its requirements to consider approval), which undermined investor support for Garabedian.

“The FDA is really more at fault,” she said. “It’s a broken system. It’s a broken drug approval process. And they finally broke Chris.”

Anonymous said...

ALS patients press FDA for quick access to controversial biotech drug

Then in the fall, a small California biotech company named Genervon began extolling the benefits of GM604, its new ALS drug. In an early-stage trial with 12 patients, the results were “statistically significant,” “very robust” and “dramatic,” the company said in news releases.

Such enthusiastic pronouncements are unusual for such a small trial. In February, Genervon took an even bolder step: It applied to the Food and Drug Administration for “accelerated approval,” which allows promising treatments for serious or life-threatening diseases to bypass costly, large-scale efficacy trials and go directly to market.

ALS patients responded by pleading with the FDA, in emotional videos and e-mails, to grant broad access to the experimental drug. Online forums lit up, and a petition calling for rapid approval attracted more than a half-million signatures.

“Why would anyone oppose it?” asked ALS patient David Huntley in a letter read aloud in the past week at a rally on Capitol Hill. Huntley, a former triathlete, can no longer speak or travel, so his wife, Linda Clark, flew from San Diego to speak for him.

“This disease is evil,” Huntley wrote. “It doesn’t just kill you; it takes away everything that you care about, one at a time, then it kills you. Tell me how some as-yet-to-be-detected side effect is going to degrade my quality of life?”

Anonymous said...

Mark Veilleux: FDA needs to move quickly to save young lives

You might ask how do I know all this? My son Mark succumbed to this cruel and hideous disease on Sept. 30, 2013. Though most days I find it difficult to set my own two feet on the floor and get moving, I made a promise to him to help those afflicted with Duchenne enjoy a better life. Through Mark’s life and strength, my family found its own. We will continue to fight this disease so that others affected will have more of an opportunity to celebrate their own sons’ and daughters’ strength — one more day, then another, and another.

The Food and Drug Administration has made it clear it does not share our urgency. The FDA should be held accountable for its lack of action taken in not approving a drug called Eteplirsen. The FDA instituted its accelerated approval program to allow for earlier approval of drugs that treat serious conditions, and that meet three main criteria. The drug must treat a serious condition, address an unmet medical need, and be reasonably likely to lead to a clinical benefit. Eteplirsen meets all three.

For more than three years, a group of 12 boys have been enrolled in a clinical trial of Eteplirsen, an experimental therapy being developed by Sarepta Therapeutics of Cambridge.

During that trial, the drug has proven to be 100 percent safe; muscle biopsies have confirmed that all of the boys are now producing dystrophin, the missing protein that leads to Duchenne; and the study has consistently demonstrated dramatic improvement in mobility for boys on Eteplirsen when compared to those who are not being treated. Dr. Jerry Mendell, a pediatric expert at Nationwide Children’s Hospital in Columbus, Ohio, who is heavily involved with the trial stated the following: “Clearly it’s a breakthrough drug. It has minimal side effects. I say minimal, we haven’t seen a single one, which is incredibly remarkable, and we unequivocally showed efficacy over a two-year period, which is unheard of in clinical trials.”

Despite these very positive results, the FDA has not yet allowed the company to file a New Drug Approval (NDA), the first formal step in the FDA approval process.

The FDA has failed to provide consistent guidance to the company.

The FDA continues to inexplicably add requirements and delay the process — while boys with Duchenne continue to suffer, getting worse every day.

The FDA must be consistent and Congress must hold them accountable.

Anonymous said...

The push for an ALS drug, and why the FDA has such a tough job
In King’s eyes, the small trial size and short duration are not valid arguments for the FDA’s not allowing patients access to the drug, called GM604. The life expectancy for people with ALS is two to five years. Her symptoms emerged two years ago. In a very real sense, she has little to lose.
“If this drug is as promising as the clinical trials suggest it could save thousands of lives, including my own,” she told me. “The approval of the speedy release of GM604 by the FDA could be the only hope for many of us that have already been diagnosed with this awful disease have of survival.”
King is just one of 30,000 Americans who suffer from the disease. Another is Rob Letendre, a 63-year-old Ludlow, Masachusetts, resident who has a slow-progressing form of the disease which only affects his arms. He told me this week he just found out in the last year-and-a-half that he has the disease. While in his case the disease will probably not be fatal, he said he’s pushing for approval of GM604 for the sake of all the people half his age who will die, since the only drugs now available for the disease only extend a patients life for a couple months. He believes the Ice Bucket Challenge that swept the nation last year, raising awareness of the need for research on new drugs, could help convince the FDA to grant accelerated approval to GM604.
“I think the FDA is going to have to come out and bargain with the ALS community,” he said.
The ALS patients have an uphill battle, to say the least, to convince the FDA to approve a drug with such little data, especially considering it has as yet been reluctant to approve Sarepta’s Duchenne drug based on far more data. But talking to such patients would make anyone question the role of the FDA and its rules regarding drugs when it comes to deadly, rare diseases. Should the FDA judge drugs differently when there are no alternatives, and the disease will surely result in death otherwise? What’s the point of the FDA’s desire to make sure drugs for deadly diseases are “safe,” anyway?

Anonymous said...

After 13 years of wariness, FDA approves five potentially harmful new diet drugs

After 13 years of rejecting new diet drugs, the U.S. Food and Drug Administration has allowed five potentially harmful products on the market in the last three years — including two in the last four months.

The agency approved the drugs despite the potential for serious side effects — including suicidal thinking, increased heart rate and cancer risk — and no proof the drugs improve the main health concern posed by obesity: heart attacks and other cardiovascular problems.

Critics worry the new products will repeat the diet-drug mistakes of the past, which have led to decades of injuries, deaths and, in the end, products forced off the market.

The FDA’s about-face comes after pressure from the companies that manufacture the drugs, medical societies that get pharmaceutical company funding and even the U.S. Senate, which in 2011 called on the FDA to approve new obesity treatments.

A Milwaukee Journal Sentinel/MedPage Today investigation found diet-drug manufacturers paid at least $9 million to doctors to promote their products and to medical societies that advocate their use since 2013.

Those same companies also spent $51 million lobbying Congress and the FDA on a host of issues, including obesity, in the last five years, records show.

The Journal Sentinel/MedPage Today investigation found 3,000 cases in the FDA’s own “adverse event reports” system where drugs used as components in one of these new diet drugs were the “primary suspect” in a patient’s death.

Another 11,000 hospitalizations were reported with those drugs as the primary suspect.

The drug bupropion, part of the formula for Contrave, was the primary suspect in at least 1,500 patient deaths since 2004, according to the data. Phentermine and topiramate, the drugs used in Qsymia, were connected with a combined 670 deaths.
In an email, FDA spokesman Eric Pahon said the four weight-loss drugs were approved because the benefits were determined to outweigh the risks.

“All drugs carry risks of potential side effects,” he said. “Each drug is evaluated individually, and the decision whether to approve a drug must consider the balance of its benefits and the known risks for its intended use.”

well that says it all...recurring sales more important than life saving drugs for those with no time to spare.

Anonymous said...

Rally for Faster Drug Approval

We are people with ALS (PALS) and their families and friends and we're advocating faster drug approvals to treat ALS. With over 100,000 people dying from ALS every year, the conventional drug approval process (10-15 years) is too long!

Please join us to express your concern about the slowness of the FDA to utilize the "accelerated approval" program (AAP) to provide quicker access to promising new drugs, especially for fast-moving terminal illnesses.

Anonymous said...

"Scientists value prestige and security no less than anyone else, which inevitably fosters convergences of interests with political agendas that control where the money and jobs come from. And far from the least, scientists are members of a social structure with its own system of accepted norms and rewards, commanding loyalties that at times can approach fanaticism, and with rejection and ostracism being the ultimate unthinkable." J. P. Hogan

Anonymous said...

J&J Changes ‘Compassionate’ Care Independent panel to review requests from seriously ill patients for unapproved medicines

Amrit Ray, chief medical officer of J&J’s Janssen pharmaceuticals unit, said the setup should be easier for patients because the company is establishing a single website and toll-free hotline for requests, rather than the current patchwork of entry points across the company and its drug trials. Dr. Ray expects the committee could issue recommendations within days for urgent requests.

In its arrangement with NYU, J&J physicians will first see if a patient could be the subject of a clinical trial or some other early-access program. If not, J&J will forward the request to the independent panel for review. J&J said it is possible the company could decide differently, but it expects to take the committee’s advice. The patient would still have to get compassionate use clearance from FDA.

Arthur Caplan, the head of NYU School of Medicine’s division of medical ethics, who will oversee the new committee, said the panel would start slowly, focusing on a single, still-undetermined experimental drug and taking a few months to figure out criteria for making decisions. He said the goal was making sure each request is reviewed on its merits, rather than influenced by media campaigns or personal connections.

“Most people will have a fair shot by having a process that is really going to be hard to lobby and manipulate,” he said.

The Compassionate-Use Advisory Committee will report to NYU School of Medicine, but J&J will compensate the committee’s nine to 12 members and subsidize expenses such as travel and telephone fees, according to Dr. Caplan, who will serve as a nonvoting member and not receive a salary himself. J&J doesn’t charge patients for any unapproved drugs given for compassionate use.

Anonymous said...

Sarepta....for video.

Austin has been on drug 25 weeks. We saw undeniable benefit that shocked us both today

kid should not be able to do that...even the FDA should know that???????????????????

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