Stories
Slash Boxes
Comments

SoylentNews is people

posted by n1 on Thursday April 28 2016, @09:03AM   Printer-friendly [Skip to comment(s)]

A U.S. Food and Drug Administration advisory panel has recommended against the approval of Sarepta's eteplirsen, a drug intended to treat Duchenne muscular dystrophy (DMD). Two other experimental DMD drugs have already been rejected. The recommendation came despite the emotional testimony of children who had apparently seen improvements due to the experimental treatment. Representative Mike Fitzpatrick, R-Pa. also spoke on behalf of a constituent with DMD. However, concerns were raised about the small sample size of the trial:

"I am very sorry to say that approval of eteplirsen based on today's data would set a dangerously low bar for all drugs in the future," said Gottschalk, a senior fellow at the National Center for Health Research, a nonprofit in Washington, D.C. "Treatments for rare diseases can be proven on small samples, but not based on 12 patients in a poorly designed study with ambiguous results. These boys and their families deserve better."

The problem, FDA scientists said earlier in the day, is that, due to its small size and design, the study Sarepta submitted to the agency cannot prove that eteplirsen deserves credit for the boys' ability to remain on their feet. Although the company says dozens more boys are now taking the drug, its case with the FDA rests on only the study involving the 12 boys in the orange t-shirts. Except for the first 24 weeks, all of the boys in that study have been taking the drug. With no long-term placebo group, Sarepta chose to compare them to untreated boys from a registry of DMD patients. These types of studies tend to have more favorable results than studies that randomly assign participants to the active treatment or a placebo, Dr. Robert Temple, deputy director of the FDA office that evaluates nervous system drugs, told the advisory committee.

The advisory panel's 7-3 recommendation (with three abstentions) is not the final word on eteplirsen, but the FDA generally follows such recommendations. Sarepta's shares plummeted on the news.


Original Submission

Related Stories

Nonviral CRISPR-Gold Editing Technique Fixes Duchenne Muscular Dystrophy Mutation in Mice 2 comments

A new and non-viral approach to CRISPR has been used to treat Duchenne muscular dystrophy in mice:

A new version of the CRISPR-Cas9 gene-editing technology called CRISPR-Gold has successfully restored the correct sequence of the dystrophin gene in a mouse model of Duchenne muscular dystrophy (DMD), a new study revealed.

Researchers found that an injection of CRISPR-Gold into DMD mice led to an 18-times-higher correction rate and a two-fold increase in a strength and agility test compared to control groups, according to a press release.

The study, "Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair," [DOI: 10.1038/s41551-017-0137-2] [DX] was published in the journal Nature Biomedical Engineering.

[...] Unfortunately, methods of delivering the components of this system, which include an RNA molecule called a guide RNA, a protein called the Cas9 nuclease, and the correct DNA sequence to replace the mutation (via donor DNA), have not been fully developed for human use. A primary technique used to deliver the components of this system relies on viruses, but this technique is plagued by complications and unwanted side effects.

In response, researchers at the University of California, Berkeley have developed a new approach called CRISPR-Gold, which used gold nanoparticles to deliver the components of this system in a mouse model of DMD. This method works by using gold nanoparticles to coat a modified DNA molecule that binds the donor DNA, which in turn is bound to Cas9 and the guide RNA.

This entire system is then coated by a polymer that will interact with a cell membrane and allow entry into a cell. Then, the components of the system are released into the cell as the coat breaks apart upon entry. The guide RNA, the Cas9 nuclease, and the donor DNA can then make their way into the nucleus and correct the mutation.

Also at TheScientist.

Previously: FDA Panel Recommends Rejection of Duchenne Muscular Dystrophy Treatment
Marathon Pharmaceuticals is Part of the Problem
Marathon Pharmaceuticals Cashes Out on Regulatory Loopholes
What is a Muscle Protein Doing in the Brain?


Original Submission

CRISPR Used to Cure Duchenne Muscular Dystrophy in Dogs... by Further Damaging DNA 7 comments

Gene editing of dogs offers hope for treating human muscular dystrophy

Fighting fire with fire, researchers working with dogs have fixed a genetic glitch that causes Duchenne muscular dystrophy (DMD) by further damaging the DNA. The unusual approach, using the genome editor CRISPR, allowed a mutated gene to again make a key muscle protein. The feat—achieved for the first time in a large animal—raises hopes that such genetic surgery could one day prevent or treat this crippling and deadly disease in people. An estimated 300,000 boys around the world are currently affected by DMD.

The study monitored just four dogs for less than 2 months; more animal experiments must be done to show safety and efficacy before human trials can begin. Even so, "I can't help but feel tremendously excited," says Jennifer Doudna of the University of California, Berkeley, who heard the results last week at a CRISPR meeting she helped organize. "This is really an indication of where the field is heading, to deliver gene-edited molecules to the tissues that need them and have a therapeutic benefit. Obviously, we're not there yet, but that's the dream."

[...] The study offers little evidence that dogs regained muscle function, however, and that, coupled with the short duration of the study and the small number of animals studied, left some scientists less enthusiastic. One researcher in the tight-knit DMD field who asked not to be named wonders whether the study was rushed to help draw investment in Exonics Therapeutics, a Boston-based company Olson launched last year to develop the potential treatment.

[...] Another challenge was to alter billions of muscle cells throughout a living animal. So the team enlisted a helper: a harmless adeno-associated virus that preferentially infects skeletal muscle and heart tissue. Two 1-month-old dogs received intramuscular injections of the virus, engineered to carry CRISPR's molecular components. Six weeks later, those muscles were making dystrophin again. Those results led the researchers to give an intravenous infusion to two more dogs, also 1 month old, to see whether the CRISPR-carrying viruses could add the genome editor to muscles throughout the body. By 8 weeks, Olson told the meeting, dystrophin levels climbed to relatively high levels in several muscles, reaching 58% of normal in the diaphragm and 92% in the heart. But because the dogs were euthanized, Olson could show little evidence that they had avoided DMD symptoms, save for a dramatic video of a treated dog walking and jumping normally.

Also at Science News.

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy (DOI: 10.1126/science.aau1549) (DX)

More about Duchenne muscular dystrophy at Wikipedia.

Related: Scientists Create Extra-Muscular Beagles
FDA Panel Recommends Rejection of Duchenne Muscular Dystrophy Treatment
Nonviral CRISPR-Gold Editing Technique Fixes Duchenne Muscular Dystrophy Mutation in Mice
CRISPR Used to Epigenetically Treat Diseases in Mice


Original Submission

This discussion has been archived. No new comments can be posted.
Display Options Threshold/Breakthrough Mark All as Read Mark All as Unread
The Fine Print: The following comments are owned by whoever posted them. We are not responsible for them in any way.
  • (Score: 0) by Anonymous Coward on Thursday April 28 2016, @09:11AM

    by Anonymous Coward on Thursday April 28 2016, @09:11AM (#338337)

    Not enough bribes.
    Treatment too effective.

    • (Score: 2) by ledow on Thursday April 28 2016, @12:26PM

      by ledow (5567) on Thursday April 28 2016, @12:26PM (#338379) Homepage

      Sorry, did you miss this:

      "Treatments for rare diseases can be proven on small samples, but not based on 12 patients in a poorly designed study with ambiguous results."

      Everyone's up in arms when a doctor hints that a vaccination might cause autism (with ZERO documented cases among millions of treated individuals" but you think that a BAD sample of 12 is enough to decide on an experimental drugs viability? Drugs have got through much further trials and then literally killed experimental patients in later trials because they just didn't affect everyone.

      You can't do anything on a sample size of 12. Except get a trial of a sample size of 24. FDA approval will be years away from something that tiny, especially if the results are poor or the trials performed badly.

      If anything, this reads as "Big Pharma trying to push drug into market for a quick-sell, blocked by due process" or even "PhD research stymied because of the last-minute rush to hand in the paper meaning the trials were junk".

      • (Score: 0) by Anonymous Coward on Thursday April 28 2016, @01:34PM

        by Anonymous Coward on Thursday April 28 2016, @01:34PM (#338413)

        "The problem, FDA scientists said earlier in the day, is that, due to its small size and design, the study Sarepta submitted to the agency cannot prove that eteplirsen deserves credit for the boys' ability to remain on their feet."

        Im interested to know how a large sample size would allow the study to prove the drug deserves credit. That sounds suspiciously like the null hypothesis is false so my favorite theory is true.

      • (Score: 1) by Francis on Thursday April 28 2016, @01:54PM

        by Francis (5544) on Thursday April 28 2016, @01:54PM (#338423)

        With some of these conditions 12 is a large portion of the possible population that needs the treatment.

        But, lowering the standards further could have huge ramifications for other medications that are more widely prescribed. People are outraged, but the FDA committee made the right call. It's not just a matter of whether or not the drug works, there's also the question of side effects. A medication with minimal upside and a risk of a huge downside shouldn't be approved no matter how badly needed a treatment is. And in this case it's not clear whether or not there's an upside to the medication.

    • (Score: 1, Interesting) by Anonymous Coward on Thursday April 28 2016, @03:52PM

      by Anonymous Coward on Thursday April 28 2016, @03:52PM (#338491)

      This is more along the lines of 'you did not do your homework, come back when it is done correctly and we will give you a grade'

  • (Score: 4, Insightful) by wonkey_monkey on Thursday April 28 2016, @09:52AM

    by wonkey_monkey (279) on Thursday April 28 2016, @09:52AM (#338339) Homepage

    The recommendation came despite the emotional testimony of children

    Uh... well, good. Emotional testimony of children, or anyone else for that matter, shouldn't be a factor. Double blinded scientific studies have been in use for over a century.

    If Sarepta are on to something they now know how they have to improve their future studies.

    --
    systemd is Roko's Basilisk
    • (Score: 0) by Anonymous Coward on Thursday April 28 2016, @01:58PM

      by Anonymous Coward on Thursday April 28 2016, @01:58PM (#338425)

      I'm for the most part against the FDA assessing the effectiveness of drugs, but that seems to be quite the peek over the fence. At least the FDA approval process requires a veneer of legitimacy to be applied.

  • (Score: 3, Insightful) by anubi on Thursday April 28 2016, @09:52AM

    by anubi (2828) on Thursday April 28 2016, @09:52AM (#338340) Journal

    Sure seems like a small sample to me, too.

    I would have a problem *denying* treatment using this if the patient wanted it this way, but I would have a really hard time vouching for it as an effective treatment based on so little evidence.

    What I saw looked like a witch doctor or faith healer could make like statistics - as well as have equivalent testimonials.

    Our populace looks to our government to screen out generic snake oils from our pharmaceuticals. I am not saying the treatment is useless, rather I don't see enough evidence to persuade me that it is truly effective. This kinda research is really tricky when humans are involved as we have a huge placebo effect - and in this case, the hawthorne effect [wikipedia.org] is in play as well.

    Based on what I read, I think they acted prudently - I would have done the same.

    --
    "Prove all things; hold fast that which is good." [KJV: I Thessalonians 5:21]
    • (Score: 2) by sjames on Thursday April 28 2016, @11:18AM

      by sjames (2882) on Thursday April 28 2016, @11:18AM (#338360) Journal

      The problem is that the FDA has forgotten it's proper mission of assuring safety. I'm not opposed to a secondary mission of ensuring safety but would urge that it be kept separate.

      That is, a requirement for safety being all that is required for limited marketing, and a secondary efficacy endorsement. Selling can happen if it is found safe OR if it is found effective enough that a risk is warranted.

      I would also suggest that if an M.D. prescribes it, it may be taken regardless of the FDA. Or perhaps even if a customer signs a suitably dire warning, they can buy and take whatever they want.

      • (Score: 0) by Anonymous Coward on Thursday April 28 2016, @12:09PM

        by Anonymous Coward on Thursday April 28 2016, @12:09PM (#338369)

        With the direct marketing to patients and hypochondriacs, I prefer the FDA to require efficacy. Other countries ban direct marketing and just regulate safety of new drugs.

        Luckily, the US is a large enough market that companies will try to meet the higher standard even if they are already approved in other countries.

        • (Score: 2) by sjames on Thursday April 28 2016, @12:30PM

          by sjames (2882) on Thursday April 28 2016, @12:30PM (#338382) Journal

          They don't have to permit marketing of drugs that haven't fully met the higher standard. It's a matter of not denying people the natural right to attempt to improve their condition.

          • (Score: 1, Informative) by Anonymous Coward on Thursday April 28 2016, @02:51PM

            by Anonymous Coward on Thursday April 28 2016, @02:51PM (#338454)

            That is already covered under "compassionate use", which allows patients to take drugs currently under clinical trials even if they aren't enrolled, as long as the pharmaceutical company allows it. Doctors can also prescribe medicine off-label if they have been approved for other indications.

      • (Score: 3, Insightful) by ledow on Thursday April 28 2016, @12:29PM

        by ledow (5567) on Thursday April 28 2016, @12:29PM (#338381) Homepage

        Wonder what Michael Jackson, his family and lawyers would say about that?

        You can't just let someone prescribe ANYTHING, based on a patient's wishes. That would basically turn doctors into legal drug-dealers, bought-out advertisers, and unaccountable murderers overnight (literally, the doctors are the people who judge whether someone is of sound mind or not, and then if they get them to write out or forge a bit of paper, they can kill off the patient with no legal comeback).

      • (Score: 2) by Thexalon on Thursday April 28 2016, @02:15PM

        by Thexalon (636) on Thursday April 28 2016, @02:15PM (#338437)

        The problem is that the FDA has forgotten it's proper mission of assuring safety. I'm not opposed to a secondary mission of ensuring safety but would urge that it be kept separate.

        Wait, are you saying that they should "assure" safety without actually "ensuring" safety? As in, tell everybody that everything's OK, whether or not it is? The IT equivalent would be an account manager carefully assuring you that the software is completely secure even though you know that it's vulnerable to a simple SQL injection attack.

        Also, efficacy is absolutely relevant to the safety question: Medical treatments typically have side effects, which makes an ineffective treatment worse than no treatment. In addition, an ineffective treatment that doctors and patients believed would work might cause them to forego the use of other treatments that would be more effective.

        --
        Alcohol makes the world go round ... and round and round.
        • (Score: 2) by sjames on Thursday April 28 2016, @04:06PM

          by sjames (2882) on Thursday April 28 2016, @04:06PM (#338498) Journal

          Clearly I meant I don't see a problem with a secondary mission of assuring efficacy.

        • (Score: 3, Informative) by physicsmajor on Thursday April 28 2016, @04:13PM

          by physicsmajor (1471) on Thursday April 28 2016, @04:13PM (#338503)

          You misunderstand, I think - there is a difference between assuring something is safe, and ensuring it actually is effective.

          The FDA is tasked to assure drugs are safe to administer, that what the label says is actually what the medicine contains, and to tell providers and patients what the possible effects/reactions are.

          They are also tasked to evaluate what "indications" a drug can be "labeled" for. This is important, because generally labeled usage is reimbursable by Medicare/Medicaid while off-label use is more difficult to get paid for.

          In this story, the drug appears to be safe from the perspective of significant adverse effects, when dosed appropriately. That's the former thing - assuring safety. The potential rejection is due to low statistical power/poor study design in order to label this drug for the indication of DMD. This is the latter task - labeling a drug as effective for a given condition.

          The main question is if this compound should remain available for off-label or compassionate use, despite unclear evidence if it truly helps DMD patients, given that there is no current therapy... Or should it be rejected entirely.

    • (Score: 1) by Francis on Thursday April 28 2016, @02:00PM

      by Francis (5544) on Thursday April 28 2016, @02:00PM (#338428)

      There are people who will go to all sorts of lengths for a treatment or a cure. And I can't blame people with serious illnesses like ALS or Parkinson's to be willing to go way beyond what would normally be considered as ethical in search of a cure, those conditions are pretty nightmarish.

      But, people do die and we do have to have some standards in place to ensure that we don't wind up conducting the sort of "research" that the Nazis and Japanese were conducting in WWII.

      Unfortunately, that means that there's medications that don't receive the sort of testing that they probably ought to.

  • (Score: 3, Insightful) by Gravis on Thursday April 28 2016, @10:41AM

    by Gravis (4596) on Thursday April 28 2016, @10:41AM (#338350)

    begin conducting larger trials and gather more data to support your product then resubmit it for approval if it works. how is this even news?

    • (Score: 0) by Anonymous Coward on Thursday April 28 2016, @02:05PM

      by Anonymous Coward on Thursday April 28 2016, @02:05PM (#338430)

      begin conducting larger trials and gather more data to support your product then resubmit it for approval if it works.

      Unfortunately this is what it amounts to. Which will happen first? 1) You run out of money for trials or 2) a random statistical significance. Actually it is amazing to me that "sampling to a foregone conclusion" has no Wikipedia page, since that process has played such a major role in what has been getting published the last 50-60 years.

    • (Score: 0) by Anonymous Coward on Thursday April 28 2016, @02:27PM

      by Anonymous Coward on Thursday April 28 2016, @02:27PM (#338444)

      True, but what do you say to the blind group if this drug really does work miracles? "Sorry you can't walk anymore... better luck next life" I think this is the crux of the matter, people will not get access to the treatment while the red tape is slowly unwrapped. It is emotional prospect to the max.

      • (Score: 3, Insightful) by tibman on Thursday April 28 2016, @05:57PM

        by tibman (134) Subscriber Badge on Thursday April 28 2016, @05:57PM (#338571)

        Because it could easily turn into "Sorry we didn't cure you and (mostly) destroyed your liver in the attempt."

        --
        SN won't survive on lurkers alone. Write comments.
      • (Score: 0) by Anonymous Coward on Thursday April 28 2016, @06:59PM

        by Anonymous Coward on Thursday April 28 2016, @06:59PM (#338587)

        The trial would be stopped for efficacy and all trial participants would be allowed access to the drug.

        Here is a couple recent immunotherapy examples: https://soylentnews.org/article.pl?sid=15/04/17/2157254 [soylentnews.org]

  • (Score: 0) by Anonymous Coward on Thursday April 28 2016, @11:55AM

    by Anonymous Coward on Thursday April 28 2016, @11:55AM (#338365)

    Learn from Addyi's playbook.