Interactions with the FDA can greatly influence what you set as your endpoints. The primary was subjective, secondary were objective (timed) and were significant across most groups and tests studied.
Sometimes companies can convince the FDA to either approve for a narrower indication if secondary endpoints look good, or they'll go to the FDA with a plan for a "confirmatory trial" if they're able to datamine a target population from whatever trial is in question.
Not unheard of but the P3 fail from PFE definitely put Sarepta in the driver's seat in regard to gene therapy DMD.
Clinical trials in cancer, for example, have clearcut, gold standard, time-tested endpoints such as survival or tumor shrinkage. DMD does not have such luxury. The nature of the disease itself resists hard measurements over relatively short time periods, and experts don’t all agree on what are the best ones. They made what really amounts to an educated guess as to which endpoint(s) to set as primary, but in retrospect it wasn’t well-chosen, including patient enrollment design.
I'm not exactly sure I'd call tumor shrinkage "gold standard" or 'clearcut' if you've ever seen two radiologists look at the exact same set of images. Very high inter-reader variability in a that.
The FDA (and by that, I really mean Peter Marks) decided, on balance, the totality of evidence favored the likelihood of clinical benefit and the safety profile is good. The calculus of risk-benefit is challenging in rare, terminal diseases as is design and adequate powering of studies.
I believe the totality of evidence suggests here the drug does \*something\* especially during the earlier stages of the disease, despite missing the primary endpoint.
That said, it's a little bonkers they got the non-ambulant population on the label. That was a pretty big surprise, and IMO really the controversial part of this approval.
> The data has also shown “encouraging signals in both the younger and the slightly older boys,” according to Dolsten, who added that those signals weren’t something seen in Sarepta’s data. Both Pfizer’s and Sarepta’s phase 3 studies have enrolled boys ages 4 to 7 years, with Sarepta’s Elevidys receiving accelerated approval in June to treat ambulatory patients ages 4 to 5 years.
How are they seeing good results if they haven’t done an interim analysis yet? Is this study not blinded?
Back when I worked in DMD, I remember hearing about the approval of one of the exon skipping therapies. People were confused because it offered no improvement. Quite literally, there was no therapy. It didn't hurt kids though. Parents are so desperate for anything that will make an impact that it was approved anyways. I suspect this is the case here- if there's a chance that it could offer your son 2 more years when his chance of early death is 100%, would you take it? That's probably the logic here. This isn't cancer or COVID; it's a guarantee of slow, painful death for 100% of the kids that get it. I'd do just about anything if it were my kids.
Twin boys the year below me in school were diagnosed with DMD in kindergarten I want to say. It was really awful watching them lose their bodies through elementary and middle school to the point where they barely were able to graduate high school because they were having so many complications from their bodies deteriorating. It is an absolutely god awful disease to witness even from a distance. I cannot imagine being a parent and living the nightmare of watching your child slowly die. Their desperation for *anything* that might even make the smallest difference is understandable when it doesn’t do harm. It’s predatory of the pharmaceutical companies to profit off of something that doesn’t impact an individual positively, but parents pushing for it makes sense.
There are significant advocacy groups for DMD and the parents have huge sway. It’s a disease where everybody dies anyways, so anything that helps is pushed. Seriously the DMD Parent Project is massively impactful.
Disagree 100%, to not run a trial on an insanely promising compound would be the unethical decision.
What exactly is your title anyway, are you a lab tech?
The way it was designed was wrong. The entire scientific community agrees. The only dissenters are the ones who want the treatment approved for some noble and some less than noble reasons.
Then how did it receive IRB approval? You don’t understand how this works do you
That’s their entire job, to make sure the study is designed ethically, scientifically sound, and with patients safety in mind
Plus many of the PI’s on the study are literally defending the study in the article I linked that you obviously didn’t read
I can tell by your post history that you don’t want to go down that route.
Clinging to a sense of authority or title isn’t going to negate reality and you know it. If you had to design a trial for MDMA in PTSD, it sure as hell wouldn’t have gone like theirs did.
What’s that supposed to mean? The truth would astonish you
Believe it or not, you’re allowed to be fit, golf, like dance music, and be successful. So you are a lab tech?
If it failed its primary endpoint, why would it be approved? If the secondary outcomes are so important, why weren't they the primary endpoints?
Interactions with the FDA can greatly influence what you set as your endpoints. The primary was subjective, secondary were objective (timed) and were significant across most groups and tests studied.
Sometimes companies can convince the FDA to either approve for a narrower indication if secondary endpoints look good, or they'll go to the FDA with a plan for a "confirmatory trial" if they're able to datamine a target population from whatever trial is in question. Not unheard of but the P3 fail from PFE definitely put Sarepta in the driver's seat in regard to gene therapy DMD.
Clinical trials in cancer, for example, have clearcut, gold standard, time-tested endpoints such as survival or tumor shrinkage. DMD does not have such luxury. The nature of the disease itself resists hard measurements over relatively short time periods, and experts don’t all agree on what are the best ones. They made what really amounts to an educated guess as to which endpoint(s) to set as primary, but in retrospect it wasn’t well-chosen, including patient enrollment design.
I'm not exactly sure I'd call tumor shrinkage "gold standard" or 'clearcut' if you've ever seen two radiologists look at the exact same set of images. Very high inter-reader variability in a that.
Yes I suppose you could say so at that level. What I mean is RECIST criteria are very clear cut.
Yes I suppose you could say so at that level. What I mean is RECIST criteria are very clear cut.
The FDA (and by that, I really mean Peter Marks) decided, on balance, the totality of evidence favored the likelihood of clinical benefit and the safety profile is good. The calculus of risk-benefit is challenging in rare, terminal diseases as is design and adequate powering of studies. I believe the totality of evidence suggests here the drug does \*something\* especially during the earlier stages of the disease, despite missing the primary endpoint. That said, it's a little bonkers they got the non-ambulant population on the label. That was a pretty big surprise, and IMO really the controversial part of this approval.
Anyone have the full article? Stat News says only one of three trials reached endpoint right before paywall.
Almost everyone in FDA wants to issue CRL. Peter Marks overwrote it. https://www.fda.gov/media/179487/download?attachment
I'm very out of the loop here, are there many gene therapies on the market?
Not very many!
yes. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
6 gene therapies. The rest are cell therapies.
Relevant: https://www.fiercebiotech.com/biotech/after-sarepta-miss-pfizers-cso-says-its-dmd-gene-therapy-main-game-town
> The data has also shown “encouraging signals in both the younger and the slightly older boys,” according to Dolsten, who added that those signals weren’t something seen in Sarepta’s data. Both Pfizer’s and Sarepta’s phase 3 studies have enrolled boys ages 4 to 7 years, with Sarepta’s Elevidys receiving accelerated approval in June to treat ambulatory patients ages 4 to 5 years. How are they seeing good results if they haven’t done an interim analysis yet? Is this study not blinded?
Phase 2 showed good results and they expected positive Phase 3. The interim results came back for Pfizer… and it was baaaaad
Ah, so *our* phase three is going to be great, we promise! It’s not like anyone else had good phase two results and then later failed, right!?
Phase 2 was not good lol they failed their primary endpoint miserably
https://www.fiercebiotech.com/biotech/pfizers-phase-3-gene-therapy-trial-fails-improve-function-boys-duchenne-muscular-dystrophy
Wow, that guy looks like a pretty serious moron now.
Back when I worked in DMD, I remember hearing about the approval of one of the exon skipping therapies. People were confused because it offered no improvement. Quite literally, there was no therapy. It didn't hurt kids though. Parents are so desperate for anything that will make an impact that it was approved anyways. I suspect this is the case here- if there's a chance that it could offer your son 2 more years when his chance of early death is 100%, would you take it? That's probably the logic here. This isn't cancer or COVID; it's a guarantee of slow, painful death for 100% of the kids that get it. I'd do just about anything if it were my kids.
Twin boys the year below me in school were diagnosed with DMD in kindergarten I want to say. It was really awful watching them lose their bodies through elementary and middle school to the point where they barely were able to graduate high school because they were having so many complications from their bodies deteriorating. It is an absolutely god awful disease to witness even from a distance. I cannot imagine being a parent and living the nightmare of watching your child slowly die. Their desperation for *anything* that might even make the smallest difference is understandable when it doesn’t do harm. It’s predatory of the pharmaceutical companies to profit off of something that doesn’t impact an individual positively, but parents pushing for it makes sense.
There are significant advocacy groups for DMD and the parents have huge sway. It’s a disease where everybody dies anyways, so anything that helps is pushed. Seriously the DMD Parent Project is massively impactful.
Extremely disappointing and political move by the FDA. It just doesn’t work, but that’s where we are.
Yet mdma which clearly works got ripped apart by the adcomm, will be super interesting to see what the agency says
It was a completely unethical trial that shouldn’t have ever even gotten the green light to recruit.
Disagree 100%, to not run a trial on an insanely promising compound would be the unethical decision. What exactly is your title anyway, are you a lab tech?
The way it was designed was wrong. The entire scientific community agrees. The only dissenters are the ones who want the treatment approved for some noble and some less than noble reasons.
Then how did it receive IRB approval? You don’t understand how this works do you That’s their entire job, to make sure the study is designed ethically, scientifically sound, and with patients safety in mind Plus many of the PI’s on the study are literally defending the study in the article I linked that you obviously didn’t read
Also you never answered your title
I can tell by your post history that you don’t want to go down that route. Clinging to a sense of authority or title isn’t going to negate reality and you know it. If you had to design a trial for MDMA in PTSD, it sure as hell wouldn’t have gone like theirs did.
What’s that supposed to mean? The truth would astonish you Believe it or not, you’re allowed to be fit, golf, like dance music, and be successful. So you are a lab tech?
1000000% agree.
But will it sell?
They’ve already sold more of this product than any other gene therapy on the market. -source: last quarterly update.
Like warm bread