An ALS drug fails, again

https://www.science.org/content/blog-post/als-drug-fails-again

by kurthr • 2 years ago

137 111 2 years ago

kurthr• 2 years ago

This drug was approved after Phase II trials largely failed and a second review panel was convened to override the first. Now it has failed again in Phase III after being given to many hopeful patients at great cost.

The last lines rang true:

   You need what you've always needed: efficacy and safety. Boring, tedious,
   expensive efficacy and safety. Desire and despair don't figure in much - in a
   much different universe, one whose physical laws respected and validated human
   emotions and human suffering, they would. But we don't live in that world.

thenerdhead11• 2 years ago

How about we fix that with this?

https://www.congress.gov/bill/118th-congress/senate-bill/190...

Give patients access and do the right science. Make sure it is safe and allow people the right to try.

capitainenemo• 2 years ago

In the case of the parent article drug, it claims it was the pressure of patient advocacy groups that got the drug approved. Giving people the right to try unfortunately at present means everyone else paying for it (or paying for the harm it causes), unless unapproved drugs were required to be covered by the individual on their own.

" But ALS patients (or their insurance companies) had the chance to pay for a drug ($158,000/yr list, who knows what the real price was somewhere below that) for what is in the end a combination of two generic medicines. And they might as well have been given peppermint candy for all the good it did. ... patient advocacy groups took victory laps after Relyvrio was approved, and they were a big part of the pressure that made the FDA reverse its initial correct decision "

peeters• 2 years ago

Can you expand on this? This bill seems to enable exactly what the author is attacking: exploiting the desperate hopes of terminally ill patients to sell ineffective drugs.

I agree with removing red tape and allowing accelerated trials when the drugs are for these purposes, but it seems like today, drug companies can make a profit off of selling snake oil. They already stand to benefit from the reduced regulations, so why allow them to sell the drug at all under these circumstances? If they're so confident in the efficacy, they should be willing to give the drug away for free to benefit from an accelerated path to approval.

This bill seems to allow drug companies to continue to sell under these regulations, and in fact goes even further by removing most liability from them.

msie• 2 years ago

It's crazy how this drug got approved despite the evidence. A mixture of greed from the drug manufacturer and wishful thinking from the afflicted. Ugh. I've lost my trust in the system.

frodo8sam• 2 years ago

Agree, the Alzheimer's and ALS treatments that were approved recently were both cases where the patient advocacy groups stopped listening to experts and ironically harmed the people they are trying to help. It shows how important it is that the FDA keeps some emotional distance from the people they are trying to protect.

ta8645• 2 years ago

That's an interesting narrative, but are you sure that's actually what happened? It seems to elide the role of the drug manufacturer who pays for all these trials in the first place. Why would they pay for such doomed trials, just for the emotional hopes of patients? Are they that irresponsible with their stockholder's money? If so, they should probably be ousted and replaced with people who have more business savvy.

Or alternatively, this really didn't have anything to do with hopeful patients or their advocates, but rather the greed of the pharma companies, hoping to push through unproven drugs for the sake of profit.

I don't have any special insight into which narrative is true, but we've seen a lot of the second narrative historically.

rafaelero7• 2 years ago

And, curiously, the Alzheimer drug do work, just like hypothesized by the "dumb advocacy groups". You just have to take them earlier in the profession of the disease.

sambull• 2 years ago

A symptom of larger problems

rafaelero7• 2 years ago

Nonsense. I'ld rather have a safe drug with >50% of chance of working approved than waiting for 3 more years and find out when I am already debilitated. That some drugs turn out to not work is not a reason to "lose trust in the system", unless you are an immature child.

lotsofpulp4• 2 years ago

Who is paying for these drugs that have insufficient evidence of efficacy?

lotsofpulp4• 2 years ago

A mixture of greed from the drug manufacturer and wishful thinking from the afflicted.

Neither of those entities have the power to approve a drug.

mlyle5• 2 years ago

Regulators are political amalgamations; as we've seen recently with Alzheimers and this drug, those entities can be quite powerful.

slibhb2• 2 years ago

The drug didn't hurt patients, did it?

This kind of failure seems relatively benign.

tester89• 2 years ago

It’s not as bad, true. But you have to consider the amount of money wasted in the phase 3 trial, resources which could’ve been put to better uses.

contravariant2• 2 years ago

If you still think that kind of false hope doesn't hurt then I sincerely wish you never have to find out otherwise.

CamperBob2• 2 years ago

This would be true if research funding weren't a zero-sum game. Every dollar spent developing and marketing a drug that doesn't help is a dollar another research team needs badly but doesn't get.

lostlogin• 2 years ago

This kind of failure seems relatively benign.

You saw the price? $158k per year list price, though it is implied people probably paid less.

dghughes• 2 years ago

Lack of care is harm.

That's why quacks are so infuriating other than money they take (even in social medical systems) time is lost which means disease progression. For many diseases there is now cure but there may drugs to slow it down. The drugs may take a long time to work so years spent on fake crap may mean it's too late for a person to go on a drug.

ethanbond2• 2 years ago

What? It didn’t get approved. It failed Phase III as designed.

mlyle5• 2 years ago

What? It got approved, on dubious evidence from a dubious phase II, against the original advisory committee's recommendation.

The manufacturer had agreed to conduct a phase III and remove it from the marketplace if it failed the next trial.

It has now failed that trial.

light_hue_12• 2 years ago

We sometimes have posts here from patients who are desperate. And everyone dumps on the FDA in those threads.

This is the flip side of that.

This was patients lobbying Congress to skip safeguards. The FDA did not want to do this. https://apnews.com/article/science-business-health-lobbying-...

Now it's just getting worse and worse. ALS patient communities used the questionable approval of Aduhelm by desperate Alzheimer’s patients to strongarm the FDA into approving this. Every junk pharma product is now going to come with an advocacy group that says "let's just try it and see".

Grifter pharma corporations will of course take advantage of this. They'll mobilize patient communities to keep skipping the science. And the result will be more wasted lives and more misallocated resources. Instead of working toward drugs that help people, we'll be working toward drugs that sound good to patient communities and Congress. This is a disaster.

The FDA might be slow. But it's slow and deliberate for a reason.

rafaelero7• 2 years ago

But what's the harm here? The drug is safe. The only burden patients had was financial. Now what if the drug was effective? The harm it would incur to patients by delaying it would be much more extreme.

ejb9992• 2 years ago

the harm is not all drugs are safe - even if this one was (and we aren't 100% sure of that either), and pharma companies using social media and/or sympathy stories to pressure regulators into approving a drug that would not otherwise get approved is gross.

SoftTalker3• 2 years ago

Even if it's safe, the harm is in rewarding drug companies for producing very expensive products that don't work, and selling them to desperate people and their families who will sell off everything they own and go as far into debt as they can to pay for them. This creates incentives that we don't or should not want.

bsder• 2 years ago

The harm here is the medical industry sticking with the amyloid hypothesis in the face of repeated and expensive failures.

The funding needs to move on to something that might actually work. Propping up these failed drugs with "what does it hurt" is in the way of getting an Alzheimer's drug that might actually benefit people.

pcwalton• 2 years ago

It's a ton of wasted money. We should spend limited resources on treatments that actually work.

I feel tremendously for patients and their loved ones frustrated with the FDA's sluggishness, but results like these illustrate why it's needed. Especially since many of the drugs have much worse side effects than this one.

ethanbond2• 2 years ago

It’s extremely hard for people to look past the current environment of, in general, knowing that whatever drug they can get their hands on (commercially) is going to at least be safe and probably quite effective.

GenerWork• 2 years ago

My hot take is that if you have a disease like ALS that's pretty much always fatal, you should be able to skip whatever safeguards the FDA has setup as long as you're informed that this medicine could hurt you or even kill you before the disease does.

arrosenberg3• 2 years ago

Its a nice sentiment, but it ends with desperate families spending all their savings on an ayahuasca-carrot juice cleanse to try and save their loved one.

Still need some kind of process to weed out the grifts.

y-c-o-m-b• 2 years ago

Seconded, I think that's the most rational approach. I also think the patients should be thoroughly coached by medical professionals or maybe even be required to take a required orientation session on potential down-sides so that the risk is truly emphasized. We consume some pretty harmful things on a daily basis - alcohol and tobacco at the top of the list - and those are perfectly legal for people to decide whether or not they want to put into their bodies. It's not a huge leap to give people that same personal choice when it comes to experimental drugs that might give them even a small chance of surviving a terminal illness.

starky• 2 years ago

Imagining the perspective of someone with ALS I can see why they rightly would be advocating for a quicker process even with the risk. Most people diagnosed with ALS die within 1-5 years depending on how quickly it progresses. They don't have the benefit of waiting on the normal timeline for FDA approvals. The downsides of taking an experimental drug that harms them or just doesn't work is likely worth it for someone in that situation when they look at the potential upsides if it does work.

For quickly degenerative diseases maybe we need a different process that takes into account the context of what the drug is used for and what the acceptable risk is by the regulatory bodies. Making the standards and process clear will help provide the framework to reject those with unreasonable demands.

SoftTalker3• 2 years ago

The other approach is simply accepting one's fate. No, there isn't some cure just around the corner with the only roadblock being FDA approval. There just isn't. There are cancer treatments with terrible side effects but they are approved because they have measurable efficacy. There are no ALS drugs because none of them work. Wishing hard doesn't change that.

thenerdhead11• 2 years ago

The FDA is not that slow though. People misinterpret that it is actually the trials that are slow. Many things get approved quickly for as large of an enterprise as the FDA.

dddddaviddddd• 2 years ago

The Phase III trial has just read out, and Relyvrio shows no hint of actually working.... It did have a very good safety profile, fortunately, so it seems unlikely that anyone was physically harmed.

Phase II trials are more about safety than efficacy, so I'd say the system worked as designed.

iechoz6H• 2 years ago

One wonders how they got as far as Phase III trials without actually working.

zeroonetwothree• 2 years ago

Phase III is when you test efficacy so it’s exactly how it’s meant to be

dredmorbius2• 2 years ago

Final 'graph of the article:

[T]he patient advocacy groups took victory laps after Relyvrio was approved, and they were a big part of the pressure that made the FDA reverse its initial correct decision.

Motivated reasoning, whether by commercial interests, patient advocates, or any other group, is inimical with truth-finding.

Though on the grounds of potential benefit vs. known harm (which is assessed in Phase I/II trials) and partial knowledge, a provisional approval in the case of a treatment for a chronic, progressive, and fatal condition is reasonably defensible. The FDA's conditional approval was based on Phase III trials showing efficacy. The dice were rolled, though the gamble in this case proved fruitless.

pama• 2 years ago

The problem is not the trial. The problem was an out of order early approval after only a phase two trial with very weak evidence. The phase three trial of course would go on even without such an out-of-order approval. The false hope such an approval creates doesn’t just affect patients directly. It may lead other companies to abandon or slow down therapies that might have competed in this indication. Approval of a drug is a huge deal. Perhaps eventually our drug approval system will change, but right now approval gives a company the power to market a drug to doctors, and doctors can prescribe it to patients, patients can ask for it, insurers cover it, and so on… This one was a conditional approval and the condition failed, which means the system still works, however it now has a possible loophole for how to bootstrap a pharma company. It is not clear yet if that loophole may increase human suffering on average, or not, and it likely depends on how the companies that take advantage of such a loophole grow. Drug discovery, design, and development are capital intensive operations and suffer from lack of innovation, but they also attract greedy people at the executive level who don’t bring therapeutic innovations to the table but rather find out how to draw investor money.

NotYourLawyer• 2 years ago

No, phase 2 is absolutely about efficacy.

dlevine• 2 years ago

There was a good article on this in the New Yorker a while back: https://www.newyorker.com/magazine/2023/06/26/relyvrio-als-f...

It's sad that the drug didn't work (and I had a cousin recently die of ALS), but it's important to let the FDA do their work.

thenerdhead11• 2 years ago

What work does the FDA do here? It is the work of large investments or initiatives to prove safety and efficacy and the FDA makes decisions.

If anything we live in a world where we need better provisions for these illnesses similar to https://www.congress.gov/bill/118th-congress/senate-bill/190...

Waiting for phased trials when you understand the research and hypothetical risks is torture. Especially when many drugs have proven safety profiles where the only harm is financial.

ProjectArcturis3• 2 years ago

This particular drug was just a combination of two already-approved generic drugs. Anyone could have tried them with a doctor's Rx without a change in the law.

hash872• 2 years ago

but it's important to let the FDA do their work

The FDA has been 'working' on authorizing sunscreen widely used in the rest of the developed world for the last 20 years, or since the original Dubya administration. This is not a typo. They are glacially, bureaucratically slow & cautious

AuryGlenz• 2 years ago

Isn’t the real problem on that from that no company will put up funds to do the trials since they aren’t patentable at this point?

That said, I feel like there should absolutely be an almost automatic approval for stuff sold in multiple other countries for decades.

cat_plus_plus• 2 years ago

Said no patient ever. Everyone wants right to try, understandable that insurance would only cover sufficiently proven treatments. But if I can raise money, I want to at least take the most promising currently and if it doesn't work, oh well.

ryukoposting• 2 years ago

I think the important detail here is that, to anyone paying attention to the results of the clinical trials, this drug never showed promise in the first place.

The system we have is slow because it's thorough. Sometimes we have to move faster, and that's what EUAs are for. The worst versions of "right to try" policy would open the floodgates to all kinds of quack drugs with astronomical price tags. The resulting system would extract money from the desperate, and do very little to cure the ill.

thenerdhead11• 2 years ago

Not true. You can mark certain confirmed illnesses with provisions.

Quacks won’t be allowed in such regulated environments.

https://www.congress.gov/bill/118th-congress/senate-bill/190...

karaterobot• 2 years ago

An uncharitable view would be that Amylyx ended up presenting the clinical package from the only angle that made it even possible to believe that the drug worked, and the FDA advisory committee ended up voting against approval... I hate to be this way, but I continue to believe that unmet medical need is not by itself enough reason to approve a drug. You need what you've always needed: efficacy and safety. Boring, tedious, expensive efficacy and safety.

I can either take from this that he believes the FDA and Amylyx were engaged in irresponsible behavior letting it get this far, or that (thank God!) an ineffective drug will not be approved, and we should all be glad there is a rigorous testing process that worked again. I get the sense that he believes the former, but can't ethically say so.

ProjectArcturis3• 2 years ago

It's both. The FDA erred in approving this ineffective drug based on weak P2 data.

j7ake• 2 years ago

Failing so late in the drug process can literally bankrupt a company.

StanAngeloff• 2 years ago

Amylyx Stock Wipes Out Nearly All Of Its Value, Crashing 82%, After Pivotal ALS Drug Failure[0]

[0] https://finance.yahoo.com/m/b15fb91a-1e90-3259-844e-cfdb2563...

consp• 2 years ago

Probably someone made money off it as according to the article this was the clear outcome.

thenerdhead11• 2 years ago

As it should. That’s the risk they take. Either you have a well designed trial that shows your drug is effective or you don’t.

What you don’t do is make lofty promises to vulnerable patients.

sudosteph• 2 years ago

My Dad has ALS and has participated in a couple trials for different treatments. It's hard to say if any of them made a difference at all, and the justification behind some of these drugs seems extremely flimsy (one he was doing was for a drug that had some weak correlation during covid for slightly slower progression in one symptom), and the quality life impact of participating in that trial (having to fly to Boston, drug side effects, multiple lumbar punctures) leaves me frustrated that doctors recommend these at all. I feel like they're trading favors to get patients into studies with doctors they know, meanwhile, there are more promising ones that are being tested that he should be a candidate for, but the doctor won't even have a conversation about trying to get him in those trials. It leaves a bitter taste in my mouth. I hope something comes from all this, but right now I don't have a high view of the drug research and treatment process for this condition.

lambdaba• 2 years ago

I hope this is not inapropriate but I wanted to share this interview with a person using a high fat diet for ALS: https://youtu.be/GoF4GZ1NoBQ?si=Y-yEnquZsLXXb2po

Noting that ketogenic diets are already proven to improve outcomes in other neurodegenerative diseases.

randomgiy3142• 2 years ago

There are bigger things than a failed trial. There was a lot of money invested in this and when it was found to not be harmful there was a large push to show success. A lot of careers will be cut short because of this. There’s a lot of motivation to show something works. I was told to avoid research because of this kind of thing. There were a lot of highly paid people in a room that were not scientists but tasked with showing how much money could be made. That sounds evil but their intentions are good, that doesn’t help ALS people but there’s enough money put into this I wouldn’t be surprised if some progress is shown somewhere.

tibbydudeza• 2 years ago

ALS or as Americans call it Lou Gehrig disease is a high-profile disease because of the ice bucket challenge despite the low incidence (6 out of 100,000) compared to other diseases like coronary disease or some cancers.

The disease is cruel, and it hits home for many of us as there are no mental deterioration like with dementia, Alzheimer's or FPD but you lose the ability to use your body and survival less than 3 years.

I can see why the FDA and congress are desperate to be seen to do something.

katherinebhana72• 2 years ago

ALS is a cruel disease. My mum is 83 and had great difficulty speaking and swallowing much of anything. Food was getting trapped in her throat and blocking her air way was happening more often. she battled for each breath. The riluzole did very little to help her. The medical team did even less. Her decline was rapid and devastating. The psychological support from the medical centre was non-existent and if it were not for the sensitive care and attention of our primary physician, there she would have died. There has been little if any progress in finding a cure or reliable treatment. Acupuncture eased her anxiety a bit. this year our primary physician started her on Natural Herbs Centre ALS/MND Ayurvedic treatment, 6 months into treatment she improved dramatically. It has been a complete turnaround with her speech, she no longer needs the feeding tube to feed, the treatment is a miracle. She recovered significantly! Visit Naturalherbscentre. com

katherinebhana72• 2 years ago

I’m a little bit hesitant posting about my moms progress using Ayurvedic treatments but I’ll post in hope that someone finds this helpful despite the many herbal snake oil I see been advertise on this group. My mother who had been diagnosed with Lou Gehrig’s disease for 3 years at the age of 82 had all her symptoms reversed with Ayurveda medicine from natural herbs centre after undergoing their ALS/MND Ayurvedic protocol, she’s now able to comprehend what is seen and she no longer needs the feeding tube to feed,. God Bless all ALS disease Caregivers. Stay Strong, take small moments throughout the day to thank yourself, to love your self, and pray to whatever faith, star, spiritual force you believe in and ask for strength, their website is naturalherbscentre. com She’s getting active again since starting this treatment program...

An ALS drug fails, again

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