[HN Gopher] An ALS drug fails, again
___________________________________________________________________
An ALS drug fails, again
Author : kurthr
Score : 80 points
Date : 2024-03-09 16:20 UTC (6 hours ago)
(HTM) web link (www.science.org)
(TXT) w3m dump (www.science.org)
| kurthr wrote:
| 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.
| thenerdhead wrote:
| 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 wrote:
| 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 wrote:
| 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.
| yieldcrv wrote:
| > but it seems like today, drug companies can make a profit
| off of selling snake oil
|
| anybody can sell sugar pills or any 'generally approved as
| safe' consumptive good, repackaged as _something big pharma
| is hiding from you_
| ProjectArcturis wrote:
| You can't make specific claims like "cures Alzheimer's"
| without a clinical trial. You have to use weasel words
| like "boosts immunity".
| thenerdhead wrote:
| You don't seem to understand the bill and perhaps people
| are downvoting because they don't understand either.
|
| I recommend you read it yourself and understand what it is
| saying. Not to make broad assumptions that "snake oil" will
| be allowed.
|
| Here is a summary I wrote about this bill based on a
| condition I have that can benefit from it:
|
| https://www.lctreatments.com/legislation
| msie wrote:
| 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 wrote:
| 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 wrote:
| 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.
| jfengel wrote:
| They can't profit if it doesn't work. There is that bizarre
| case with the Alzheimer's drug, but that seems rare and not
| something they should pin their hopes on.
|
| It sounds to me as if the drugmakers and the patient
| advocates are coming from the same place. They are
| desperate for it to work, and will convince themselves of
| it on any thin evidence. Probably something like "it did X
| in a petri dish so it must work eventually."
|
| There are surely executives making a calculated risk, but I
| think they couldn't do it if there weren't also scientists
| who feed them over-optimistic guesses because they want it
| to work for the patients too.
| rafaelero wrote:
| 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 wrote:
| A symptom of larger problems
| rafaelero wrote:
| 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.
| lotsofpulp wrote:
| Who is paying for these drugs that have insufficient evidence
| of efficacy?
| rafaelero wrote:
| I don't know and don't really care. It's about giving
| people the option, not forcing them to buy it.
| lotsofpulp wrote:
| Are people prevented from paying for it?
|
| Or do manufacturers simply not think it is worth their
| while / liability if Medicare and other governments will
| not pay for it?
|
| If a billionaire went to the employees of Amylyx Pharma,
| and asked them to make this medicine for them, would they
| refuse?
| lotsofpulp wrote:
| > 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.
| mlyle wrote:
| Regulators are political amalgamations; as we've seen
| recently with Alzheimers and this drug, those entities can be
| quite powerful.
| ejb999 wrote:
| not to mention the revolving door between drug company
| execs and regulators - which is ripe for conflicts of
| interest.
| azinman2 wrote:
| What percent of FDA scientists and committee members who
| are in charge of approving drugs have been part of the
| "revolving door?" And how do we know this is inherently
| bad? It may be, but I can also see how niche expertise
| would cause you to float between entities as appropriate.
|
| Keep in mind 90% of drugs fail clinical trials. The
| situation cannot be THAT bad.
| lotsofpulp wrote:
| While the current participants in the system might not be
| perfect, it should be appreciated that humanity has seldom
| had it better in terms of being able to trust civic
| institutions.
|
| I don't see the purpose of complaining about it in a
| situation where the institutions are working as intended
| (and desired).
| mlyle wrote:
| Here, the institution has approved a couple Alzheimers
| drugs and an ALS drug that do nothing-- overcome by both
| things mentioned above that should not have the power to
| approve a drug -- "greed from the drug manufacturer and
| wishful thinking from the afflicted" -- indeed, the exact
| purpose of drug regulators is to safeguard is from those
| things.
|
| So: there's a purpose in complaining about it and hoping
| that regulator and regulation can be improved.
| slibhb wrote:
| The drug didn't hurt patients, did it?
|
| This kind of failure seems relatively benign.
| tester89 wrote:
| 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.
| rafaelero wrote:
| You don't have to worry about that, because companies are
| the ones financing it and if they don't believe the drug
| have a good chance of working they won't fund it.
| skwirl wrote:
| I don't think there were many better hopes out there for
| ALS. That's why they approved the drug despite weak data
| supporting it. This outcome is devastating for people with
| ALS and their families.
| Karunamon wrote:
| As someone with ALS, This drug was prescribed for me by
| my doctor as equivalent to other ALS medications, namely
| that they barely slow the progression of the disease. We
| are talking three to six months of life extension.
|
| You are overselling the effects of this drug harder than
| the manufacturer did.
| contravariant wrote:
| If you still think that kind of false hope doesn't hurt then
| I sincerely wish you never have to find out otherwise.
| slibhb wrote:
| I'm strongly in favor of experimental drug trials, most of
| which will fail. "False hope" is a small price to pay.
|
| According to the article, the evidence for this drug was
| never substantial. We know it doesn't work now, onto the
| next.
| ryanschaefer wrote:
| Could you explain more what you mean by this?
|
| I guess there's the fact it made it to Phase III before
| they canned it meaning more people were hopeful than if
| action were taken to stop progress sooner.
|
| But, how can progress be made if failure is disallowed
| because of unknowingly giving people false hope?
| contravariant wrote:
| I'm not saying to disallow it, but please at least
| understand that it still hurts.
| mlyle wrote:
| It made it to phase III: fine, there was enough evidence
| in the dubious phase II to perhaps justify a further
| trial.
|
| But _selling it to patients as an ALS therapy in the
| meantime outside of that trial_ , when it looked very
| dubious that it did anything-- that was a little
| questionable. The FDA overruling their own advisory
| committee to make this possible looks like a regulatory
| failure.
| dageshi wrote:
| I suppose we can try no new drugs and give nobody any false
| hope, presumably we'll be better off then?
| CamperBob2 wrote:
| 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 wrote:
| > 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 wrote:
| 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.
| ethanbond wrote:
| What? It didn't get approved. It failed Phase III as designed.
| mlyle wrote:
| 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_1 wrote:
| 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.
| rafaelero wrote:
| 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.
| ejb999 wrote:
| 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.
| rafaelero wrote:
| That's what Phase II is for.
| SoftTalker wrote:
| 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.
| rafaelero wrote:
| The FDA could impose a ceiling over the price the company
| is allowed to charge if they are in a situation where there
| is reasonable expectation of efficacy but the trials
| haven't been consistent. Would that appease your concerns?
| JoshuaRogers wrote:
| Extending this further, the belief that a competitor has an
| effective drug gaining traction in the market while you are
| still at an unpromising point in research could reasonably
| lead companies to focus their research elsewhere. After
| all, your costs don't go down for research if a competitor
| is already delivering, but your likely returns do drop.
| bsder wrote:
| 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.
| ethanbond wrote:
| 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 wrote:
| 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.
| arrosenberg wrote:
| 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.
| firejake308 wrote:
| Is it wrong for desperate patients to spend all their
| savings on ayahuasca-carrot juice? I don't think it's very
| ethical of the juice seller to exploit patients by selling
| them hope, but it doesn't feel like it should be illegal,
| since the patient does get some value out of the purchase,
| even if it's just (false) hope
| y-c-o-m-b wrote:
| 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 wrote:
| 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.
| SoftTalker wrote:
| 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.
| thenerdhead wrote:
| 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 wrote:
| > 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 wrote:
| One wonders how they got as far as Phase III trials without
| actually working.
| zeroonetwothree wrote:
| Phase III is when you test efficacy so it's exactly how it's
| meant to be
| moritzwarhier wrote:
| considering costs this doesn't sound very utilitarian
| pc86 wrote:
| Why would you test something for efficacy before you're
| sure it's safe? You'll end up testing a bunch of harmful
| substances that don't actually do anything.
| moritzwarhier wrote:
| Fair point, although it also seems nonsensical to test
| safety for human consumption before having a robust
| hypothesis for desired effects.
|
| It's not true that safety is fast and easy to check.
| SoftTalker wrote:
| Maybe because the real standard is "the benefits out
| weigh the risks" you might want a drug that has a 10%
| chance of harm if it has a 90% chance of benefit, for a
| condition that is terminal if untreated.
| arrosenberg wrote:
| Is there utility in knowing the lethal dose of a drug
| before you administer an efficacy study. Libertarians
| wonder...
| dredmorbius wrote:
| In this case, the FDA _had_ approved the drug, though
| conditionally.
|
| Second 'graph of TFA:
|
| _A second advisory committee meeting was convened, and if
| that phrase sounds odd to you, it should. That 's a very
| unusual thing to do. This one voted for approval, and the
| FDA did approve the drug in September of 2022. There was a
| condition, though: Amylyx was already working on a Phase
| III trial, and they committed to withdrawing the drug if
| this trial showed no efficacy._
| dredmorbius wrote:
| 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 wrote:
| 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.
| dlevine wrote:
| 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.
| thenerdhead wrote:
| 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.
| ProjectArcturis wrote:
| 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.
| thenerdhead wrote:
| Ah so a patent company who wanted to make a profit?
|
| https://www.regulations.gov/docket/FDA-2023-E-2605
|
| Interesting!
| cat_plus_plus wrote:
| 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 wrote:
| 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.
| thenerdhead wrote:
| 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...
| marcinzm wrote:
| > Quacks won't be allowed in such regulated environments.
|
| Presumably, however, pharmaceutical companies striving to
| maximize shareholder value at all costs are allowed which
| is probably much worse in the end.
| thenerdhead wrote:
| Yes they are free to do that if their drugs work. That's
| allowed in any capitalist market.
| marcinzm wrote:
| You can't lower the thresholds for determining if a drug
| works also also argue that you're not lowering
| thresholds.
| thenerdhead wrote:
| You clearly didn't read or understand what the bill is
| saying.
|
| This might be helpful to understand context too:
| https://youtu.be/ma0xH0EI7Us?si=Qhg5pz6-FgYC0j_o
| karaterobot wrote:
| > 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.
| ProjectArcturis wrote:
| It's both. The FDA erred in approving this ineffective drug
| based on weak P2 data.
| j7ake wrote:
| Failing so late in the drug process can literally bankrupt a
| company.
| StanAngeloff wrote:
| 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 wrote:
| Probably someone made money off it as according to the
| article this was the clear outcome.
| thenerdhead wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| 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.
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