FDA approves first gene therapy treatment of Duchenne muscular dystrophy | Hacker News Reader

FDA approves first gene therapy treatment of Duchenne muscular dystrophy

fda.gov

239 pointsWaitWaitWha73 comments

I appreciate that most people in this thread are not intimately familiar with this disease, but the casual attitude to it is woefully missing it’s savageness.

It unfortunately took my nephew’s good friends life at 13 years of age. You would have never known he had a disease until well past the age of 5. His family provided the most cutting age treatments available including those not yet FDA approved. Yet he deteriorated rapidly between the ages of 10 and 13.

For those that don’t know, it is almost impossible to survive past 25 with DMD

I cannot speak to the efficacy of this particular drug, but I will optimistically celebrate its approval in hopes that no other family has to watch their child suffer.

My friend’s boy died just after entering college with it. Ugh.

It's definitely possible to survive past 25, that's just the average life expectancy.

That doesn't sum it up at all.

Without ventilation almost everyone dies by 25 which was the case until the 70s. The poster is right there's a marked decline by your early 20s. And depending on when and where their story happened it could be very accurate: it was almost impossible to make it past 25.

Almost everyone needs to be on ventilation to make it further and then the median survival is just shy of 30. That significantly impacts your quality of life unfortunately.

I think it would be better for the quality of discourse if people online would stop going into discussions about numbers like this without easily googleable sources.

Meta analysis from end of 2021:

https://n.neurology.org/content/97/23/e2304

"The median survival age from the pre-1970 birth cohort was 18.3 years (95% CI 18.0, 18.9) compared to 24.0 years in the 1970 to 1990 birth cohort (95% CI 22.8, 25.0) and 28.1 years in the post-1990 birth cohort (95% CI 25.1, 30.3)."

"The cohort analysis is also likely to represent a comparison of ventilated and nonventilated patients because ventilation was introduced in many clinical settings only in the 1990s."

Sorry, I'm unfortunately aware, a friend of mine succumbed to DMD at just 21 even with significant medical care. I was just taking issue with the rather absolute "impossible to survive".

This is exciting, although the cost of treatment is very high. Contributing factors to the high cost is that gene therapy is a cutting edge approach with a high failure rate and thus high development costs, and DMD is a rare disease with a small patient population. In time, as the development of gene therapy treatments become more refined, costs will go down.

Successes in gene therapy treatments are exciting, as the success rate of traditional small molecule therapies have stagnated over the last 10-20 years. Moreover, small molecule therapies may never prove effective in treating many genetic diseases.

The disease itself is incredibly expensive. The price of breakthrough treatments will come down faster than the costs of having the disease.

I don’t know the specifics of the costs of caring for one with DMD, but I strongly agree that in general, new disease therapies are the only sure way to drive down medical costs in the medium and long term. This represents a victory, no doubt.

It is very expensive. We will likely have $2M USD in insurance claims for medical this year, and our son is currently aged out of the approved label. At a gross cost of $3.2M for this treatment, its expensive but definitely cost effective relatively speaking.

Considering this new treatment is just a single dose[^1] that hopefully lasts for quite a while[^2], it might actually cost a lot less in the long run.

[^1] see FDA press release and monograph. addditional doses won't do much because by then the immune system has learned to attack the AAV vector -- a different vector strain would be needed and that would be a new drug to be approved

[^2] no idea what the turnover rate is. and honestly, the FDA isn't even sure it helps with anything, hence conditional.

It is exciting! As others in the thread are saying, the cost of individuals with severe rare diseases are also very high.

Here’s a recent attempt at quantifying the costs across all rare disease:

https://chiesirarediseases.com/assets/pdf/chiesiglobalraredi...

I remember over lunch with a person researching custom DNA vaccines and he mentioned to get personalized injectable grade DNA made per person costs a million dollars. My mind was blown.

I agree: It is mind-blowing -- the cost, but the science is also mind-blowing. This stuff really is science fiction. When I was a kid, I could never imagine it was possible. Think how primitive computers were 30 years ago. All of these bio-breakthroughs are impossible without staggering amounts of compute and improved laboratory hardware.

My thinking: How long for each divide-by-ten step? 1M USD today, 100K USD next, 10K USD later. At 10K USD, for these life threatening diseases, it is a drop in the bucket. Any insurance company would pay for it, because it would easily save many times more in avoided treatments for the illness.

Think about the revolution that 3D printers brought. I could see something similar for custom DNA vaccines. They should be targeting wealthy people who want cosmetic effects, like hair regrowth, less wrinkles, hormones like a 30 year old, etc. They can pay, and it will help to mature the industry and production pipeline.

If the rate of price-decline of DNA sequencing is any referece: it took 14 years for the price of that to be devided by 100.000.

So 3,5M USD cost now would be 35 USD in 14 years (not taking into account any hyperinflation that I think is likely in that same time-frame).

    hyperinflation that I think is likely in that same time-frame

What a laugh. Every time I see people talk about economics on HN, the level of discourse is so poor and uneducated. "[H]yperinflation" - you mean like Weimar Republic where people needed wheelbarrows of money to buy a loaf of bread? Forget it. It is the stuff of fantasy. You would have a constitutional crisis in any modern democracy before it got that far. Look at the Oil Crisis(es) in the 1970s. Inflation got so out of control that Central Banks needed to jack up rates to nearly 20%, but they won. No wheelbarrows of money. We had nothing even close since then. (Here it comes: "Oh, but this time is different!" No, it isn't. So many people forget what _some_ inflation feels like. It's been 30 YEARS without inflation over 1% in Japan and it has mentally stunted the economic thinking and planning for multiple generations.)

If I could, I would sell "insurance" against hyperinflation all day long. Like taking candy from a baby; it would be such easy money. For example, write options on Fed Funds rate at 25%. You can pay me your option premium all you want.

The cost has nothing to do with the cost of sequencing DNA. DMD is extremely rare and expensive. The gene therapy itself is very cheap. The cost of the drug is entirely due to the value it provides.

The company is already talking about upping the price to $12 million.

To be fair, research isn't free. If the total addressable population of sick people is very tiny, then the fee needs to be enormous for each person. I am OK with some kind of rich gov't programme to negotiate and pay this fee. After R&D is paid for, plus some handsome profit, the fees can drop and we can export to developing countries.

I'm not criticizing the cost at all. It's a deadly disease that ravages people's bodies and over a lifetime costs tens of millions. Even $12 million seems fair.

Just pointing out that genetics getting cheaper has no effect here.

In principle, these costs could be 1000x less. Much like minicomputer -> dell price shift.

This treatment targets the dystrophin protein which "helps keep the body’s muscle cells intact".

Turns out issues with dystrophin also affect telomere length (at least as studied in the heart of DMD patients [0]).

Is this a possible route for natural aging-related research?

From [1], "Overall, these data suggest that age-dependent alterations in dystrophin leave the muscle membrane and NMJ more susceptible to contraction-induced damage even before changes in muscle mass are obvious." (tests on rodents)

[0] https://med.stanford.edu/cvi/mission/news_center/articles_an...

[1] https://academic.oup.com/biomedgerontology/article/72/5/640/...

So far, most age related medicine only come in two forms, those that reduce cell division which improves longevity, and those that increase cell division which improves youthfullness and cancer. Telomeres seem to be a natural counter to reduce aging cells from becoming cancer.

It's not so simple. Long and short telomeres can lead to cancer.

Short telomeres or their loss can lead to genome rearrangements and other chromosomal problems. This can set the stage for oncogenesis.

Long telomeres can allow cells to continue to divide many times. This also can lead to an accumulation of oncogenic drivers. https://www.nejm.org/doi/full/10.1056/NEJMoa2300503

As with many things in biology, maintaining balance is important. Many factors are at play. The message that longer telomeres are better is beguiling, but nature would not make such a simple mistake.

Yes, nature intentionally made telomeres shorten in several animals including humans. Genetic variety results in an increased chance of a species surviving rapidly changing environments. Eliminating the longer lived increases the genetic variety within a species by favoring breeding among the shorter lived. Telomere shortening results in the elimination of the longer lived.

Everytime cells divide they have an increased risk of becoming cancer cells. But not allowing cells to divide is certain death.

Interestingly, after months of chopping along at the whims of the FDA, the stock actually sold off a little today after the news came out at 2pm.[1]

A good example of what it means for news to to be "already priced in," and how in fact, too many traders in a name can overcrowd it and destroy the alpha. It's like game theory.

[1] https://yhoo.it/3pbC6aB

I somewhat understand your point but the facts imperfectly support it. If information was already priced in, say 90% chance of success, a positive outcome would still provide a lift from the remaining 10%.

The decrease sounds like something else is going on.

2% is nothing for a single name stock. Who cares. It is just noise.

Looking at the close price history here: https://www.google.com/search?q=SRPT+price&rlz=1C1GCEB_enJP1...

Overall, the last one year has been pretty flat for this stock.

"Buy the rumor, sell the news"

The approved label reduced access to 4 and 5 year olds, shrinking the market opportunity in the short term.

It’s more like ppl sell because they know bull with this environment will keep buying till news hits

Stock prices have nothing to do with the successes or failures of a company, and everything with hype, marketing, and mainstream appeal. Same with cryptocurrencies and the likes. It's not a rational market, but everyone talks about it like it is.

Gene therapies continue to be delivered using adeno-associated viruses (AAV), which means the essential issue of overexpression hasn't been adequately addressed. This impending clinical trial could very likely result in robust immune responses, potentially necessitating patients to take immunosuppressive drugs for the rest of their lives.

Could someone clarify, does gene therapy cause a permanent gene mutation that can be passed on to offspring?

It could. This is administered via an AAV rh74 vector, an adenovirus isolated from Rhesus monkeys. There is nothing stopping it from getting into the germ line. Notably, this effect may be primarily seen in males, as gametogenesis (cell divisions leading to sperm/eggs) is ongoing throughout life, in contrast to females where gametogenesis has completed at birth.

1. They're using a modified protein 1/4th the size of the regular muscle protein. 2. They only showed they can hit a surrogate endpoint, not a clinical benefit yet.

It'll be interesting to see what happens. I hope these kids have better lives as a result of this treatment.

As a first of kind treatment, they really didn't pick the right endpoints. Seeing videos of kids able to walk up stairs with confidence, after treatment, when they couldn't before, is rather compelling as evidence. Evidence will also be hard to come by in normal quantities given the disease rarity.

For a marketing video that contains both untreated, and before and after DMD with this med, the outcomes are remarkable. https://youtube.com/watch?v=IolcG-a2yeY&feature=share8

This is reassuring. My wife's family has a hyper-rare form of mostly-harmless DMD -- like, every genetic test says my father in law has DMD but he's a healthy octogenarian when most sufferers never saw 30. But it means I always worry about mys son and nephews that may have the gene.

Serum CK testing would be a reasonable cost available surrogate test, if in normal range than muscle isn't being destroyed as one would see in traditional DMD cases. If high, run the genetic test, free in the US and Canada via Decode Duchenne.

Recent Nature article on the treatment https://www.nature.com/articles/d41586-023-01799-z

Is this the disease they had the telethon about when we were kids? The Jerry Lewis one, maybe I’m showing my age

Those were for the Muscular Dystophy Association, who cover DMD along with many other neuromuscular diseases.

Remember Jesse Gelsinger

It's unfortunate that biotech funding also depends on the same low rate environment that tech does, because while the tech industry has mostly been spinning its wheels on nonsense after the iPhone (like crypto), there's real innovation in biotech.

> unfortunate that biotech funding also depends on the same low rate environment that tech does

Maybe this is me peak Chesterton’s fencing it, but there appears to be merit to the peristalsis of exuberant optimism followed by pruning discipline. Absent the first, we wouldn’t have the science. Absent the second, the pressure to push a product diminishes.

Partially disagree. a lot of bio is jam packed with people pre maturely hyping mouse model success. In that way (the hype machine), it's not that different from tech.

As someone who works in the life sciences, I will come to the defense of my colleagues working in tech. A fair amount of life science progress is driven by innovations borne in tech. For instance, deep learning, and specifically GANS, is helping transform image analysis. Also the tech industry is making it possible to process the vast amounts of data produced in the life sciences. Hats off to you guys, great work, seriously.

I will say that some aspects of tech (I.e social media driven partisanship, surveillance capitalism, click-back attention stealing advertisement and ‘engagement’) is a (large) net negative, but hopefully over time we will better learn how to manage these negatives.

I mean, older tech now, but CAT and CT scans wouldn't have been possible without the huge amounts of processing power and analysis algorithms that the tech industry came up with. One high resolution CT scan generates 350GB of raw data: https://xraylab.esci.umn.edu/frequently-asked-questions#Data

CAT=CT

Yeah ChatGPT and Stable Diffusion are just a bunch of nonsense...

overly defensive. kind of proves the point.

The us military wastes 2.01 trillion dollars a year, any alignment between ending human suffering and capitalism is merely incidental.

> us military wastes 2.01 trillion dollars a year

Do you think gene therapies are developed while the scientists are dealing with food insecurity and competing warlords?

Is that what $2T a year is buying? Looking at the wars over the last twenty years, it's far from clear that the presence of the US military has really helped reduce or end conflict.

Not living in a war-torn country like Ukraine where schools and scientists are being hit by missiles?

You might make a compelling argument that us defense spending hasn't helped conflict abroad, but the last military conflict of note on us soil was Pearl Harbor in World War II.

A reasonable person might conclude that us defense spending has been very effective at preventing military conflicts on us soil.

And maybe the case that us defense spending even increases the number of global conflicts if it reduces the chance of conflict at home.

The question isn't if the US defense spending increases or decreases total conflict, but for whom it increases or decreases conflict

The US is creating that war-torn country so that it can test it's capabilities and weaken Russia at the same time.

Your point still stands though, but I don't think in the way you meant it.

Russia invaded Ukraine. Unless you think Russia is a US puppet helping the US weaken Russia, I think you should check your prejudices.

> Russia invaded Ukraine. Unless you think Russia is a US puppet helping the US weaken Russia, I think you should check your prejudices.

The US had been supporting Ukraine before that, both by proxy and explicitly (https://www.state.gov/u-s-security-cooperation-with-ukraine/). The Russian invasion was incidental to, not a trigger to instigating, the US support of Ukraine. The over-arching behavior, of weakening Russian influence in a region, has been consistent.

I think it's a valid point and the meaning is clear. If you want me to spell it out, it would be to the advantage of the US military security if every combat capable Ukrainian and Russian were dead.

Ukrainian life isn't a threat as much as trivial cost.

Given this priority, it should be no surprise that US military policy results in great death and destruction abroad but not at home.

> it's far from clear that the presence of the US military has really helped reduce or end conflict

This is difficult to answer. What can be shown is the post-WWII era has been unusually peaceful within the scope of the modern era of nation states. We’re coming up against the century of no great power conflicts of the Metternich Era.

The fact is that US military spending is not to prop up the military. A lot of it is basically just a make work program for civilians.

Military leaders have warned for years that one of our biggest threats is our deficit and borrowing money. Every time that the military tries to close unneeded bases and get rid of weapons that aren’t needed, they are thwarted by Congress who doesn’t want to lose jobs in their district.

There is a reason that military weapon makers spread out manufacturing throughout the US.

The worldwide US military presence has a suppressive effect on wars; I'm confident south-east Asia would have been in multiple wars since WW2 if it wasn't for US presence, and Russia would've tried to take back its former soviet countries if it wasn't for NATO which is mostly the US's $2T army.

And I don't think the US has had to deploy its full capacity for a long time, not even Iraq / Afghanistan. That's more of a logistics issue though, they could've multiplied their forces and materials but it wouldn't be any more beneficial.

The entire US military budget is approximately $800B. The first clause of your sentence is factually incorrect; the second is a non sequitur.

1) That's the amount google returns when asking "What is the US military budged?", forgive me if I wrongly trusted it.

2) Non sequitur? You really believe that spending on war technology (War as in kill-humans-we-dont-like-department) is in no clear way in opposition to spending on health technology? (health as in lets-make-everything-possible-to-make-humans-not-die-department)

Not sure why you're being down voted, here's the data:

https://www.usaspending.gov/explorer/budget_function

Here's what the whitehouse thinks it is, https://www.whitehouse.gov/wp-content/uploads/2023/03/budget... (page 63)

I made a typo which I’ve corrected ($800M —-> $800B).

$800B

Correct, $800B, not $800M. Thank you for catching the typo. I edited the original post.

The first Neuro lab I worked in was funded by the department of defense. Focus was the effects of traumatic brain injury and mechanisms that cause it. It wasnt 2.1 trillion in funding so I can't account for a lot of that I guess

US government military spending is all driven by central planning...

It's driven by the MIC to buy expensive shit they don't need and doesn't work like the F-35.

I hardly think lobbying is unique to capitalism. The USSR was famous for political games to win favor with those who allocated things, just like the US military contractor system. Politics are a human issue, not a capitalism one.

Saying US military spending reflects poorly on capitalism is just about the dumbest possible anti-capitalist argument. There is so much more low-hanging fruit. Start with non-centrally-managed monopolies and work your way around various nasty corporate practices from there.

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