Path open for HIV/AIDS cure
August 19, 2023 10:56 AM Subscribe
Gene splicing treatment cures Simian Immunodeficiency Virus in non-human primates, next will be HIV in humans. "Analyses showed that EBT-001 was broadly distributed, reaching tissues throughout the body, with evidence of gene editing of SIV proviral DNA in all significant viral reservoirs. Moreover, EBT-001 was well-tolerated at all dose levels, with no evidence of toxicity in clinical examination of the animals or following histopathological investigation." [Medical Express]
This is fucking incredible, but outside my field of expertise, and based on a press release.Can anyone in the field talk about how seriously we should take the paper?
The technique itself passes the smell test. They use techniques that may be novel but in a logical way to eliminate the reservoir of SIV from the cells using a proven delivery method. PreP for example is usually two NRTIs which stop the HIV from integrating itself into the genome. Using CRISPR after infection is the pound of cure that goes along with the proverbial ounce of prevention that is PreP.
posted by Your Childhood Pet Rock at 12:19 PM on August 19, 2023 [11 favorites]
The technique itself passes the smell test. They use techniques that may be novel but in a logical way to eliminate the reservoir of SIV from the cells using a proven delivery method. PreP for example is usually two NRTIs which stop the HIV from integrating itself into the genome. Using CRISPR after infection is the pound of cure that goes along with the proverbial ounce of prevention that is PreP.
posted by Your Childhood Pet Rock at 12:19 PM on August 19, 2023 [11 favorites]
It seems very promising. Do keep in mind, however, that a treatment at this stage of testing is (barring extenuating circumstances and mega-international investment of the type we saw for Covid) at least 10 years out from being fully approved and available.
The other current major impediment to gene therapy type treatments is their cost. It is some billions to take a treatment like this through regulatory approval, and then the amount charged per treatment is usually somewhere in the millions. Here is a decent discussion of the economics of gene therapy treatments.
The good news is, it's situations like this that have the potential, at least, to bring the cost way, way down. There are currently 39 million people worldwide living with HIV. So that gives the potential, at least, for treatments that cost more in the hundreds than in the millions.
If you're wondering why the cost for treatments like this is so high: Say this treatment costs $5 billion to develop and get through regulatory approval. Say there are 1.2 million people in the U.S. who need to be treated. If you treat every single one of those people, you have 5 billion/1.2 million = $4200 per person.
That's just to cover regulatory/development costs. Then of course there are production/distribution costs and the normal cost of medical care etc etc . Probably easily $10000/person altogether.
So that seems expensive but still well worth it as the lifetime cost of living with HIV infection is likely to be w-a-y higher than $10000. Still, $10000 is a lot of dough for most people to come up with at one go, especially those who are uninsured or whose insurance won't cover it - which is most likely to be the case for at least the first several years it is available.
So if you're the drug company trying to figure out how much to charge for your new drug, you can't depend on 100% coverage - probably more like 5% even if you're being extremely optimistic. Now instead of $4200/treatment to cover development/regulatory costs you're more like $83,000. And of course at $83,000 even fewer people can afford it so maybe it's 1% of eligible patients instead of 5%. Oopsie, now it's more like $500,000/patient just to cover development & regulatory costs.
So on the one hand, you can see how these drugs end up costing in the millions. Charging $1 million per dose with a goal of reaching 0.5% of eligible patients is actually a pretty realistic goal. Whereas charging $5000/dose with the goal of reaching 100% of patients is a great idea but many, many orders of magnitude more difficult to achieve - if you can do it at all.
So it's a bit of a chicken and egg situation. If you could break through and reach the majority of eligible patients - not even all patients but, say, the majority - then cost would be high but realistic. But it's way more achievable for any individual company to shoot for the top 0.5% or even 0.1% of the market and charge the price they can for that piece of the market.
It's probably going to take government intervention of some sort to break that deadlock. Something like an HIV treatment - which has a large and pretty activist patient base - has a better than average chance for breaking through on something like this.
And . . . we haven't even talked about the remaining 38 million or so worldwide infected with HIV. But the point is, if the developers can recoup their costs in the U.S. (and a few other high-income countries) then the cost per treatment should come way down after that. So that's your most likely (and probably most realistic) path for getting to a treatment that has a per-treatment cost low enough to reach the millions and millions it really needs to.
posted by flug at 1:58 PM on August 19, 2023 [18 favorites]
The other current major impediment to gene therapy type treatments is their cost. It is some billions to take a treatment like this through regulatory approval, and then the amount charged per treatment is usually somewhere in the millions. Here is a decent discussion of the economics of gene therapy treatments.
The good news is, it's situations like this that have the potential, at least, to bring the cost way, way down. There are currently 39 million people worldwide living with HIV. So that gives the potential, at least, for treatments that cost more in the hundreds than in the millions.
If you're wondering why the cost for treatments like this is so high: Say this treatment costs $5 billion to develop and get through regulatory approval. Say there are 1.2 million people in the U.S. who need to be treated. If you treat every single one of those people, you have 5 billion/1.2 million = $4200 per person.
That's just to cover regulatory/development costs. Then of course there are production/distribution costs and the normal cost of medical care etc etc . Probably easily $10000/person altogether.
So that seems expensive but still well worth it as the lifetime cost of living with HIV infection is likely to be w-a-y higher than $10000. Still, $10000 is a lot of dough for most people to come up with at one go, especially those who are uninsured or whose insurance won't cover it - which is most likely to be the case for at least the first several years it is available.
So if you're the drug company trying to figure out how much to charge for your new drug, you can't depend on 100% coverage - probably more like 5% even if you're being extremely optimistic. Now instead of $4200/treatment to cover development/regulatory costs you're more like $83,000. And of course at $83,000 even fewer people can afford it so maybe it's 1% of eligible patients instead of 5%. Oopsie, now it's more like $500,000/patient just to cover development & regulatory costs.
So on the one hand, you can see how these drugs end up costing in the millions. Charging $1 million per dose with a goal of reaching 0.5% of eligible patients is actually a pretty realistic goal. Whereas charging $5000/dose with the goal of reaching 100% of patients is a great idea but many, many orders of magnitude more difficult to achieve - if you can do it at all.
So it's a bit of a chicken and egg situation. If you could break through and reach the majority of eligible patients - not even all patients but, say, the majority - then cost would be high but realistic. But it's way more achievable for any individual company to shoot for the top 0.5% or even 0.1% of the market and charge the price they can for that piece of the market.
It's probably going to take government intervention of some sort to break that deadlock. Something like an HIV treatment - which has a large and pretty activist patient base - has a better than average chance for breaking through on something like this.
And . . . we haven't even talked about the remaining 38 million or so worldwide infected with HIV. But the point is, if the developers can recoup their costs in the U.S. (and a few other high-income countries) then the cost per treatment should come way down after that. So that's your most likely (and probably most realistic) path for getting to a treatment that has a per-treatment cost low enough to reach the millions and millions it really needs to.
posted by flug at 1:58 PM on August 19, 2023 [18 favorites]
This is indeed promising, but in addition to the hurdles flug mentioned above, the Trumpists and other assorted antivaxxers are going to have a field day with this. Remember, these are people who already think PREP is immoral and shouldn’t be paid for by the government.
posted by TedW at 3:54 PM on August 19, 2023
posted by TedW at 3:54 PM on August 19, 2023
PreP for example is usually two NRTIs which stop the HIV from integrating itself into the genome. Using CRISPR after infection is the pound of cure that goes along with the proverbial ounce of prevention that is PreP.
PrEP
posted by They sucked his brains out! at 5:05 PM on August 19, 2023
PrEP
posted by They sucked his brains out! at 5:05 PM on August 19, 2023
From a little earlier this summer: Excision BioTherapeutics Receives FDA Fast Track Designation for EBT-101, a First-in-Class CRISPR-Based Gene Therapy Candidate to Functionally Cure HIV-1.
posted by mittens at 6:12 PM on August 19, 2023 [2 favorites]
posted by mittens at 6:12 PM on August 19, 2023 [2 favorites]
This sounds amazing ..... and it's going to push so many anti-vaxxer numpty buttons ....
posted by mbo at 6:51 PM on August 19, 2023
posted by mbo at 6:51 PM on August 19, 2023
Can anyone in the field talk about how seriously we should take the paper?
The major question that will have to be addressed are off-target effects (ie are the benefits greater than the risks). CRISPR based techniques you want to know you aren’t cutting the genome in a place that results in cancer by dysregulation of cell cycle. This is the same concern for lentivirus (HIV) which can insert anywhere in open genome, and even the first FDA approved gene therapies that use AAV which mostly only inserts in a few known genomic loci. These techniques are only used in already very sick patients due to the same concerns. It’s an interesting example because we’re talking about removing insertions that have already occurred and risky, plus the risk of the actual HIV virus, compared to the risk of any new additional cuts. I think the greatest hurdle is that for the ultrawealthy markets who would drive initial use… we live in an era in which PreP already results in a functional cure: once previously HIV positive individuals no longer test positive they are considered non-transmissive. PreP too has side effects. I worry the monetary costs, the to-be-determined off-target effects, and incomplete removal of all HIV genomes, compared with functionally effective treatments that already exist, means this treatment might not be as useful as one might hope. But the good news is we already have good treatments (functional cures) that just didn’t seem possible in the 1980s. An example might be, would you get gene therapy to cure migraines if there are effective migraine treatment drugs (multiplying out all the increased risks and efficacy that is the difference between migraines and HIV, and it’s treatment).
Gilead did make a very promising and extremely specific HIV viral capsid inhibitor https://www.science.org/doi/full/10.1126/science.abb4808
posted by rubatan at 12:46 AM on August 20, 2023 [1 favorite]
The major question that will have to be addressed are off-target effects (ie are the benefits greater than the risks). CRISPR based techniques you want to know you aren’t cutting the genome in a place that results in cancer by dysregulation of cell cycle. This is the same concern for lentivirus (HIV) which can insert anywhere in open genome, and even the first FDA approved gene therapies that use AAV which mostly only inserts in a few known genomic loci. These techniques are only used in already very sick patients due to the same concerns. It’s an interesting example because we’re talking about removing insertions that have already occurred and risky, plus the risk of the actual HIV virus, compared to the risk of any new additional cuts. I think the greatest hurdle is that for the ultrawealthy markets who would drive initial use… we live in an era in which PreP already results in a functional cure: once previously HIV positive individuals no longer test positive they are considered non-transmissive. PreP too has side effects. I worry the monetary costs, the to-be-determined off-target effects, and incomplete removal of all HIV genomes, compared with functionally effective treatments that already exist, means this treatment might not be as useful as one might hope. But the good news is we already have good treatments (functional cures) that just didn’t seem possible in the 1980s. An example might be, would you get gene therapy to cure migraines if there are effective migraine treatment drugs (multiplying out all the increased risks and efficacy that is the difference between migraines and HIV, and it’s treatment).
Gilead did make a very promising and extremely specific HIV viral capsid inhibitor https://www.science.org/doi/full/10.1126/science.abb4808
posted by rubatan at 12:46 AM on August 20, 2023 [1 favorite]
(PrEP, not PreP. Sorry, the distinction matters!)
posted by They sucked his brains out! at 1:34 PM on August 20, 2023
posted by They sucked his brains out! at 1:34 PM on August 20, 2023
Wow.
I know it's a long way from a usable treatment for the masses, if it ever gets there, but the fact that things are capable of moving in that direction gives me so much hope. If we can just get past all the stupid things humans do that stop medical care being given to the people who need it.
posted by mathw at 1:55 AM on August 21, 2023
I know it's a long way from a usable treatment for the masses, if it ever gets there, but the fact that things are capable of moving in that direction gives me so much hope. If we can just get past all the stupid things humans do that stop medical care being given to the people who need it.
posted by mathw at 1:55 AM on August 21, 2023
the fact that things are capable of moving in that direction gives me so much hope
There have been so many promising false starts, but this one feels like it's the real deal. As have been mentioned upthread, there are issues with making sure it's only editing HIV DNA and nothing else, but as a layman reading through the Nature paper it seems like they did due diligence to make sure that it was well focussed.
There are lessons being learned here in this research which will also be applied much more widely, similar to mRNA vaccine research and how that's being leveraged toward cancer research and many other subjects.
This isn't going to come quickly but it's so much more than we've ever seen before, I just can't help but see this as entirely hopeful.
posted by hippybear at 2:52 PM on August 21, 2023 [1 favorite]
There have been so many promising false starts, but this one feels like it's the real deal. As have been mentioned upthread, there are issues with making sure it's only editing HIV DNA and nothing else, but as a layman reading through the Nature paper it seems like they did due diligence to make sure that it was well focussed.
There are lessons being learned here in this research which will also be applied much more widely, similar to mRNA vaccine research and how that's being leveraged toward cancer research and many other subjects.
This isn't going to come quickly but it's so much more than we've ever seen before, I just can't help but see this as entirely hopeful.
posted by hippybear at 2:52 PM on August 21, 2023 [1 favorite]
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posted by agentofselection at 11:20 AM on August 19, 2023 [1 favorite]