We have news of a failed trial for what was not going to be a huge drug, but this one could have larger implications given the current state of the FDA. Ionis, a company that has been hammering away at antisense for a very long time now, had previously licensed a compound called tofersen to Biogen. That’s an antisense oligonucleotide drug aimed at a particular form of ALS, the subgroup where the major problem seems to be mutation of the SOD1 protein.
SOD1 is one of the three isoforms of superoxide dismutase, an enzyme that clears out superoxide free radicals from the mitochondrial and general cellular environment. It turns them into hydrogen peroxide, which is then broken down by another enzyme, catalase. There’s no real way for oxygen-using life to avoid such reactive species being formed, thus the various cellular systems that have evolved to deal with them. You’d think that this would be a situation where some sort of less-active SOD1 would lead to the disease, but instead, it actually seems to be something else, and the details aren’t quite clear. Deleting SOD1 entirely in animal models, for example, does indeed cause problems, but ALS isn’t one of them, and the mutant forms of SOD1 associated with the disease maintain their ability to process superoxide. There are clues pointing in several different directions: it appears that SOD1 re-localizes to the nucleus in some ALS cases, perhaps trying to protect against oxidative damage to DNA. And there’s trouble with misfolded SOD1 inclusions in the neurones of ALS patients carrying mutations in other genes entirely. Tofersen was in fact targeted at a particular SOD1 subset where the mutation in the protein sequence led directly to such toxic misfolding.
And whatever the mechanism, you would imagine that interfering with the production of mutant SOD1 protein could be a valuable intervention in the smaller cohort of ALS patients that fit that profile. Thus the antisense idea – as usual, the drug is a DNA oligonucleotide that is designed to perfectly complement the mRNA strand for the targeted protein: by binding to it, the translation of that mRNA is blocked, and no protein gets produced. This ability to reach in and block production of any given protein species is a powerful and exciting idea, but for at least the last thirty years it has been painfully difficult to turn it into the magic wand that it might sound like. Some of that is due to difficulties in making oligos that can survive dosing, enter the cells, and do the targeted job that you’re picturing. But some of it has also been due to the sorts of targets that get proposed for such a technology. No one reaches for antisense if they have easier alternatives, so it (and other such ideas) tend to accumulate really hard, risky, back-to-the-wall targets. And that’s when we find out that we didn’t know quite as much about the biology as we thought.
That might well be what happened here. Tofersen completely missed its primary endpoint of slowing the progression of the disease, unfortunately. This is in spite of data showing that it did indeed reduce levels of the mutant SOD1 protein – it’s just that this didn’t do anywhere near as much good as had been hoped. Biogen is talking up signs of improvement in some secondary markers, but the fact remains: this drug did not do what it was supposed to do. On a widely used scale of function for ALS patients, there was no statistical difference between the people taking the drug and the ones getting standard of care (which for ALS is sadly not much). Tofersen did not make anyone better. It did not slow down the rate at which they were getting worse. It did not work.
But you know, neither did Biogen’s antibody for Alzheimer’s, and we see what happened there. No one knows if the company is going to try a similar “Approve us anyway!” strategy for this drug and to be honest, I doubt it, because the Alzheimer’s success or failure could affect Biogen’s entire survival, and this form of ALS is in the end a very small orphan indication. Biogen’s press release says that they are “actively engaging with regulators, the medical community, patient advocacy groups and other key stakeholders around the world to determine potential next steps“. Now, that’s just the sort of thing that everyone always says when their drug fails, and often those “next steps” are just what you’d think they would be, i.e. folding up the tents and leaving. But after the recent approval for Alzheimer’s, everyone in that field seems to have gone back and shoveled the dirt off their buried clinical candidates with a thought of taking them to the FDA, under what we might call the “No worse than Aduhelm” regulatory standard.
I continue to think that that is a terrible state of affairs. I just can’t understand the reasoning behind this idea of “Give the patients something that doesn’t help them, because there’s nothing else to give them”. This isn’t even the libertarian paradise of “Right to Try”, because under that sort of regulatory regime you don’t even run efficacy trials if you go all the way with the idea. You just prove safety and let everyone have at everything to sort it out. I don’t much like that one, either (as I’ve said at length here over the years), but you know what? It’s still better than deliberately approving things that have already been shown that they don’t work at all.
So if Biogen comes up with some ideas about new patient subgroups (how small would those be?) or a new dosing schedule, anything like that, and they want to go back into the clinic to show efficacy, well, I wish them the best and I hope something works. But if they try to make a case for approval of this drug on the data that we have now, then we will all have to ask ourselves what the hell is going on. Because let’s not kid ourselves: “Approve us anyway!” is another way of saying “Let us sell this stuff anyway!” and that is exactly what we don’t need. We are in the business of selling treatments that will help people. Right? What would we call the business of selling them stuff when we have proven it doesn’t?
Whatever you call it, I don’t think I particuarly want to be part of it. I’d rather seek honest work instead.
