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Recently, Seelos Therapeutics released an update on its top-line results with IV trehalose, a treatment for amyotrophic lateral sclerosis (ALS) that’s been very promising to date. The results were not received positively by the markets—which gave us pause, as we saw some cause for hope that progress was being made. Here’s what stood out to us:
- Despite not meeting its primary endpoint, trehalose appeared to perform better than previous treatments in the Healey trial, and is worthy of further evaluation, both for ALS and Parkinson’s disease.
- Despite that ongoing potential, market reactions to the results were extremely negative, showcasing the possible disconnect between scientific progress and investor expectations.
- There’s also a disconnect between the preclinical and clinical data in that Seelos chose to administer IV rather than orally. To assess the potential of trehalose from here, we need to better understand the difference in efficacy between oral and IV.
(Disclosure: Atuka has received a grant from the Weston Foundation to better understand how to optimize oral trelahose dosing in Phase II trials.)
Patrick Howson: The Healey ALS platform trial was created by Massachusetts General Hospital, so that instead of just doing a traditional study, where you’re looking at, say, one compound in one study, a platform trial will have multiple arms to it, so you’re essentially assessing multiple treatments against a common placebo in the same environment. Particularly when you’re looking at diseases like ALS, where there are relatively few people with the disease, it’s a way of maximizing the number of studies you can do, strengthening evaluations, and reducing the resources needed. Each treatment arm lasts for six months, and six months in an ALS trial is always a very hard barrier to hit. Nothing in the Healey trial has come close to achieving statistical significance on the primary endpoint .
While trehalose didn’t meet its primary endpoint, if you look at the actual breakdown of the data, trehalose performed better on the primary endpoint (ALSFRS-R) than anything that has previously been in the trial, such as pridopidine or CNM-Au8, and both of these compounds are planned to enter Phase III studies in ALS in 2024. Many compounds in the Healey platform trials, unless they are an absolute wonder drug, will fail to meet the primary endpoint. The question is whether there’s enough in the results to say that we should continue looking at trehalose in ALS. My feeling is that the improvement in ALSFRS-R, when people taking Relyvrio were excluded, is such that the compound is worthy of further evaluation.
Jonathan Brotchie: The interesting thing though was how the market responded to the results, because if you look at its Nasdaq price you can see how the share value dropped in the 48 hours following the announcement of results, with a more than 75% fall in the value of the company.
Patrick: It was a lot. With all these companies, especially of Seelos’s size, people are buying on rumour, so the price is going up beforehand. You’ve got to see that price drop in context—with the expectation of data coming out, the price was going to go up.
Jon: Still, the market responded as though this was bad news. Whereas you’re saying that if you look at the slope of progression of ALS in these patients, it’s actually looking as good as anything that has been in Healey. And had it been a twelve-month study, or had it included twice as many patients—you could do that calculation to work out what it might have required to get to significance.
Patrick: The Healey platform trial evaluates all compounds in a similar way. However, to see a significant effect on ALSFRS-R in six months it may be necessary to select a cohort of people with fast progressing ALS. This approach was taken for the pivotal edaravone clinical study, which showed a significant reduction in the ALSFRS-R of 33% over 24 weeks. Possibly, if trehalose had been evaluated in a similar population, a significant effect could have been observed. Alternatively, a longer clinical trial could also have demonstrated efficacy. The TRICALS platform in Europe, the only other ALS platform trial, is currently running a trial on lithium carbonate that could run for 24 months.
Jon: So these trehalose results are a signal to actually do more studies, rather than this is a signal to exit your investment in the company, or kill the project.
Patrick: Scientifically, yes. I can see from an investor’s point of view, the data are such that they’re saying you’re going to need more money, more time to get the positive result. So I can see why investors leave, especially for a company like Seelos that would have to raise more money to perform another study.
Jon: To be clear, we’re not here to give investment advice, but to think about the science. What does this study tell us about the science? Is it that trehalose, no matter how it might be working, looks reasonably positive?
Patrick: It’s an interesting one. We should note that all of Seelos’s preclinical work with trehalose was orally administered, whereas for this study they used their once-a-week IV formulation. Given that there was no preclinical evidence in models of ALS of the IV treatment having an effect, then to see an effect, even if it’s not a statistically significant one, is very surprising.
Jon: Is surprising the right word? Isn’t it rather lucky? We hypothesize trehalose should have efficacy, but to see the beginnings of an efficacy signal when you switch from oral preclinically to IV clinically, without any obvious bridging work to ensure appropriate target engagement, you’d have to be very lucky. A lot of us have been interested in trehalose, not only for ALS but for Parkinson’s. Does this change our enthusiasm for trehalose and Parkinson’s? Or does it change our enthusiasm for non-IV trehalose? Does it change anything?
Patrick: It’s a shame that Seelos went with an IV formulation for this study, when all the preclinical data on trehalose in ALS is orally administered. If they had followed the preclinical data they might have seen even better results. Still, the fact that you’ve got some clinical data and some preclinical data saying trehalose is positive suggests it’s a good thing to move forward with. But whether the IV is the one that’s going to drive the most efficacy, or the oral one, or a combination, the jury is still out.
June is ALS awareness month in Canada. Nearly 4,000 Canadians live with ALS and approximately 1,000 Canadians are diagnosed each year. Four out of five people living with ALS will die within two to five years of their diagnosis. Atuka is proud to join with the broader research and scientific community in working towards better therapeutics and potentially life-changing treatments.
Patrick Howson is Atuka’s Chief Innovation Officer and one of our lead scientists. Jonathan Brotchie is Atuka’s founder, CEO, and Chairman.
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