Edit: tomorrow’s post will be on this subject too, with some information that I’ve been learning today. . .
Today brought the rather surprising news that the Chinese government’s National Medical Product Administration (NMPA) has approved a new Alzheimer’s drug. What’s more, it’s an unusual (and unexpected) mechanism, so this is worth a close look. What’s going on?
A key paper to read is this one from September published in September in Cell Research. That’s a Nature group journal published in collaboration with the Chinese Society for Cell Biology, and the paper describes work from the Shanghai Institute of Materia Medica and Green Valley Pharmaceutical Co. on a seaweed-derived oligomannate preparation (GV-971). The clinical trials for this have been going for a while now, although the whole effort, it’s safe to say, has not gotten very much attention (here’s a 2018 article on the Phase III results, which to the best of my knowledge have not yet been published).
Why a polysaccharide and why for Alzheimer’s? The story is that there was epidemiological data that suggested a lower incidence of Alzheimer’s among populations that consumed this variety of seaweed. GV-971 appears to be “a mixture of acidic linear oligosaccharides ranging from dimers to decamers”. So this would be polymers of mannose, beta 1,4-linked, that have some of the hydroxy groups sulfated. These are pretty numerous in some seaweed species – apparently the genus Codium (to pick one) uses such polymers as major component of its cell walls, largely replacing cellulose. These sorts of sulfated polysaccharides have been investigated as antiviral agents, but there’s a huge amount of structural variety in this area, and generalizations could be tricky.
I note that the proposed mechanism of action of GV-971 seems to have gone through some stages. This paper from August talked about its ability to interact with and sequester various beta-amyloid species, while noting that its MOA was still up for debate. The September paper linked to in the second paragraph, though, concentrates instead on a gut-bacteria immunology/inflammation mechanism, which frankly is more plausible in its way than any effect on beta-amyloid. Not least because it’s quite difficult to imagine a mannan polysulfate making its way past the blood-brain barrier. But the gut-bacteria explanation, which quite interesting, does make some leaps along the way. People who have been following this field (gut microbiota influencing human disease) will appreciate that it can be very difficult to prove real connections, and that the number of confounding variables is huge. Still, there can be little doubt that this point that such connections are/can be real – the question is, are they real for Alzheimer’s? Here’s the current hypothesis:
We have revealed that gut microbiota patterns and amino acid-derived metabolites are important for the infiltration of specific types of immune cells, which drives neuroinflammation during AD progression. GV-971 therapeutically harnesses the abnormal production of amino acids, infiltration of immune cells to the brain, and in turn neuroinflammation via remodelling the gut microbiota.
The team uses the 5XFAD mouse model, one in which amyloidogenic mutations have been knocked in (similar to what happens in human cases of familial early-onset Alzheimer’s). Like all AD mouse models, there is room to argue about this one. There is no doubt that these animals develop plenty of amyloid plaques and other brain pathology, but I note that there are ongoing arguments about their memory deficits and how those are measured (see that link above), depressingly similar arguments to the ones I used to hear first-hand when I worked in the AD field myself in the early 1990s. Here’s more on that model, specifically on attempts to get it out of the inbred C57 black mouse strain and into a more genetically diverse population that might recapitulate the heterogeneous human etiology of the disease.
The paper notes significant changes in the gut microbiota of the transgenic mice as they age, as compared to the relative stability of wild-type controls, and they relate that to inflammatory changes seen in the brain tissue (such as the infiltration of immune cells from the blood supply). Treatment with GV-971 did seem to alter this progression, and the treated mice also showed improvement on cognitive tests.
Thus the human trials. As mentioned, the data from these has not been published, so it’s very hard to comment on the NMPA decision. The Phase II trials are apparently discussed in this reference (Chin. J. Pharmacol Toxicol. 31, 459-460, 2017), but so far I cannot find the paper itself, only references to it, so I don’t know how detailed it is, either. Here’s all that’s available on the Phase III, from Green Valley’s press release:
The Phase 3 clinical trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 36 week study led by Peking Union Hospital and Shanghai Jiaotong University Medical School Mental Health Center. The study was conducted in 34 Tier-1 hospitals across China. A total of 818 patients with the diagnosis of mild to moderate Alzhemer’s disease completed the study. The trial was conducted in collaboration with IQVIA (formally Quintiles) and Signant Health (formerly Bracket) among other partners.
Trial results demonstrated that Oligomannate statistically improve cognitive function in mild-to-moderate AD patients as early as week 4 and the benefit was sustained at each follow-up assessment visit. The mean difference between Oligomannate and placebo groups in ADAS-Cog12 Score (a standard cognitive measure commonly used in AD studies) was 2.54 (p< 0.0001), with sustained efficacy from first month of treatment to the end of 9 months of treatment. Oligomannate was safe and well tolerated with side effects comparable to the placebo.
This is a conditional approval, with monitoring for safety. The company says that it plans a multinational Phase III trial next year to support regulatory filings in other countries, so we’re going to have to wait to see how that goes to be able to say anything more.
My take: new mechanistic approaches to Alzheimer’s are very much needed, and this certainly is one of those. But the improvements noted in this trial seem to come on very quickly, which makes me wonder, frankly, if they’re real and reproducible. Alzheimer’s is not a disease where one expects such results, and we have to remember that modulating neuroinflammation has been tried before as an AD therapy, without seeing anything like this. In addition, it’s very hard to comment on the ADAS-Cog scores mentioned, because there are significant variations in the way such tests are administered and I am quite leery of generalizing from a single number in a press release. I am very glad, then, that there’s going to be another large Phase III. If this is real, it could be quite significant, and I certainly hope that turns out to be the case. But I can’t say it’s real – none of us can – until we see more data.