When you look at the stock charts of the major pharma companies, there’s not a lot of excitement to be had. Until you get to Eli Lilly, that is. Over the last year, the S&P 500 is up about 5%, and most of the big drug stocks are actually negative (Merck -0.4%, Sanofi down 6%, J&J down 7%, AstraZeneca down 13%). Pfizer pulled away from the index in February, and has held on to that gain (up 13% from a year ago), but Lilly – those guys were doing about as well as Pfizer until the last month or two, but have just ratcheted up since then, for a 1-year gain of over 32%. Why them?
It’s all Alzheimer’s speculation, as this Bloomberg piece goes into. And as has been apparent recently, Alzheimer’s is getting a lot of speculation these days. BIogen really revved things up with their own early-stage data a few months back, and since then, if you’re got an Alzheimer’s program – apparently, any Alzheimer’s program whatsoever – you’re worth throwing money at. Lilly, of course, has been (to their credit) pounding away at the disease for many years now, expensively and to little avail. One of their compounds (a gamma-secretase inhibitor) actually made the condition slightly worse in the treatment group (more here), while their beta-secretase inhibitor failed in the usual way. But they’ve also been major players in the antibody field. Their solanezumab was not impressive in the clinic, except possibly in the subgroup of early-stage patients, and Lilly (showing a great deal of resolve, and arguably some foolhardiness) has been running another Phase III trial in that population.
They also extended the existing trial in that patient group, and are due to report data on that effort very soon – thus the run-up in the company’s stock. This is going to be very interesting, for sure – it would be great for Alzheimer’s patients (and for Lilly) if the results are clearly positive, but that (sad to say) is the least likely outcome. (I’m not just being gloomy for the sake of being gloomy – Alzheimer’s antibodies have had a very hard time showing efficacy under any circumstances, and the all-mechanisms clinical success rate against the disease is basically zero). The same goes, of course, for the new Phase III trial itself. Things could well come out clearly negative, with the possible good results from the earlier trial evaporating the way subgroup analyses tend to when you lean on them. Or – and this is the results I fear the most – there could be wispy sorta-kinda hints of efficacy, in some people, to some degree. Pretty much like the last trial, after which Lilly began beating the PR drums to make things look not so bad.
The reason I think that this would be the worst result is that there is so much demand for something, for anything that might help in Alzheimer’s that there would be a lot of pressure on the FDA to approve Lilly’s drug, even if it still hasn’t proven to do much. And this latest trial really is its best chance. It’s in exactly the population (the only population) that showed any possible efficacy last time, so if the numbers still come out all vague and shimmery under these conditions, that’s a failure, as far as I can see. No one wants to be in the position of explaining statistics and clinical trial design to a bunch of desperate families who may be convinced that a real Alzheimer’s drug is being held up by a bunch of penny-pinching data-chopping bureaucrats.
And this brings us to TauRx. I still get mail about them, seven years after they made big news with a methylene-blue-based Alzheimer’s therapy program. When last heard from, they were in Phase III, with some unusual funding, but there were no scientific results from them for a while. The company, though, has published several papers recently (many available on their web site), talking about their program.
Here’s a paper on their Phase II results. It’s a bit confusing. Their 138 mg/day dose was the most effective; the higher dose was complicated by PK problems (see below). When you look at the clinical markers, it appears that the “mild” Alzheimer’s patients were hardly affected at all (although the SPECT imaging results did show a significant difference on treatment). But the “moderate” Alzheimer’s treatment group showed several differences in various cognitive decline scores at the 138mg/day dose, but no difference in SPECT at all. Another paper, from JBC talks about compound activity in various cell models of tau aggregation. And this one, from JPET, is their explanation for the PK trouble. It appears that the redox state of the methylene blue core has a big effect on dosing in vivo. There are problems with dissolution, absorption (particularly in the presence of food), and uptake of the compound in the oxidized (methylene blue) state (which they abbreviate as MTC, methylthioninium chloride), but these can be circumvented with a stable dosage form of the reduced leuco compound (abbreviated as LTMX). There’s apparently a ph-dependent redox step going on in gastric fluid, so things have to be formulated carefully.
One of the other things that showed up in all this work was a dose-dependent hematological effect, apparently based on methylene blue’s ability to oxidize hemoglobin. It’s not known (at least in these publications) whether dosing the reduced form helps out with this, but it’s potentially a dose-limiting toxicity. So here’s the current state of the art:
Although we have demonstrated that MTC has potential therapeutic utility at the minimum effective dose, it is clear that MTC has significant limitations relative to LMTX, which make it an inferior candidate for further clinical development. MTC is poorly tolerated in the absence of food and is subject to dose-dependent absorption interference when administered with food. Eliminating the inadvertent delayed-release property of the MTC capsules did not protect against food interference. Therefore, as found in the phase 2 study, MTC cannot be used to explore the potential benefit of higher doses of MT. Nevertheless, the delayed-release property of the MTC capsules permitted the surprising discovery that it is possible to partially dissociate the cognitive and hematologic effects of the MT moiety. Whether the use of LMTX avoids or reduces the undesirable hematologic effects remains to be determined. . .
The Phase III trials are ongoing with the reduced form, and will clearly be a real finger-crossing exercise, both for efficacy and tox. I wish TauRx luck, though, as I wish everyone in the AD field good luck. None of us, you know, are getting any younger.