Here is the new negative CC Abbott seeking alpha article. I think there is not that much new not already discussed as the weaker points of the trial such as TEAE issues. In terms of SIGMA WT from what I can see would have always been harder to show stat sig WT vs variant (assuming not stat sig) with only 30% in variant 'n'.
"On Thursday, Oct. 31, Anavex (NASDAQ:AVXL) announced new data from their phase 2b/3 Alzheimer's Disease (AD) trial, claiming that "blarcamesine (ANAVEX®2-73), once daily orally, demonstrates pre-specified clinical efficacy through upstream SIGMAR1 activation". [bold added for emphasis] In the PR, the company said that these data were presented "at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, which is taking place October 29 - November 1, 2024, in Madrid, Spain". The market reacted positively to this news, sending the stock up 15.94% to close at $6.62, from the previous close of $5.71 on Oct 30. For those who are new to this company or their AD program, you can find coverage in my previous SA articles (with the most recent first): July 30, 2024, Sep 15, 2023, and Dec 4, 2022, if interested. In this article, I'll focus primarily on the new data disclosed in the PR and the CTAD Conference 2024 presentation, and discuss why I think caution is warranted in understanding this news. The [positive?] news in a nutshell Looking at the headline and sub-headlines of the PR (see below), one would likely think that it's very positive news. In the PR, the company further explained:
SIGMAR1 is an integral membrane protein which activates an upstream compensatory process: Blarcamesine induces autophagy through SIGMAR1 activation resulting in restoring cellular homeostasis.In Alzheimer's disease patients, mutations (variants) of genes have generally been identified as disease risk factors. Likewise, impaired SIGMAR1 function (gene mutation, variants) leads to potential suboptimal function. Hence, patients who carry the non-mutated, common SIGMAR1 wild type ((WT)) gene, are expected to have stronger beneficial response to blarcamesine than patients with a SIGMAR1 mutation (variant), who nevertheless also benefited from treatment.(emphasis added)
In other words, in this trial, AVXL has "pre-specified" criteria for their efficacy data analysis, namely SIGMAR1 gene analysis (WT vs. variant). According to their hypothesis, blarcamesine, their AD drug, would produce "a stronger beneficial response" in the treated AD patients who carry SIGMAR1 WT gene than those with SIGMAR1 variant gene. Thus, confirming the drug's MoA (mechanism of action), if/when this difference occurs. Remember, for the purpose of this "pre-specified" criteria, namely the "SIGMAR1 gene variant analysis", it's about the comparison in "beneficial response" between trial patients who are either WT or variant SIGMAR1 gene carriers. It's the difference between the two gene-type groups that is the focus here and whether such a difference, if it exists, is statistically significant or not. The Protocol Before we get into the new data, let us look at the trial protocol first. See below. a slide
There are two doses (50mg, 30mg) being studied in this trial, besides the placebo group. There are two co-primary endpoints (ADAS-Cog 13 and ADCS-ADL) and one key secondary endpoint (CDR-SB) in this trial. "SIGMAR1 gene variant analysis" is listed under "Other endpoints".
The new Data that "confirm[?] upstream SIGMAR1 activation" In the PR, one can find the summary of the new data:
Over 48 weeks, blarcamesine significantly slowed clinical progression by 36.3% in the primary endpoint ADAS-Cog 13 [LS mean ADAS-Cog 13 difference of -2.027; P=0.008] in the ITT [intend-to-treat] analysis. This signal was even stronger in the pre-specified common SIGMAR1 wild type (WT) group with slowed clinical progression by 49.8% at 48 weeks in the active group vs. placebo, respectively [LS mean ADAS-Cog13 difference of -2.317; P=0.015]. Equal analysis with CDR-SB led to comparable consistent results.
AVXL reported only the pooled data from the two treatment groups. Of the two co-primary endpoints, AVXL only reported ADAS-Cog 13 results, i.e. no ADCS-ADL data is reported, beneficial or otherwise. AVXL reported ADAS-Cog 13 results from the ITT patients and a subgroup of "Common SIGMAR1 WT Carriers", but not from the SIGMAR1 variant Carriers. Though not indicated, it's doubtful that the difference in response between ITT's 2.027 and SIGMAR1 WT Carriers' 2.317 would be statistically significant. Though not disclosed, it's doubtful that the difference in response between SIGMAR1 variant's unknown data and SIGMAR1 WT Carriers' 2.317 would be statistically significant.
In summary: Re the co-primary endpoints, it seems unlikely that there is any statistically significant difference in (beneficial) responses in ADAS-Cog 13 or ADCS-ADL between SIGMAR1 WT & variant carriers.
Slide 17 Key secondary endpoint CDR-SB data
AVXL reported only the pooled data from the two treatment groups. AVXL reported CDR-SB results from the ITT patients and a subgroup of "Common SIGMAR1 WT Carriers", but not from the SIGMAR1 variant Carriers. Though not indicated, it's doubtful that the difference in response between ITT's 0.483 and SIGMAR1 WT Carriers' 0.601 would be statistically significant. Though not disclosed, it's doubtful that the difference in response between SIGMAR1 variant's and SIGMAR1 WT Carriers' 2.317 would be statistically significant.
In summary: Re the key secondary endpoint, there's unlikely any statistically significant difference in beneficial responses in CDR-SB between SIGMAR1 WT & variant carriers. Discussion 1 New data On the surface, AVXL's AD news seem positive indeed, which no doubt accounted for the market's bullish reaction (>15% increase in stock price). However, as summarized above, the news may not actually be as positive as it seems.
The top and bottom sections (in gray box) were dealt with in greater details in my July 2024 article on AVXL, which I will not repeat here. Suffice to say that the co-primary, key secondary efficacy endpoints and various biomarker results are mixed at best, and therefore far from being conclusive. As for the middle section (the new data regarding SIGMAR1 gene variant analysis), the word "greater" in the phrase "greater clinical benefit in pre-specified Common SIGMAR1 wildtype (WT) carrier population" [relative to SIGMAR1 variant carrier population] is not supported by the data disclosed, in my opinion. Namely, there is no data disclosed for the patients who carry a mutated gene to compare to those with WT gene, nor does the differences in ADAS-Cog & CDR-SB between the ITT and those with WT gene look likely to be statistically significant. Therefore, in my opinion, any claim suggesting that these results confirm "beneficial clinical effect through SIGMAR1 activation" should be received with caution. In fact, in my opinion, it's not accurate to say that SIGMAR1 gene type, WT vs. variant, does not appear to be a differentiator in the AD patients' response (or the lack of, in the case of ADCS-ADL test) in this trial.
It's interesting to note that though WT treated patients showed numerically bigger response over the WT placebo than did ITT treated patients over ITT placebo, the p values are bigger [less significant] in WT than in ITT, e.g. for ADAS-Cog data, p=0.015 in WT patients vs. p=0.008 in ITT. In summary: in my opinion, the new efficacy data does not appear to support nor confirm the drug's MoA, i.e. there's no meaningful nor statistically significant difference in responses between the AD patients, per their SIGMA1 gene type.
2. Safety data In terms of safety data, there's no new data disclosed. The company maintains that the drug has "good comparative safety profile (no ARIA)" [Amyloid-related imaging abnormalities] (see CTAD 2024 presentation, slide 20). In my opinion, this so-called "good comparative [to Amyloid-targeting drugs] safety profile", needs to be understood in its proper context. Namely, that blarcamesine does not target amyloid protein for removal, raising the question of whether it is at all meaningful to disclose that ARIA is not an adverse effect in its trial? On the other hand, blarcamesine seems to have a very high discontinuation rate (30.7% in the pooled data) due to treatment-emergent adverse events (TEAE), as disclosed this July in AVXL's AAIC 2024 Presentation. a table Slide 22 (red box added) (AVXL AAIC 2024 Presentation) In comparison, other AD drug trials showed lower discontinuation rates. Drug Name Discontinuation rate due to TEAE Memantine 18.2% Donepezil 20.9% Lecanemab 6.9% Donanemab 8.9% It should be noted that both memantine and donepezil, like blarcamesine, are oral pills that do not target amyloid protein, i.e. don't have ARIA as an adverse effect either. Therefore, from the perspective of the discontinuation rate due to TEAE, I doubt that it's meaningful to claim that blarcamesine shows a "good comparative safety profile" vs. other AD drugs or drug candidates. Financials According to AVXL September 2024 presentation, the company has $138.8M in cash and cash equivalents, an annual net loss of $27.8M in 2023. The company estimates a 4-year cash runway sufficient to support its operation. a slide Slide 31 (AVXL Sept 2024 Presentation)
Concluding Thoughts In the Oct. 31 PR, the company has stated that they "are on track for regulatory submission of blarcamesine in Europe (EMA) in the current quarter 2024." No guidance is given regarding the filing in the US. Similar to opinions I expressed previously, I find this latest data disclosure problematic, e.g. incomplete data and/or statements that are over-reaching. In this current article, I have discussed why I think the new efficacy data per SIGMAR1 gene analysis, though sounding positive, does not confirm the drug's MoA, nor strengthen the mixed efficacy results, per prior disclosures. Overall, I view the regulatory prospect of AVXL's blarcamesine in treating early Alzheimer's to be highly risky and uncertain, due to the inconclusive or mixed efficacy data, unproven MoA, and high trial discontinuation rate due to TEAE. Even if the company does manage to file its application with the EMA in Q4 2024, I'd estimate a low likelihood of an approval, conditional or regular. Regarding the US, I think that it's most likely that the FDA would require AVXL to conduct one or two bigger, longer, placebo-controlled phase 3 trials, in order to generate conclusive results. And if that is the case, it would require a lot more financial resources and likely 3-5 years before these phase 3 trials conclude, with little to no guarantee of better or successful phase 3 data. Therefore, for the rating, I choose Sell, as I'm bearish on AVXL's long-term prospect.
Risks As a long-only biotech investor, I don't experience the risks due to FOMO or short squeeze. If AVXL does succeed in obtaining the market approval in AD and/or in other indications, I will be thrilled for the patients, the company and the investors. However, for those who do engage in short-selling, please know that there are significant risks associated with short-sell of a highly volatile, speculative R&D biotech stock like AVXL, which include but are not limited to company-specific positive news, e.g. EMA application filing, potential EMA approval, other positive trial data news, macro-market moves that affect biotech sector, e.g. the interest rate cuts etc. As the saying goes, "Markets can remain irrational longer than you can remain solvent". All this is to say that, for any short-sellers, please be mindful of the significant risks of doing so."
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