Approval For Anavex’s (AVXL) Blarcamesine Looks Inevitable

Based on Phase 2 data alone, the FDA has granted emergency approval to the Biogen/Eisai (BIIB) Alzheimer’s drug, Lecanemab. As summed up by the prestigious science journal Nature:

The FDA’s decision does not take the phase III study into account — Biogen and Eisai asked for accelerated approval on the basis of phase II data, which they submitted before the latest trial results were announced. The phase II study found that lecanemab decreased plaques in the brains of 856 patients, but did not assess whether this affected patients’ cognitive abilities. This is the same pathway used to approve its predecessor, aducanumab, a similar antibody also made by Biogen and Eisai.

The FDA trumpeted the drug, now christened Leqembi, in its press release:

Leqembi is the second of a new category of medications approved for Alzheimer’s disease that target the fundamental pathophysiology of the disease. These medications represent an important advancement in the ongoing fight to effectively treat Alzheimer’s disease.

Did the FDA just say that Leqembi is disease-modifying? Read the next paragraph in the FDA press release of January 6th:

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”

Amyloid-clearer versus Sigmar1 agonist

The FDA declared that excess amyloid is part of the “underlying disease process.” The logic is that excess amyloid is part of the cause of the disease; Leqembi reduces the amyloid in the brain (which also causes brain bleeding in some people); therefore Leqembi is disease-modifying, and should be approved on its ability to clear amyloid alone.

Thing is, many neurologists now see amyloid build-up as a symptom and not the cause of Alzheimer’s disease, even as Leqembi, a drug that targets amyloid, seems to be effective.

The relevance of the Aβ [amyloid] cascade hypothesis to the development of therapeutics for AD [Alzheimer’s disease] appears disproven. Drugs targeting tau appear to be suffering the same fate but may yet produce better results. Alternative approaches are being pursued, some of them with initial small-scale, but promising, results.

One important new understanding of Alzheimer’s is that the root cause of the disease is the malfunction in autophagy, the body’s own self-maintenance system.

Anavex Life Sciences’ drug, Blarcamesine, apparently spurs the autophagy systems by manipulating Sigmar1 genes and gene receptors; it appears to be more effective than the amyloid-clearing drugs, according to drug trials.

A groundbreaking, earlier study using Blarcamesine (Anavex2-73) as a Sigmar1-agonist (Sig-1R agonist) found the following:

Taken together, the in vitro and in vivo data so far clearly show that the Sig-1R agonist ANAVEX2-73 [Blarcamesine] induces autophagy, as indicated by autophagic flux measurements.

The study was completed by independent scientists and funded by German research foundations. Researchers focused also on how Sig1-R activation increased autophagic activity, which in turn would help the brain to maintain the correct levels of various chemicals:

Taken together, in both independent cell assays and in two different human cell lines, Sig-1R activation induced a significantly increased autophagic flux.

The study utilized both human tissue (in vitro) and live nematode worms injected with human tissue (in vivo):

Excitingly, ANAVEX2-73 is a potent inducer of autophagic flux in vitro and in vivo and ameliorates protein aggregate formation and paralysis in C. elegans.

For those who wonder exactly what “autophagic flux” encompasses:

autophagic flux refers to the whole process of autophagy, including autophagosome formation, maturation, fusion with lysosomes, subsequent breakdown and the release of macromolecules back into the cytosol…

In a journal publication in 2021, scientists who have been focusing on Sigmar1 as an activator of autophagy declared in their abstract that

Autophagy activation by the σ-1Rs [Sigmar1’s] along with other neuroprotective effects makes it an interesting target for the treatment of Alzheimer’s disease. AF710B, T-817 MA, and ANAVEX2-73 [Blarcamesine] are some of the σ-1R agonists which have shown promising results and have entered clinical trials. These molecules have also been found to induce autophagy and show cytoprotective effects in cellular models.

Upon publication of this important research, Anavex published a press release with two matter-of-fact bullet points:

SIGMAR1 is activated by ANAVEX-compounds

ANAVEX®2-73 has been shown to induce autophagy

Anavex Life Sciences is clearly making the case that Blarcamesine manipulates a specific biomarker (Sigmar1), and that that biomarker modifies the function of autophagy, which is at the heart of neurdegenerative diseases such as dementia and Alzheimer’s. This sets up Blarcamesine for an emergency approval by the FDA based on Phase 2b/3 data demonstrating disease-modifying changes in a crucial biomarker, just like Leqembi.

New Efficacy News

The Blarcamesine Phase 2b/3 results are more impressive than the Leqembi Phase 3 results. The cognitive test results clearly favor Blarcamesine.

Blarcamesine reduced cognitive decline by 45% as measured by the ADAS-Cog, performing 40% better than Leqembi, and it did so in 11 months instead of 18 months. For a much more detailed comparison see my previous article.

New news: on a January 12 presentation at the J.P. Morgan Healthcare Conference, Anavex CEO Christopher Missling doubled down on the fact that Anavex’s Blarcamesine is more effective and safer than Biogen’s Leqembi.

This time, CEO Missling focused entirely on the reduction in cognitive and functional decline as measured by the CDR-SB. Both Blarcamesine and Leqembi succeeded in slowing decline by 27%, but Blarcamesine did so in 48 weeks and Leqembi took 78 weeks.

A never-before-seen graph was presented, showing the CDR-SB scores of the patients in the Blarcamesine Phase 2b/3 trial. We can see on this graph the decline in the cognitive/behavioral function of both the placebo group and the group who took the drug. After 24 weeks, the level of cognitive decline is about even. By 36 weeks, those taking Blarcamesine enjoy less cognitive decline than the placebo group, and by week 48 the lead held by the Blarcamesine group has widened considerably.

In fact, by Week 48, the worst score among the Blarcamesine group is better than the best score among those taking the placebo, according to this graph. Zero overlap. Every single one of those taking Blarcamesine was performing better than every single person taking the placebo.

Will the FDA grant approval of Anavex’s Blarcamesine?

If the FDA was willing to grant emergency approval to Leqembi based solely on what it does in altering levels of a biomarker (amyloid), it seems certain that the FDA will grant emergency approval and/or ultimate approval to a drug that is more effective, likely far cheaper, and certainly safer.

First, will Anavex request emergency approval? I believe it will request emergency approval, as it called its trial a Phase 2b/3 trial. If it was not interested in approval using data from this trial, it would not have labeled the trial Phase 2b/3.

Second, will the FDA require evidence of substantial changes in biomarkers in addition to clinical data? Not sure. Blarcamesine has demonstrated significant biomarker changes in its previous trials, and Anavex will reveal the biomarker data for the Phase 2b/3 trial in the coming weeks or months.

Third, will Medicare pay for Blarcamesine if it is given emergency approval? Yes, I believe so. The drug appears to be more effective than any drug ever developed. And it is far safer than any of the Biogen drugs recently approved.

In contrast, Leqembi is an amyloid-clearing drug and often swells and bleeds the brains of patients; Medicare will not pay for Leqembi until it has full approval by the FDA. Because Anavex’s Blarcamesine is not an amyloid-clearer this policy does not apply to it.

Therefore, Medicare can approve of Blarcamesine based solely on an emergency approval by the FDA.

It is conceivable that Blarcamesine could reach the Medicare constituency before Leqembi, even if Leqembi is ultimately approved by Medicare.

The Biogen Investigation and Extension Study

During, or soon after, a 6-week open-label extension study on Leqembi, three patients taking Leqembi died. Two of the deaths were directly attributed to use of Leqembi; see my previous articles for details. Six weeks is not a long time for three out of some hundreds of patients to die in a study.

The FDA has not examined Leqembi’s Phase 3 data, nor has it examined data from its extension study. Biogen/Eisai claims that the deaths were unrelated to use of Leqembi, but skeptical parties like ICER do tend to get involved in analyzing situations like this.

After Congressional investigation found FDA misconduct in the approval of Biogen’s previous Alzheimer’s drug, Aduhelm, the FDA will certainly try to avoid a similar situation. Nature did not pull any punches in its succinct assessment:

Many researchers thought that aducanumab, which also goes by the brand name Aduhelm, did not show a strong signal of cognitive decline. The FDA’s own scientific advisory panel recommended against approving the antibody in an 8–1 vote, and three panel members resigned after the FDA authorized it anyway. The FDA did not hold a public advisory meeting for lecanemab [Leqembi] before approving it.

I imagine that there will be public hearings before Leqembi (Lecanemab) can be ultimately approved, especially after the details of the three deaths are finally examined. In fact, one family seems determined to make public the assertion that their loved one was killed by use of Leqembi.

The use of blood-thinning drugs may have contributed to the three deaths, but nothing is clear as of this point. A long investigation and public discussion may delay the drug for months. The FDA met with Biogen on 115 occasions in order to get Aduhelm approved, and many of those meetings were not documented. This time, everything will have to be above-board, and that takes time.

The need to avoid the appearance of impropriety and the patient deaths makes it more likely that Leqembi is not granted final approval, or that it may be severely delayed.

The Blarcamesine Extension Studies

The Phase 2b/3 trial ended after Week 48, but participants were given the option of continuing on in an extension study of Blarcamesine.

It will be exciting to see whether the slope for the Blarcamesine-takers remains the same in Weeks 60 and 72 and 84. If so, the reduction in cognitive decline will be far greater than that achieved by Leqembi in 78 weeks.

Examining the slopes on the graph, it is likely that by the time Week 78 rolls around, those who have been taking Blarcamesine all along will have achieved a 50% reduction in cognitive decline. In that case, Blarcamesine would have achieved a reduction in cognitive decline approaching twice that of Leqembi in the same time frame.

When comparing their extension studies, Blarcamesine will almost certainly perform better than Leqembi in the area of safety. The side effects for Blarcamesine do not include brain bleeding, brain swelling, or death; they include dizziness and confusion in some users, which might be resolved by taking the drug before bed rather than in the morning, as required by the trial.

Also, Blarcamesine’s Phase 2a extension study went on for over 200 weeks, and there were no terrible side effects associated with the drug. The number of participants was very small though.

Considering the approvals of both Aduhelm and Leqembi, the FDA should approve Blarcamesine based on its greater effectiveness, safety, and lower price. Medicare may reject Leqembi and approve of Blarcamesine based solely on the extreme expense of Leqembi compared to Blarcamesine. Conceivably, Leqembi may cost tens of billions of dollars a year to purchase, administer and deal with side effects like brain bleeding. Blarcamesine may only be in the billions.

Analyst Opinions and the “High Dose” of Blarcamesine

Since last I wrote, HC Wainwright slapped a $50 price target on AVXL stock; the stock is valued at about $10 at the time of this writing. I could not find any published opinion associated with the price target.

Investor Alex Carchidi published a headline on Dec. 17 declaring that AVXL could multiply its value by 5X by 2025! But they warn that “the biotech [company] will first need to assuage the concerns of experts by elaborating on its latest clinical trial data.”

During the January 12 presentation, CEO Missling said that the next step is to publish the data and its analysis in a peer-reviewed journal and to meet with the FDA to see what they think.

The most sophisticated recent analysis came from Tom Bishop of the small firm, BI Research. Bishop reminded Forbes readers in January that while the Phase 2a data showed that Anavex at 50 mg performed considerably better than the 30 mg dose, the data available so far from the Phase 2b/3 trial combines the two groups into one data set. Bishop writes:

While the data already released was superior to Lecanemab [Leqembi], once the 50 mg alone cohort data comes out the results should be considerably better than the combined group.

Indeed the previous Alzheimer’s studies conducted with Blarcamesine showed a major difference between the effect of the lower doses and the higher doses of Blarcamesine. SA writer and Anavex expert Lane Simonian has written on this extensively, and he tells readers that those in the highest dose showed a 3 point IMPROVEMENT in their MMSE scores after week 70! The number of patients taking the high dose in the extension study was 4, but that is still a stunning result; after 70 weeks, Alzheimer’s patients typically suffer a substantial downslide in cognitive ability.

The same was found in the Phase 2, placebo-controlled Blarcamesine trials for Parkinson’s Disease Dementia (PDD); patients taking the higher dose were much more likely to actually IMPROVE in their memory, cognition, and behavior.

Both of these trends toward actual improvement is likely why Anavex doubled down on a certain type of measure that has been looked down upon by critics. That measure is the increased probability that the patient actually improves. Why does Anavex insist on repeating that the 30 mg and the 50 mg dose-takers pooled together have a 167% greater chance of improving compared to placebo, when measured on the ADCS-ADL? STAT writer Adam Feuerstein and other writers were certainly not impressed by this finding.

I believe Anavex focuses on actual improvement rather than “reduction in decline” to prepare us for the even more impressive “improvement” numbers to be released when we see the data for the 50 mg dose group. I believe we will likely see an even greater probability of clinical improvement than we saw for the combined group. What would the public think if they saw that they have triple the probability of getting better by taking the 50 mg dose of Blarcamesine?

Most of those who took the high dose in their Alzheimer’s 2a (not the recent 2b/3) trial demonstrated improvement in their mental measurements.

Now, let’s look at the patients in the Parkinson’s Dementia placebo controlled Phase 2 trial. The vast majority of those in the 50 mg group of the PDD Phase 2 trial demonstrated actual improvement in the “episodic memory” measure, which includes “events and names”. Most of the placebo got worse, and the 30 mg group was about half-half. Each of the three groups had 44 participants, so that includes 88 drug-takers in total.

In a press release in June 2021, describing further analysis of the Parkinson’s Dementia Phase 2 trial, Anavex stated

ANAVEX®2-73 high dose demonstrated statistically significant improvements compared to placebo (ITT population) for MDS-UPDRS Total score (p = 0.034). From baseline to end of trial at 14 weeks, MDS-UPDRS Total score improved by -10.98 points in the ANAVEX®2-73 high dose group and worsened by 3.53 points in the placebo group, an adjusted mean difference of -14.51 points (p = 0.034). This corresponds to a relative improvement of 18.9 % over 14 weeks.

Not only is there a difference between the 30 and the 50 mg doses in effectiveness, the 50 mg dose produces never-before-seen improvements in Parkinson’s patients.

When the 50 mg data for Alzheimer’s come out, it will have an effect on the stock price, good or bad.

In the hands of the FDA

If Anavex asks for emergency approval for Blarcamesine, that approval could come very quickly. Biogen/Eisai presented its Phase 3 Leqembi trial data in November; the FDA granted emergency approval in January based solely on the Phase 2 data.

Anavex will likely present and publish in a peer-reviewed journal the Phase 2b/3 data in Q1 2023. Emergency approval by the FDA could come in Q2 2023. I am thinking as early as May.

The FDA could also reject emergency approval or demand another trial. The FDA last week rejected Eli Lilly’s Alzheimer’s drug, Donanemab, for emergency approval. The FDA required a minimum of 100 patients for an amyloid-clearing drug, if the drug is to be approved for emergency approval. Eli Lilly, for an unknown reason, did not have enough patients. This demonstrates that the FDA, despite its declaration of Leqembi as a disease-modifying drug, also has rules in place that require higher bars for the more dangerous amyloid-clearing drugs. There is some balance there.

Ultimately, the FDA seeks efficacy and safety, and it takes into account the need for a drug. In the US, 6.5 million people suffer from Alzheimer’s and they need an effective treatment. They do not have one. The FDA is likely willing to trade off a bit on safety in order to meet that need, as in the case of Leqembi.

When in May the FDA might have the opportunity to grant emergency approval to Blarcamesine, it will not have to compromise on safety, in my opinion.

Upon FDA emergency approval, Medicare may decide to pay for Anavex’s Blarcamesine. And when that happens, the value of Anavex Life Sciences may exceed $15 Billion as discussed in my above mentioned article; and if one takes into consideration the Parkinson’s and the Rett syndrome applications, the company may be worth $20 Billion.

I have not mentioned the Rett syndrome approval which may also occur in the first half of 2023. Upon approval, some Alzheimer’s patients may be able to buy Blarcamesine for “off-label” use; they will have to pay cash, and it will be in a liquid form rather than a pill. But people like myself, whose mother has Alzheimer’s, we may be happy to pay that out-of-pocket price. I am guessing it will certainly be less than one-third the cost of Leqembi’s $26.5K price tag and does not require several brain MRIs or biweekly trips to the doctor.

The Rett syndrome approval may prove to be the catalyst for the stock skyrocketing, if it happens before any movement on Alzheimer’s.

Conclusion

On January 12, CEO Missling declared that Anavex had enough cash for 4 years of continued operation. However, the value of the company may increase a great deal this year if its Rett application is approved in H1, if the FDA looks favorably at its Parkinson’s drug in H1, or if the Alzheimer’s drug is given emergency approval or put on track for conventional approval.

If Blarcamesine is approved, the value of the stock will skyrocket; its market cap should break through $10 billion upon final approval. The current market cap is well-below $1 billion.

The next shoe to drop may be the publication of a scientific journal article featuring the full data set for the Phase 2b/3 trial of Blarcamesine. I suspect this will happen within a month or so.