BIIB - Anavex: Drug Treatments For Early Alzheimer's Disease

Summary

• Anavex 2-73/blarcamesine at high concentrations in early Alzheimer's disease leads to improvements in cognition and activities of daily living that are largely sustained for 148 weeks in most individuals.
• Alzheon's ALZ-801 reduces cognitive decline in ApoE4 carriers by about the same amount as Eisai and Biogen's Leqembi and Aduhelm, but without the risks of brain bleeds and swelling.
• Cyclo Therapeutics Trappsol Cyclo by reducing cholesterol levels in the brain inhibits the processes that lead to the onset and at least the early progression of Alzheimer's disease.
• These three drug candidates offer the best hope for the treatment of early Alzheimer's disease.  In many cases, they may be more effective when used in combination.

This is my first installment examining drugs and drug candidates for Alzheimer’s disease. In the next article, I will examine potential treatments for moderate to severe Alzheimer’s disease. Both articles will make use of the following chart which captures critical pathways involved in several neurological diseases, including Alzheimer's disease, Autism Spectrum Disorders , Parkinson’s disease , and Multiple Sclerosis .

A few general observations to begin with. First, there are many factors acting on a variety of receptors that can trigger Alzheimer’s disease, but only a few receptor types. In the chart above, metabotropic glutamate receptors are one of several g-protein receptors that when over-activated can lead to Alzheimer’s disease. The over-activation of receptor tyrosine kinases via phospholipase C can also result in Alzheimer’s disease. Receptors that increase calcium influx such as nicotinic acetylcholine receptors can play a role in the disease, as well. However because there are so many factors and specific receptors that can potentially be involved blocking any specific factor or any particular receptor in most cases is likely to be ineffective. Amyloid is a partial exception because it can increase the damage elicited by primary triggers for the disease, but mainly in ApoE4 carriers who have a heavier amyloid burden than non-carriers. The second major point is that oxidation and nitration largely cuts off the receptors and enzymes that lead to the activation of NMDA [N-methyl D-aspartate] receptors which marks a transition from early to moderate Alzheimer’s disease. This includes the oxidation of g-protein coupled receptors and the nitration of protein kinase C. Thus while it is often said that Alzheimer’s has to be treated early before too much damage is done, the truth is that certain treatments only work early (by inhibiting steps that otherwise would lead to the over-activation of NMDA receptors) while others works later on (by inhibiting steps after the over-activation of NMDA receptors). With these observation in minds, here are some of the treatments being studied for early Alzheimer’s disease and their likelihood of success (for those with the disease, for caregivers, and for investors). Referring often to the chart above will help make more sense of the following analysis.

Anavex Life Sciences Anavex 2-73/blarcamesine

Anavex Life Sciences (AVXL) Anavex 2-73/blarcamesine is a sigma-1 receptor agonist which inhibits the release of intracellular calcium into the cytoplasm in part by transferring it to the mitochondria. Aricept/donepezil is also a sigma-1 receptor agonist, although it may preferentially bind to acetylcholinesterases. In any case, at high concentrations Anavex 2-73 vastly outperforms not only a placebo at one year (an expected decline of between 4 and 8 points in the Alzheimer’s Disease Assessment Scale-Cognitive subscale) but also donepezil (about a 2 point decline in ADAS-Cog scores).

At high concentrations in early Alzheimer’s disease and in those with a functioning sigma-1 receptor, Anavex 2-73 led to an average 2 point improvement in Mini-Mental Examination Score at 57 weeks (the rough equivalent of a 4.6 improvement in ADAS-Cog scores). Four out of six patients improved, one remained at baseline, and one declined in this cohort ( 57 weeks results ). At 148 months, there was only about a one point mean decline in MMSE scores at high concentrations which would make Anavex 2-73 a disease modifying treatment for Alzheimer’s disease ( 148 week results ). The change in the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores was not as dramatic at 57 weeks mostly because there is relatively little change in basic abilities during the early stages of the disease, but the gap grew much larger at 148 months.

The phase 2a trial was a very small trial. In the much larger phase 2b/3 trial the combined 30mg and 50mg met the cognitive endpoints as measured by ADAS-cog and CDR-SB (Clinical Dementia Rating-Sum of Boxes) scores ( amended CTAD presentation ). Moreover, Anavex Life Sciences has said that the findings in this trial were consistent with the phase 2b trial in which the medium concentration group performed no better than placebo but in which the high concentration group performed better than any previous drug or drug candidate for early Alzheimer’s disease. In the phase2b/3 trial, those who improved at 48 weeks by more than -.5 ADAS-Cog scores did so by an average of approximately 4 points which is right in line with the high concentration group in the phase 2a study.

Anavex Life Sciences has not released (or perhaps still has not completed) its full data set which has left the company open to various broadsides. However, the only thing that matters is the actual data and how the FDA views it. The negotiations between the company and the FDA may well center around the question of whether there were enough participants in the high dose group to establish statistical significance despite having achieved clinical significance. If the FDA grants accelerated approval, then Anavex would be able to sell blarcamesine, while it undertakes trials in the U.S. with larger numbers of participants taking the high dose. If the FDA requires Anavex to undertake a larger trial before approval that will hurt the company’s stock and deplete some of its reserves, although this may be slightly offset by potential approvals in Australia and Europe. In either case, a partnership is likely needed for commercialization of blarcamesine. For investors, it is a matter if it will take a little bit more patience or a lot more patience.

Blarcamesine appears to work as well as it does because it intervenes at a critical junction in the process that leads to the onset and early progression of Alzheimer’s disease. By limiting the release of intracellular calcium, blarcamesine produces a myriad of benefits including the following: it maintains levels of neurotransmitters needed for the retrieval of short-term memory, sleep, mood, social recognition, and alertness, inhibits the breakdown of acetylcholine (which is needed for the retrieval of short-term memories), regularizes neurotransmissions, prevents mitochondrial dysfunction, lowers neuroinflammation, allows for the regeneration of neurons, synapses, and axons, and prevents the death of neurons. Perhaps most importantly, it limits oxidation and nitration which is why it ameliorates many of the problems listed above ( study ). Blarcamesine may also directly limit the influx of calcium further inhibiting oxidation and nitration, scavenge the oxidants hydrogen peroxide and peroxynitrite (ONOO-), and partially reverse oxidative and nitrosative damage, although studies in this regard are inconclusive. In any case, one of the best ways to greatly slow the progression of early Alzheimer’s disease is with an effective sigma-1 receptor agonist such as blarcamesine ( study ).

Blarcamesine can produce dizziness and confusion at the highest dose which caused 17 dropouts and 24 down-titrations in Anavex’s latest trial (although giving blarcamesine before bedtime may partially address at least the problem of dizziness), and it is considerably less effective in those with sigma-1 receptor variants. Two questions, then: what treatments might help these type of patients and what combination therapies might help others, especially ApoE4 carriers who progress more rapidly in early Alzheimer’s disease?

Anti-Amyloid Approaches

Amyloid is part and parcel of the process that leads to oxidative and nitrostative damage in Alzheimer’s disease. Peroxynitrite mediated molecular damage leads to the upregulation of interleukin-6 and the secretion of the amyloid precursor protein . The amyloid precursor protein is first cut by the calcium dependent gamma secretase and then further cut by the beta secretase which is regulated by caspase-3 . Amyloid monomers aggregate into amyloid oligomers and then via nitration into amyloid plaques. The amyloid oligomers which are considered to be the toxic “species” then further add to oxidative and nitrostative stress mainly via g protein-coupled receptors. However, amyloid oligomers only appear to reach high enough levels to substantially do so in those individuals with one or two copies of the ApoE4 gene. By contrast, non-carriers barely benefit from treatments that directly or indirectly target amyloid oligomers ( previous article) . Carriers indeed show a statistically significant response from anti-amyloid treatments, but it is debatable whether they receive a clinical benefit. In addition, pulling out amyloid can cause brain bleeds and swelling. This applies to anti-amyloid drugs such Aduhelm and Leqembi produced by Eisai ( ESALY ) and Biogen ( BIIB ) and to Eli Lilly’s ( LLY ) donanemab. Leqembi is likely to face the same skepticism from doctors, private insurers, and Medicare as Aduhelm, which makes investing in Eisai and Biogen (and Eli Lilly) at best a crap shoot and probably not a good investment at least until everything is sorted out.

Alzheon Alz-801/tramiprosate produces similar results as other anti-amyloid drugs but without the risk of brain bleeds and brain swelling because it prevents monomers from being converted into oligomers, rather than removing oligomers. It would be the best anti-amyloid drug to pair with blarcamesine in ApoE4 carriers.

Protein Kinase C inhibition

Protein kinase C inhibition would seem like a helpful treatment for Alzheimer’s disease but this has not panned out to date. Some of it may be dose and certainly stage dependent. The following quote is somewhat tantalizing in terms of the prospects, although one cannot simply cut out protein kinase C activity:

Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active. ( source of quote )

Cyclo Therapeutics TrappsolCyclo

TrappsolCyclo is a polysaccharide compound (hydroxypropyl beta cyclodextrin) that through the removal of cholesterol reduces the size of lipid rafts in which most of the processes that lead to the onset and at least early progression of Alzheimer’s disease take place. Lipid rafts amplify the triggers for Alzheimer’s disease and they are of greater size in ApoE4 carriers. TrappsolCyclo may also be a peroxynitrite scavenger. The company is conducting a phase 2 clinical trial for early Alzheimer’s disease. It is a small company whose current stock price is hovering around $2 a share, and only has one positive case to go on for now (besides the science). But it may turn out to be one of the better treatments for the disease.

Recommendation for Investors

My recommendation would be to ignore the noise regarding Anavex 2-73 and the hype being produced for Leqembi and donanemab. Investment in Anavex Life Sciences should pay better “dividends” as well as lead to a more effective treatment for early Alzheimer’s disease.

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