AVXL - Anavex And The Antioxidant Treatment Of Alzheimer's Disease

2023-05-04 08:00:00 ET

Summary

• Many treatments for Alzheimer's disease limit the formation of peroxynitrite, which can for a while slow down the progression of the disease.
• A few treatments for Alzheimer's disease can also scavenge peroxynitrite and reverse some of the damage that it does to the brain via oxidation and nitration.
• Anavex's blarcamesine, aromatherapy, and panax ginseng do all three. Blarcamesine by limiting peroxynitrite formation early on can nearly stabilize early stage Alzheimer's disease.
• Aromatherapy and panax ginseng by limiting peroxynitrite formation early on and later on can also potentially slow down the progression of moderate to severe Alzheimer's disease.
• Anavex's stumbles in regards to not fully releasing its data from its phase 2b/3 clinical trial have hurt its stock value, but the underlying evidence supports its effectiveness.

The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite ( source of quote ).

This is a follow-up to an article I wrote on Anavex ( AVXL ) last month . I've covered AVXL extensively, and have held a bullish outlook.

In this report, I wanted to take a closer look at the phase 2a clinical trial results in which the medium concentration group did better than the low concentration group and the high concentration group did much better than the medium concentration group. Both Aricept and Anavex's blarcamesine are sigma-1 receptor agonists with Aricept binding at lower concentrations. For mild cognitive impairment and mild Alzheimer's disease, those who were around baseline at 57 weeks may have been on Aricept (there was one extremely positive outlier whose performance defies explanation). At medium concentrations everyone fell below baseline which is consistent with a placebo response, while most of those at high concentrations with early stage Alzheimer's disease were above baseline. It could be that blarcamesine out competes Aricept at medium concentrations but at lower receptor occupancy rates whereas at higher concentrations it outcompetes Aricept with the same occupancy rate as Aricept. If the latter is the case then blarcamesine may be more effective than Aricept because it also acts as a direct antioxidant. And if the high dose group (50 mg) in the phase 2b/3 clinical trial corresponds closely to the high concentration group in the phase 2a clinical trial, then blarcamesine should lead to improvements in this group just like it did in the phase 2a clinical trial (an equal number of patients were on Aricept in the placebo and in the 30mg and 50mg groups). The reason I consistently give Anavex a buy rating is because based on both results and mechanisms of action, blarcamesine appears to have the ability to nearly stabilize mild cognitive impairment and mild Alzheimer's disease for nearly three year at least.

There are many drugs and drug candidates for Alzheimer’s disease that limit the formation of peroxynitrite, and in doing so may slow down the progression of Alzheimer’s disease for a while, but there are very few medications that also scavenge peroxynitrite, and reverse part of its damage. This article will focus on one drug candidate - Anavex’s blarcamesine, and two natural products - essential oils via aromatherapy and panax ginseng that do all three. Blarcamesine may help largely stabilize early Alzheimer’s disease because it impedes the release of intracellular calcium which limits the initial formation of oxidants and because it also acts as a direct antioxidant. By contrast essential oils via aromatherapy and panax ginseng can potentially also slow down the progression of moderate to severe Alzheimer’s disease because these natural products disrupt later points in the pathway leading to oxidation and nitration as well as being direct antioxidants.

Before turning to the main subjects of this article, I want to briefly mention two struggling drug candidates - Green Valley’s GV-971 , and Cyclo Therapeutics’ Trappsol Cyclo ( CYTH )- that fit the same profile and therefore may someday also help in the treatment of Alzheimer’s disease. GV-971, an oligosaccharide, and Trappsol Cyclo, a polysaccharide, limit the size of lipid rafts by removing cholesterol. This is important because lipid rafts amplify the processes which lead to the onset and at least to the early progression of Alzheimer’s disease (notably, APOE4 carriers , who are at greatest risk for Alzheimer’s disease, have more extensive lipid rafts than non-carriers). Oligosaccharides and polysaccharides can also maintain a healthy microbiome in the gut, which can limit the formation of peroxynitrite in the brain. They also can directly scavenge peroxynitrite ( study one , study two ). Unfortunately, Green Valley which gained conditional approval for GV-971 in China has suspended its ambitious multi-center phase 3 clinical trials for its drug candidate, and Cyclo Therapeutics whose stock value is languishing probably needs an infusion of cash to complete its trials ( first step , possible second step ).

Anavex's Blarcamesine

Anavex’s blarcamesine is a sigma-1 receptor agonist which by inhibiting the release of intracellular calcium reduces acetylcholinesterase activity , the production of amyloid oligomers , the hyperphosphorylation of tau , and the oxidation and nitration of critical transport systems, receptors, and enzymes in the brain ( calcium peroxynitrite/ONOO- pathway , figure three). However, the impact of sigma-1 agonists declines with the progression of Alzheimer’s disease due to the depletion of intracellular calcium stores and with the nitration of protein kinase C ( PKC peroxynitrite pathway ).

The evidence that blarcamesine acts as a direct antioxidant is much more scarce. There are some studies suggesting that blarcamesine is a hydrogen peroxide scavenger ( most relevant study ). Potentially, then it could limit the damage done by hydrogen peroxide during the very early stages of Alzheimer’s disease. As a tetrahydrofuran derivative, blarcamesine may donate electrons and hydrogen atoms which is the key to scavenging both hydrogen peroxide and peroxynitrite. It may also increase levels of the brain’s most important endogenous antioxidant: glutathione ( peroxynitrite glutathione/GSH depletion pathway ).

That blarcamesine appears to largely stabilize mild cognitive impairment and mild Alzheimer’s disease for nearly three years ( figure 2 ) are indirect indicators that it may not only slow the production of oxidants, but also scavenge them and reverse part of their damage.

In a small phase 2a clinical trial, patients with the highest concentrations of Anavex 2-73/blarcamesine, who had mild cognitive impairment or mild Alzheimer’s disease, and who did not have a sigma-1 receptor or catechol-o-methyltransferase variant saw a mean improvement of 2 points as measured by MMSE (Mini-Mental State Examination) at 57 weeks. For future reference, this is roughly equivalent to a -3.4 point improvement in ADAS-Cog scores (Alzheimer’s Disease Assessment Scale-Cognition Subscale) ( phase 2a trial results ).

In its phase 2b/3 clinical trial, Anavex combined the 30mg and 50mg group. The company also limited participation to those with mild cognitive impairment and mild Alzheimer’s disease. In this trial, blarcamesine met its primary cognitive endpoint by producing a 1.85 point slower decline in cognition as measured by ADAS-Cog scores versus placebo and its secondary cognitive endpoint by producing a .41 point slower decline in cognition versus placebo as measured by CDR-SB (Clinical Dementia Rating-Sum of Boxes). Anavex stated that it met its other primary endpoint: less decline in activities of daily living as measured by the Alzheimer’s Disease Cooperative Study scale (ADSC-ADL) but did not provide specific numbers to back up this assertion ( phase 2b/3 trial results , pp. 17, 21-22,).

In its phase 2a clinical trial, individuals with mild cognitive impairment and mild Alzheimer’s disease did much better at high concentrations than at medium concentrations. Those also on Aricept seemed to do better at lower concentrations than at medium concentrations of blarcamesine, but blarcamesine performed better than Aricept at high concentrations ( chart, p 23 ). This may be a reflection of Aricept binding to sigma-1 receptors instead of blarcamesine at low concentrations, with blarcamesine binding to sigma-1 receptors at a high occupancy rate at high concentrations.

Anavex has stated that its phase 2b/3 clinical trial results complement and are consistent with its phase 2a trial results. For those who were not titrated down, the company most likely knows that the 50mg group (which largely corresponds to the high concentration group in the phase 2a trial) did better than the 30mg group in the phase 2b/3 trial. Why Anavex still has not provided data for both groups (after untangling the titration issue) remains a mystery. It could be that Anavex is concerned that the number of participants remaining in the 50mg after dropouts and down titrations is not large enough to gain full approval from the Food and Drug Administration (FDA). The FDA could still grant accelerated approval allowing for the sale of blarcamesine while requiring a larger (and perhaps more lengthy trial) to firmly determine efficacy and safety. Anavex may also approach other regulatory agencies in Australia and Europe, for example, before or while engaging with the FDA in hopes of earlier approvals there.

Aromatherapy and Panax Ginseng

The use of antioxidants from natural products for the treatment of Alzheimer’s disease has produced mixed results. Rapid metabolism, poor absorption, inability to cross the blood-brain barrier, a change from an anti-oxidant to pro-oxidant function, and weak scavenging abilities explain several of the antioxidant trial failures. However, trials with the most effective antioxidants have been successful albeit with small numbers of participants in most cases. But two obstacles exist to pursuing this approach to Alzheimer’s disease. First, the domination of the amyloid hypothesis for Alzheimer’s disease, and now the rising focus on tau and neuroinflammation have relegated antioxidant approaches to the sidelines. In a sense, the dominant theories of Alzheimer’s disease have sucked all the oxygen out of the room. Secondly, the widely held belief, particularly in much of the Western world that natural products cannot be used to treat diseases in general, and especially not Alzheimer’s disease hinders funding for potentially confirmatory clinical trials. The charges of pseudoscience, thus, have gotten in the way of real science.

A long search for the most effective natural product antioxidants for Alzheimer’s disease suggest that aromatherapy with certain essential oils and panax ginseng are at the top or near the top of the list, in part because they partially avoid the limitations of many other antioxidants (as discussed later). Their impact on multiple aspects of Alzheimer’s disease can be seen in the following quotes.

For Aromatherapy:

In summary, the natural drug volatile oil may play a role in improving cognition by reducing the neurotoxicity of A?, anti-oxidative stress, regulating the central cholinergic system, anti-acetylcholinesterase activity, improving microglia-mediated neuroinflammation, reducing inflammatory factor levels, inhibiting neuronal apoptosis, and regulating the balance of central amino acid levels. Compared to existing drugs, volatile oils from natural medicines are a unique health service resource because they are convenient and inexpensive, have fewer side effects and easily cross the blood–brain barrier. The combination of aromatic inhalation therapy, based on the olfactory pathway, can better reflect the characteristics of volatile oils, which are not affected by peripheral metabolism and BBB to deliver drugs into the brain to improve cognition, and can be used as a treatment or as an adjunctive therapy to improve CI [Cognitive Impairment], with clear efficacy and simple safety ( source of quote ).

For Panax Ginseng:

Dementia has become one of the most important diseases threatening human health. Alzheimer's disease ((AD)) and vascular dementia (VaD) have the highest incidence rates among the types of dementia, but until now, therapeutic methods have been limited. Panax ginseng has been used in China for thousands of years to treat dementia, and modern medical studies have found that it contains multiple active components, such as ginsenosides, polysaccharides, amino acids, volatile oils and polyacetylenes, many of which have therapeutic effects in treating AD and VaD. Studies have found that ginsenosides have multitarget therapeutic effects in treating dementia, such as regulation of synaptic plasticity and the cholinergic system, inhibition of A? aggravation and tau hyperphosphorylation, anti-neuroinflammation, anti-oxidation effects and anti-apoptosis effects. Other active components of Panax ginseng , such as gintonin, oligosaccharides, polysaccharides and ginseng proteins, also have therapeutic effects on AD and VaD. The effectiveness of ginseng-containing Chinese medicine compounds has also been confirmed by clinical and basic investigations in treating AD and VaD. In this review, we summarized the potential therapeutic effects and related mechanisms of Panax ginseng in treating AD and VaD to provide some examples for further studies ( source of quote ).

The following are the results from four clinical trials using either aromatherapy or panax ginseng to treat Alzheimer’s disease:

Effect of aromatherapy in patients with Alzheimer's disease: a randomised controlled clinical trial

Conclusions : Aromatherapy can improve sleep, alleviate psychobehavioural symptoms and improve quality of life in patients with AD, which may be related to reducing the level of oxidative stress in patients and inhibiting inflammatory factors; it is a non-drug intervention that can be widely applied. " [Lavender, sweet orange, and bergamot essential oils were used in this trial ]

Effect of aromatherapy on patients with Alzheimer's disease

Results: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

Conclusions: In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients. [Rosemary, lemon, orange, and lavender essential oils were used in this trial ].

Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease [Panax ginseng steamed at higher temperatures]

Results: The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

Discussion: These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD. ( trial )

Improvement of Cognitive Deficit in Alzheimer’s Disease Patients by Long Term Treatment with Korean Red Ginseng [Panax Ginseng]

A 24-week randomized open-label study with Korean red ginseng ((KRG)) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease. ( trial )

The advantage of aromatherapy is the relatively easy entrance of essential oil compounds into the brain via the nose. The advantage of panax ginseng is that it contains multiple beneficial compounds some of which at least enter the brain in large enough concentrations to make a difference.

What is not clear at this point is if combining antioxidants such as blarcamesine, aromatherapy, and panax ginseng produces better results than either used separately. It is possible that there are limits to how much peroxynitrite-mediated damage can be reversed by antioxidants in Alzheimer’s disease. For example, more damage can be reversed in the hippocampus where neurons can be regenerated than in the frontal cortex where they cannot be regenerated. Memories associated with the hippocampus such as object recognition, facial recognition, sense of place and time, repetitive memory (reciting numbers, the alphabet, etc.) can improve, but memories at least partially associated with the frontal cortex such as memory of recent events and lucidity may slightly improve if at all. On the other hand, the treatments listed in this article may help reduce delusions and anxiety, and improve overall alertness and awareness. In addition, these treatments can potentially stabilize or nearly stabilize cognitive and non-cognitive aspects of early stage Alzheimer’s disease for years, and perhaps in the case of aromatherapy and panax ginseng significantly slow down the progression of later stages of the disease as well. That is not a complete victory over Alzheimer’s disease, but marks a major advance over current treatments.

Patience with Anavex is beginning to wane in some quarters (and has disappeared altogether in others). Even long-term supporters of the company such as myself are wondering what lies behind Anavex’s slow and selective release of data and what kind of negotiation strategy is it employing with various regulatory agencies. Good results from Anavex’s pediatric Rett Syndrome trial and a possible accelerated approval of blarcamesine for Alzheimer’s disease would certainly help alleviate some of the stress on both investors and the company, and lead to at least a modest increase in the company’s stock value, even after factoring in the almost certain chorus of criticisms from detractors. Most importantly, Anavex’s blarcamesine is close to providing an effective drug “solution” to early stage Alzheimer’s disease.

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