Anavex Life Sciences Corp (AVXL)

[sokol]

If Anavex can show a link between changes in biomarkers and a beneficial change in a patient’s cognitive abilities, it appears that the FDA will likely approve AVXL 2-73. It seems that some years ago Anavex realized this to be the case. The Biogen Aduhelm FDA precedent strengthens Anavex's chances for an accelerated approval of Blarcamesine if Anavex's clinical trials demonstrate a surrogate biomarker that is reasonably likely to predict clinical benefit such as a reduction in the rate of clinical decline. Biogen gained approval of Aduhelm by showing reduction of amyloid beta plaques and a very slight rate of clinical decline. Moreover, the FDA has recently raised the possibility that the agency could now be more willing to fast-tract treatments for many neurodegenerative diseases where there is an unmet need. The FDA has indicated that the oncology accelerated model may be replicated with neurodegenerative diseases. Anavex surmised this as early as 2018 by "borrowing from the cancer playbook to find treatment for Alzheimer's disease" as referenced in number 4 below, and is following through with the cancer model that the FDA spokesman cited in number 3 below says may be replicated with neurodegenerative diseases. I include 5 references below that, together with what we know about the science behind AVXL 2-73, suggest that Anavex has a reasonable chance of gaining fast-track approval for Blarcamesine for multiple neurodegenerative diseases.

1. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease

"We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit. In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy."

https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease

2. ''The accelerated approval of ADUHELM has been granted based on data from clinical trials showing the effect of ADUHELM on reducing amyloid beta plaques, a surrogate biomarker that is reasonably likely to predict clinical benefit, in this case a reduction in the rate of clinical decline.''

https://investors.biogen.com/news-releases/news-release-details/open-letter-alzheimers-disease-community-our-head-research-and

3. Controversial Alzheimer’s drug approval could affect other diseases

"The recent controversial approval of the Alzheimer’s drug aducanumab by the US Food and Drug Administration (FDA) has raised the possibility that the agency could now be more willing to fast-track treatments for a swathe of neurodegenerative diseases — illnesses that have so far thwarted drug developers. ....

...Asked by Nature to elaborate on the implications for Parkinson’s disease, Huntington’s disease and ALS, an FDA spokesperson replied that “the FDA stands ready to work with research communities and drug developers to study more therapies for Alzheimer’s disease and other neurodegenerative disorders”.

Patrizia Cavazzoni, a high-ranking FDA official, has given a nod to aducanumab’s broader impact. “The accelerated approval pathway has been an incredibly useful tool in oncology,” she said in a press meeting. “We believe it serves as a model that we hope can be replicated with neurodegenerative diseases.”.....

https://www.nature.com/articles/d41586-021-01763-9

4. Borrowing from the cancer playbook to find treatment for Alzheimer’s disease - 2018

...Dr. Harald Hampel, a professor at Sorbonne University in Paris, explained that the experimental drug, Anavex 2-73, a precision medicine candidate from specialty pharmaceutical company Anavex Life Sciences Corp., activates the Sigma-1 receptor.

A worthy target for precision medicine, the Sigma-1 receptor “is involved in several important pathways related to Alzheimer’s disease,” Hampel said. It reduces beta amyloid (the signature plaque deposits seen in the brains of deceased Alzheimer’s patients) and hyperphosphorylated tau (the signature protein tangles also seen in patients’ brains), he said. It also lessens oxidative stress and inflammation in the brain, both of which have been linked to aging and age-related diseases.

The advantage of targeting the Sigma-1 receptor is that it “activates the body’s own defense mechanism to restore cellular balance,” Hampel said.

In their study presented at the Alzheimer’s conference, Hampel and his colleagues researched the drug’s effect in 32 mild-to-moderate Alzheimer’s disease patients. The study showed that “patients improved both cognition and activities of daily living” after taking the drug for 57 weeks.

blitzer alzheimers drug champions_00041904.jpg
Is Alzheimer's disease preventable?
“Some also experienced positive effects on insomnia, a common problem among Alzheimer patients, and improved sleep,” Hampel said.

Beneficial effects, however, varied among patients based on their individual genetic profiles.

“We were able to identify certain genetic variations for certain patients that explain their improved response,” Hampel said. Specific genetic features, shared by about 80% of the study participants, correlated with a strong, “clinically meaningful” response to the medicine, he said.

” ‘Clinically meaningful’ means that the improvements are noticeable for the patient and the people around the patient,” Hampel said. Participants with the conducive genetic profile also showed improved scores on gold-standard tests of cognition and activities of daily living, the study presentation indicated.

Though only 32 Alzheimer’s patients participated in the study, Hampel feels confident of the results.

“Genetic patient data is more precise, and therefore not many patients are required. Examples are genetic studies in oncology, where even smaller studies are performed,” he said. The next step, which has already begun, is a larger safety study of the drug in 450 participants with Alzheimer’s.

Ultimately, Hampel said, he and his co-authors follow the concept of precision medicine, which means “to treat the right patient with the right drug at the right time.”

Clearing an FDA hurdle
Overall, he said, there is some good news yet also “a host” of challenges to develop effective and safe drugs for the treatment of Alzheimer’s disease.

Alzheimer's Disease Fast Facts
First among the difficulties is getting a drug across the blood-brain barrier, the membrane that surrounds the intellectual organ with the purpose of stopping that from happening, he said. Another challenge is monitoring what’s happening inside the brain.

“Increasingly, there are imaging technologies that allow you to look at deposited amyloid plaque and even deposited tau in the brain,” Williamson said. These deposits of amyloid plaque and tau tangles are considered “biomarkers” of Alzheimer’s disease.

A past study as well as the new results for an experimental drug jointly produced by Eisai Co. Ltd. and Biogen Inc. have shown that certain treatments can reduce the buildup of plaque in the brain. But what has not been demonstrated to the satisfaction of the US Food and Drug Administration is an association between a reduction in the plaque biomarker (as seen on a scan) and positive changes in the mental functioning of patients, Williamson said.

The good news is that once a link has been established between changes in biomarkers and a beneficial change in a patient’s cognitive abilities, the FDA has indicated it will no longer require drug developers to prove that each potential new drug can modify Alzheimer’s disease, Williamson said.

Once a firm connection is established, drug developers will need only to show their candidate drugs affect the biomarkers.

“An analogy to this would be cholesterol-lowering drugs and heart disease,” Williamson said. Once the link between lowering cholesterol and heart disease was established, scientists no longer needed to conduct thousands of patient studies to show that a drug reduced heart disease. “You just needed to show you could reduce cholesterol.”

https://www.cnn.com/2018/07/30/health/alzheimers-treatment-precision-medicine-immunotherapy/index.html

5. ANAVEX®2-73-AD-004 STUDY

Name of the study

ANAVEX2-73 for Treatment of Early Alzheimer's Disease

During the study, participants will have to undergo brain scan (MRI) and CSF examination (spinal tap) to see if they have amyloid pathology in their brain.

Who cannot participate in the study?

Exclusion criteria include:

Contraindication to PET imaging, MRI procedures and lumbar puncture

https://www.alzheimer-europe.org/Research/Clinical-Trials-Watch/Phase-III-trials/ANAVEX-R-2-73-AD-004

(Note: What is not known is what other surrogate biomarkers may be acceptable to the FDA besides amyloid plaque, but the FDA’s language cited above leads one to believe that the FDA may accept other biomarkers together with beneficial changes in cognitive abilities of clinical trial participants.)