Anavex Life Sciences Corp (AVXL)

[sokol]

As slide 18 points out, the patients in the AVXL 2-73 trial were more advanced in the disease than the patients in the Lecanemab trial. See also Seeking Alpha article published in December: “The patients in Anavex's Blarcamesine trial were substantially more cognitively impaired than those in Biogen's Lecanemab trial.” How Well Does Anavex's New Alzheimer's Drug Compare Against Biogen's New Drug? That SA article also states: “The patients in the Anavex Phase 2b/3 trial started the trial with an ADAS-Cog of around 29; this is a serious level of cognitive impairment, and this group typically gets worse by about 4.5 points in a year's time.” However, at 24 to 36 weeks as shown on slide 18, the once daily oral Blarcamesine begins to compare favorably compared to 12 weeks. Blarcamesine at 36 weeks, one half the time period of the 72 week Lecanemab trial, begin to perform more favorably compared to the placebo and even more so at 48 weeks.

In comparing Blarcamesine to Lecanemab the above SA article also had this to say:

“…the Blarcamesine patients started off their drug trial with a good deal more cognitive dysfunction than the Lecanemab patients. The average ADAS-Cog scores of the Lecanemab trial was 24.45. The average ADAS-Cog scores of the people being administered Blarcamesine was 28.75. That's a 4.3 point difference, a very substantial difference in starting points.

Blarcamesine is 40% more effective than Lecanemab at 48 weeks, and on patients who are significantly more cognitively impaired. To be fair Lecanemab's trial continued for another 7 months and continued to slow impairment. Blarcamesine's trial ended at 48 weeks, and patients have the option to continue treatment in another study; will Blarcamesine continue to hold its 40% lead over Lecanemab? It is unclear, but it seems one's first year of Alzheimer's treatment should be on Blarcamesine.

Regarding the CDR-SB. The Blarcamesine patients were suffering from greater global impairment than the Lecanemab patients, as measured by the CDR-SB. At BASELINE (at the start of each study) the Blarcamesine patients had an average CDR-SB score of 3.81 versus Lecanemab's 3.17, representing significantly more impairment among the Blarcamesine group.

The Blarcamesine patients at baseline were suffering from Very Mild Dementia or Mild Dementia, while patients in the Lecanemab trial were suffering from Very Mild Dementia, Mild Dementia, but also "Questionable Impairment" (very little impairment, if any). See this link for a full discussion.

In this context, it is quite remarkable that the Blarcamesine patients reduced their cognitive decline by 27% over 48 weeks, while Lecanemab produced a similar 27% reduction in cognitive decline, except it took Lecanemab over 78 weeks (18 months). What would Blarcamesine accomplish given another 7 months?

Anavex hints that the drug would continue to reduce decline such that by 78 weeks, Blarcamesine would have a healthy lead over Lecanemab. The suggested logic is, if Blarcamesine at 11 months is equal to Lecanemab at 18 months, then given an equal amount of time to work, Blarcamesine should stretch to at least a 50% lead over Lecanemab.

Regarding ADCS-ADL. It is on the ADCS-MCI-ADL that Biogen's Lecanemab produced its best results. Those who took the drug saw a 37% reduction of decline compared to placebo over the course of over 78 weeks. Some strange numbers hang over the results. Men reduced their decline by almost 3x what women did. And Hispanics reduced their decline by about 3x-8x what non-Hispanics did (3x in the US and 8x outside of the US). Hispanics made up a major portion of their trial population, while Blacks did not.

In their initial readout, Anavex did not present much data on its ADCS-ADL results, one of their main endpoints. The company will release the full data set, including all the ADCS numbers before they submit a paper for publication in a peer-reviewed journal and before they meet with the FDA to discuss approval.

Perhaps the results of the ADCS were disappointing. This possibility is contradicted by a statistic the company did report: those who took Blarcamesine were 167% more likely to improve their ADCS-ADL score by 3.5 points than placebo.

Alzheimer's patients, especially those as deteriorated as the ones in the Blarcamesine trial were, are expected to get worse over the course of 48 weeks unless they are given a placebo or medication. In this case, I would expect very reasonably that maybe 12% of the placebo group improved 3.5 points on a measure that has far more to do with morale and mood than the ADAS-Cog. For instance, one question asks the caregiver how much help does the patient need in eating? The more optimistic one feels, the more likely one will refuse help and find a way to eat even if it requires a great deal of effort. Placebos provide optimism.

So, if 12% of the placebo arm improved by 3.5 points, then more than 32% of those who took Blarcamesine improved by 3.5 points or more. If that is the case, then a major portion performed magnificently with the help of Blarcamesine.

What about the other two-thirds? The ADCS is a questionnaire taken by the caregiver regarding the previous four weeks of helping the patient. In a trial that lasted only 48 weeks and for a psychotropic medication that may take numerous weeks to ramp up, the 44th week may not have been so pretty as the 47th week. Plus the caregiver may have their own biases. I would consider the ADCS scores to be the least reliable of the three measures that Anavex used as endpoints.”

A simple comparison of the Lecanemab trial with the Blarcamesine trial is not an apples to apples comparison. Clearly, the differences between the two trials, and in particular the differences in the disease condition of the patients in the two trials needs to somehow be taken into consideration. Note also that the above article says that “…a psychotropic medication … may take numerous weeks to ramp up…”. See for example: “Antidepressant and antipsychotic medications may take 6 weeks or more to fully work.” https://www.nami.org/About-Mental-Illness/Treatment/Mental-Health-Medications/What-to-Expect-From-Your-Medications

Frankly, I believe that making comparisons between Lecanemab and Blarcamesine is more complicated than many of us here seem to think. However, I also believe that regulators in Europe, Asia and the USA, are equipped to fairly and adequately make comparisons between the two drugs by taking into consideration the differences between the the two clinical trials and differences between the two drugs.

I believe neither drug (neither trial) has produced enough evidence to obtain final approval. Thus, the conditional approval of Lecanemab. Only time will tell how all of this will play out. I think that MacFarlane is correct in saying that it will take a combination of drugs to treat AD. Perhaps Lecanemab and Blarcamesine will play a part in that combination. Or, perhaps other drugs may be added to produce an Alzheimer’s “cocktail” form of treatment.

It will also be interesting to see how the EU regulators may react to Lecanemab given the failure of EU approval of Aduhelm. The EU said in its refusal to approve Adu, along with Adu’s side effects, noted this: “The European Medicines Agency noted that although Aduhelm reduces amyloid beta in the brain, the link between this effect and clinical improvement had not been established.” See: https://www.ema.europa.eu/en/documents/medicine-qa/questions-answers-refusal-marketing-authorisation-aduhelm-aducanumab_en.pdf