Summary
The Phase 2b/3 trial of Anavex's Blarcamesine demonstrates major, statistically significant effects in slowing Alzheimer's Disease.
The drug slowed cognitive decline by about 45% over 48 weeks on the ADAS-Cog test, a measure of cognitive ability. It appears more effective than Biogen's Lecanemab.
A number of patients on the drug demonstrated cognitive/behavioral IMPROVEMENT (rather than slowing of decline); the initial readout of results indicate some showed extreme improvement (a super-response).
The patients in Anavex's Blarcamesine trial were substantially more cognitively impaired than those in Biogen's Lecanemab trial.
Dementia and Occupational Therapy - Home caregiver and senior adult woman
FredFroese/E+ via Getty Images
Anavex (NASDAQ:AVXL) has just completed a Phase 2b/3 trial of its new Alzheimer's drug, Blarcamesine, and the company reported initial results on December 1. It will report the full set of results and data before meeting with the FDA about what to do next.
In November, Biogen (BIIB) published its full set of results for its new Alzheimer's drug, Lecanemab.
Analyzing both sets of results, it seems apparent to me that dementia patients will prefer Anavex's Blarcamesine, based on both performance and side effects (see below).
[In separate 48-week tests, Blarcamesine trounces the currently available Alzheimer's treatment, Donepezil, in performance]
In Blarcamesine's 48 week trial, patients on the drug benefited from a 45% reduction in cognitive decline (versus placebo) based on the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) scores of patients. The ADAS is a test of thinking ability and memory. The worse your brain is working, the higher you score on the test. Those who took the placebo got worse by 4.11 points and those who took Blarcamesine got worse by only 2.26 points over 48 weeks.
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. So, the 2.26 point decline among those treated with Blarcamesine represents about a halving of decline compared to the untreated.
Some patients taking Blarcamesine in their Phase 3 trial actually improved, rather than reducing decline. And those individuals who did improve, according to Anavex, improved by a whopping 4.06 points on average on their ADAS-Cog scores! This is an absolute improvement over their individual baseline measurements.
A 4-point improvement versus a 4-point decline? The 8-point difference can mean the difference between being normal and being diseased. Stunning.
Those taking Blarcamesine were divided into two equal groups of 169 patients. One group took 30 mg of Blarcamesine each morning and the other group took 50 mg each morning. In the previous trial, (Phase 2), the drug was more effective at the 50 mg dose than at the 30 mg dose. The latest trial was a Phase 2b/3 trial and may lead to FDA approval of Blarcamesine.
The results seem to indicate that those taking the 50 mg dose of Blarcamesine may have benefited much more than those who took the 30 mg dose each morning.
Blarcamesine also reduced decline in overall impairment by 27% as measured by the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), a more global measure of cognition and behavior. This is very impressive, however, it is not as impressive as Blarcamesine's performance regarding the ADAS-Cog, a test that is purely focused on cognition and memory.
Perhaps Blarcamesine does not improve everyday functioning as much as it improves brain function. The Alzheimer's Disease Cooperative Study – Activities of Daily Living Scale (ADCS-ADL) measures performance of patients' daily living habits, based on caregiver interviews regarding the previous four weeks. Anavex did not report the mean change in ADCS-ADL.
Anavex only stated that those taking Blarcamesine were 167% more likely to improve their ADCS-ADL score by at least 3.5 points than were those on placebo pills. This means that if 12% of the placebo group improved their scores by at least 3.5 points, then about 32% of those taking Blarcamesine improved their scores by a very practically relevant 3.5 points or more on a 78-point scale. Of course, without any medication, patients are expected to decline in their performance.
Nevertheless, the lack of complete information seems to indicate that the overall ADCS-ADL numbers were not better than those of Biogen's Lecanemab, to which Anavex actively compared its drug in its most recent public presentation.
Comparing Blarcamesineemine And Lecanemab In Treating Alzheimer's Disease
While Anavex (AVXL) produced a partial readout of results for its daily pill, Blarcamesine, on December 1, Biogen (BIIB) produced a full readout of Phase 3 trials for its vaunted new biweekly intravenous treatment, Lecanemab, in November.
The results for Biogen's Lecanemab are encouraging despite some people suffering terrible side effects. But if Lecanemab's results were encouraging, then Blarcamesine's results are downright exciting.
Regarding the ADAS-Cog Scores. Cognitive decline was measured by the difference in change in the ADAS-Cog score versus change in ADAS-Cog score in the placebo arm over 48 weeks. In both studies, the placebo arm deteriorated in cognition at a faster rate than the treatment arm. Blarcamesine reduced deterioration by 40% more than Lecanemab at 48 weeks.
Furthermore, 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.
Regarding Side Effects. Blarcamesine trounces Lecanemab. About 3% of those who took Biogen's drug suffered from symptomatic brain hemorrhaging. Many more suffered asymptomatic brain hemorrhaging as well as noticeable brain swelling. Such symptoms may not prevent millions of desperate people from taking Biogen's Lecanemab, if it is approved and if there is no other alternative.
But 3% of one million is 30,000 people who must get treated or examined for brain hemorrhaging at an advanced age.
Further, two people in Biogen's Lecanemab study died under circumstances that suggested brain hemorrhaging contributed to their deaths. The doctor who performed one of the autopsies had this to say, as reported by Fierce Biotech.
Rudolph Castellani, a Northwestern University Medical Center neuropathologist who autopsied the body at the request of the patient’s husband, is quoted in Science as being unequivocal about the role lecanemab played in the death. Talking in a personal capacity, Castellani is reported as saying: “There’s zero doubt in my mind that this is a treatment-caused illness and death. If the patient hadn’t been on lecanemab she would be alive today.”
Having one patient die due to brain hemorrhaging, a known side effect of Lecanemab, represents a tiny fraction of the patient population.
Biogen reports that 859 patients took Lecanemab. If only 1 patient dies for every 900 patients, and 3 million people desperate for a cure decide to take Lecanemab, then 3,333 people will die from this Lecanemab side effect. While millions will certainly find the risk acceptable, it does seem like an avoidable catastrophe (avoided by taking the safer drug).
Because of these brain damage risks, those taking Lecanemab must get MRI tests done on their brains on a regular basis to check on the common side effect of brain swelling (a 600% increase in risk of brain swelling compared to placebo).
And finally, Lecanemab is taken through an IV infusion into a vein, every two weeks at the doctor's office. This can result in injection problems. And a lot of hassle and expense.
Blarcamesine is a once-daily pill, and patients in the trial were required to take the pill in the morning. Some of the patients complained about dizziness and confusion, and a small fraction of patients dropped out due to these side effects. Anavex suggested that some of these symptoms may be alleviated by taking the drug at night rather than in the morning. Interestingly the complaint of "falling" was reduced among those taking the Anavex drug. No drug-related deaths were reported.
Allowing Patients To Use Blarcamesine Rather Than Lecanemab May Save Thousands Of Lives.
Some Patients Improved Rather Than Reduced Decline
Biogen reported no actual patients improving after using Lecanemab or using placebo. This does not mean that there were no patients in their trial who improved. I would expect at least 10% of their patients under placebo to have improved. The placebo effect is powerful and it is the most consistent effect in all drug trials. The sense of optimism one feels under placebo can be especially powerful in helping patients being measured in their behavior and to a lesser degree their cognition.
Improvement on any measure was not an endpoint that Biogen claimed for its trial.
Anavex claims that substantial, clinically relevant improvement is one of its goals. And its measure for this is the probability that one will actually improve rather than slow decline while using its drug, Blarcamesine, versus placebo. In this measure, which some people find little use for, Anavex succeeded spectacularly.
On the ADAS-Cog, Blarcamesine-takers were 85% more likely to improve their scores by at least .5 points, a level of improvement that Anavex claims is noticeable in one's quality of life. Based on this statistic I am happy to buy some Blarcamesine for my mother, who has Alzheimer's, and myself too, when I show signs.
On the ADCS-ADL, the measure of everyday habits, Blarcamesine-takers were 167% more likely to have improved by at least 3.5 points, indeed a substantial improvement. And of course, this makes me want to utilize the drug even more. I like those odds.
But, for a traditional drug trial, these numbers are not what many scientists want to see. They are more interested in numbers such as the mean change in ADAS-Cog relative to placebo, as presented and discussed above.
30 mg Vs. 50 mg Of Blarcamesine And Super-Responders
FOR THOSE ON BLARCAMESINE WHO DID IMPROVE their ADAS-Cog scores, the average improvement was an amazing 4.06 points. This was weird. The overall average change among those taking Blarcasemine was a deterioration by over 2 points. How can these two numbers be part of the same drug trial?
If we assume that the distribution of changes in ADAS scores is normal -- a normal distribution -- then I would expect the average improvement to be closer to 1 point. There should be a lot of 1-point improvements, fewer 2 or 3 point improvements, and even fewer 4 or 5 point improvements.
One possibility is that it is a very flat curve on the side that represents improvement and a very sharp drop-off on the other side of the bell curve. The tail on the side of improvement must be very long and would likely have to extend beyond 10.
Of course, if one improves one's ADAS-Cog from 30 to 20 over the course of 48 weeks, this would likely be called a miracle.
Another possibility is that there are two clusters of those who improved. Perhaps the people who took 30 mg improved by 1 point on average. And perhaps among those who took the 50 mg dose, there were also some who improved by only one point or so, but rather than there being a "tail" on the curve, there is another cluster of improvers who improved by an average of 7. If you want an average of 4, after all, and you have a cluster of 1's, you have to have an equivalent cluster of 7's, or a smaller cluster of say, 10's, or three times as many 5's than 1's. The last case does not seem to gibe with the overall average.
This hypothetical group who improved by an average of 7 points or more may be called "super-responders." I am not validating any unverified blogs that claim researchers have reported "super-responders". I am ONLY looking at the data, and I am trying to understand how the average person who improved did so by over 4 points. The simplest explanation is the emergence of super-responders, who likely benefit far more than others due to genetic factors or because of the nature of their disease.
Of course, I am willing to go to many lengths to find out if my mother or I are super-responders. I want access to the drug, and so do many others.
Thoughts On Why The Stock Tanked
In my opinion, Anavex stock has not zoomed up based on the initial results of the Phase 2b/3 trial because:
1. Anavex did not provide the mean change in ADCS-ADL scores versus placebo; they only provided the statistic that those who took Blarcamesine were 167% more likely to improve their scores by 3.5 points. There may be some level of poor performance on this endpoint.
2. Immediately after Anavex published their data on December 1, many powerful "reporters" and "influencers" began claiming that Anavex's numbers were incorrect. Some of these influencers had a reputation for "bashing" companies. The chief accusation was that Anavex purposefully, or accidentally, made a simple subtraction error and the actual change in mean ADAS-Cog scores was less than the 45% reported.
The next day, CEO Christopher Missling explained how the ADAS-Cog calculations were made in an Investors Business Daily article. The explanation was expanded upon in a public presentation on December 5. One subtracts the final ADAS-Cog score from the original score for each individual; and then one finds the average of these individual differences. If there was no final measurement, then the individual difference was omitted. Makes sense, right?
Writers continued to claim that Anavex calculated their numbers wrongly. Interestingly, none of these meticulous data-combers, as they might characterize themselves, said anything about the glaring contradictions in Biogen's Lecanemab presentation. For instance, on two separate lines, both on page 34 of their presentation, Biogen stated that use of Lecanemab accelerated the cognitive decline of Hispanic and Black patients by 222% and 221%, respectively, compared to placebo. On those same respective lines, Biogen claimed that these apparently terrible results represented a slowing of cognitive decline relative to placebo.
3. Biogen's Lecanemab's successful Phase 3 trial was covered by all major mass media outlets, both upon presentation of their initial results as well as the final presentation of results. Famed financial analyst Jim Cramer has spoken extensively on both of Biogen's Alzheimer's drugs, sometimes being quite critical.
Anavex's Blarcamesine's successful Phase 3 trial was covered only by financial opinion and news outlets, and no other media outlets.
The Alzheimer's Association has 13 press releases regarding Lecanemab documented on its website. It has zero regarding Blarcamesine. As I continue to communicate with the Alzheimer's Association, I have not yet met anyone who has heard of Blarcamesine, nor anyone who has called me back regarding my questions about the drug.
Some of the influencers who speak on Anavex have been critical or accusatory with little evidence. "@InvestorsClubSpringer" is one live-streaming investing "guru" who favors Cassava Sciences over Anavex; he produced a number of videos on AVXL, but the most amusing one is "LLY and AVXL Sabotage SAVA? Five Biotechs Set To Double, and One Going 179x." Watch the first three minutes to get the gist of the conspiracy theories he hints at; you decide if he has presented any real evidence.
The Financial Potential
Worldwide 55 million people suffer from Alzheimer's disease. I believe that this number is an underestimate, as many people who suffer from Alzheimer's are never diagnosed.
If one out of eleven afflicted people, or 5 million people, pay for Blarcamesine, and they each pay $4000 per year, mostly in the high and middle-income nations, then that represents $20 billion per year in revenue.
If Blarcamesine is approved for the entire spectrum of cognitive impairment, then the numbers will increase. If Blarcamesine is prescribed as a preventative measure for those at high risk of Alzheimer's, that's an additional source of revenue.
When Biogen presented its initial results for its Phase 3 Lecanemab trail, the company's market cap increased by about $14 billion, the share price increasing from about 200 to 300 dollars. The stock has dribbled downward since around the time of the Anavex announcement; this may or may not be coincidental.
Health insurance companies will prefer Anavex's Blarcamesine over Biogen's Lecanemab, as widespread use of the Biogen drug may result in millions of additional MRIs each year, in order to monitor for brain hemorrhaging caused by Lecanemab. Also, Lecanemab may cause thousands of deaths and possible lawsuits.
Blarcamesine seems to be a good deal more effective than Lecanemab in slowing cognitive decline.
Blarcamesine also seems likely much better at actually improving cognition.
Blarcamesine certainly presents far better, non-lethal side effects.
My being at high risk of dementia, I would certainly prefer trying Blarcamesine for a couple of years before even considering Lecanemab.
Financial Risks
Some have said that Anavex has presented information that is not correct. If this is the case, and the drug actually does not work for Alzheimer's, then the value of the company may be limited to the 100s of millions, assuming that it will be approved for the Rett syndrome treatments (already-successful Phase 3 trials). Note that Anavex, via a Phase 2 trial, has demonstrated promise in treating Parkinson's Disease as well. A Fragile X treatment (orphan drug designation) and other treatments are further upstream.
If the ADCS-ADL scores turn out to be disappointing, but the ADAS-Cog and CDR-SB scores remain what they have been reported, the FDA will still approve Blarcamesine for Alzheimer's treatment, in my opinion. In this scenario, Blarcamesine would be approved on the grounds that it slows cognitive decline even if it does nothing to improve the eating or shopping habits of patients. In fact, it would be approved on the basis that it slows cognitive decline better than any known drug as of yet.
If Anavex needs to be subsumed by a Big Pharma corporation such as Eli Lilly (LLY), then Anavex may be bought out at a lower stock price than it would have otherwise reached if it were to market Blarcamesine on its own. Lilly could easily front $14 Billion dollars (based on the Biogen numbers above), and profit handsomely. Lilly is worth $342 Billion as of this writing.
Price Targets
Cantor Fitzgerald has a price target of $11 on AVXL stock, and Jones Trading believes AVXL will reach $80. I would prefer not to opine on a price target for Anavex stock. It is such a binary situation.
Given that, I believe that if the FDA rejects Anavex's Alzheimer's application, and if it only has the other ongoing drug trials to fall back on, the stock is worth 9 dollars a share, until one of its drugs is approved by the FDA. The Rett Syndrome application is worth in the 100s of millions and a Parkinson's approval is worth in the billions. The stock trades in the mid-8s as of this writing.
If Blarcamesine is approved for Alzheimer's, I believe the stock is worth over $180 per share based on the $14 billion estimate, and not including the value of the treatments for Rett, Parkinson's, Fragile X, and others. Please investigate the exciting Phase 2 placebo-controlled trial of Anavex's Parkinson's treatment, which may be worth billions, in my opinion.
The remaining data for the Blarcamesine drug trial might be made available during Anavex's presentation at The J.P. Morgan Healthcare Conference on January 12, 2023. The Anavex session starts at 8:15 a.m., Pacific Time.
