Anavex Life Sciences Corp (AVXL)

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Anavex 2-73-RS-001 Adult Low Dose Rett Trial (U.S.)

To precede commentary on Anavex 2-73-RS-001 data, I want to bring investor attention to a particular portion of the 21 June 2021 Rett press release. “This study demonstrates for the first-time that a biomarker correlates with clinical efficacy in Rett Syndrome”. This claim underscores the importance of Anavex and their precision medicine approach and is crucial in evaluating the data provided to investors today. Most of the data provided was specific to the Sigma-1 receptor (S1R) wild type (WT) gene and how those patients responded to treatment vs. placebo.

Uninformed investors will claim that Anavex cherry-picks their data, that the company is not being fully transparent, or complain that Blarcamesine does not work equally for all patients. In reality, Anavex is using a pre-specified biomarker (found in over 80% of the population) to prove that patients with that biomarker respond to treatment. The only data that will matter to the FDA for ultimate approval is data involving S1R WT patients. The fact that non-WT patients still respond (just less) is a bonus. Bottomline: the company is not trying to prove that everyone responds equally, nor do they need everyone to respond equally.

Slide Deck
Phase 2: Improvement in All Key Domains

This is the only slide to show the entire patient population (25 patients in phase 2, 15 dosed, 10 placebo). We see that all key endpoints were met with statistical significance by week 7, which includes RSBQ, CGI-I, and ADAMS. RSBQ is a 45-point assessment which includes general mood, motor impairment facets, and sleep, amongst other behaviors. CGI-I is a review of the patient by a clinician in which the clinician assesses whether they think their patient has improved relative to a baseline state (a state prior to drug trial). And finally, ADAMS measures anxiety, mood, and depression, amongst other facets. Interestingly, CGI-I is only seen in this slide, with data suggesting clinicians overwhelmingly believed dosed patients holistically improved. Anavex may have excluded a deeper look of this data on account of it being the least objective of the three measures listed.



Favorable Efficacy Already at Low Anavex 2-73 Doses

This slide shows RSBQ improvement in S1R dosed patients vs. placebo for Anavex and general dosed patients vs. placebo in Trofinetide (developed by Neuren). Amazingly, we see that Anavex had a 14.5-point difference between S1R WT patients and placebo vs. Trofinetide benefit of 4.4-points. Despite massively lower dosing and dramatically older patients, Anavex superseded Neuren results by many times. This is exceedingly encouraging because diseases like Rett typically see higher response in younger patients.



ADAMS Total Score

This chart shows clinically meaningful and statistically significant improvement (p=0.005) at week 7 for the ADAMS assessment. Week 7 saw a 12.9-point improvement between dosed (-10.10 point) and placebo (2.75 point), with negative scores representing improvement and positive representing worsening. As a note, the term ‘clinically meaningful’ is the absolute gold standard for drug approval. A clinically meaningful drug meets a certain established threshold which indicates the drug will have a genuine positive effect on daily life.



ADAMS Subscale Score

This chart shows balanced improvements across all subscales. The subscales include Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, General Anxiety, and Obsessive-Compulsive Behavior. The Cohen’s d effect size is 1.31, which implies a massive effect. A massive effect such as this means that most dosed patients saw improvements on the highest end of measurement, above the mean. While all the ADAMS data was impressive, three of the measures were particularly interesting. Obsessive compulsive disorders had a whopping 64% difference between dosed and placebo, which was the highest difference of any ADAMS measure. Secondly was general anxiety, with a 46% measure. Differentiation between dosed and placebo score for general anxiety leads me to believe this is a ‘true score’, a benefit that is likely indisputably due to the drug. Lastly, depression had a 40% difference between dosed patients and placebo. Once again, there was a substantial differentiation between placebo and dosed, which I would consider to be a true score. Social avoidance and manic/hyperactivity had dosed/placebo differences of 30% and 28% respectively. The ADAMS data seems to confirm the Anavex 2a AD trial data which saw markedly lower depression and better mood in those patients.



Rett Syndrome Behavior Questionnaire (RSBQ) Total Score

This chart shows clinically meaningful and statistically significant improvement at week 4 (p=0.006) and week 7 (p=0.009) for RSBQ. Week 7 saw a 14.5-point improvement between dosed (-8.92 point) and placebo (5.56 point), with negative scores representing improvement and positive representing worsening. It is interesting that RSBQ was able to garner statistical significance at week 4 as well as week 7, opposed to ADAMS which saw statistically significant at week 7 only. This does seem logical to some degree based on emotional and mental response to natural healing. If one’s body begins to heal it may take some time after until their emotional disposition responds to their repair. This is only conjecture and there could be several logical reasons for ADAMS taking additional time to reach statistical significance. In any case, 7 weeks is not a long trial, and it would be interesting to see the OLE data at some point.



RSBQ Subscale Scores

This chart shows balanced improvements across all subscales by end of week 7. The subscales include General Mood, Breathing Problems, Hand Behaviors, Repetitive Face Movements, Body Rocking and Expressionless Face, Night-time Behavior, Fear/Anxiety, and Walking/Standing. Once again there are some subscales that proved to be exceptionally interesting. First being the night-time behaviors subscale, which saw a massive 61% difference between dosed and placebo patients. Differentiation between dosed and placebo score heavily indicate this being a true score. Nighttime behaviors were also noted to be dramatically improved in the Anavex 2a AD trial. The next subscale of interest is general mood with a large 43% general mood, followed by body rocking and expressionless face at 41%, repetitive face movements at 38%, and breathing problems at 32%. Breathing problems are one of the more significant problems when it comes to Rett safety concerns, so it is very promising to see such an effect in that category. To finish the subscales, fear/anxiety saw a 24% difference, walking and standing at 12%, and hand behaviors at 11%. I believe walking and standing as well as hand behaviors saw smaller effects due to the age of participants. These patients have gone many, many years with impaired motor skills. To be able to reverse these symptoms dramatically in a short 7-week period seems unrealistic. It is likely the pediatric group would see greater effect here due to their age and stage of development.



Summary

The Anavex 2-73-RS-001 data is overwhelmingly positive with broad therapeutic effect noted with statistical significance and clinical meaning in all primary endpoints. Anavex continues to impress upon investors the importance of precision medicine and the role of S1R as a diverse healing agent. Many of the subscale facets and impressive safety data synergized with Anavex 2a AD and PDD trial data.

Considering the adult cohort and low dose of this trial, the Anavex 2-73-RS-002 and RS-003 data will likely command even greater therapeutic effect with younger patients and higher dosing. It is my opinion that Anavex will receive accelerated approval from regulators for Rett syndrome.