2023-03-16 04:06:18 ET
Summary
- The ANAVEX2-73-AD-004 trial was mostly positive.
- A reputable journal article on the missing data would allay fears of a 'spin'.
- If the company's lead drug candidate did slow functional decline due to AD compared to the placebo, FDA approval is almost assured.
Anavex Life Sciences Corp. ( AVXL ) is a small (~$700 million market cap) clinical-stage biopharmaceutical company developing treatments for Alzheimer's disease ("AD"), Parkinson's disease ("PD"), Rett syndrome and other central nervous system diseases (Figure 1). In its February 7 quarterly report , Anavex listed the following key near term pipeline data updates:
- AD: Full data ANAVEX2-73-AD-004: Potentially pivotal Phase 2b/3 clinical trial
- PD dementia: Data of 48-week open label extension ("OLE") Phase 2 study
- Publications: Several clinical publications involving blarcamesine, ANAVEX3-71 and Rett syndrome Burden of Illness study
Investors should be familiar with these catalyst events to build a complete picture of the two core programs and make informed decisions in the near-term (within 1-3 months).
Figure 1. Anavex Therapeutic Candidates
During December's Clinical Trials on Alzheimer's Disease (CTAD) Congress 2022, Anavex announced positive topline results from its Phase 2b/3 ANAVEX2-73-AD-004 trial of oral blarcamesine for the treatment of mild cognitive impairment and mild AD (collectively known as early AD). The company claimed that blarcamesine "met" the primary endpoints ("PEP") AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL), as well as key secondary endpoint Clinical Dementia Rating-Sum of Boxes (CDR-SB). 'Met' typically means the results were statistically significant. A lot of information was shared (Table 1), yet actual results for ADCS-ADL were not.
Table 1. ANAVEX2-73-AD-004 Top Line Data
Placebo | Blarcamesine | |
Baseline Characteristics (Full Analysis Set), mean (standard deviation) | 170 | 338 |
Mini-Mental State Examination Score | 23.11 (2.69) | 23.57 (2.92) |
ADAS-Cog | 30.25 (8.93) | 28.75 (8.67) |
ADCS-ADL | 66.48 (7.08) | 66.72 (7.59) |
CDR-SB | 4.10 (1.76) | 3.81 (1.73) |
Intent-to-Treat ("ITT") Population, mean (standard error) | ||
ADAS-Cog, baseline | 29.18 (0.61) | 27.62 (0.5) |
ADAS-Cog, Week 48 | 33.26 (0.98) | 30.36 (0.83) |
CDR-SB, baseline | 4.11 (0.14) | 3.78 (0.1) |
CDR-SB, Week 48 | 5.61 (0.26) | 4.89 (0.17) |
Safety Population | 161 | 301 |
Any treatment emergent adverse events (TEAE), n (%) | 113 (70.2) | 248 (82.4) |
Serious TEAE, n (%) | 15 (9.3) | 47 (15.6) |
Adverse Events ?7.5% | ||
Dizziness | 9 (5.6) | 76 (25.2) |
Confusional State | 4 (2.5) | 40 (13.3) |
Fall | 16 (9.9) | 21 (7.0) |
After 48 weeks among randomized patients (the ITT population), blarcamesine significantly reduced cognitive decline compared to placebo as measured with ADAS-Cog by 45%; the treatment difference in mean score change of -1.85 points (p=0.033). Mean baseline scores for patients who took blarcamesine were 27.62, which worsened to 30.36 after 48 weeks of treatment, or an increase of 2.26 points , a correctly calculated figure according to Chief Executive Officer Christopher Missling. Blarcamesine also slowed decline of cognition and function assessed by the CDR-SB compared to placebo (-1.11 vs 1.52), a treatment difference of -0.42 points (p=0.040), representing 27% reduction.
Non-head-to-head trials aren't really comparable. That said, blarcamesine's ADAS-Cog scores appear in line (Table 2) with Biogen's ( BIIB ) Aduhelm and Leqembi (co-commercialed with Eisai ( OTCPK:ESALY )), which received marketing authorization, and Eli Lilly and Company's ( LLY ) donanemab, which could've but was rejected on a technicality . However, blarcamesine can't be approved on the basis of ADAS-Cog alone, because according to the FDA's guidance document on AD, "An integrated scale that adequately and meaningfully assesses both daily function and cognitive effects in early AD patients is acceptable as a single primary efficacy outcome measure." ADAS-Cog only measures cognitive effects, not function.
Table 2. ADAS-Cog Endpoints in AD Trials of Approved and Approvable Drugs
Study | Approved dose | Study duration | n | Placebo | Difference | % Difference | p |
Aduhelm 10 mg/kg every four weeks | 78 weeks | 547 | 5.16 | -1.40 | -27% | 0.01 | |
ENGAGE | Aduhelm 10 mg/kg every four weeks | 78 weeks | 555 | 5.14 | -0.59 | -11% | 0.258 |
donanemab | 52 weeks | 93 | 2.37 | -0.84 | -35% | ||
donanemab | 76 weeks | 93 | 4.77 | -1.86 | -39% | ||
Leqembi 10 mg/kg biweekly | 79 weeks | 398 | 4.90 | -2.31 | -47% | 0.017 | |
Leqembi 10 mg/kg biweekly | 18 months | 859 | 5.58 | -1.44 | -26% | <0.001 |
CDR-SB is an acceptable PEP. Indeed, Aduhelm and Leqembi were controversially approved on the strength of their statistically significant 22% and 27% reduced declines , which were comparable to blarcamesine (Table 3). As discussed in the preceding article, investors should note that the absolute score differences compared to placebo demonstrated by Aduhelm, Leqembi, and blarcamesine on the CDR-SB scale that ranges from 0 to 18 were 0.39, 0.45 and 0.42 points, respectively, which cannot be detected by clinicians. These lackluster results led the Centers for Medicare and Medicaid Services ("CMS") to implement a National Coverage Determination (NCD) denying coverage of Aduhelm and future monoclonal antibodies targeted against amyloid (including donanemab), outside of clinical trials. CMS upheld its decision after Leqembi's approval under the rationale that "to provide coverage nationally, CMS is required to examine whether a medication is reasonable and necessary [emphasis supplied]. This standard differs from the criteria used by the FDA to assess whether medications are safe and effective." As Sigma-1 receptor agonist and muscarinic receptor modulator, blarcamesine is exempt from the NCD, for now. Nevertheless, the small molecule can't be approved for its CDR-SB performance either, since it was only a secondary endpoint in ANAVEX2-73-AD-004.
Table 3. CDR-SB Endpoints in AD Trials of Approved and Approvable Drugs
Study | Approved dose | Study duration | n | Placebo | Difference | % Difference | p |
EMERGE | Aduhelm 10 mg/kg every four weeks | 78 weeks | 547 | 1.74 | -0.39 | -22% | 0.012 |
ENGAGE | Aduhelm 10 mg/kg every four weeks | 78 weeks | 555 | 1.56 | -0.03 | -2% | 0.833 |
TRAILBLAZER-ALZ | donanemab | 52 weeks | 93 | 1.21 | -0.59 | -49% | |
donanemab | 76 weeks | 93 | 1.58 | -0.36 | -23% | ||
lecanemab 201 | Leqembi 10 mg/kg biweekly | 79 weeks | 398 | 1.50 | -0.40 | -26% | 0.125 |
Clarity AD | Leqembi 10 mg/kg biweekly | 18 months | 859 | 1.66 | -0.45 | -27% | <0.001 |
Financials and Takeaways
Anavex has one of the stronger cash positions among biotechs at $143.6 million with no debt. The latest quarterly burn was $13 million, comprising general and administrative expenses of $3.3 million and larger research and development expenses of $12.1 million, slightly offset by grants and tax incentive credits. Even if the company does initiate 4 clinical trials as planned, their funds should be sufficient for at least 12 months as forecast. Therefore, any price near-term movement will be mainly due to clinical developments. An article on the Phase 1 study of ANAVEX 3-71 in healthy volunteers probably won't move the needle at this time, but a confirmation from the OLE of the Phase 2 which demonstrated proof-of-concept in PD dementia could, depending on endpoints presented. But really, the company's future boils down to one critical catalyst.
Publication in a peer-reviewed journal of the full ANAVEX2-73-AD-004 data is much awaited in the AD world. To say that ADCS-ADL is crucial is an understatement. A trial with two PEPs needs statistical significance on both to be positive, so anything short of p<0.05 in the ITT population would demote the trial from "pivotal" to "supporting". A dose-dependent reaction would be nice but not necessary. Aside from this co-PEP uncertainty, any not yet reported serious safety issue is another risk. Overall, it is more likely than not that ADCS-ADL is indeed positive and not fudged by management, making Anavex a Buy. Traders looking to hedge should probably look further ahead in the option chain to at least July 21 at the earliest and straddle the most popular $10 strike. Prices are unlikely to stay at that level no matter which direction the data flows.
For further details see:
Buy Anavex For Its Likely Positive Alzheimer's Disease Data