ANAVEX NY TRÅD JULI - PRÆVENTIV BEHANDLING AF ALZHEIMER!!!
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Anavex
Er desværre (meget) travlt beskæftiget i øjeblikket, men følger naturligvis stadigvæk med herinde. Kunne dog ikke dy mig for en kommentar oven på udgivelsen i Nature. Det er helt klart et skulderklap, og en indikation af, at Anavex kan være på vej i den rigtige retning. MEN - og nu gentager jeg mig selv - det er et præklinisk studie, og man kan IKKE omsætte prækliniske data til kliniske resultater. Beklager, Tasso. Den går ikke, også selvom MOA er den samme i pattedyr. Nuvel vi er pattedyr, men selv om MOA er den samme, så er alt omkring MOA ikke nødvendigvis den samme. Menneske-hjernens struktur er endog meget forskellig fra en mus. Det er bare at pille hjernen ud på en mus. Man behøver ikke engang mikroskop for at se tydelige forskelle mellem muse-hjerne og menneskehjerne; og her taler vi ikke om størrelsen men selve kompositionen af hjernen. Desuden er forsøgsdyr ofte ikke "wildtype", men genetisk ret ens. Man har så at sige indavlet rotter og mus, så de bliver så genetisk identiske som muligt. Det har man gjort for at reducere den biologiske varians, så vi ikke skal bruge 100 dyr hver gang vi skal køre et forsøg. Desuden får alle dyrene ens føde, har ens døgnrytme etc. etc. etc. Alle faktorer spiller potentielt ind, hvilket gør det farligt at sætte lighedstegn ml. prækliniske og kliniske resultater.
Vi skæver jo så alligevel til prækliniske studier for at få en ide om, hvad vi måske kan finde i os mennesker. Og noget tyder jo på, at kliniske data viser en effekt af medicinen.Kort sagt: Ja, Nature er flot og absolut et af de bedste steder man kan præsentere sine data. Ingen tvivl. Men det er et dyre-studie, og jeg ville absolut IKKE pantsætte huset for at smide pengene på Anavex fordi man ser en tydelig effekt i mus. Men ja, casen er ikke forringet efter en Nature publikation.
PS: Apropos genetik. Man har benyttet sig af knockout mus i forsøget. Det er normal kutyme, men når man knockouter et gen, så ved vi reelt ikke hvilke andre gener som bliver opreguleret. Så selvom medicinen virker i disse mus og på fragilt-X, så er det ikke sikkert den virker i andre indikationer.
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Anavex Fint du kom på banen Boersboe!
Alt det du skriver er sikkert helt korrekt - er jo ikke selv inde for fagområdet.
Derfor er det vigtigt at få din faglig kompetance ind i casen.
Håber du har mulighed for at give os din vurdering af Peer Reviewet?Det vi dog i praksis har set er dog, at Anavex netop har kunnet omsætte prækliniske resultater til tilsvarende kliniske resultater, med reelle og livsforberende virkning i patienter, hvor der ikke tidligere var nogen behandlingsmulighed.
Det er dette faktum der gør, at jeg er investerer i Anavex! -
Okay vi kan konkludere at der er forskel på mus og mænd.
Det er stadig meget bedre at ha noget publiceret i Nature end et sagsanlæg fra et anerkendt advokat firma i New York. Det burde market reagere på når den synker ind.
Er spædt på om Missling kommer med en udmelding i dag.
Den Nature rapport skriver Bla andet i sin konklusion:
Furthermore, clinical efficacy was demonstrated in a placebo-controlled Phase 2 study in Rett syndrome (NCT03758924) and previously in a smaller PK cohort of patients with this neurodevelopmental disorder39, as well as significant cognitive improvements in a Phase 2 trial in Parkinson's disease dementia (NCT03774459). Late-stage clinical studies of blarcamesine in adult and pediatric patients with Rett syndrome (NCT03941444, NCT04304482) and Alzheimer's disease (NCT02756858, NCT03790709) are currently ongoing. Continued findings from these clinical studies with blarcamesine, combined with the presented data strengthens the rationale for potentially a dependable and effective treatment strategy for FXS and other neurological disorders targeting the S1R with blarcamesine.
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Så kom den officielle. Men åh nej, han siger intriguing:-). Nå, vi må se, det må give på kursen
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Anavex Life Sciences Announces Publication of Foundational Data for ANAVEX
2-73 (blarcamesine) in Fragile X Syndrome (Autism)Lidt fra rapporten:
"We look forward to initiating a double-blind, placebo-controlled Phase 2/3 ANAVEX
2-73 study in Fragile X Syndrome," said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. "We are intrigued about the clear preclinical data providing potential to expand the therapeutic profile of ANAVEX2-73 into the largest portion of addressable market of autism spectrum disorder, Fragile X Syndrome. This is further evidence of the potential of ANAVEX2-73 as a platform technology of precision medicine." -
Anavex. Flad fornemmelse.
Det må være en flad fornemmelse, efter disse 15-17 forsker har brugt uger eller måneder på et Peer Review, der efter deres mening formodentlig må have en eller anden værdi, må se at markedet egentlig er bedøvende ligeglade!
Vi skal måske endda være glade for, hvis aktienholder sig i plus i dag???
Måske er MOA i mus og mænds hjerner så forskellige, som Boersboe antyder, at en sådan forskning egentlig er fuldstændig irrelevant!Der er måske blevet brugt ufattelig ressourcer på forskning, som er total ubrugeligt?
Måske skulle man skippe al præklinsk forskning i CNS området og tage chancen og gå direkte i kliniske forsøg.- evt. lige stikke musene et par piller og se om de falder døden om inden.
Nej - selvfølgelig er der en sammenhæng!
Vi skal bare have nogle kompentente analytikere frem til at oversætte dette tunge stof til os alm. dødelige! -
Der er en på Ihub som har kigget på resultaterne:
TempePhil Thursday, 08/26/21 09:51:31 AM
Re: None 0
Post # of 327609Here's A2-73s murine treatment score for FragileX Syndrome:
This is the 30000 foot, view of the results of the Murine Fragile X study. I like to evaluate efficacy by how far does a drug returns the afflicted back to normal. This will be given as a percentage, with 100% being the afflicted was returned to complete normalcy. Oh yes, the afflicted in this case were, of course, mice.
The efficacy (% of normal) was based on these three tests:
1) Hyperactivity - Open Field Test................100%
2) Fear Freezing Response - Fear Conditioning.....100%
3) Perseverance and Anxiety - Marble Burying......50%Also shown above is the percentage that each was improved, compared to normalcy. Hyperactivity and Freezing were totally returned to normal, while "Marble Burying" returned half way to normal.
Weighting each of the three equally, an overall efficacy score would be:
For these three tests, the mice on A-73 returned 83.3% back to normal!The primary biomarker was BDNF(brain-derived neurotropic factor). BDNF levels effect cognitive and sensorimotor deficits.
BDNF returned 93% back to normal!I am not sure why two other biomarkers were included (pGSK3B and Rac1) as they did not show much change. Maybe they were just included to show they were not affected. If anyone has insight here, please post. The previous (unreviewed) manuscript (posted by TTT?) showed pAkt and pERK. I think these two were excluded because BDNF is already a function of them.
CONCLUSIONS:
It is clear why Fragile X expert, Dr.Hagerman, is very enthusiastic about getting A2-73 trials going for humans, with a hopeful improvements of 83.3%! As quoted in the article "...this neurodevelopment disorder continues to have an unmet therapeutic need.".
The efficacy numbers are amazingly good. The biomarker improvement supports and validates the efficacy.
This study adds to the growing body of evidence, validating A2-73 as a powerful new drug.The usual caveats exist, this is a murine study(not humans), there were not a lot of mice used, there were limited efficacy tests, etc.
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Hi Tasso. Jeg er 100% sikker på, at hovedforfatterne og medforfatterne til Nature artiklen er enormt tilfredse og glade for at have fået publiceret en artikel i et high rated tidskrift. Bortset fra Missling og måske et par af de andre forfattere (som kan have en økonomisk interesse i den reaktion artiklen udløser på aktiekursen), så tror jeg, at de mere ser på den betydning som en sådan publikation kan have for deres karriere inden for forskningsverdenen, hvor den afgørende faktor for en glorværdig karriere netop er deres publiceringer og hvor ofte disse senere bliver citeret i diverse tidsskrifter. På forskernes vegne tror jeg således, du er (lidt) for pessimistisk. Mht. os som investorer, så tror jeg (ligesom du?) at en eller flere af de analytikere, der følger AVXL nok snart skal give positiv lyd fra sig. Se bare dagens nyhed vedr. reaktionen på CRTX' resultater fra i mandags.
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Det er bare sket så mange gange før. Gode nyheder og shorterne tager købelysten fra markedsdeltagerne.
Måske ikke kun shorterne, men sikkert også de institutionelle investorer, der pt akkumulerer og snart runder 40% ejerskab.
Enten skal vi have helt afgørende gode nyheder eller også skal de store investorer flytte AVXL op i det fortjente niveau.
Hvornår det sker ved ingen.
Jeg har er par gæt - partnerskab, udlicensering, PDD peer review og/eller mulighed for ansøgning om approval på nu kendte data, Avatar-data ....
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Ja, det er træls at se på. Ser dog at 50% af mine bioteks vendte fra plus til minus på en lille time. Altså en overordnet markedsretning. Han skulle nok have sagt: we are exited about the intriguing results.... Nå, folk er nok ikke til sjov i dag. Vi må vente yderligere.
Pøj pøj til os
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Her lidt om det vi tidligere har skrevet om. At bakterier i kroppen kan have en sammenhæng med sygdomme, herunder alz. Umiddelbart jo ingen relevans til dagens pr, og så alligevel. Vi ved det ikke endnu. Her fra CRTX igår: https://finance.yahoo.com/news/cortexyme-presents-data-demonstrating-evidence-120000034.html
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Anavex
Har desværre ikke haft tid til at dykke ned i artiklen for alvor; men kan fornemme en vis frustration herinde
Nu er det nemt at sige når US børsen er åben, men jeg havde faktisk ikke regnet med, at den artikel i Nature ville rykke meget ved kursen. Med ét ben i hver lejr - ét i klinikken og ét i det prækliniske - så kender jeg til de begrænsninger der findes i begge dele. Der er en grund til at vi har begge dele, men man skal bare være bevidst om hvilke konklusioner man kan drage på baggrund af de forskellige studier og metoder. Og det ville faktisk undre mig, hvis nogle analytikere hæver kurs-target på baggrund af den her artikel. Jeg har meget lidt indsigt i aktieverdenen sammenlignet med flere herinde, men fra et videnskabeligt synspunkt er der ikke holdepunkter for at man skal købe aktier i Anavex med arme og ben. Skal jeg tage udgangspunkt i det jeg har læst i artiklen, så vil jeg give anbefalingen "hold" (jo jo, lidt lidt aktie-lingo har man vel tillagt sig).
Der skal kliniske studier til før det bør rykke på kursen. Et stort randomiseret studie. Det undrede mig eksempelvis at PDD studiets resultater ikke rykkede mere ved kursen. Dengang var jeg anelse skuffet, må jeg erkende.
Jeg har ikke solgt en eneste anavex aktie endnu. Faktisk havde jeg råd til at købe 70 mere forleden... ikke en formue; men det kan det vel blive til
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Promising Results of Preclinical Study of ANAVEX®2-73
Anavex Life Sciences announced today that preclinical data of the ANAVEX®2-73 (blarcamesine) study in Fragile X syndrome were published in the journal, Scientific Reports.
FRAXA Research Foundation - Finding a Cure for Fragile X Syndrome (www.fraxa.org)
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Anavex er faktisk en del længere fremme end hvad flere tror.
Jeg mener, at PDD data var utroligt stærke og undrer også mig som boersboe, at kursen ikke steg mere end vi har set.
Men da PDD data kom solgte ANXL også selv et ganske betydeligt antal aktier og kvalte hermed stigningerne.
Jeg tror på, at de der akkumulerer og shorterne har fælles interesse i at holde kursen nede. Det vil de lykkes med indtil det er åbentlyst for alle at ANXL vil blive en succes.
Det sidste anser jeg for meget sandsynligt. Ikke pga museforsøg, men mest af alt pga de forsøg vi allerede har set data på. Vi har set god effekt og bivirkninger, der er overordentlig overkommelige - en meget vigtig parameter.
Senere har vi set videnskablige resultater fra andre kilder, der bekræfter at SIGMA1 receptoren kan være vejen til succes i CNS sygdomme. Ikke blot i AD, PDD etc, men også meget overraskende Rett, Fragile X, autisme etc.
De meget omfangsrige dataindsamlinger på alle pts i behandling ser ud til at øge sandsynligheden for succes. Nogle pts vil kunne få rigtig god effekt, mens andre ikke får megen effekt af behandlingen. Netop det forhold er forudsætningen for, at godkendelser af Blarcamesine er meget sandsynlig i de grupper der er effekt i - selv om en evt første analyse af samtlige pts ikke viser signifikans.
Misslings tiltagende selvsikre udsagn om, at ANXL er i en transformativ fase i 2021 styrker også min tro på selskabet.
Jeg er nok mere risikovillig end de fleste, men jeg tror meget på casen - ikke nødvendigvis tro på succes i alt, men mindre kan også gøre det - specielt med den værdiansættelse vi ser nu.
Jeg sælger ikke en eneste aktie før AD forsøget har readout.
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Anavex 100 % enig i dine betragtninger Solsen!
Vi skal have en godtaget markedsansøgning og efterfølgende markedsgodkendelse i RETT fra FDA, så får vi en seriøs afspejling i kursen og senere når 2-73 kommer på markedet, måske også muligheden for hurtig at udvide salget til andre relaterede indikationer.
Dvs. at patienter med Fragil X, autisme mm. burde kunne få adgang til 2-73, før der ligger en særskilt godkendelse i disse indikationer.
Uanset må denne sidste Peer Review have positiv indflydelse på de beslutninger og hvilke retningslinjer FDA giver Anavex i det videre forløb.
Presset fra FRAXA kan måske også skubbe lidt til processen med FDA.
FRAXA varetager jo primært interesser for børn og unge patienter - dette burde i sig selv give en højere prioritering hos FDA - især når der ikke er nogen alternativ behandling.Tak for linket Budweis!
Promising Results of Preclinical Study of ANAVEX®2-73
Anavex Life Sciences announced today that preclinical data of the ANAVEX®2-73 (blarcamesine) study in Fragile X syndrome were published in the journal, Scientific Reports.
FRAXA Research Foundation - Finding a Cure for Fragile X Syndrome (www.fraxa.org)
"We look forward to initiating a double-blind, placebo-controlled Phase 2/3 ANAVEX
2-73 study in Fragile X syndrome""The next phase for Anavex will be Phase 2 double-blind, placebo-controlled study. There are good indications that the results from the next phase will also be promising for both Fragile X syndrome and Autism."
FRAXA ser også mulighed for en effekt af 2-73 i autisme generelt og de vil forsætte samarbejdet med Anavex.
MM - Missling brugte også ordet "clear", udover "intrigued" i beskrivelsen af resultaterne - måske blev dette opfattet uklart af markedet:)
Vi må se - måske får vi en forsinket reaktion, som ved CRTX.
Vi havde jo en relativ lille omsætning af Anavex aktier - tror SAVA hev os med ned i faldet i dag. -
Anavex-tråd: Biogen's New Alzheimer's Drug Beyond Reach for Many Patients
Doctors say insurers' reluctance to pay for the controversial medication, Aduhelm, results in patients being put on waiting lists https://www.wsj.com/articles/biogens-new-alzheimers-drug-beyond-reach-for-many-patients-11630077741?mod=e2tw -
Meget fin artikel om Anavex igen i Seeking Alpha.
Skribenten har aktier i Anavex og regner med ca 75% chance for godkendelser i RETT og PDD.
Pga af lav patient antal i fase 2a i Alz toer skribenten ikke at give ods på hvad chancerne er der, men er rimelig positiv. -
Det er en mega god artikel. Dejligt med noget for og imod i samme skriv. Tak for den Kyed
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Anavex. Udskrift Seeking Alpha
Super positiv kyed01 - tak.
Ser ikke umiddelbar ud til, at det er Lane S., der har forfattet artiklen - han er ellers også meget positiv på Anavex.
Forfatteren glemmer dog at nævne det planlagte Fragile X fase 3 forsøg på baggrund af bl.a. den sidste Peer Review.
Han nævner heller ikke den meget vigtige nyhed, at Anavex planlægger et forebyggende demens forsøg med 2-73.Ellers kunne man næsten få lyst til at købe Anavex aktier mandag - hvis man da ikke lige i forvejen var fyldt helt til skorsten med dem i forvejen.
Måske mangler SAVA folkene et sted, hvor de har muligheden for at tjene lidt af det tabte hjem igen.
( Har selv solgt det meste ud i SAVA )Anavex Life Sciences: Still Room To Run
Aug. 29, 2021 8:11 AM ETAnavex Life Sciences Corp. (AVXL)33 Comments13 Likes
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SummaryLead candidate ANAVEX2-73 has shown impressive results in placebo-controlled Phase 2 studies in Parkinson's disease and Rett syndrome.
Ongoing studies in Rett syndrome could lead to a filing in 2022 if results are positive.
Encouraging results have been generated in a small study in Alzheimer's disease but are difficult to evaluate since it was not a placebo-controlled study.
Phase 2b/3 study in Alzheimer's disease is fully enrolled with top line data expected mid-2022.
Despite a 4-fold share price increase over the past year, we see continued upside based on Rett and PD, plus anticipation of a positive AD study readout next year.
Volunteer and old people
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Anavex Life Sciences (AVXL) is developing ANAVEX 2-73 as a potential treatment for Alzheimer's Disease (AD), Rett Syndrome, and Parkinson's Disease Dementia (PDD).The positive news on these studies has driven an increase in the share price by 4-fold in the past year to a market cap of $1.5 billion. Given the current investor appetite for any company that is showing a hint of success in AD, we think the share price still has room to run over the next 6-9 months in anticipation of Phase 2B/3 AD results. In addition, two additional Rett studies should read out in 2021, providing the basis for a potential filing in 2022.Brief History and Background of ANAVEX 2-73
ANAVEX 2-73, also named blarcamesine and hereafter abbreviated as A2-73, was described by Professor Alexandre Vamvakides and his group in a 1997 patent application and two publications in 2002. In 2007 the patent rights to ANAVEX 2-73 and other compounds were acquired by Anavex. Since then, the company has been advancing the compound through clinical development at a very slow pace, perhaps due to lack of financial resources.
According to their most recent 10-K, ANAVEX 2-73 binds the sigma-1 receptor (S1R) in the high nanomolar range and the muscarinic receptor in the low micromolar range. This means the compound has quite weak binding to S1R. In their August earnings conference call, CEO Missling stated: "ANAVEX 2-73 is the only available small molecule activator of the Sigma 1 receptor." This is a puzzling statement. While there are no FDA-approved drugs that are S1R agonists, it is now well known that several approved drugs are S1R agonists. The best comparison for AD treatment is Aricept (donepezil). Aricept was approved as an acetylcholinesterase inhibitor in 2004, but has subsequently been shown to be a potent agonist of S1R with low nanomolar binding (14.6 nM). (Lower numbers correlate with increased binding). This means Aricept is at least 50-fold more potent than A2-73 as an SIR agonist.
AVXL has touted data from a PET study that showed A2-73 achieved 70% SIR receptor binding in rat brains at high doses, as shown in the figure below, copied from the AVXL investor presentation.
Anavex - Anavex2-73
In a poster presentation, Anavex authors conclude that the mice equivalent human plasma exposures correspond to human doses of 10-50 mg, the doses that are being studied in clinical studies.
Aricept has also been shown to have SIGMAR1 receptor occupancy in rodent brains, achieving 93% receptor occupancy at 10 mg/kg, substantially higher than the 70% level determined with A2-73 at the same dose. Based on PET studies in human brains, doses of 5 mg and 10 mg Aricept bound to SIR with occupancies of approximately 60% and 75%, respectively. While we don't have a head to head comparison, I think it is safe to conclude that 50 mg A2-73 will not provide higher occupancy than 10 mg Aricept in humans. Since Aricept is marginal at best in treating AD, it seems likely that A2-73 will not be effective for any disease for which SIR binding is the primary mode of action.
A2-73, however, is active on several other brain receptors that may also be involved in neurological diseases. It is an antagonist of muscarinic M1-M4 receptors (with micromolar affinity), Na+ channel site 2, and NMDA receptor (NMDAR). While AVXL is branding A2-73 as a "selective SIGMA1R receptor agonist," the data are more consistent with a poly-pharmacological effect by binding with several receptors, perhaps some that are yet unknown, to achieve efficacy in a range of diseases that include AD, Parkinson's, and Rett Syndrome.
We also note that A2-73 is metabolized in humans to its des-methyl analog, A19-144. Based on data provided in a patent, the potency of A19-144 is similar to A2-73 with low micromolar binding to S1R.
While some of the pre-clinical data raise concerns about A2-73, the clinical data are proving these concerns unfounded. AVXL now have proof-of-concept data in three indications, Alzheimer's Disease, Parkinson's Disease, and Rett Syndrome. We cover each disease indication below in the following order: Rett Syndrome, PDD, and AD.
Rett Syndrome
Rett Syndrome is a severe neurological disease primarily affecting girls. Most cases are caused by a mutation in the MECP2 gene which is needed for nerve development in the brain. The FDA has granted A2-73 fast track and orphan drug designation for this indication.
A placebo-controlled Phase 2 study conducted in the US was completed in December 2020 with 25 adult female patients with Rett syndrome over a 7-week treatment period. Fifteen patients received 5 mg of A2-73 as an oral liquid formulation while 10 received placebo. As shown in the slide below, robust and statistically significant responses were seen in 3 relevant measures. This is impressive data considering the very small size of the study and the quite low dose of only 5 mg.
Anavex - Rett Syndrome
Two additional studies are underway. The second study in Rett began in June 2019 and is similar to the first except that a higher dose is being studied (dose not disclosed). The study involves 33 female adult participants for 7 weeks. The company announced that this study exceeded enrollment targets with top line data available this year.
The third clinical trial is studying A2-73 in 69 pediatric patients, aged 5 to 18, over a 12-week treatment period. The company has confirmed they expect completion of this study this year.
CEO Missling noted on the August conference call that they are in discussions with the FDA regarding whether these studies can be considered pivotal for registration. Given the robust results in the small Phase 2 study, the probability of success in the current two studies is high, perhaps 75%. The main risk is if A2-73 acts differently in adult vs pediatric patients. The average lifetime of a Rett patient is only 24 years, so those who survive longer may have a somewhat different disease than younger patients.
The market opportunity for this indication alone could approach $1 billion annually. The company notes there are about 11,000 Rett patients in the US. Since Rett will be the first indication that gets approved for A2-73, AVXL will be able to price it similarly to drugs for other rare diseases - in the $500,000 range per year. As an example, Orladeyo, approved in Dec 2020 for hereditary angioedema, is a drug that is dosed orally and priced at $495K per year. Assuming net pricing after insurance negotiations is $300K per year and half of the patients in the US take the drug, then 5500 patients x $300,000 = $1.65 billion annual revenue. The company would also likely partner this drug for Europe and Asia where the incidence of Rett is similar to that in the US. A2-73 for Rett is a liquid formulation while PDD and AD are tablets, so there is a possibility of different pricing if A2-73 ultimately gains approval for AD or PDD.
The primary competition for Rett is trofinetide. Acadia (ACAD) has completed a Phase 3 study with results expected by year end. As noted on the AVXL corporate presentation, trofinetide is less efficacious than A2-73 and causes GI problems in a high percentage of patients. Since the mechanism of action of the two drugs is different, it is likely that both could be used concomitantly in patients. In any event, having a competitor should not greatly limit the potential revenue of A2-73 for Rett.
As a final note, the FDA has awarded AVXL a rare disease pediatric review voucher which affords the sponsor a priority review. This review could be up to 6-months accelerated vs a standard review. These vouchers are generally sold to a large pharma company. A voucher has been sold as much as $350 million although most of the recent ones have sold in the $100 million range. This would be a nice bonus for AVXL if A2-73 is approved to treat Rett.
Parkinson's Disease Dementia
In October 2020, AVXL completed a blinded placebo-controlled Phase 2 trial with A2-73 to study its effect on the cognitive and motor impairment of Parkinson's disease. The study enrolled 132 patients for 14 weeks, randomized 1:1:1 to A2-73 doses of 30mg and 50mg, or placebo. The results showed dose-dependent and statistically significant improvements in the primary cognitive efficacy endpoints, CDR system Continuity of Attention (COA) (p = 0.029) and CDR system Power of Attention (PoA) (p = 0.015), and secondary Parkinson's efficacy endpoints Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038). The company has not yet published the data nor presented at a conference so we don't have much information other than the top line data. However, it is impressive that in a small study they were able to generate statistically significant improvement in all primary and secondary endpoints. The company has released two slides on this study in the corporate presentation. The first is improvement in memory, which showed statistically significant dose-dependent (p = 0.003) improvement of CDR system Episodic Memory. Not only is this significant for PDD treatment, but this measure has also been shown to be highly correlated (70%) with the Alzheimer's Disease Assessment Scale-Cognitive score (ADAS-Cog), which we will discuss in the next section.
Anavex - Significant improvements in Episodic Memory with Increased Dose
The second slide shows the improvement in MDS-UPDRS score. This is a global composite score of Parkinson's disease symptom severity and may be considered the most important in the evaluation of overall improvement in these patients. This was one of the secondary endpoints that was perhaps unexpected since the drug is primarily targeting cognition, not the other aspects of PD.
Anavex - Anavex2-73
Based on the Phase 2 study, we believe the probability of success in PDD, and perhaps PD in general, is high, perhaps 75%. The company noted that the patients in this study continued to take other PD medications during the trial, including dopaminergic therapy, levodopa and other anti-PD medications. That A2-73 is showing an effect after 14 weeks of treatment on top of standard of care is remarkable. The timeline and next steps for the company in PDD have not yet been disclosed. In their latest 10-K, the company notes that Shake It Up Australia Foundation for Parkinson's Research has agreed to fund up to 50% of the costs of an Australian clinical study to develop A2-73. The proposed clinical trial would be for at least 48-weeks. If they could initiate a study in 2022 we could perhaps see data by 2024.
Alzheimer's Disease (AD)
Before discussing the Phase 2A data in AD, we start with the Phase 1 study in healthy volunteers since two important findings were determined in this study: (1) at a dose of 60 mg, 3 of 4 subjects experienced headaches and dizziness, limiting the top dose in future studies to 50 mg; and (2) the des-methyl metabolite A19-144 had a 5-fold higher concentration in plasma than the parent compound. The half life of the parent compound was 8.5 hours while that of the metabolite was 29 hours. This suggests that the metabolite may be producing most of the pharmacological effect.
The Phase 2A study in AD was an open-label study in 32 mild to moderate AD patients studying doses of 30 mg and 50 mg A2-73 for 57 weeks. The doses in the primary part of the study, from week 5 to 52, were 10mg, 20mg, 30mg, and 50mg. Patients were provided the opportunity to continue treatment in the extension study for up to 5 years. Currently, 21 patients have progressed to the 3 year timepoint.
Below is a figure that is based on data provided in the journal article that discussed the 2A study. The low, medium, and high dose graphs are based on data in supplemental Figure 1c from the article. We are only showing the 57 week data since the Phase 2B/3 study of 48 weeks will provide the data for potential approval. The gray line is the expected decline in ADCS-ADL score based on historical data of untreated AD patients (decline of 6.7 points in a year). The blue line slightly above this is the score (-5.24) for the 21 participants that completed the study which shows overall almost no treatment effect relative to historical controls. The orange line is for 8 patients who responded well with no decline during the year of treatment - this group had high plasma levels of A2-73 (mean > 4 ng/mL). Most of this group also had MMSE scores >20 (mild disease) and the wild type SIR. The purple line represents the group with middle concentration levels of A2-73. The bottom black line represents the group with low A2-73 plasma levels. This bottom group also included some patients with an SIR variant. The dose effect gives confidence that the effect is real but could be due to the other variables between the two groups. We don't want to over-interpret since this is such a small study without placebo control.
As also seen in the Phase 1 study the metabolite is 5-fold higher than the parent compound in all dose groups. The results are the same whether plotting concentration of parent, metabolite, or sum of both.
Anavex - Phase 2A ADCS-ADL Score
In July 2018, a 48-week Phase 2B/3 trial in Australia began enrolling patients with mild cognitive impairment or early dementia, plus PET or CSF confirmation of AD pathology. Enrollment was completed in June 2021 with 509 participants randomized 1:1:1 to 30 mg or 50 mg A2-73 or placebo for a duration of 48 weeks. Criterion for enrollment was an MMSE score between 20-28, which means that only mild AD patients were studied. Top line results are expected in mid-2022. The primary efficacy outcomes are change in ADAS-Cog and ADCS-ADL. The data from the Phase 2A study suggest the 30mg and 50 mg doses should provide adequate drug levels to achieve efficacy. The improvement in memory effects seen in the placebo-controlled PDD study provides additional confidence in a positive AD outcome.
Bottom Line
A $1.5 billion valuation is high for a company with no approved drugs. The share price is already anticipating a lot of success. Nonetheless, more upside is likely over the next 6-9 months as a build-up of expectations of Phase 2B/3 readout in AD in mid-2022. As a comparison, Phase 3 results for Cortexyme's (CRTX) drug for AD by treating gingivitis are expected in November and the share price has run to >$100, giving the company a market cap of $3 billion.
Pursuing Rett Syndrome is an excellent strategy since this indication is not linked to cognition and may succeed even if PDD and AD do not. The data from the placebo-controlled trials in Rett are exceptional - could not ask for much more out of this small proof-of-concept study. With two additional Rett studies underway we could see a filing in 1H2022 with potential approval by late 2022 or early 2023. Success in Rett will provide a cushion for the share price should AD not be successful.
The Phase 2 study in Parkinson's delivered more than expected. A2-73 showed benefit not only with memory but also with overall motor and non-motor effects of PD. The opportunity in PD is large given the estimated 1 million patients in the US.
Investing in biotech is risky. My general approach is to buy shares then use option collars, which involves buying puts and selling calls. This limits the upside but provides protection to the downside. There are many ways to do this. One example for AVXL that is cost neutral is to sell January 2022 call options at a strike price of $30 for $2.3 and buy January 2022 put options at a strike price of $14 for about the same price. This limits the upside to 58% (30/19) but also protects the downside loss to 25% (14/19).
This article was written by
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Small Pharma Analyst
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A veteran of the pharma industry. Specializing in the analysis of small pharma companies with a focus on th... more
Growth, Long/Short Equity, Biotech, HealthcareContributor Since 2010
A veteran of the pharma industry. Specializing in the analysis of small pharma companies with a focus on the pipeline and opportunities for licensing or major deals with large pharma. Financial analysis including burn rate, venture capital funding, and cash flow.
Disclosure: I/we have a beneficial long position in the shares of AVXL either through stock ownership, options, or other derivatives. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
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