Anavex Life Sciences Announces Presentation of Phase 2 Clinical Biomarker Data from ANAVEX®2-73-PDD-001 Parkinson’s Disease Dementia Study

[John_morris71]

finance.yahoo.com/news/anav...

All MDS-UPDRS Part I, II, III, IV sub-scores improved, including substantial majority of individual items between 71% and 92%

SIGMAR1 mRNA expression significantly increased in ANAVEX®2-73-treated patients vs placebo (p=0.035) and was significantly associated with improvements of MDS-UPDRS scores and cognitive efficacy endpoints CDR system

NEW YORK, March 15, 2022 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced the presentation of Phase 2 clinical biomarker data from the ANAVEX®2-73-PDD-001 Parkinson’s Disease Dementia (PDD) study at AD/PD™ 2022 International Conference on Alzheimer’s & Parkinson’s Diseases and related neurological disorders, taking place in Barcelona, Spain, and virtually on March 15–20, 2022.

The poster presentation titled, “ANAVEX®2-73 (blarcamesine) - Analysis of Movement (MDS-UPDRS) and Cognitive (CDR System) Pharmacodynamic-Biomarker Outcome Measures of Placebo-Controlled Phase 2 Trial in 132 Parkinson’s Disease Dementia Patients” is being presented by the Principal Investigator of the trial, Dr. Jaime Kulisevsky, MD, PhD, Full Professor of Neurology & Vice-Dean Faculty of Medicine Autonomous University of Barcelona and Director of the Movement Disorders Unit, Department of Neurology, Sant Pau Hospital.

MDS-UPDRS1 Total score improved significantly by -14.51 (p=0.034) for patients treated with ANAVEX®2-73 high oral once-daily dose compared to placebo. The improvement is clinically relevant corresponding to a relative improvement of 18.9% over 14 weeks.

Balanced and global improvements were observed within all MDS-UPDRS sub-scores Part I-IV:

MDS-UPDRS Part I: 92.23% items improved (12 items out of 13)

MDS-UPDRS Part II: 76.92% items improved (10 items out of 13)

MDS-UPDRS Part III: 88.23% items improved (30 items out of 34)

MDS-UPDRS Part IV: 71.42% items improved (5 items out of 7)

MDS-UPDRS Total score is defined by the sum of all Parts:

Part I: Non-motor Experiences of Daily Living

Part II: Motor Experiences of Daily Living

Part III: Motor Examination

Part IV: Motor Complications

SIGMAR1 mRNA expression significantly increased in ANAVEX®2-73-treated patients vs placebo (p=0.035) over the course of treatment and was significantly associated with improvements of MDS-UPDRS scores and cognitive efficacy endpoints CDR system.

Dr. Jaime Kulisevsky, MD, PhD, Principal Investigator of the trial, commented, "PDD is a debilitating disorder with significant co-morbidities and there has not been a mechanistically novel medication approved for PDD in over 20 years. Hence, new therapies are urgently needed to alleviate this suffering and disability. I am impressed with the robust improvement of the MDS-UPDRS across all sub-score parts I-IV coupled with the biomarker correlated outcome measures and I support the implementation of the ANAVEX®2-73 Phase 3 studies in Parkinson's disease and Parkinson's disease dementia, respectively.”

Christopher U Missling, PhD, President & Chief Executive Officer of Anavex, remarked, "ANAVEX®2-73 (blarcamesine) demonstrated dose-dependent efficacy for both motor impairment (MDS-UPDRS) and cognition (CDR system), which correlated with SIGMAR1 mRNA as a pharmacodynamic biomarker, respectively. These results support continued development of ANAVEX®2-73 in Parkinson’s disease and Parkinson’s disease dementia as well as currently ongoing Precision Medicine biomarker-driven late-stage clinical studies in Rett syndrome and Alzheimer’s disease. We would like to thank all the patients and participating families as well the investigators and clinical site coordinators for their dedication to this study."

The presentation of the Abstract #519 / 336 is available on the Anavex website (anavex.com).

About Parkinson’s Disease (PD)

Parkinson’s disease is a chronic and progressive neurological disorder that is characterized by well-known motor symptoms including tremors, stiffness of limbs, slowness of movements, and difficulties with posture and balance, as well as by non-motor symptoms. It is the second most common neurological disorder and approximately one million people in the United States, and more that 10 million people worldwide, live with this disease. Parkinson’s disease is more common in people over 60 years of age and its prevalence is expected to increase significantly as the average age of the population increases. Current Parkinson’s treatments are only effective in managing symptoms of the disease, mainly through the use of levodopa and dopamine agonists. As the disease progresses and dopaminergic neurons continue to be lost, these drugs eventually become less effective at treating the symptoms.

About Parkinson’s Disease Dementia (PDD)

Parkinson’s disease is a fairly common neurological disorder in older adults, estimated to affect nearly 2 percent of those older than age 65. The Parkinson’s Foundation estimates that 1 million Americans have Parkinson’s disease. It is estimated that up to 80 percent of those with Parkinson’s disease eventually experience Parkinson’s disease dementia. The brain changes caused by Parkinson’s disease begin in a region that plays a key role in movement. As Parkinson’s brain changes gradually spread, they often begin to affect mental functions, including memory and the ability to pay attention, make sound judgments and plan the steps needed to complete a task.

About ANAVEX®2-73-PDD-001 Clinical Study (NCT03774459)

The ANAVEX®2-73-PDD-001 study was an international, double-blind, multicenter, placebo-controlled proof of concept Phase 2 clinical study that randomized 132 patients with Parkinson’s disease dementia (PDD) equally (ratio of 1:1:1) to target doses of 30 mg, 50 mg ANAVEX®2-73 or placebo, respectively. As previously reported, in addition to prespecified ANAVEX®2-73-related biomarker of response, SIGMAR1, safety and cognitive efficacy, MDS-UPDRS, actigraphy and sleep function was assessed during the study duration of 14 weeks.

Study inclusion required diagnosis of idiopathic Parkinson's disease (PD) consistent with the UK Parkinson's Disease Society Brain Bank diagnostic criteria and diagnosis of probable PD dementia (PDD) according to the Movement Disorder Society Task Force clinical diagnostic criteria as well as Montreal Cognitive Assessment (MoCA) score of 13 to 23. DNA and RNA from blood samples were analyzed using NGS.

Study participants were allowed to be on stable regimen of anti-Parkinson's disease medications (including levodopa, dopamine agonists, MAO-B inhibitors, or entacapone). Treatment with cholinesterase inhibitors, rivastigmine, donepezil and galantamine (Exelon®, Aricept®, or Reminyl®) were also permitted.

The study found that ANAVEX®2-73 was well tolerated in oral doses up to 50 mg once daily. The results showed clinically meaningful, dose-dependent, and statistically significant improvements in the Cognitive Drug Research (CDR) computerized assessment system analysis. The study validated the precision medicine approach of targeting SIGMAR1 as a genetic biomarker of response to ANAVEX®2-73, confirming that ANAVEX®2-73 acts through SIGMAR1 activation.

Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD.

Statistically significant dose-dependent (p = 0.003) improvement of Episodic Memory, which has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale–Cognitive score (ADAS-Cog; r = 0.7).

ANAVEX®2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder.

ANAVEX®2-73 was generally safe, well tolerated, and improved safety profile compared to dementia drugs associated with typical adverse effects.

After completing the ANAVEX®2-73-PDD-001 trial, participants were able to enroll in a voluntary 48-week open-label extension study, ANAVEX®2-73-PDD-EP-001, which continues to assess safety, long term efficacy and changes in gut microbiota.

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About Anavex Life Sciences Corp.

Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a clinical trial for Alzheimer’s disease, a Phase 2 proof-of-concept study in Parkinson’s disease dementia and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer’s disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson’s Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson’s disease. ANAVEX®3-71, which targets sigma-1 and muscarinic M1 receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer’s disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at anavex.com.

[JCRO]

More than a glimmer of hope. Thx.

[John_morris71 in reply to JCRO]

They have a 48 week OLE going on and most(95% if I am not mistaken) in the original trial opted to continue. That is a good sign.

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[park_bear]

14.5 point Improvement on the UPDRS is a big deal!

[JCRO in reply to park_bear]

It really is.

[John_morris71 in reply to park_bear]

fyi : Got this info from another board

Blarcamesine versus levodopa:

BLARCAMESINE (Anavex 2-73):

Per today's PR, examining results over a 14 week, properly controlled trial of 132 subjects:

"MDS-UPDRS [1] Total score improved significantly by -14.51 (p=0.034) for patients treated with ANAVEX®2-73 high oral once-daily dose compared to placebo. The improvement is clinically relevant corresponding to a relative improvement of 18.9% over 14 weeks."

LEVODOPA:

L-dopa's effect on total UPDRS scores for 361 subjects with early Parkinson's Disease over 42 weeks was described in a New England Journal of Medicine article published in 2004 (nejm.org/doi/full/10.1056/n...

"The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and –1.4 in those receiving 600 mg daily (P<0.001)."

In other words, the high dose l-dopa arm improved over 42 weeks by a UPDRS total score of -9.2 UPDRS units (representing the difference between the high dose arm of -1.4 units versus the placebo arm of 7.8 units).

Furthermore, Anavex reports, "Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD. Statistically significant dose-dependent (p = 0.003) improvement of Episodic Memory, which has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale–Cognitive score (ADAS-Cog; r = 0.7). ANAVEX®2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder." (Citations omitted)

In terms of side effects, Anavex has reported transient dizziness and headache during titration. Temporary dizziness, of course, would have to be managed among a PD population already prone to balance issues. Per the NEJM article linked above, "The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo." Use of a lesser dose of l-dopa to avoid these side effects reduces efficacy to -5.9 UPDRS units (versus -14.5 reported for blarcamesine).

The comparison above is not quite apples to apples; the trial durations are different as are the trial populations. L-dopa is known to work only over a limited period. But what we have seen shows blarcamesine promises to hold a significant advantage over the current PD standard of care.

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[jeffmayer]

Can anyone translate into english

[Jana86]

I have been watching this company for about a year. Their approach is different (based on my knowledge). NOT a scientist, but will try to explain (Simon Stott where are you?) Anavex has discovered what they call a therapeutic discovery platform based upon their recognition that all CNS diseases have a common root...Sigma 1 receptors. "The sigma-1 receptor, one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum that modulates calcium signaling through the IP3 receptor. In humans, the σ₁ receptor is encoded by the SIGMAR1 gene. The σ₁ receptor is a transmembrane protein expressed in many different tissue types" . Wikipedia

Anavax has developed a family of drugs that improves the signalling capacity of these receptor cells. They believe that this approach will help any human with CNS disease...from pediatrics to old age and have set about testing their theory in some very difficult popultations: kids with Retts, Alzheimers, and PD Dementia. What John published are the results of the PD Dementia trial. They now have a couple of Stage Two trials complete...a couple more underway...all show similar positive results. Looking for Stage 3 trial funding.

What is unusual I think is that in the PD Dementia trial, UPDRS scores went down across the entire scale...not just the focal point problem of dementia. This could have implications for all of us???

I have to give them credit...adults with Retts, PD dementia? Not easy problems to solve. And I love their belief that no one is untreatable. From their website:

The vision of Anavex Life Sciences is only made possible if patients have equitable access to healthcare. As a result, the team at Anavex Life Sciences takes its role in helping to address health equity across the healthcare institutional continuum seriously. Through inclusive, person-focused approaches to clinical trial design and the sheer determination to improve the lives of people of all ages and backgrounds impacted by CNS disorders, the team at Anavex Life Sciences is working diligently to bring quality of life improving treatments for a widespread variety of neurodevelopmental and neurodegenerative disorders.

From infants to the elderly, Anavex Life Sciences remains dedicated to addressing the devastating impact of neurological disorders through the development of its' proprietary SIGMACEPTOR™ discovery platform.

As a large body of evidence indicates that sigma-1 receptors (SIGMAR1) are important drug targets for a number of neurological disorders, the team at Anavex Life Sciences is proud of its accomplishments thus far and looks forward to continuing the work required to achieve its' life-saving therapeutic discovery goals.

Hope that helps.

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[jeffmayer in reply to Jana86]

Thanks it's clearer now

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[Bolt_Upright]

PDD Patients Given Anavex 2-73 at High Dose Show Range of Benefits parkinsonsnewstoday.com/202...