blarcamesine (Anavex 2-73) / Anavex - LARVOL DELTA

Pre-specified SIGMAR1 Gene Variant Analysis in Phase IIb/III Trial Supports Precision Medicine Mechanism of Action (MoA) with Improved Treatment Effect of Blarcamesine in Early Alzheimer Disease (CTAD 2024) - No abstract available

P2/3 data • P2b data • Alzheimer's Disease • CNS Disorders • SIGMAR1

ATTENTION-AD: OLE of Phase 2b/3 Study ANAVEX2-73-AD-004 (clinicaltrials.gov) - P2/3 | N=300 | Completed | Sponsor: Anavex Life Sciences Corp. | Active, not recruiting ➔ Completed | Phase classification: P2b ➔ P2/3 | N=450 ➔ 300

Enrollment change • Phase classification • Trial completion • Alzheimer's Disease • CNS Disorders

Anavex Life Sciences Reports Fiscal 2024 Third Quarter Financial Results and Provides Business Update - "Completed last patient last visit in the ATTENTION-AD open-label extension 96-week trial. Interim data expected in the second half of 2024...Initiation of ANAVEX 2-73 Phase 2b/3 >6-month trial, including biomarkers, which we believe may be key to understanding drug effects on Parkinson’s disease pathophysiology and account for the recently changing context in the field of Parkinson’s disease is expected in the second half of 2024."

New P2/3 trial • P2/3 data • Alzheimer's Disease • CNS Disorders • Parkinson's Disease

Results from Anavex Life Sciences Landmark Phase IIb/III Trial of Blarcamesine Presented at Alzheimer's Association Conference (GlobeNewswire) - P2/3 | N=509 | NCT03790709 | Sponsor: Anavex Life Sciences Corp. | "Anavex Life Sciences...presented comprehensive results from the Phase IIb/III study showing that blarcamesine (ANAVEX 2-73), once daily orally, significantly slowed clinical decline in people with early Alzheimer's disease (AD)....Blarcamesine significantly slowed clinical progression by 38.5% and 34.6% at 48 weeks in 50 mg and 30 mg groups vs. placebo, respectively, on the prespecified primary cognitive endpoint ADAS-Cog13....The functional co-primary endpoint, ADCS-ADL, was trending positive but did not reach significance at Week 48. A possible explanation is that the ADCS-ADL scale is designed for AD with overt dementia and is less sensitive for early AD.2 The prespecified key secondary composite endpoint CDR-SB...is significant at both 30 mg and 50 mg at Week 48....'Full regulatory submission of blarcamesine in Europe (EMA) is expected in Q4 2024'."

EMA filing • P2/3 data • Alzheimer's Disease

Central role of Sigma-1 receptor in ochratoxin A-induced ferroptosis. (PubMed, Arch Toxicol) - "In this investigation, cell viability, malondialdehyde (MDA) levels, glutathione (GSH) levels, and protein expressions in HK-2 cells treated with OTA and/or Ferrostatin-1/blarcamesine hydrochloride/BD1063 dihydrochloride were assessed. The results indicate that a 24 h-treatment with 1 μM OTA significantly induces ferroptosis by inhibiting Sig-1R, subsequently promoting nuclear receptor coactivator 4 (NCOA4), long-chain fatty acid-CoA ligase 4 (ACSL4), arachidonate 5-lipoxygenase (ALOX5), autophagy protein 5 (ATG5), and ATG7, inhibiting ferritin heavy chain (FTH1), solute carrier family 7 member 11 (SLC7A11/xCT), glutathione peroxidase 4 (GPX4), peroxiredoxin 6 (PRDX6), and ferroptosis suppressor protein 1 (FSP1), reducing GSH levels, and increasing MDA levels (P < 0.05). In conclusion, OTA induces ferroptosis by inhibiting Sig-1R, subsequently promoting ferritinophagy, inhibiting GPX4/FSP1 antioxidant systems, reducing GSH levels, and ultimately increasing..."

Journal • ACSL4 • AIFM2 • ATG7 • GPX4 • NCOA4 • PRDX6 • SLC7A11

Blarcamesine in Early Alzheimer Disease Phase 2b/3 Randomized Clinical Trial (AAIC 2024) - "In this phase 2b/3 randomized clinical trial, we found that among participants with early AD, blarcamesine significantly slowed clinical progression on prespecified primary outcome global and cognitive measures at 48 weeks in the ITT population. These results suggest that blarcamesine may be an effective, safe, and novel scalable oral treatment for early AD."

Clinical • P2/3 data • P2b data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding. (PubMed, ACS Chem Neurosci) - "While the precise details of the mechanism of action of these molecules remain to be determined, the present work forms the basis for further investigation of these compounds in preclinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer's disease, respectively, this work has immediate implications for the treatment of human prion disease."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Ischemic stroke • Mental Retardation • Neuralgia • Oncology • Pain • Psychiatry

The involvement of SigmaR1K142 degradation mediated by ERAD in neural senescence linked with CdCl2 exposure. (PubMed, J Hazard Mater) - "In the in vivo models, the administration of the SigmaR1 agonist ANAVEX2-73 rescues neurobehavioral inhibition and alleviates cellular senescence and AD-like pathology in the brain tissue of CdCl2-exposed mice...CdCl2 exposure activated SEL1L/HRD1-mediated ERAD and promoted the ubiquitinated degradation of SigmaR1, activating p53/p21/Rb pathway-regulated neuronal senescence. The results of the present study suggest that SigmaR1 may function as a neuroprotective biomarker of neuronal senescence, and pharmacological activation of SigmaR1 could be a promising intervention strategy for AD therapy."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Metabolic Disorders • Targeted Protein Degradation • NOTCH1

BLARCAMESINE IN EARLY SYMPTOMATIC ALZHEIMER DISEASE PHASE 2B/3 RANDOMIZED CLINICAL TRIAL (ADPD 2024) - P2b | "Among participants with early symptomatic AD, blarcamesine was generally safe, well tolerated and significantly slowed clinical progression at 48 weeks, which is also corroborated by biomarkers from the A/T/N spectrum, including plasma Aβ42/40 ratio increase and reduction of brain atrophy in several key regions of the brain measured by MRI. ClinicalTrials.gov Identifier: NCT03790709."

Clinical • P2/3 data • P2b data • Alzheimer's Disease • CNS Disorders • Aβ42

Anavex Life Sciences Announces Grant of U.S. Patent Covering Blarcamesine (ANAVEX 2-73) for Treatment of Neurodevelopmental Disorders (GlobeNewswire) - "Anavex Life Sciences Corp...announced today it was granted new U.S. Patent No. 11,839,600...from the United States Patent and Trademark Office (USPTO) for its patent application number 17/890,083. Anavex’s newest patent expands coverage of ANAVEX 2-73 (blarcamesine) therapy to ameliorate various conditions associated with loss-of-function mutations of the gene encoding methyl-CpG binding protein (MeCP2). The patent claims protect use of ANAVEX 2-73 (blarcamesine) to address a range of symptoms exhibited by patients suffering from neurodevelopmental and neurological conditions related to McCP2..."

Patent • CNS Disorders • Developmental Disorders

Anavex Announces First Entire Clinical Gene Pathway Data of ANAVEX2-73 from AVATAR Study in Patients with Rett Syndrome (GlobeNewswire) - P3 | N=33 | AVATAR (NCT03941444) | Sponsor: Anavex Life Sciences Corp | "Anavex Life Sciences Corp...announced the first entire clinical gene pathway data from the ANAVEX^®2-73-RS-002 AVATAR Rett syndrome trial....ANAVEX^®2-73 transcriptomics analysis (RNAseq) identified gene networks that are differentially expressed in Rett syndrome patients treated with ANAVEX^®2-73 compared to placebo. Patient samples that were analyzed contained on average over 20 million unique reads in both placebo and ANAVEX^®2-73 treated patients. Biological relevance of this pool of genes was assessed through pathway analysis and confirmed the impact of ANAVEX^®2-73 treatment on pathways involved in neurodevelopmental diseases."

P3 data • CNS Disorders • Developmental Disorders

Anavex Received Agreement from the Committee for Medicinal Products for Human Use (CHMP) for the Submission of a Marketing Authorisation Application of Oral Blarcamesine for Alzheimer’s Disease (GlobeNewswire) - "Anavex Life Sciences Corp...announced today that the Committee for Medicinal Products for Human Use (CHMP) within the European Medicines Agency (EMA) agreed that oral blarcamesine for Alzheimer’s disease is eligible for submission of an application for a Union Marketing Authorisation in the EU under the European Medicines Agency’s centralised procedure....Anavex is aiming to submit the Marketing Authorisation Application as early as possible in 2024."

European regulatory • Alzheimer's Disease • CNS Disorders • Immunology

Anavex Initiates Regulatory Submission of Oral Blarcamesine for Alzheimer’s Disease to European Medicines Agency (EMA) (GlobeNewswire) - "Anavex Life Sciences Corp...announced today that representatives of Anavex met with team members of the European Medicines Agency (EMA)....These meetings discussed the debilitating pathology of Alzheimer’s disease and Anavex’s blarcamesine (ANAVEX 2-73) Alzheimer’s disease clinical program results, including data obtained in the ANAVEX 2-73-AD-004 study....Pursuant to discussion at the meetings, Anavex initiated the process for submitting a Marketing Authorisation application to the EMA with the submission of the Centralised Procedure request with the goal of the Authorisation allowing direct access to the market of the European Union for oral blarcamesine for the treatment of Alzheimer’s disease."

European regulatory • Alzheimer's Disease • CNS Disorders

Cognitive Impairment in Parkinson's Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches. (PubMed, Medicina (Kaunas)) - "Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Movement Disorders • Parkinson's Disease • FGF21

Anavex’s Phase 2b/3 Trial of Blarcamesine (ANAVEX 2-73) in Patients with Alzheimer’s Disease Shows Robust Clinical Efficacy and Slows Neurodegeneration (GlobeNewswire) - P2b/3 | N=508 | NCT03790709 | Sponsor: Anavex Life Sciences Corp. | "Anavex Life Sciences Corp...announced today that a follow-on analysis of the landmark Phase 2b/3 study to treat early Alzheimer’s disease with the investigational drug blarcamesine (ANAVEX®2-73) did demonstrate a statistically significant slowing in cognitive decline associated with Alzheimer’s disease....The trial is successful in meeting the co-primary endpoints if the significance of each endpoint is P < 0.05, or if the significance of only one co-primary endpoint is P < 0.025....In addition, validated biomarkers of amyloid beta pathology, plasma Aβ42/40 ratio increased significantly (P = 0.048), demonstrating strong anti-amyloid effects of blarcamesine in Alzheimer’s disease patients..."

P2/3 data • Alzheimer's Disease • CNS Disorders

ATTENTION-AD: OLE of Phase 2b/3 Study ANAVEX2-73-AD-004 (clinicaltrials.gov) - P2b | N=450 | Active, not recruiting | Sponsor: Anavex Life Sciences Corp. | Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders

EXCELLENCE: ANAVEX2-73 Study in Pediatric Patients With Rett Syndrome (clinicaltrials.gov) - P2/3 | N=92 | Completed | Sponsor: Anavex Life Sciences Corp. | Active, not recruiting ➔ Completed

Trial completion • Developmental Disorders • Movement Disorders • Pediatrics

Anavex Life Sciences Reports Fiscal 2023 Third Quarter Financial Results (GlobeNewswire) - "Alzheimer’s disease: Full data ANAVEX^®2-73-AD-004, including newly available preliminary results of surrogate biomarkers of pivotal Phase 2b/3 clinical trial. The Company intends to discuss these findings with regulatory authorities in the context of the ongoing clinical development of ANAVEX^®2-73 in this indication, with the goal of providing a much-needed treatment to the millions of patients living with Alzheimer’s disease with a convenient once-daily oral treatment. Company expects to announce data in the second half of 2023. Parkinson’s disease: Initiation of ANAVEX^®2-73 pivotal clinical trial. Parkinson’s disease: Initiation of ANAVEX^®2-73 imaging-focused clinical trial."

New P2/3 trial • New trial • Alzheimer's Disease • CNS Disorders • Parkinson's Disease

The New Big Is Small: Leveraging Knowledge from Small Trials for Rare Disease Drug Development - Blarcamesine for Rett Syndrome. (PubMed, Br J Clin Pharmacol) - "We demonstrate how knowledge can be gained, with supporting strength of evidence, from a small (data) clinical trial with a low dose of blarcamesine in the treatment of Rett syndrome (RTT). Based on a small data paradigm, pharmacometrics item response theory modeling and Bayes factor analysis were used to show that blarcamesine is efficacious in RTT."

Journal • Review • Developmental Disorders • Movement Disorders • Rare Diseases

"Congratulations RETT community on ANAVEX®2-73 Blarcamesine, finally a real treatment!" (@UnaKerensa)

ANAVEX2-73 (blarcamesine) Receives Compassionate Use Authorization for Pediatric Patients with Rett Syndrome (GlobeNewswire) - "Anavex Life Sciences Corp...announced that the first patients with Rett syndrome from the ANAVEX®2-73-RS-003 study (EXCELLENCE) are able to continue treatment with ANAVEX®2-73 (blarcamesine) thanks to Health Canada’s approval of the Special Access Program (SAP), allowing for compassionate use following completion of the 48-week Open-Label Extension study. Special Access Program (SAP) applications are granted at a physicians’ request on behalf of patients. Based on the safety profile of ANAVEX®2-73 (blarcamesine), as well as clinical evidence that the study drug will continue to benefit patients, Anavex will continue its responsibility to support patients post study by facilitating the supply of ANAVEX®2-73 (blarcamesine) to patients in Canada. Approved compassionate programs are also ongoing in the United Kingdom and Australia, representing all regions of the Rett Syndrome study participation."

Canadian regulatory • Commercial • CNS Disorders • Developmental Disorders

Anavex Life Sciences Reports Publication in Medical Journal Signifying Continued Commitment for Improvement of the Rett Syndrome Caregiver Outcome Measure RSBQ (GlobeNewswire) - "Anavex Life Sciences Corp...announced the publication of a relevant new peer-reviewed study in the American Journal on Intellectual and Developmental Disabilities, entitled ‘Rett Syndrome Behaviour Questionnaire in Children and Adults With Rett Syndrome: Psychometric Characterization and Revised Factor Structure’...The study, which represents the largest ever analysis of the RSBQ and the first report of the instrument in adults with Rett Syndrome, was the result of an international collaboration including anonymized databases from the United States, Australia, United Kingdom, and Denmark...All analyses performed in the study are available to the community through a website hosted by IRSF...'We are looking forward to the topline data from the EXCELLENCE Phase 2/3 ANAVEX®2-73-RS-003 Rett syndrome pediatric clinical trial in the second half of 2023'."

Clinical data • P2/3 data • CNS Disorders • Developmental Disorders

63% of American Caregivers Believe in Link Between Inflammation In Alzheimer’s Disease (Times of San Diego) - "Our survey shows nearly half of caregivers (43%) would guess there are at least 3-4 drugs targeting inflammation with 16% of respondents guessing that there are 5 or more of these drugs in development. This, however, is wrong. According to an article by Jeffrey Cummings that looked at all Alzheimer's clinical trials underway...31 Alzheimer's agents in Phase 3, NE3107 is the only drug candidate addressing inflammation."

Media quote

"Anavex 2-73" (@bdgengineer)

"Anavex 2-73" (@bdgengineer)