Date: 2016-12-08
Type of information: Presentation of results at a congress
phase: 2a
Announcement: presentation of results at the Clinical Trials on Alzheimer's Disease (CTAD) meeting
Company: Anavex Life Sciences (USA - NY)
Product: ANAVEX2-73 (tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride)
Action
mechanism: Anavex2-73 is an agonist of the intracellular sigma-1 chaperone protein. The compound is a mixed muscarinic receptor/sigma 1 ligand. It has been reported to have memory-preserving and neuroprotective effects in mice treated with the muscarinic receptor antagonist scopolamine, with synthetic ABêta oligomer injection, or with the NMDA receptor agonist dizocilpine. A recent study suggested that Anavex 2-73 may block tau hyperphosphorylation.
Disease: Alzheimer's disease
Therapeutic area: Neurodegenerative diseases
Country: Australia
Trial
details: The multicenter Phase 2a clinical trial of ANAVEX 2-73 consists of two parts and a total of 32 mild-to-moderate Alzheimer’s patients. PART A is a simple randomized, open-label, two-period, cross-over between oral (30mg/50mg) and IV (3mg/5mg) administration, adaptive trial lasting up to 5 weeks for each patient. PART B is an open-label extension for an additional 52 weeks. Initially planned for 26 weeks, PART B was extended to 52 weeks as a result of requests from patients and caregivers. The primary endpoint of the Phase 2a trial is evaluation of safety and tolerability of ANAVEX 2-73, which had shown potential in preclinical studies to prevent, halt and/or reverse the course of the disease. Secondary endpoints were dose response, bioavailability, and exploratory cognitive effects using electroencephalographic (EEG) activity and event-related potentials (ERP), Cogstate battery, Mini Mental State Examination (MMSE), and evaluation of Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory (ADSC-ADL) as well as the exploration of ANAVEX 2-73 as a potential add-on therapy to donepezil, the current standard of care. (NCT02244541)
Latest
news: * On December 8, 2016, Anavex Life Sciences announced a positive 57-week update from its Phase 2a study in mild-to-moderate Alzheimer’s disease (AD) patients for ANAVEX 2-73, which targets cellular homeostasis. The study met both primary and secondary endpoints. At 57 weeks, Alzheimer’s patients taking a daily oral dose between 10mg and 50mg, ANAVEX 2-73 was well tolerated. There were no clinically significant treatment-related adverse events and no serious adverse events. Published AD studies confirmed substantial declines of cognitive (MMSE) and functional (ADCS-ADL) measures as well as Cogstate and EEG/ERP over 12 month in similar AD populations. Pre-specified exploratory analyses of the current study included the cognitive (MMSE) and the functional (ADCS-ADL) as well as Cogstate, HAM-D and EEG/ERP changes from baseline. Specifically, in comparison to historical control from a pooled placebo arm cohort study conducted by the Alzheimer Disease Cooperative Study Group in mild-to-moderate AD patients of comparable ages and MMSE baselines, over 12 month the ANAVEX 2-73 data shows a calculated treatment benefit of 1.8 points on the MMSE scale (p<0.016) and a calculated treatment benefit of 4 points on the ADCS-ADL score (p<0.019). Furthermore, the correlation was positive with all measured scores (MMSE, ADCS-ADL, Cogstate, HAM-D and EEG/ERP). Despite non-optimized dosing of ANAVEX 2-73 throughout the 12-month study, continued significant improvements from baseline of cognitive, functional and behavioral scores in a group of patients were observed, respectively. This data will be analyzed using refined mathematical modeling methods in conjunction with the detailed pharmacokinetic (PK) information. * On July 27, 2016, Anavex Life Sciences announced efficacy data through 31 weeks from the ongoing ANAVEX 2-73 Phase 2a study in mild-to-moderate Alzheimer’s patients presented in the second of two posters at the Alzheimer’s Association International Conference® (AAIC2016). Overall, efficacy results demonstrate what appears to be a converging and consistent response for all quantitative endpoints through 31 weeks, including cognitive and functional measures: Mini Mental State Examination (MMSE), Alzheimer’s Disease Co-operative Study - Activities of Daily Living (ADCS-ADL), Cogstate and electroencephalographic activity and event-related potentials (EEG/ERP). In a disease state where progression is invariable over time, a sustained or stable MMSE and ADCS-ADL score is considered a positive outcome. “The demonstration of an extended period of both cognitive and functional stability out to 31 weeks in a patient population that would normally be expected to experience ongoing cognitive decline is an encouraging milestone in the development of ANAVEX 2-73. The 31-week data also validates the earlier observation of improvements on tasks within the Cogstate battery. The specificity and consistency of these benefits suggest that ANAVEX 2-73 can sustain activation of attentional and working memory functions with repeated dosing in Alzheimer’s disease,” said Associate Professor Stephen Macfarlane, FRANZCP, Head of Clinical Governance, Dementia Centre HammondCare, who is conducting the study. “Of noticeable interest was also HAM-D data showing beneficial effects of ANAVEX 2-73 on insomnia, agitation and anxiety at 31 weeks, which might suggest an additional important role of ANAVEX 2-73 for the amelioration of behavioral and psychological symptoms of dementia (BPSD).” “This clinical data together with prior preclinical findings seem to confirm ANAVEX 2-73’s selective activation of the specific stress reducing and survival protein, Sigma-1 receptor. This seems to present a potential common pathway for rescuing major neurodevelopmental and neurodegenerative disease mechanisms, like in Autism-related disorders and Alzheimer’s disease. I believe the distinct mechanistic nature suggests the compound could be a candidate treatment for a precision medicine approach across a spectrum of different neurological and psychiatric diseases,” said Professor Harald Hampel, MD, PhD, Professor and AXA Research Fund Chair at Sorbonne Universities’ Pierre and Marie Curie University (UPMC), Paris, France and member of Anavex’s Scientific Advisory Board. Avanex is now planning a phase 2/3 trial. * On March 10, 2016, Anavex Life Sciences announced that the Company has received the approval from the Ethics Committee in Australia to extend the ongoing Phase 2a Alzheimer’s trial, which had been requested by patients and their caregivers. The trial extension is designed to allow participants who complete 52 weeks in PART B to roll-over into a new trial and continue taking ANAVEX 2-73 for an additional 104 weeks, providing an opportunity to gather extended safety and efficacy data. The trial is independent of the Company’s planned larger Phase 2/3 double-blinded, placebo-controlled study of ANAVEX 2-73 in Alzheimer’s disease. The company will also present detailed dose-response analysis of data from the ongoing Phase 2a Alzheimer’s trial of ANAVEX 2-73 PART A at the 14th International Symposium on Advances in Alzheimer Therapy (AAT). The findings will include: Despite the relative small sample size of this proof-of-concept randomized open-label study, dose-response analysis seems to indicate that in 32 patients treated with doses of ANAVEX 2-73 ranging from 3 mg (IV) to 50 mg (oral) per day, both the MMSE-? and the ERP/P300 data showed a positive slope with confidence intervals not including the zero-value, consistent with a dose dependent improvement in MMSE scores over five weeks. The dose-response results were robust to statistical resampling (bootstrap analysis x 10,000 resamples). Analysis of variance and post hoc tests as well as Bayesian hierarchal analysis further confirmed that the higher doses achieved a statistical significant improvement in the MMSE-? score over 5 weeks compared to the lower doses. Based on these findings, it was estimated that an oral dose of 30 mg ANAVEX 2-73 had approximately 80% probability of achieving a +2 points or higher improvement in MMSE score over 5 weeks of treatment. Doses in this range have thus far been well tolerated by the study’s subjects, with no adverse events reported above grade one. Detailed information on the results will be provided in an upcoming scientific meeting. * On September 28, 2015, Anavex Life Sciences announced that patient enrollment for the Phase 2a clinical trial of ANAVEX 2-73 has been completed ahead of schedule. The ongoing, multicenter Phase 2a adaptive trial of ANAVEX 2-73 in both male and female mild-to-moderate Alzheimer’s patients has enrolled 32 patients. It started in January 2015 and all the 32 patients, most who are also taking donepezil, have initiated PART A of the two-part trial. Lasting up to 36 days for each patient, PART A is a simple randomized, open-label, two-period trial with an on-off-on not-yet-optimized dosing regimen to assess bioavailability, and cross-over between oral (30mg/50mg) and IV (3mg/5mg) administration. Event-related potentials (EEG/ERP) are used to assess cognitive effects and optimize dosing of ANAVEX 2-73. PART B is an open-label extension for an additional 52 weeks, with daily oral dosing so as to establish a longer drug effect. With the Phase 2a trial now fully enrolled, Anavex expects to release topline data for PART A before the end of the year.
* On November 22, 2016, Anavex Life Sciences announced a positive 41-week update from its Phase 2a study in mild-to-moderate Alzheimer’s disease (AD) patients for ANAVEX 2-73, which targets cellular homeostasis. At 41 weeks, Alzheimer’s patients taking a daily oral dose of ANAVEX 2-73 in the exploratory, not yet dose optimized Phase 2a clinical trial, showed a stabilization of cognitive and functional measures. This data of stabilization is promising since Alzheimer’s disease is a progressive disease where current therapeutics are only able to temporarily slow the worsening of dementia symptoms and not stop the disease from progressing.At 41 weeks, oral daily dosing between 10mg and 50mg, ANAVEX 2-73 was well tolerated, and no patients discontinued treatment due to adverse events. There were no clinically significant treatment-related adverse events, and no serious adverse events. Pre-specified exploratory analyses included the cognitive (MMSE) and the functional (ADCS-ADL) changes from baseline. A continued stabilization of both cognitive (MMSE) and functional (ADCS-ADL) measures in patients treated with ANAVEX 2-73 was observed. This correlation was positive with all measured scores (MMSE, ADCS-ADL, Cogstate, HAM-D and EEG/ERP). Published Alzheimer disease studies confirm substantial declines of both the cognitive (MMSE) and the functional (ADCS-ADL) measures over this timeframe in a similar AD population. In comparison to historical control from a pooled placebo arm cohort study conducted by the Alzheimer Disease Cooperative Study Group in mild-to-moderate AD patients of comparable ages and MMSE baselines, over nine months the ANAVEX 2-73 data shows a potential treatment benefit of several points on both the MMSE scale and on the ADCS-ADL score.
Low-High dose was statistically significant to affect MMSE-? and ERP-? scores with MMSE-? (p=0.0285) and ERP-? (p=0.0168), respectively. Results were confirmed by Bayesian and bootstrap analyses.
A minimum dose of 14 mg of ANAVEX 2-73 seem to be required to achieve a therapeutic effect and to keep MMSE score unchanged.
Similar positive MMSE score effect and no notable difference between ANAVEX 2-73 alone and ANAVEX 2-73 with donepezil (ANAVEX PLUS) were observed.
* On January 11, 2016, Anavex Life Sciences reported a positive dose-response relationship has been observed in a pre-planned interim analysis of data from the ongoing Phase 2a trial of ANAVEX 2-73 for treatment of mild to moderate Alzheimer’s disease. The change in Mini Mental State Examination score (MMSE-?) (MMSE difference recorded for every single study subject at the beginning and the end of the five week period) from baseline to 5 weeks as a function of ANAVEX 2-73 dose was examined using linear regression analysis. Among 32 patients treated with doses of ANAVEX 2-73 ranging from 3mg to 50mg/day, the MMSE-? data showed a positive slope with confidence intervals not including the zero-value, consistent with a dose dependent improvement in MMSE scores over 5 weeks. The effect was unidirectional and also positive on another pharmacodynamic readout, the ERP-? P300 amplitude.
