Anavex Life Sciences Corp (AVXL)

[Investor2014]

Has Anavex progressed too slowly and not kept shareholder abreast with developments?

A review of the evidence and timeline would suggest that Anavex have very carefully planned and executed on a path leading to a modern pivotal CNS study and “the first of its kind to broaden the scope of drug development in Alzheimer’s disease and other central nervous system diseases,” said George Perry, PhD, Dean of the College of Sciences at The University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer’s Disease.

I conclude that the time it is taking Anavex to launch the next confirmatory P2/3 trial in AD, is entirely determined by the study design timelines and the thorough pre-planned data analysis needed to minimise the risk and cost of failure.

Please take your time to carefully digest the progression below and tell me where the company could have done better on the timing and release of information.

I would also suggest taking a look at the timelines and cost of recent failed Alzheimer's studies to see how they compare.

December 16, 2014: Anavex Begins Enrollment of Alzheimer’s Patients in Phase 2a Clinical Trial of ANAVEX 2-73 and ANAVEX PLUS

http://www.anavex.com/anavex-begins-enrollment-of-alzheimers-patients-in-phase-2a-clinical-trial-of-anavex-2-73-and-anavex-plus/

July 22, 2015: Anavex Presents Positive Initial Phase 2a Study Data with ANAVEX 2-73 showing Early Evidence of Improving Cognition in Patients with Alzheimer’s Disease at AAIC 2015

http://www.anavex.com/anavex-presents-positive-initial-phase-2a-study-data-with-anavex-2-73-showing-early-evidence-of-improving-cognition-in-patients-with-alzheimers-disease-at-aaic-2015/

“Subsequent to the positive initial feedback, we are applying to expand the extension period from 26 weeks to 52 weeks at the request of the participants.”

September 28, 2015: Anavex Completes Patient Enrollment for Phase 2a Alzheimer’s Trial Ahead of Schedule

http://www.anavex.com/anavex-completes-patient-enrollment-for-phase-2a-alzheimers-trial-ahead-of-schedule/

Comment: Add 52 weeks for the last patient enrolled to complete the study gets us to end September 2016!

November 9, 2015: Anavex Announces Positive Primary and Secondary Endpoints were Achieved in a Phase 2a Clinical Trial of ANAVEX 2-73 in Alzheimer’s Disease?

http://www.anavex.com/anavex-announces-positive-primary-and-secondary-endpoints-were-achieved-in-a-phase-2a-clinical-trial-of-anavex-2-73-in-alzheimers-disease%e2%80%8e/

“In the interim analysis of the first 14 patients at week 12, the PART B portion of the study demonstrated a positive trend towards improvement over 12 weeks of ANAVEX 2-73 treatment on the secondary functional outcome measure, the Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory (ADCS-ADL) by +3.21 points.”

Comment: Notice that at this point the readout is based on data for the first 14 patients at week 12 of the original 26 weeks Part B study.

November 11, 2015: Anavex Confirms Data for Phase 2a Alzheimer’s Trial for ANAVEX 2-73

http://www.anavex.com/anavex-confirms-data-for-phase-2a-alzheimers-trial-for-anavex-2-73/

Comment: In the wake of attacks on the data as meaningless and drop in share price, Anavex chooses to confirm that the science and data presented 9th November really is true

November 18, 2015: Anavex Announces Preparation of Regulatory Filings based on Guidance From the FDA

http://www.anavex.com/anavex-announces-preparation-of-regulatory-filings-based-on-guidance-from-the-fda/

Comment: The Phase 2a Part B study as extended to 52 weeks is still at this point ongoing with the last enrolled patient, according to my maths, expected to complete the study end September 2016. One could say this is very timely preparation looking ahead to start the detailed pre-planned data analysis. We know that the FDA are themselves using the Ariana KEM technology and have most likely guided Anavex to do the same perhaps in the presence of Dr. Fadiran.


No Post-Hoc mining here!

January 11, 2016: Anavex Announces Positive Dose-Response Data for ANAVEX 2-73 in Alzheimer’s Disease Patients

http://www.anavex.com/anavex-announces-positive-dose-response-data-for-anavex-2-73-in-alzheimers-disease-patients/

Comment: The Dose-Response data is based on the 5 weeks Part A data. The first patient was enrolled in December 2014 and the last patient would have completed Part A around end September 2015 coinciding with beginning the enrolment for the 52 weeks extension study completed.

March 10, 2016: Anavex Announces Two-Year Clinical Extension Study of ANAVEX 2-73 and Presents Phase 2a Dose-Response Analysis at AAT Conference

http://www.anavex.com/anavex-announces-two-year-clinical-extension-study-of-anavex-2-73-and-presents-phase-2a-dose-response-analysis-at-aat-conference/

Comment: This is the NEW 104 weeks extension study A2-73– 003 on top of the Part A 5 weeks + Part B 52 weeks study (replacing the original 26 weeks Part B study).

July 24, 2016: Anavex Presents 31-Week Safety Data from Phase 2a Study of ANAVEX 2-73 in Alzheimer’s Patients at AAIC 2016

http://www.anavex.com/anavex-presents-31-week-safety-data-from-phase-2a-study-of-anavex-2-73-in-alzheimers-patients-at-aaic-2016/

July 27, 2016: Anavex Presents 31-Week Efficacy Data from Phase 2a Study of ANAVEX 2-73 in Alzheimer’s Patients at AAIC 2016

http://www.anavex.com/anavex-presents-31-week-efficacy-data-from-phase-2a-study-of-anavex-2-73-in-alzheimers-patients-at-aaic-2016/

July 29, 2016: Anavex Confirms Data from Phase 2a Study of ANAVEX 2-73 in Alzheimer’s Patients Presented at AAIC 2016

Comment: Anavex again gets hammered by the market’s interpretation of the data and share price drops. Dr. Norman Relkin, MD, PhD, confirms how to interpret the data.

October 5, 2016: Anavex Life Sciences and Ariana Pharma Collaborate to Accelerate Timelines and Improve Efficiency of Alzheimer’s and Parkinson’s Clinical Development Programs

http://www.anavex.com/anavex-life-sciences-and-ariana-pharma-collaborate-to-accelerate-timelines-and-improve-efficiency-of-alzheimers-and-parkinsons-clinical-development-programs/

“Anavex’s 32-patient Alzheimer’s study utilizing KEM® will enable systematic analysis of more data on each patient in the disease group, on par with similar studies of significantly larger size, while providing greater cost and time efficiency.”

“The ongoing Phase 2a Alzheimer’s clinical trial was specifically designed to learn as much as possible about ANAVEX 2-73 in order to optimize trial parameters for future pivotal trials and potentially reduce the risk of failure in a later, larger Phase 2/3 study and in a planned Parkinson’s Phase 2 study. We believe that the collaboration with Ariana Pharma will potentially accelerate the development process,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex.”

Comment: The last patient would have completed the 52 weeks Part B extension around end September 2016, meaning that the Ariana collaboration announcement is coinciding with having all the required data available. Little doubt in my mind that the use of Ariana KEM Analysis was planned well in advance as per the November 18, 2015 PR when “Anavex Announces Preparation of Regulatory Filings based on Guidance From the FDA”

From the 2nd quote above, I think we may also infer that the AD and PD trials will share the relevant parts of inclusions/exclusion criteria and elements of trial design, especially when the PD P2 trial is followed by a pivotal PD trial. At this point the Rett P2 grant etc. was not yet known, so not sure to what extent the Rett trial will share criteria and design with the upcoming PD and AD trials – time will tell.

November 22, 2016: Anavex Life Sciences Announces Data on 41-Week Treatment of ANAVEX 2-73 for Patients with Alzheimer’s Disease

http://www.anavex.com/anavex-life-sciences-announces-data-on-41-week-treatment-of-anavex-2-73-for-patients-with-alzheimers-disease/

December 8, 2016: Anavex Life Sciences Announces 12-Month Data of ANAVEX 2-73 in a Phase 2a Study in Mild-to-Moderate Alzheimer’s Disease Patients

http://www.anavex.com/anavex-life-sciences-announces-12-month-data-of-anavex-2-73-in-a-phase-2a-study-in-mild-to-moderate-alzheimers-disease-patients/

“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.”

Comment: Given enrolment timelines, the 52 weeks of data for all patients is finally available and KEM Analysis can start.

October 12, 2017: Anavex Life Sciences Reports PK and PD Data from Phase 2a Trial of ANAVEX®2-73 in Mild-to-Moderate Alzheimer’s Disease Patients; Conference call today at 8:30am ET

http://www.anavex.com/anavex-life-sciences-reports-pk-pd-data-phase-2a-trial-anavex2-73-mild-moderate-alzheimers-disease-patients-conference-call-today-830am-et/

“I welcome such a thorough analysis of data before moving into a Phase 2/3. The intriguing ANAVEX2-73 data shown thus far exemplifies a precision medicine approach, to my knowledge, the first of its kind to broaden the scope of drug development in Alzheimer’s disease and other central nervous system diseases,” said George Perry, PhD, Dean of the College of Sciences at The University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer’s Disease.

“The Company is identifying the best responders to ANAVEX2-73 by using Ariana Pharma’s KEM® advanced Artificial Intelligence technology. This cutting edge trial analysis will be used to more effectively design the upcoming Phase 2/3 clinical study, raising the odds of late stage trial success.”

Comment: I conclude that the Ariana KEM Analysis has taken less than 11 months to conclude. 52 weeks data from all 25 patients was finally available December 2016 and KEM Analysis was presented November 2017. During this time Anavex is quiet regarding the A2-73 study in AD, but announces several pre-clinical and clinical milestones in other indications and for A3-71.

Is less than 11 months a long time to conduct a multi-factor Population PK/PD study?

Considering the cost implication of a failed confirmatory trial, it makes huge sense to spend sufficient time to secure the veracity of data in a Population PK/PD study in the case of Anavex using modern KEM Analysis. Not least because of the ethical implications regarding the patients and before spending the money and effort on a pivotal trial. The paper below gives some insights to the importance.

“
Project Management Aspects

Reviews of filings in the United States and Europe made between 1991 and 2001 showed that the average success rate for all candidate drugs in all therapeutic areas was ~11%,41 and that the success rate was lower during preclinical development. With the cost of conducting clinical trials increasing with each stage in drug development, failure at late stages of development is problematic. The costs associated with drug development are staggeringly high. In 2010, the cost of developing a new drug was estimated to be ~$1.2 billion (costs vary depending on the therapeutic indication).42 Part of the problem is difficulty in making informed decisions at critical junctures during the drug development process.
In 1997, Sheiner43 introduced the concept of “Learn and Confirm” as a means to improve decision making by using information more effectively. Sheiner outlined a drug development process that involved two cycles of learning and confirming (Table 3). During the learning phases of each cycle, studies should be designed to answer broader questions, and require more elaborate evaluations to answer; in contrast, during the confirming phases, questions are typically of the “yes/no” variety and can be answered using traditional statistical approaches. Sheiner advocated the use of modeling as a means of addressing the learning questions and of improving the information from confirming questions by providing a basis for explaining the variations in the data and increasing the power to detect meaningful clinical results.44”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606044/

November 4, 2017: Anavex Life Sciences-New Clinical Data on Alzheimer’s Disease

http://www.anavex.com/new-clinical-data-alzheimers-disease/

“Data presented include new results from the Phase 1 study (ANAVEX®2-73-001), the Phase 2a study (ANAVEX®2-73-002), and data from the first year of the Phase 2a long-term extension study (ANAVEX®2-73-003).
At 109 weeks and halfway into the long-term extension Phase 2a study ANAVEX®2-73-003, data from the cohort of patients with the highest ANAVEX2-73 concentrations point towards the continued ability of the medication to stop the decline in the exploratory secondary endpoints cognition (MMSE) and function (ADCS-ADL). At 57 weeks, this cohort had demonstrated improvement of the measures MMSE and ADCS-ADL compared to baseline. For the primary endpoint, ANAVEX2-73 demonstrated continued favorable safety and tolerability through 109 weeks.”

Comment: Note that we are going all the way back to Single Ascending Dose (SAD) Phase 1 clinical study in healthy volunteers conducted in Germany. Another sign that we are looking at a well-planned route navigated with precision over nearly 3 years to deliver a modern CNS study and “the first of its kind to broaden the scope of drug development in Alzheimer’s disease and other central nervous system diseases,” said George Perry, PhD, Dean of the College of Sciences at The University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer’s Disease.