Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Not misleading at all. You have your opinion...and I have mine. My opinion is based on my interpretation of Dr. Kun Jin's resume.
You've been ranting for some time that Dr. Missling needs to learn his lesson about crafting a proper trial...and now that he has hired a big gun like Dr. Kun Jin, all you do is minimize his experience as just another biostatistician. Really? That's absurd when you read his resume. Anyone with an open mind can see that he is loaded with firsthand experience in all kinds of trials.
BTW, do you still claim that Dr. Kun Jin is not an expert on AD trials after reading this part of his resume? (See below in bold)
"Prior to joining Anavex, Dr. Jin had a distinguished career of more than 27 years at the FDA. During his tenure at the agency, Dr. Jin has contributed extensively to statistical review issues and trial designs surrounding the regulatory approval of drugs for the treatment of neurological diseases including Alzheimer’s disease, Parkinson’s disease, migraine, epilepsy, and multiple sclerosis, as well as rare diseases, such as ALS and DMD. Dr. Jin was the lead author in top theoretical statistics, biostatistics, and molecular genetics journals. He was also a winner in a worldwide innovation competition on clinical cardiology data processing (Predicting Acute Hypotensive Episodes).
Dr. Jin has extensive research experience in Alzheimer’s clinical trials. He has been an invited speaker and has authored publications on topics in Alzheimer’s disease endpoints and trial designs. He conducted FDA/CDER The Oak Ridge Institute for Science and Education (ORISE) Summer Fellowship projects, built the Integrative Alzheimer’s Trial Database, FDA/CDER Regulatory Science and Review (RSR) Project and the results have been communicated at Accelerate Cures/Treatments for All Dementias (ACT-AD), Drug Information Association (DIA), and Joint Statistical Meetings (JSM). Before joining the FDA, Dr. Jin was Assistant Professor at the Division of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Dr. Jin received his Ph.D. in Statistics from the University of California at Berkeley, California."
Bravo, Steve!
Falconer...I just want to extend my appreciation for all of the great posts that you've made. Your contributions have been very instrumental in understanding how everything works in layman's terms!
Rest assured, we will all eventually be joining bennyboy...some of us sooner than the rest. But eventually we will all be there!
The difference is that some of us have taken the time to know our creator...and are quite comfortable passing on to the next life.
May God's peace be with you falconer!
That's an amazing story, Lacey1.
God's not finished with you here!
Anavex didn't hire Dr. Kun Jin for his good looks. With all of his experience, they will be relying on him to craft a very comprehensive P3 trial.
Will other staff members make suggestions for the P3 trial? Yes, of course....but I guarantee that Dr. Kin Jun will have the final word.
********************************************************************************************
Dr. Jin will draw on his extensive experience, including recently as the Statistical Team Leader at the U.S. Food and Drug Administration (FDA). Dr. Jin provided statistical review coverage and expertise for neurological drug products for the Center for Drug Evaluation and Research (CDER), and performed timely and quality reviews of marketing applications, including New Drug Applications (NDA), Biologic License Applications (BLA), and Investigational New Drug (IND) applications. Under the leadership of Dr. Jin, the neuropharmacological statistical team has completed several hundred statistical reviews of NDAs, BLAs, and efficacy supplements.
"I'm excited to welcome Dr. Jin to Anavex at this pivotal time. Dr. Jin has significant experience that will be instrumental as we continue our efforts to maximize value for patients and shareholders," said Christopher U Missling, Ph.D., President and Chief Executive Officer of Anavex. "Dr. Jin's deep and extensive biostatistics experience within clinical development and regulatory process will be invaluable as we advance key mid- and late-stage programs, to provide clinical and regulatory biostatistics leadership in support of Anavex’s goal to bring transformational medicines to the market."
“I’m honored to be joining Anavex and I am very much looking forward to helping guide the Company to secure access to better healthcare outcomes for families around the world,” said Dr. Jin. “There is such a significant unmet medical need around the globe caused by Alzheimer’s disease, Parkinson’s disease, and neurodevelopmental diseases like Rett syndrome and Fragile X syndrome. Anavex has a cutting-edge technology that can make a great deal of difference to those patients. I believe I can make a substantial contribution at this very important time in the Company’s transition towards commercialization.”
Prior to joining Anavex, Dr. Jin had a distinguished career of more than 27 years at the FDA. During his tenure at the agency, Dr. Jin has contributed extensively to statistical review issues and trial designs surrounding the regulatory approval of drugs for the treatment of neurological diseases including Alzheimer’s disease, Parkinson’s disease, migraine, epilepsy, and multiple sclerosis, as well as rare diseases, such as ALS and DMD. Dr. Jin was the lead author in top theoretical statistics, biostatistics, and molecular genetics journals. He was also a winner in a worldwide innovation competition on clinical cardiology data processing (Predicting Acute Hypotensive Episodes).
Dr. Jin has extensive research experience in Alzheimer’s clinical trials. He has been an invited speaker and has authored publications on topics in Alzheimer’s disease endpoints and trial designs. He conducted FDA/CDER The Oak Ridge Institute for Science and Education (ORISE) Summer Fellowship projects, built the Integrative Alzheimer’s Trial Database, FDA/CDER Regulatory Science and Review (RSR) Project and the results have been communicated at Accelerate Cures/Treatments for All Dementias (ACT-AD), Drug Information Association (DIA), and Joint Statistical Meetings (JSM). Before joining the FDA, Dr. Jin was Assistant Professor at the Division of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Dr. Jin received his Ph.D. in Statistics from the University of California at Berkeley, California.
77Port...although I appreciate your response, you need to understand that LTBR has spent 10s of millions of dollars to protect their technology with patents recognized worldwide. You can't copy their technology and then "tweak it" to create a new paint job...without violating one of their patents.
Thanks for the detailed explanation. Much appreciated!
I've been in and out of LTBR for the last 18 years. I recently bought quite a few shares as an investment after watching the movie about nuclear energy produced by Oliver Stone.
No more trading for me. It's now an investment. 40k
77Port...Would appreciate your thoughts on the question that I just posted on the LTBR board. Thanks
Quote: "Under the agreement, BWXT will evaluate the requirements for siting a fuel fabrication facility in Wyoming. The roughly 18-month effort will evaluate such matters as potential factory locations, product specifications, facility design and engineering, estimated capital expenditures and operating costs, staffing and worker skill requirements, supply chain necessities, licensing and other requirements.
"This new effort will help establish the baseline for facilities necessary to meet anticipated demand for this specialised nuclear fuel and includes establishing the scale necessary for economic viability," the company said.
TRISO fuel comprises spherical kernels of enriched uranium oxycarbide (or uranium dioxide) surrounded by layers of carbon and silicon carbide, giving a containment for fission products which is stable up to very high temperatures. High-assay low-enriched uranium (HALEU) TRISO fuels are being considered as the preferred fuel in several advanced reactor designs currently under development."
***************************************************************************************
A few questions are in order here...
1) Doesn't TRISO's new fuel pose a direct competition to LTBR's fuel?
2) And why is TRISO authorized to create a new HALEU fuel while LTBR is required to conduct test after test after test for their fuel?
All comments are welcome!
Thanks
One thing we know for sure is that the EMA has rejected two AD drugs from Big Pharma due to safety issues. This bodes well for Anavex and it (at least partially) explains why they were eager to have us submit our NDA for approval. If our OLE results are positive, I give us a solid 83% chance for approval by the EMA...assuming our application is accepted by the CHMP.
EMA’s advisory committee (CHMP) recommends not granting ...
www.alzint.org/news-events/news/emas-advisory...
Today, 26 July 2024, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended refusing the marketing authorisation for lecanemab in the treatment of mild cognitive impairment or the mild dementia stage of Alzheimer’s disease.
EMA rejects Alzheimer's drug aducanumab – DW – 12/22/2021
www.dw.com/en/ema-rejects-alzheimers-drug...
EMA rejects Alzheimer's drug aducanumab. Fabian Schmidt. 12/22/2021. Aducanumab is approved in the United States, but the EU's regulatory authority is blocking its use. The drug is designed...
Agreed. I think that is pretty much implied with his statement...but thanks for clarifying it further.
Exactly. I think the analyst, Ram Selvaraju, was the one that brought everything to light in his statement/question below
Ram Selvaraju
The involvement of the CHMP, that review committee that typically looks at drug candidates that are subjected -- submitted to the EMA for approval and renders a positive or a negative opinion prior to an approval decision being taken. Just wanted to know when you expect the CHMP to get involved in the review of the blarcamesine MAA and what criteria you expect them to use to determine what their opinion should be?
IMO, that is exactly why there is an 83% approval rate for those companies that submit their applications to them. They basically get a thumbs up or down prior to an approval decision.
Agreed. I also figured out why there is an 83% approval rate for companies that submit their applications to the EMA. Apparently there is a very strong line of communication between the two parties before the application is submitted. (See below)
Operator
Our next call is coming from Ram at H.C. Wainwright. Ram, you should be live.
Ram Selvaraju
Okay. With respect to the regulatory process with the European authorities, can you give us a sense of A, when you expect the MAA filing to be completed, and B, how you anticipate the process to evolve with respect to the CHMP review, how and when they are likely to become involved in the review of the application and what do you understand to be the principal criteria they are going to use to evaluate the suitability of blarcamesine for approval in the European Union? Thank you.
Dr. Christopher Missling
So we stated that just a minute ago that we are filing as soon as possible, definitely this year and the team is really working overtime to put together a package which has to be done in one submission. There’s also interactions taking place with the EMA to be aligned on the technicalities, so that precedes this submission. We also are, sorry, what was the second question?
Ram Selvaraju
The involvement of the CHMP, that review committee that typically looks at drug candidates that are subjected -- submitted to the EMA for approval and renders a positive or a negative opinion prior to an approval decision being taken. Just wanted to know when you expect the CHMP to get involved in the review of the blarcamesine MAA and what criteria you expect them to use to determine what their opinion should be.
Dr. Christopher Missling
Right. Thank you for reminding. So the procedure of the submission involves a review of the package before it gets submitted and it’s a very healthy procedure because it allows exactly this intelligence to, feedback to be received. So we expect this to take place.
To give you a sense of the level of interest, we noted before that the reason we submitted to the EMA was not because we thought it would be a good idea, but because we shared the majority of the data with the EMA beforehand, and asked for their input and their feedback, and their response was unambiguous to request to immediately file a submission.
So we of course hope that this initial feedback will continue to be the case down the road and right now we have no belief why it wouldn’t, but that is of course up to the review. So we are coming in here, not that we push, but we were pulled into the submission, given probably the unmet need in Europe and also the fact that the European Union has not MRI or PET centers in all places in the countries of the European Union, like in certain countries, for example, like Hungary or Poland or Romania, there are not enough MRI centers, which would probably be needed for an antibody given its safety profile. So that’s the best we can say at this point.
IMO, with this strong line of communication between the two parties, it doesn't surprise me that there is an 83% approval rate...because the EMA is constantly telling the other party exactly what they expect from them. It's up to us to provide the information that they want.
Hoskuld...You asked me: What would lead you to believe that Dr. Kun Jin designed the P2 schizo trial using 3-71?
Very simple. He is probably the most experienced person on their staff...and he has successfully designed other trials. (See below)
"During his [25 years] tenure at the agency, Dr. Jin has contributed extensively to statistical review issues and trial designs surrounding the regulatory approval of drugs for the treatment of neurological diseases including Alzheimer’s disease, Parkinson’s disease, migraine, epilepsy, and multiple sclerosis, as well as rare diseases, such as ALS and DMD."
So, let me ask you a question. Why would you conclude that "he totally was not "the one that designed the trial"?
Additionally, you were incorrect to insinuate that Dr. Kun Jin is somehow responsible for designing the failed P3 Rett trial for pediatrics. Why would you insinuate that?
We've only started one new clinical trial since we hired him...and that is the current P2 schizophrenic trial using the 3-71 drug. I'm sure he was the one that designed that trial...so I'm confident that it will yield the results that we're looking for.
Once we know the proper dosage from the P2 trial, I'm sure Dr. Jun Kin will design a comprehensive P3 trial that is properly powered with a SAP that follows all regulatory guidelines.
How to Understand and Create a Statistical Analysis Plan (SAP)
What is a Statistical Analysis Plan (SAP)?
The SAP is a document outlining the planned statistical methods and procedures undertaken to analyse and interpret the data collected during the lifespan of a clinical trial. The SAP should be specific and highly detailed, offering a clear description of any data manipulation or analyses required to meet trial objectives and endpoints. To ensure high reliability and validity of the clinical trial, the SAP should be written and finalised as close to the beginning of the clinical trial as possible but can be amended at any point before First Patient First Visit (FPFV) for unblinded open trials and database Lock (DBL) for blinded trials, to document any updates occurring throughout the trial. It is essential that the SAP is transparent and reproducible as it is a key contributor to the writing of Tables, Listings and Figures (TLFs) for inclusion in the Clinical Study Report (CSR), which ultimately concludes the success of the investigational product.
What Are the Key Documents Required During a Clinical Trial?
During a clinical trial, several crucial documents guide the process and ensure the integrity of the study:
Protocol
The protocol is a comprehensive document which outlines the plan for the study, and provides detailed information on the study objectives, design, methodology, and statistical considerations.
Statistical Analysis Plan
A detailed plan of the statistical methods and analyses planned for the clinical trial.
TLF Shells
A template document including mock-ups for the Tables, Listings, and Figures, which will be used in the final presentation and reporting of study data.
Clinical Study Report
A clinical study report is a comprehensive document summarising the study findings, which provides a detailed account of the methodology, conduct, and results of a clinical trial and is a key component in the process of submitting data to regulatory authorities for the approval of new drugs or therapies.
Following Database Lock, the planned datasets and TLFs are produced based on the SAP and TLF Shells.
When Should the Statistical Analysis Plan be Written?
The optimal time to create the SAP is before data collection begins, ideally during the trial design phase and before First Patient First Visit (FPFV). Benefits to developing the SAP early in the trial include:
Bias Prevention: By developing the SAP prior to data collection, it can be proven that the analysis methods are predefined and not influenced by the data collected, reducing the risk of bias in the results.
Clear Objectives: Having the SAP for reference helps to clarify the trial objectives, hypotheses, and primary outcomes, ensuring that the analyses aligns with the trial goals.
Regulatory Compliance: For clinical trials and other regulated research, having a SAP before data collection can be a regulatory requirement. It ensures transparency and adherence to agreed-upon protocols.
Resource Planning: The SAP outlines the necessary statistical methods and resources required for analysis during the clinical trial, aiding in better planning and allocation of resources.
Error Mitigating: It allows for a thorough review of the proposed statistical methods, reducing the likelihood of errors or omissions in the analysis phase.
Creating the SAP as early as possible in the clinical trial enhances SAP robustness, but the deadline for finalising the SAP will depend on the nature of the trial. For blinded trials, the SAP must be finalised prior to DBL to ensure that planned analyses are not changed after the final data are collected. However, for unblinded or open-label trials, the primary endpoints must be well established in the SAP prior to the recruitment of the first patient, to minimise bias and enhance result credibility.
When to Submit the Statistical Analysis Plan to Regulatory Bodies
Understanding the timing of when to submit the SAP to regulatory authorities like the FDA, CHMP or MHRA (for the US, Europe and UK respectively) is highly important for achieving success in a clinical trial. While the SAP should be written and finalised as early in the trial process as possible, it is important for SAP submission to occur prior to database lock (DBL) for most blinded studies. For studies which are unblinded or have complex/adaptive designs, earlier submission may be required, sometimes during the initial protocol submission or at key milestones, such as the end-of-Phase II meeting. Ensuring timely submission of the SAP to the FDA, CHMP or MHRA helps to align the trial's statistical approach with regulatory expectations and facilitates a smoother review process.
Which Regulatory Guidelines Relate to the Writing of the Statistical Analysis Plan?
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines are a set of internationally recognised standards and recommendations which guide the development, testing, approval, and monitoring of new pharmaceutical products. The ICH was established to harmonise regulatory requirements across different countries, particularly in the United States, Europe, and Japan, and to ensure that pharmaceutical products are safe, effective, and of high-quality.
The following three guidelines are of key interest and should be closely adhered to when writing the SAP:
ICH Efficacy Guideline E6(R2) (Good Clinical Practice): Provides a unified standard for designing, conducting, recording, and reporting clinical trials involving human participants. The upcoming ICH E6(R3) revision, expected in 2025, will place an increased emphasis on patient centricity.
ICH Efficacy Guideline E8(R1) (General Considerations for Clinical Studies): Emphasises quality by design, patient-centricity, and a risk-based approach, promoting pre-specification of analyses, alignment with the protocol, and ensuring the robustness and reliability of results.
ICH Efficacy Guideline E9 (Statistical Principles for Clinical Trials): Provides recommendations on the statistical methods used in clinical trials, including the design of trials, hypothesis testing, analysis methods, and interpretation of results.
How to Write a Statistical Analysis Plan
The SAP should serve as a blueprint for all analyses, ensuring that any details relating to data manipulation and analyses methods are planned out before data collection begins. As a result, the following details are recommended to be included when writing a SAP:
- Title and Identification Information (Study title; Protocol number, Version number/date).
- Introduction and Study Overview (Background information; Study design).
- Objectives and Hypotheses (Primary, secondary, and exploratory objectives; Hypotheses).
- Endpoints/Outcomes (Primary, secondary, and exploratory endpoints and outcomes).
- Sample Size Determination (Calculation details; Interim analyses; Criteria for early termination).
- Statistical Methods (Descriptive or inferential statistics; Adjustment for covariates; Handling of missing data; Sensitivity analyses; Estimands).
- Blinding/Unblinding (Details of any blinding and unblinding processes).
- Data Presentation (TLF specifications; Statistical software and versioning).
- Assumptions and Limitations (Statistical assumptions; Potential limitations).
- Ethical and Regulatory Considerations (Compliance with guidelines; Approval and signatures).
- Appendices (Definitions; Data shells; Additional information to support the SAP).
Who Can Write a Statistical Analysis Plan?
The SAP must be written by a statistician or a biostatistician who has expertise in the relevant field of trial. However, the process often involves collaboration with other contributing key stakeholders, who are listed below:
Statisticians/Biostatisticians:
They are responsible for the technical aspects of the SAP, including the selection of appropriate statistical methods, sample size calculations, and the plan for data analysis.
They have specialised knowledge in statistics and are familiar with the regulatory requirements and guidelines pertinent to the trial's field.
Principal Investigator (PI):
The PI is usually involved in the development of the SAP, providing input on the trial objectives, hypotheses, and key outcomes to ensure the analysis plan aligns with the overall research goals.
They work closely with the statistician to ensure that the SAP is scientifically sound and practically feasible.
Clinical Researchers/Subject Matter Experts:
In clinical trials or specialised research fields, subject matter experts contribute to defining the clinical or experimental endpoints, and they ensure that the SAP accurately reflects the trial's clinical or scientific goals.
They provide insights into the practical aspects of data collection, which helps in tailoring the SAP to the trial's needs.
Regulatory Affairs Specialists:
For trials that require regulatory approval, such as clinical trials, regulatory affairs specialists may review the SAP to ensure it meets the necessary guidelines and compliance requirements.
They ensure that the SAP is aligned with regulatory expectations and standards.
Data Managers and Programmers:
Clinical data managers and programmers may provide input on the data handling procedures, data quality, and management processes to ensure that the SAP is realistic and executable with the available data infrastructure.
Both data managers and programmers work with statisticians to ensure that the data collection, storage, and retrieval processes are compatible with the analysis plan.
While the primary author of a SAP is the statistician or biostatistician, the creation of the plan is often a collaborative effort with any or all of the above disciplines to ensure that the SAP is comprehensive, scientifically valid, and aligned with the trial goals.
Should the Estimands Framework be Incorporated into the Writing of a Statistical Analysis Plan?
An estimand is a precise description of the treatment effect within a clinical trial. Contributing attributes to estimands include:
- The treatment effect of interest (e.g.: the different in mean outcomes between treatment and placebo).
- The population to which the estimand applies (e.g.: patients who adhered to the treatment).
- The outcome of interest (e.g.: reduction in blood pressure).
- The handling of potential issues/intercurrent events (e.g.: rescue medication; missing data; treatment non-compliance).
Estimands play a fundamental role during the writing of the SAP as they directly influence the design, conduct, and interpretation of statistical analyses. Specific components of the SAP which may be influenced by estimands include:
- Formulating objectives and endpoints.
- Determining statistical methods.
- Selecting analysis sets.
- Interpretation of results.
Estimands provide additional clarity and precision relating to what is being measured in clinical research, helping to reduce ambiguity, and ensuring that the selected statistical analyses align with trial objectives. Estimands also improve consistency between analysis methods and the goals of the trial, as well as improving adherence to regulatory and scientific standards by ensuring the transparency and reliability of results.
Should Interim Analyses be Considered When Writing the Statistical Analysis Plan?
Interim analyses are any planned analyses conducted at predefined points before the trial is completed. Motivations for planning interim analyses during a clinical trial include early detection of treatment efficacy or futility, which could lead to early termination of a trial if the investigational product is assessed as either beneficial or futile. Interim analyses also allow the sample size to be adjusted if the effect size and power differs to what was originally planned, as well as assessing if the trial is likely to meet its planned objectives.
However, there can be drawbacks to planning interim analyses which should be considered at the time of writing the SAP. Conducting multiple analyses throughout a clinical trial without adjustment can raise the alpha spend, which increases the chance of Type I error (false positives). Conversely, numerous interim analyses can also increase beta spend if not adjusted for correctly, which can result in a loss of power for the trial. Hence, consideration of statistical methods and spending functions (e.g.: the O’Brien-Fleming method or the beta spending function) must be considered at the time of writing the SAP to balance the benefits of early decision-making with maintaining trial integrity.
Conclusion
Clinical research is vital for advancing medical science and improving health-related quality of life. It is essential that clinical trial research in humans is performed in a safe environment which protects patient safety while accurately measuring treatment efficacy. The SAP is a key document in this process, playing a crucial role in determining the success of the investigational product, while maintaining high reliability and robustness of results.
The SAP requires input from qualified collaborators but ultimately must be written by a qualified statistician or biostatistician and meet relevant regulatory guidelines. The SAP must be detailed and comprehensive with clear instructions for suitable statistical techniques and data manipulation, which will contribute to the credibility and overall success of a clinical trial. Transparency and reproducibility are essential for honest and reliable results, for which a well-written SAP is a key contributor.
https://www.quanticate.com/blog/how-to-understand-and-create-a-statistical-analysis-plan
I think that's why they hired Dr. Kun Jin.
Anavex Life Sciences Appoints Former FDA Lead Neurology Statistician as VP Head of Biostatistics
Dr. Jin will draw on his extensive experience, including recently as the Statistical Team Leader at the U.S. Food and Drug Administration (FDA). Dr. Jin provided statistical review coverage and expertise for neurological drug products for the Center for Drug Evaluation and Research (CDER), and performed timely and quality reviews of marketing applications, including New Drug Applications (NDA), Biologic License Applications (BLA), and Investigational New Drug (IND) applications. Under the leadership of Dr. Jin, the neuropharmacological statistical team has completed several hundred statistical reviews of NDAs, BLAs, and efficacy supplements.
Prior to joining Anavex, Dr. Jin had a distinguished career of more than 27 years at the FDA. During his tenure at the agency, Dr. Jin has contributed extensively to statistical review issues and trial designs surrounding the regulatory approval of drugs for the treatment of neurological diseases including Alzheimer’s disease, Parkinson’s disease, migraine, epilepsy, and multiple sclerosis, as well as rare diseases, such as ALS and DMD. Dr. Jin was the lead author in top theoretical statistics, biostatistics, and molecular genetics journals. He was also a winner in a worldwide innovation competition on clinical cardiology data processing (Predicting Acute Hypotensive Episodes).
Dr. Jin has extensive research experience in Alzheimer’s clinical trials. He has been an invited speaker and has authored publications on topics in Alzheimer’s disease endpoints and trial designs. He conducted FDA/CDER The Oak Ridge Institute for Science and Education (ORISE) Summer Fellowship projects, built the Integrative Alzheimer’s Trial Database, FDA/CDER Regulatory Science and Review (RSR) Project and the results have been communicated at Accelerate Cures/Treatments for All Dementias (ACT-AD), Drug Information Association (DIA), and Joint Statistical Meetings (JSM). Before joining the FDA, Dr. Jin was Assistant Professor at the Division of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Dr. Jin received his Ph.D. in Statistics from the University of California at Berkeley, California.
https://www.anavex.com/post/anavex-life-sciences-appoints-former-fda-lead-neurology-statistician-as-vp-head-of-biostatistics
ANNOVIS’ LEAD COMPOUND ENHANCES COGNITION SYNERGISTICALLY WITH GLP-1 AGONIST
MALVERN, Pa., Aug. 06, 2024 (GLOBE NEWSWIRE) -- via IBN – Annovis Bio Inc. (NYSE: ANVS) (“Annovis” or the “Company”), a late-stage clinical drug platform company pioneering transformative therapies for neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), today announced new preclinical data demonstrating the synergistic effect of its lead compound, buntanetap, when combined with the glucagon-like peptide 1 (GLP-1) agonist dulaglutide (Trulicity®) in a mouse model of Alzheimer’s disease.
GLP-1 agonists, commonly used to treat diabetes, weight loss, and heart conditions, are now showing promising potential in the treatment of Alzheimer’s disease. Recent data presented at the Alzheimer’s Association International Conference® (AAIC®) 2024 revealed that another GLP-1 agonist, liraglutide (Victoza), was able to decrease cognitive decline in Alzheimer’s patients by 18% and reduce brain shrinkage in regions responsible for cognitive functions.
In 2018, Annovis Bio published data showing that buntanetap fully restored memory, learning, and synaptic potentiation in an Alzheimer’s mouse model (Teich et al. 2018). Building on this research, Annovis recently investigated whether combining buntanetap with the GLP-1 agonist dulaglutide would produce a synergistic effect in the same animal model. The results were compelling: while buntanetap alone restored cognitive function to 100% and dulaglutide alone to 80%, the combination of these two compounds not only restored cognitive function but also enhanced it beyond levels seen in healthy controls. (Figure 1).
The ability of GLP-1 agonists to penetrate the brain is linked to their molecular structure. Single-chain peptides (i.e. dulaglutide, albiglutide, exenatide) have better blood-brain barrier (BBB) permeability than bifurcated molecules containing side chains. Due to its excellent BBB permeability, dulaglutide was chosen from other GLP-1 agonists for combination with buntanetap (Figure 2).
“We are excited to see that buntanetap significantly amplifies the effects of dulaglutide on memory and learning, with a 6- to 10-fold increase in efficacy,” said Maria Maccecchini, Ph.D., Founder, President, and CEO of Annovis Bio. “This synergy is particularly important for enhancing treatment outcomes while minimizing potential side effects. As the field of Alzheimer’s research shifts towards combination therapies, we believe our approach holds great promise for offering more effective treatment options for patients.”
https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=baff4254-4f58-4454-bd87-5d67fd05c6dd
Obesity Drug Slows Alzheimer's Brain Shrinkage
Data from a small clinical trial published on Tuesday showed that a drug from the GLP-1 receptor agonist class known for weight loss slowed the loss of brain volume in people with mild Alzheimer's disease.
The trial results, published at the Alzheimer's Association International Conference, provided the first glimpse of how GLP-1 drugs may act on hard-to-treat brain disorders.
The trial studied just 204 patients in Britain, half of whom received Novo Nordisk's earlier-generation GLP-1 drug liraglutide, and the other half a placebo.
The trial did not meet its primary endpoint, or main goal, which was change in the cerebral glucose metabolic rate, an assessment of brain function.
It did meet the secondary endpoints. It showed liraglutide appeared to reduce shrinking in the parts of the brain that control memory, learning, language and decision-making by nearly 50% compared to placebo.
The trial was not sponsored by Novo. However, the Danish drugmaker is testing its new-generation, more effective GLP-1 drug semaglutide — sold as diabetes drug Ozempic and obesity drug Wegovy — in thousands of patients with early Alzheimer's. Its two trials began in 2021 and results are expected in 2025.
Rebecca Edelmeyer, senior director of scientific engagement at the Alzheimer's Association, told Reuters in an interview that the results published on Tuesday were "really intriguing."
"This is our first time really seeing this type of intervention readout in a clinical trial," she said.
Researchers told Reuters last year that diabetes regimens, from Ozempic to insulin and metformin, appear to address several different aspects of the metabolic system implicated in Alzheimer's, including a protein called amyloid and inflammation.
The hope is that improving glucose utilization and reducing inflammation in the body - including the brain - could slow progression of Alzheimer's.
Still, the trial published on Tuesday was not designed to measure cognitive benefits, and some scientists urged caution.
"The repurposing of drugs is an important avenue of research but there is a lot of uncertainty here," said Stephen Evans, emeritus professor at the London School of Hygiene and Tropical Medicine.
He said the shrinking in the memory and learning parts of the brain observed in the small trial "may not translate to important cognitive benefits" and the results did not demonstrate that liraglutide could protect against dementia, though pursuing a larger trial would be worthwhile.
© 2024 Thomson/Reuters. All rights reserved.
https://www.newsmax.com/health/health-news/alzheimers-obesity-medication/2024/07/30/id/1174485/?ns_mail_uid=7cb8dafc-ae3b-415e-81ce-33311f68ea21&ns_mail_job=DM661022_07312024&s=acs&dkt_nbr=01010244y2td
Yes. I've seen that comparison before. It's impressive! But I think we need a 2+2=4 link before the scientific community jumps on board...and the only way that we're going to do that is if we have cognitive tests that link the improvement in atrophy with an improvement in test scores. 2+2=4
I'm curious...Have they conducted any cognitive tests to link the improvement in atrophy with neuronal improvement?
Thanks
REFILE-Summit shares surge as cancer drug tops Keytruda in head-to-head study
[This is what happens when a no-name drug shows positive results against BP - e.g. Merck's Keytruda]
Sept 9 (Reuters) - Summit Therapeutics shares surged 37% [Now up 55%+] in premarket trading on Monday after a study in China showed some lung cancer patients on the company's experimental drug had better survival rates than those on Merck's blockbuster therapy Keytruda.
The U.S. firm said on Sunday its drug showed patients lived a median of more than 11 months without the disease progressing, a statistically significant improvement over Merck's Keytruda, the world's biggest selling drug.
The late-stage study, conducted by its partner Akeso , adds further details from its initial results announced in May. Since that time, Summit's stock price has more than quadrupled, bringing its market value to $8.61 billion.
Summit shares rose 37% to $16.66, while Merck's shares were down 4.3% before the bell. [On May 29th, SMMT was selling for $2.34/share]
Analysts, however, downplayed concerns around Keytruda facing a challenge from Summit's drug anytime soon.
Summit's therapy still remains years away from the market with a global late-stage trial being initiated in 2025, said J.P. Morgan analyst Chris Schott. He added that the data does not meaningfully alter the view on Keytruda, which is due to go off-patent in coming years.
The study of nearly 400 patients showed Summit's therapy had a median of 11.14 months of progression-free survival - a measurement of how long a patient lives with a disease without it worsening - compared to 5.82 months for Keytruda.
The monotherapy also reduced the risk of disease progression by 49% as a first-line treatment for patients with advanced non-small cell lung cancer, a disease in which malignant cancer cells form in the lung tissue.
The therapy is an antibody designed to block a protein called PD-1, which helps the body's immune system to fend off cancer. Keytruda also targets the same protein. (Reporting by Sriparna Roy in Bengaluru; Editing by Leroy Leo)
Even Doc thinks that Anavex 371 is "an excellent candidate for schizophrenia" (See his quote below)
Quote from Doc 328..."If doing a standard 3 + 3 MAD for part A sounds like 5 people enrolled to date with the 6th one identified. If no significant AE, they can move to the next dose soon. They should be able to start Part B by end of the year. Unless they open up additional sites for the Part B, May 2025 will be a challenge.
.....I think 3-71 in schizophrenia is an excellent candidate for schizophrenia.
I also think Missling with his penny wise pound foolish management style is setting up another phase 2 that is too small to properly guide phase 3 and will leave more questions than answers ultimately delaying possible regulatory success (compare to Karuna's SP quintupled after their successful 182 patient phase 2 because it was adequate sized adding about 2B in MC in one day November 2019 that was quickly followed by two efficient phase 3 studies)"
********************************************************************************************
Quote from Dr. Missling...With respect to ANAVEX3-71, we are quite pleased to provide an update that the placebo-controlled Phase 2 clinical trial of ANAVEX3-71 for the treatment of schizophrenia. The study is well underway with the first cohort of schizophrenia patients being fully enrolled. We are also expecting further peer-reviewed clinical publications in both -- involving both ANAVEX2-73 and ANAVEX3-71.
Time is getting squeezed...significant material information is getting closer!
I'm expecting a lot of good news in the 2H as announced in the 2Q CC (see below). As each day passes, the expected news for 2H gets squeezed closer together. September starts next week...which leaves only 4 months until the end of the year!
Dr. Christopher Missling:
(1) We’re encouraged by the very recently issued FDA guidance for early Alzheimer’s disease which states that one cognitive measure alone like ADAS-Cog could be a sufficient primary endpoint for early Alzheimer’s disease.
(2) We appreciate this new guidance and believe this opens another possible pathway for us to move forward in parallel to the initiated process of market authorization application to the European Medicine Agency, EMA, for blarcamesine for the treatment of Alzheimer’s disease which is already underway.
(3) Full data from the blarcamesine study in Alzheimer’s disease Phase 2b/3 placebo-controlled clinical trial will be published in an upcoming peer-reviewed journal, (4) as well analysis of RNA sequencing of the trial is underway and interim data is expected by mid-2024.
(5) Concurrently, the ATTENTION-AD open-label extension trial is ongoing and we expect to be able to share interim data in the second half of 2024.
(6) In Rett syndrome, continued positive real-world evidence feedback from Rett syndrome patients and caregivers participating in the ongoing open-label extension trial and Compassionate Use Program for patients who participated in the EXCELLENCE trial encourages us to continue our partnership with the Rett syndrome community and to proceed with a Phase 3 12-week efficacy study. An educational presentation will be provided at the 2024 IRSF Rett Syndrome Scientific Meeting, taking place this year June 18, 2024 to June 19, 2024.
(7) Regarding Parkinson’s disease, initiation of an ANAVEX2-73 Phase 2b/3 six-month trial is expected in the second half of 2024.
(8) In Fragile X, new specific translatable and objective biomarker data generated with ANAVEX2-73 supporting the initiation of the potentially pivotal ANAVEX2-73 Phase 2/3 clinical trial will be presented at the 19th National Fragile X Foundation Conference taking place in July 25, 2024 to July 28, 2024.
(9) Related to a new rare disease, we are also in preparation to initiate a potentially pivotal ANAVEX2-73 Phase 2/3 trial.
(10) With respect to ANAVEX3-71, we are quite pleased to provide an update that the placebo-controlled Phase 2 clinical trial of ANAVEX3-71 for the treatment of schizophrenia. The study is well underway with the first cohort of schizophrenia patients being fully enrolled. We are also expecting further peer-reviewed clinical publications in both -- involving both ANAVEX2-73 and ANAVEX3-71.
Now here's the Q & A...
Soumit Roy
Yeah. Hey, congratulations on all the progress and a few questions on the FDA guidance. It’s oftentimes a bit qualitative and trying to understand, read through the line, when they’re saying strong biomarker and strong statistical data to support the clinical outcome on the cognition front. How do you really interpret that? When you’re looking at amyloid 42 over 40 ratio, the error bars when you compare with the company is just because of the cohort size is a little larger. How many patients was there and do you see these to be considered strong or FDA would ask for a larger trial? Just curious about your thoughts.
Dr. Christopher Missling
So the key background is that for the biomarker of Aß changes in placebo versus active arm, we have to be reminded that the mechanism of our drug is not an antibody removing Aß drug, but it’s an orally available, once daily, easy-to-administer and scalable drug and has for that a lot of convenience features, which the antibodies don’t have, in addition to the fact that they are having challenges with the black box warning, which they have been given. So there’s also a challenge from safety and repeated safety measures on MRI are required.
Regarding the biomarker data of the Aß, we were intrigued, but on the other hand, not surprised that we saw a reduction of Aß in the brain measured by the plasma Aß42/40 ratio, which is the analogy of measuring a PET Aß level in the brain, which is intuitively easy -- easier to understand, because you are showing a decline in the brain. But the Aß42/40 ratio, which again is representative of this fact of reduction of Aß in the brain is then measured in the plasma and shows as an increase of this ratio, favorably showing a decrease in the brain. So if the ratio goes up, that means Aß in the brain goes down.
So since we don’t target Aß directly with our drug, but have a more upstream mechanism of action, again, we were intrigued and surprised to see in all patients, there was no sub analysis in this analysis of the Aß ratio showing a significant decline. So now it’s a question of dialogue with the agency, how this will be interpretable as a biomarker.
But I’d like to also point out we have a second strong biomarker, which probably even is stronger, specifically from a p-value perspective, which is the changes in the atrophy of the brain. So in the pathology of the Alzheimer’s disease, there is a very well understood feature of shrinking of the brain over time. And this is intuitive, if the brain is shrinking is less active, it cannot have as good memory or activities of execution and function as the brain was not shrinking.
And we noticed in our trial, a significant stopping of the shrinking of the brain with ANAVEX2-73 blarcamesine in the active arm, compared to placebo. So the placebo arm continues to shrink the brain in the patients, while they are on placebo, which is standard-of-care, by the way, it’s not placebo itself, it’s including donepezil, memantine. So all the data is always on top of standard-of-care, which is today approved, includes approved drugs.
And however, the active arm on blarcamesine or ANAVEX2-73 shows a significant separation from the placebo by not shrinking the brain any further or delaying the shrinking of the brain in many regions of the of the brain and this exact data will be part of the publication, which we’re expecting.
So I think once this data comes out, I think that we can re-discuss the impact of that biomarker in combination with the Aß biomarker. And again, with the Aß biomarker, I’d like to remind again, we did not target with our drug directly Aß. So it must be a downstream effect of the upstream feature of the sigma one receptor, showing also the impact on the entire population in our trial.
Soumit Roy
These are truly encouraging data. You have quite a few catalysts coming up in the next probably three months. I’m trying to understand what would be the strategy when you go to FDA, would you wait for the open-label extension on trial data to come out along with the publication and completion of the European filing and then approach to FDA with the totality of data with biomarker and the long-term, or would you do before that, meet with FDA before the long-term extension on trial data?
Dr. Christopher Missling
Yeah. So we really want to have the best impact, I would say. And you don’t have a second chance [to make a good] first impression, as they say. And certainly having data of the open-label study, which is 96 weeks, probably, would be favorable. However, we have not decided how to proceed on the timing exactly, but definitely this year. But also we can do, since it’s an open-label, interim cuts. So there’s a way to expedite the analysis of the open label study.
Soumit Roy
That is truly helpful. The last question on if you can provide any guidance on the timeline around completion of the European filing?
Dr. Christopher Missling
Yeah. So we definitely want to expedite this and the teams are working really over time to put together the modules, which are many pages, a significant package, we talk about a lot of documents and they all have to be completely ready. Usually this takes time and other companies are going through the same process need the same time. So we’re not in a different situation like that. But we said we want to submit this year and we are well on track to do that. So we will provide updated timing when we get closer to the filing time. But we have very good on time with that. So stay tuned.
Soumit Roy
Thank you and congratulations on all the progress.
Dr. Christopher Missling
Yeah. Thank you.
Operator
Our next call is coming from Ram at H.C. Wainwright. Ram, you should be live.
Ram Selvaraju
Okay. With respect to the regulatory process with the European authorities, can you give us a sense of A, when you expect the MAA filing to be completed, and B, how you anticipate the process to evolve with respect to the CHMP review, how and when they are likely to become involved in the review of the application and what do you understand to be the principal criteria they are going to use to evaluate the suitability of blarcamesine for approval in the European Union? Thank you.
Dr. Christopher Missling
So we stated that just a minute ago that we are filing as soon as possible, definitely this year and the team is really working overtime to put together a package which has to be done in one submission. There’s also interactions taking place with the EMA to be aligned on the technicalities, so that precedes this submission. We also are, sorry, what was the second question?
Ram Selvaraju
The involvement of the CHMP, that review committee that typically looks at drug candidates that are subjected -- submitted to the EMA for approval and renders a positive or a negative opinion prior to an approval decision being taken. Just wanted to know when you expect the CHMP to get involved in the review of the blarcamesine MAA and what criteria you expect them to use to determine what their opinion should be.
Dr. Christopher Missling
Right. Thank you for reminding. So the procedure of the submission involves a review of the package before it gets submitted and it’s a very healthy procedure because it allows exactly this intelligence to, feedback to be received. So we expect this to take place.
To give you a sense of the level of interest, we noted before that the reason we submitted to the EMA was not because we thought it would be a good idea, but because we shared the majority of the data with the EMA beforehand, and asked for their input and their feedback, and their response was unambiguous to request to immediately file a submission.
So we of course hope that this initial feedback will continue to be the case down the road and right now we have no belief why it wouldn’t, but that is of course up to the review. So we are coming in here, not that we push, but we were pulled into the submission, given probably the unmet need in Europe and also the fact that the European Union has not MRI or PET centers in all places in the countries of the European Union, like in certain countries, for example, like Hungary or Poland or Romania, there are not enough MRI centers, which would probably be needed for an antibody given its safety profile. So that’s the best we can say at this point.
Ram Selvaraju
And with respect to 3-71, just wanted to A, get a sense of how you expect to monitor the efficacy profile of this compound in schizophrenia. If you regard, for example, certain domains of the PANSS to be the most appropriate efficacy measures, as well as the extent to which you expect 3-71 to be differentiated from existing anti-schizophrenic medications and what you expect the principal areas of differentiation to be. For example, is it safety and tolerability, or so then the efficacy, or do you expect on both the safety, as well as the efficacy fronts, this drug candidate to demonstrate the differentiated profile versus currently marketed, for example, atypical antipsychotic medications?
Dr. Christopher Missling
Yeah. I think it’s exactly as you stated, it could be really both. And if you look at the landscape of drug approvals, you want to always be better than what is out there on the market. So if you’re able to show that the safety has a better feature, a better profile and also translate into stronger, more meaningful efficacy, both on the positive, as well as the negative domains of schizophrenia, then this would be extremely valuable and helpful.
We also want to point out in this study, we are focusing on EG/ERP as a considered surrogate biomarker of schizophrenia. So we are excited about finding out how the drug interacts in that regard and it’s a very elegant non-invasive methodology to identify that.
But we also have included the standard PANSS score in addition to this EG/ERP. So we might learn something about the effect of our drug in the study in those regard, which would then allow us to decide how to proceed with this drug in schizophrenia.
Ram Selvaraju
And then the last question is sort of a combination of a strategic and financial query. Let’s say hypothetically that the EMA agrees that blarcamesine is approvable for treatment of Alzheimer’s disease in the European Union. At that juncture, strategically, what do you expect your preferred strategy to be in terms of whether or not you elect to undertake independent self-commercialization activities in Europe or whether you at that point would look to identify a partner? And does your cash burn guidance of runway for the next four years take into account any pre-launch activity related expenses related to blarcamesine for treatment of Alzheimer’s disease in Europe or are you assuming that if you get an MAA approval that you will look to identify a partner with which to launch the drug in Europe? Thank you.
Dr. Christopher Missling
Thank you for the question. So what we try to decide when it comes to that point is what creates most value for shareholders. So if the most value is created by finding a partner and who has the expertise and the bandwidth and the strength of executing and maximizing sales of the drug blarcamesine for Alzheimer’s with giving us the appropriate incentive to do so with the upfront payment, with milestone payments and royalties, that would be probably the choice.
If, however, it is not the case, then there are certain combinations of such features where we could also consider a split ability to market the drug, which could also actually be beneficial for the company and shareholders because we might retain more upside down the road. So this is really a decision made at the point in time when we are there to maximize shareholder value.
On the other point, you asked about the cash utilization rate. Right now, we are not including any marketing expenses and it’s also not necessary because if it comes to approval, you would have the ability to raise funds, non-dilutive fund with debt funding and financing and these sort of, which would not dilute current shareholders.
So you would not need to have that money in equity available if you would come to the point that you need to pay expenses for marketing entry for that reason. So we would be in a position to leverage the balance sheet without diluting existing shareholders.
Ram Selvaraju
Thank you for all the clarity and congrats again on all the progress.
Dr. Christopher Missling
Thank you.
Operator
Thank you, Ram. Next question comes from Tom Bishop at BI Research. Tom, you should be live. I think you’re muted, Tom.
Tom Bishop
Okay. I wasn’t clear about this comment about the first cohort of schizophrenia being fully enrolled. And is this a 30-day trial? So would data presumably be forthcoming in H2 at least?
Dr. Christopher Missling
So we have to finish the trial. So it consists of several cohorts and several parts. So this was the first cohort in the first part. And again, I want to point out this is a testament of the execution of the team, which has done this so quickly. And again, we are ahead of time because we are anticipating starting the trial actually in this quarter and we ended up starting the trial in the previous quarter and now already have enrolled the first cohort. So it’s very encouraging. I would leave the analysis and when the study is finished, when we get closer to that point to announce that, but we are very encouraged so far about the speed and the process of the study.
Tom Bishop
What are these different cohorts, what are they targeting and how long does the trial last in terms of dosing?
Dr. Christopher Missling
So there are two cohorts in two parts. The first part is just identifying the doses of what is the best dose for the schizophrenia patients. So it’s an ascending dose escalation part. And the second part is then at the optimal dose, if you like, a longer study of almost 30 days. So that is the second part. So we are right now in the first part.
Tom Bishop
Okay. And it’s good to hear about the phase three Rett trial. What can you tell us about the timing and the number of patients? And I guess it’s to be 50-50 this time with placebo. Can you tell us more about the trial?
Dr. Christopher Missling
Right. So we really think that with Rett syndrome, we have really a good chance of what we refer to learn our lessons from the previous trial, where we really were only impacted by a very high placebo effect and that was contributed among others, as you pointed out, to the 2-to-1 randomization, which gave the sense of a participating family to think that, so 2-to-1 means that two chances are higher to be on active arm and randomizing only a small portion, one-third, to placebo. So 60 patients ended up in the active arm and 30 in placebo. But because of that, people thought or had the impression or certainly the aspiration to have a higher chance of being in the active arm.
And that leads for those who are on placebo and are completely blinded, so don’t know if they get the placebo or the active arm, to suspect or hope that they are in the active arm psychologically. So that’s what is this bias most likely. So to avoid this, we would have a 50-50 randomization, 1-to-1, so that there is no anticipated ability to expect that to be in the active arm and triggering a placebo effect in the placebo arm. So that would be one thing.
The other part is there are also features to reduce placebo response by features of the trial, which are specific to technicalities. And then we also would do a larger study, it turned out that indeed the measurements are volatile and only a few participants in the placebo arm could basically noise -- cause noise of the signal to be not significant and that’s what we observed. So there was a very good trend in directional improvement, but we have to now make sure that the signal is strong enough to be significant and that’s the ability to do that.
And the timing is, we will provide update when we get closer, but the community is receptive to this. We are engaging with the community as we speak and also we mentioned that we are presenting at the conference in June in Colorado, as a matter of fact, to connect with the community about the next steps of this trial.
Tom Bishop
And you don’t quite yet know the number in the trial, which would affect how long it takes to go on?
Dr. Christopher Missling
So the good news is that it’s a relatively short trial. It’s 12 weeks, so it’s not too long. It can be done relatively timely, because the matter of fact is it’s a not long trial to begin with. And if there is, again, ability to scale this up and there’s strong interest in an alternative marketed drug to Rett syndrome patients, this could help actually accelerate this trial to start and to kick off. Again, we will provide update as we know more.
Tom Bishop
Okay. Can you remind us of the Fragile X data to-date? Is it just Phase 1 kind of safety data or in food data or is it -- or do I forget kind of some trial results we’ve gotten that you’re considering moving to Phase 2b/3 trial?
Dr. Christopher Missling
Which indication? Sorry, I missed that.
Tom Bishop
Fragile X.
Dr. Christopher Missling
Yeah. So this is very intriguing data. It’s a biomarker, which is measurable both in patients, in humans, as well as in animals. And it’s correlating very clearly, it has been published to the pathology of Fragile X or to showing a reduction of the pathology of Fragile X.
And this will be presented for the first time at the conference in July and we’re very excited about it, because it strengthens the, first of all, the evidence that Fragile X is an extremely good indication for blarcamesine for ANAVEX2-73, but also it would give us in a clinical trial, a biomarker, which is so important in CNS, which is hard to find biomarkers of a pathology. So these are the two reasons why we’re very excited about this presentation coming up.
Tom Bishop
So you could move into a potentially pivotal Phase 2b/3 trial, just based on your biomarker data to date, is it?
Dr. Christopher Missling
Yeah. So that biomarker data we presented will also -- we also -- yeah, we have to also appreciate that there are physicians, patients, advocates group who want to learn why would you -- why want to be part of a trial? And this information would give somebody that information to say, to be excited about being part of a trial because of the fact that it would define the chances of being beneficial to a Fragile X patient in real world and that’s what this biomarker data will -- would be to get the excitement in the community to also then have a smooth enrollment and trial execution, which is important.
This is a good time to review the 2Q cc because it will shed some light on the OLE...and many other points that have been discussed here. Below is Dr. Missling's opening statement for the 2Q cc. Because he made so many good points, I broke them up and numbered each point below.
******************************************************************************************************
Dr. Christopher Missling:
(1) We’re encouraged by the very recently issued FDA guidance for early Alzheimer’s disease which states that one cognitive measure alone like ADAS-Cog could be a sufficient primary endpoint for early Alzheimer’s disease.
(2) We appreciate this new guidance and believe this opens another possible pathway for us to move forward in parallel to the initiated process of market authorization application to the European Medicine Agency, EMA, for blarcamesine for the treatment of Alzheimer’s disease which is already underway.
(3) Full data from the blarcamesine study in Alzheimer’s disease Phase 2b/3 placebo-controlled clinical trial will be published in an upcoming peer-reviewed journal, (4) as well analysis of RNA sequencing of the trial is underway and interim data is expected by mid-2024.
(5) Concurrently, the ATTENTION-AD open-label extension trial is ongoing and we expect to be able to share interim data in the second half of 2024.
(6) In Rett syndrome, continued positive real-world evidence feedback from Rett syndrome patients and caregivers participating in the ongoing open-label extension trial and Compassionate Use Program for patients who participated in the EXCELLENCE trial encourages us to continue our partnership with the Rett syndrome community and to proceed with a Phase 3 12-week efficacy study. An educational presentation will be provided at the 2024 IRSF Rett Syndrome Scientific Meeting, taking place this year June 18, 2024 to June 19, 2024.
(7) Regarding Parkinson’s disease, initiation of an ANAVEX2-73 Phase 2b/3 six-month trial is expected in the second half of 2024.
(8) In Fragile X, new specific translatable and objective biomarker data generated with ANAVEX2-73 supporting the initiation of the potentially pivotal ANAVEX2-73 Phase 2/3 clinical trial will be presented at the 19th National Fragile X Foundation Conference taking place in July 25, 2024 to July 28, 2024.
(9) Related to a new rare disease, we are also in preparation to initiate a potentially pivotal ANAVEX2-73 Phase 2/3 trial.
(10) With respect to ANAVEX3-71, we are quite pleased to provide an update that the placebo-controlled Phase 2 clinical trial of ANAVEX3-71 for the treatment of schizophrenia. The study is well underway with the first cohort of schizophrenia patients being fully enrolled. We are also expecting further peer-reviewed clinical publications in both -- involving both ANAVEX2-73 and ANAVEX3-71.
Now here's the Q & A...
Soumit Roy
Yeah. Hey, congratulations on all the progress and a few questions on the FDA guidance. It’s oftentimes a bit qualitative and trying to understand, read through the line, when they’re saying strong biomarker and strong statistical data to support the clinical outcome on the cognition front. How do you really interpret that? When you’re looking at amyloid 42 over 40 ratio, the error bars when you compare with the company is just because of the cohort size is a little larger. How many patients was there and do you see these to be considered strong or FDA would ask for a larger trial? Just curious about your thoughts.
Dr. Christopher Missling
So the key background is that for the biomarker of Aß changes in placebo versus active arm, we have to be reminded that the mechanism of our drug is not an antibody removing Aß drug, but it’s an orally available, once daily, easy-to-administer and scalable drug and has for that a lot of convenience features, which the antibodies don’t have, in addition to the fact that they are having challenges with the black box warning, which they have been given. So there’s also a challenge from safety and repeated safety measures on MRI are required.
Regarding the biomarker data of the Aß, we were intrigued, but on the other hand, not surprised that we saw a reduction of Aß in the brain measured by the plasma Aß42/40 ratio, which is the analogy of measuring a PET Aß level in the brain, which is intuitively easy -- easier to understand, because you are showing a decline in the brain. But the Aß42/40 ratio, which again is representative of this fact of reduction of Aß in the brain is then measured in the plasma and shows as an increase of this ratio, favorably showing a decrease in the brain. So if the ratio goes up, that means Aß in the brain goes down.
So since we don’t target Aß directly with our drug, but have a more upstream mechanism of action, again, we were intrigued and surprised to see in all patients, there was no sub analysis in this analysis of the Aß ratio showing a significant decline. So now it’s a question of dialogue with the agency, how this will be interpretable as a biomarker.
But I’d like to also point out we have a second strong biomarker, which probably even is stronger, specifically from a p-value perspective, which is the changes in the atrophy of the brain. So in the pathology of the Alzheimer’s disease, there is a very well understood feature of shrinking of the brain over time. And this is intuitive, if the brain is shrinking is less active, it cannot have as good memory or activities of execution and function as the brain was not shrinking.
And we noticed in our trial, a significant stopping of the shrinking of the brain with ANAVEX2-73 blarcamesine in the active arm, compared to placebo. So the placebo arm continues to shrink the brain in the patients, while they are on placebo, which is standard-of-care, by the way, it’s not placebo itself, it’s including donepezil, memantine. So all the data is always on top of standard-of-care, which is today approved, includes approved drugs.
And however, the active arm on blarcamesine or ANAVEX2-73 shows a significant separation from the placebo by not shrinking the brain any further or delaying the shrinking of the brain in many regions of the of the brain and this exact data will be part of the publication, which we’re expecting.
So I think once this data comes out, I think that we can re-discuss the impact of that biomarker in combination with the Aß biomarker. And again, with the Aß biomarker, I’d like to remind again, we did not target with our drug directly Aß. So it must be a downstream effect of the upstream feature of the sigma one receptor, showing also the impact on the entire population in our trial.
Soumit Roy
These are truly encouraging data. You have quite a few catalysts coming up in the next probably three months. I’m trying to understand what would be the strategy when you go to FDA, would you wait for the open-label extension on trial data to come out along with the publication and completion of the European filing and then approach to FDA with the totality of data with biomarker and the long-term, or would you do before that, meet with FDA before the long-term extension on trial data?
Dr. Christopher Missling
Yeah. So we really want to have the best impact, I would say. And you don’t have a second chance [to make a good] first impression, as they say. And certainly having data of the open-label study, which is 96 weeks, probably, would be favorable. However, we have not decided how to proceed on the timing exactly, but definitely this year. But also we can do, since it’s an open-label, interim cuts. So there’s a way to expedite the analysis of the open label study.
Soumit Roy
That is truly helpful. The last question on if you can provide any guidance on the timeline around completion of the European filing?
Dr. Christopher Missling
Yeah. So we definitely want to expedite this and the teams are working really over time to put together the modules, which are many pages, a significant package, we talk about a lot of documents and they all have to be completely ready. Usually this takes time and other companies are going through the same process need the same time. So we’re not in a different situation like that. But we said we want to submit this year and we are well on track to do that. So we will provide updated timing when we get closer to the filing time. But we have very good on time with that. So stay tuned.
Soumit Roy
Thank you and congratulations on all the progress.
Dr. Christopher Missling
Yeah. Thank you.
Operator
Our next call is coming from Ram at H.C. Wainwright. Ram, you should be live.
Ram Selvaraju
Okay. With respect to the regulatory process with the European authorities, can you give us a sense of A, when you expect the MAA filing to be completed, and B, how you anticipate the process to evolve with respect to the CHMP review, how and when they are likely to become involved in the review of the application and what do you understand to be the principal criteria they are going to use to evaluate the suitability of blarcamesine for approval in the European Union? Thank you.
Dr. Christopher Missling
So we stated that just a minute ago that we are filing as soon as possible, definitely this year and the team is really working overtime to put together a package which has to be done in one submission. There’s also interactions taking place with the EMA to be aligned on the technicalities, so that precedes this submission. We also are, sorry, what was the second question?
Ram Selvaraju
The involvement of the CHMP, that review committee that typically looks at drug candidates that are subjected -- submitted to the EMA for approval and renders a positive or a negative opinion prior to an approval decision being taken. Just wanted to know when you expect the CHMP to get involved in the review of the blarcamesine MAA and what criteria you expect them to use to determine what their opinion should be.
Dr. Christopher Missling
Right. Thank you for reminding. So the procedure of the submission involves a review of the package before it gets submitted and it’s a very healthy procedure because it allows exactly this intelligence to, feedback to be received. So we expect this to take place.
To give you a sense of the level of interest, we noted before that the reason we submitted to the EMA was not because we thought it would be a good idea, but because we shared the majority of the data with the EMA beforehand, and asked for their input and their feedback, and their response was unambiguous to request to immediately file a submission.
So we of course hope that this initial feedback will continue to be the case down the road and right now we have no belief why it wouldn’t, but that is of course up to the review. So we are coming in here, not that we push, but we were pulled into the submission, given probably the unmet need in Europe and also the fact that the European Union has not MRI or PET centers in all places in the countries of the European Union, like in certain countries, for example, like Hungary or Poland or Romania, there are not enough MRI centers, which would probably be needed for an antibody given its safety profile. So that’s the best we can say at this point.
Ram Selvaraju
And with respect to 3-71, just wanted to A, get a sense of how you expect to monitor the efficacy profile of this compound in schizophrenia. If you regard, for example, certain domains of the PANSS to be the most appropriate efficacy measures, as well as the extent to which you expect 3-71 to be differentiated from existing anti-schizophrenic medications and what you expect the principal areas of differentiation to be. For example, is it safety and tolerability, or so then the efficacy, or do you expect on both the safety, as well as the efficacy fronts, this drug candidate to demonstrate the differentiated profile versus currently marketed, for example, atypical antipsychotic medications?
Dr. Christopher Missling
Yeah. I think it’s exactly as you stated, it could be really both. And if you look at the landscape of drug approvals, you want to always be better than what is out there on the market. So if you’re able to show that the safety has a better feature, a better profile and also translate into stronger, more meaningful efficacy, both on the positive, as well as the negative domains of schizophrenia, then this would be extremely valuable and helpful.
We also want to point out in this study, we are focusing on EG/ERP as a considered surrogate biomarker of schizophrenia. So we are excited about finding out how the drug interacts in that regard and it’s a very elegant non-invasive methodology to identify that.
But we also have included the standard PANSS score in addition to this EG/ERP. So we might learn something about the effect of our drug in the study in those regard, which would then allow us to decide how to proceed with this drug in schizophrenia.
Ram Selvaraju
And then the last question is sort of a combination of a strategic and financial query. Let’s say hypothetically that the EMA agrees that blarcamesine is approvable for treatment of Alzheimer’s disease in the European Union. At that juncture, strategically, what do you expect your preferred strategy to be in terms of whether or not you elect to undertake independent self-commercialization activities in Europe or whether you at that point would look to identify a partner? And does your cash burn guidance of runway for the next four years take into account any pre-launch activity related expenses related to blarcamesine for treatment of Alzheimer’s disease in Europe or are you assuming that if you get an MAA approval that you will look to identify a partner with which to launch the drug in Europe? Thank you.
Dr. Christopher Missling
Thank you for the question. So what we try to decide when it comes to that point is what creates most value for shareholders. So if the most value is created by finding a partner and who has the expertise and the bandwidth and the strength of executing and maximizing sales of the drug blarcamesine for Alzheimer’s with giving us the appropriate incentive to do so with the upfront payment, with milestone payments and royalties, that would be probably the choice.
If, however, it is not the case, then there are certain combinations of such features where we could also consider a split ability to market the drug, which could also actually be beneficial for the company and shareholders because we might retain more upside down the road. So this is really a decision made at the point in time when we are there to maximize shareholder value.
On the other point, you asked about the cash utilization rate. Right now, we are not including any marketing expenses and it’s also not necessary because if it comes to approval, you would have the ability to raise funds, non-dilutive fund with debt funding and financing and these sort of, which would not dilute current shareholders.
So you would not need to have that money in equity available if you would come to the point that you need to pay expenses for marketing entry for that reason. So we would be in a position to leverage the balance sheet without diluting existing shareholders.
Ram Selvaraju
Thank you for all the clarity and congrats again on all the progress.
Dr. Christopher Missling
Thank you.
Operator
Thank you, Ram. Next question comes from Tom Bishop at BI Research. Tom, you should be live. I think you’re muted, Tom.
Tom Bishop
Okay. I wasn’t clear about this comment about the first cohort of schizophrenia being fully enrolled. And is this a 30-day trial? So would data presumably be forthcoming in H2 at least?
Dr. Christopher Missling
So we have to finish the trial. So it consists of several cohorts and several parts. So this was the first cohort in the first part. And again, I want to point out this is a testament of the execution of the team, which has done this so quickly. And again, we are ahead of time because we are anticipating starting the trial actually in this quarter and we ended up starting the trial in the previous quarter and now already have enrolled the first cohort. So it’s very encouraging. I would leave the analysis and when the study is finished, when we get closer to that point to announce that, but we are very encouraged so far about the speed and the process of the study.
Tom Bishop
What are these different cohorts, what are they targeting and how long does the trial last in terms of dosing?
Dr. Christopher Missling
So there are two cohorts in two parts. The first part is just identifying the doses of what is the best dose for the schizophrenia patients. So it’s an ascending dose escalation part. And the second part is then at the optimal dose, if you like, a longer study of almost 30 days. So that is the second part. So we are right now in the first part.
Tom Bishop
Okay. And it’s good to hear about the phase three Rett trial. What can you tell us about the timing and the number of patients? And I guess it’s to be 50-50 this time with placebo. Can you tell us more about the trial?
Dr. Christopher Missling
Right. So we really think that with Rett syndrome, we have really a good chance of what we refer to learn our lessons from the previous trial, where we really were only impacted by a very high placebo effect and that was contributed among others, as you pointed out, to the 2-to-1 randomization, which gave the sense of a participating family to think that, so 2-to-1 means that two chances are higher to be on active arm and randomizing only a small portion, one-third, to placebo. So 60 patients ended up in the active arm and 30 in placebo. But because of that, people thought or had the impression or certainly the aspiration to have a higher chance of being in the active arm.
And that leads for those who are on placebo and are completely blinded, so don’t know if they get the placebo or the active arm, to suspect or hope that they are in the active arm psychologically. So that’s what is this bias most likely. So to avoid this, we would have a 50-50 randomization, 1-to-1, so that there is no anticipated ability to expect that to be in the active arm and triggering a placebo effect in the placebo arm. So that would be one thing.
The other part is there are also features to reduce placebo response by features of the trial, which are specific to technicalities. And then we also would do a larger study, it turned out that indeed the measurements are volatile and only a few participants in the placebo arm could basically noise -- cause noise of the signal to be not significant and that’s what we observed. So there was a very good trend in directional improvement, but we have to now make sure that the signal is strong enough to be significant and that’s the ability to do that.
And the timing is, we will provide update when we get closer, but the community is receptive to this. We are engaging with the community as we speak and also we mentioned that we are presenting at the conference in June in Colorado, as a matter of fact, to connect with the community about the next steps of this trial.
Tom Bishop
And you don’t quite yet know the number in the trial, which would affect how long it takes to go on?
Dr. Christopher Missling
So the good news is that it’s a relatively short trial. It’s 12 weeks, so it’s not too long. It can be done relatively timely, because the matter of fact is it’s a not long trial to begin with. And if there is, again, ability to scale this up and there’s strong interest in an alternative marketed drug to Rett syndrome patients, this could help actually accelerate this trial to start and to kick off. Again, we will provide update as we know more.
Tom Bishop
Okay. Can you remind us of the Fragile X data to-date? Is it just Phase 1 kind of safety data or in food data or is it -- or do I forget kind of some trial results we’ve gotten that you’re considering moving to Phase 2b/3 trial?
Dr. Christopher Missling
Which indication? Sorry, I missed that.
Tom Bishop
Fragile X.
Dr. Christopher Missling
Yeah. So this is very intriguing data. It’s a biomarker, which is measurable both in patients, in humans, as well as in animals. And it’s correlating very clearly, it has been published to the pathology of Fragile X or to showing a reduction of the pathology of Fragile X.
And this will be presented for the first time at the conference in July and we’re very excited about it, because it strengthens the, first of all, the evidence that Fragile X is an extremely good indication for blarcamesine for ANAVEX2-73, but also it would give us in a clinical trial, a biomarker, which is so important in CNS, which is hard to find biomarkers of a pathology. So these are the two reasons why we’re very excited about this presentation coming up.
Tom Bishop
So you could move into a potentially pivotal Phase 2b/3 trial, just based on your biomarker data to date, is it?
Dr. Christopher Missling
Yeah. So that biomarker data we presented will also -- we also -- yeah, we have to also appreciate that there are physicians, patients, advocates group who want to learn why would you -- why want to be part of a trial? And this information would give somebody that information to say, to be excited about being part of a trial because of the fact that it would define the chances of being beneficial to a Fragile X patient in real world and that’s what this biomarker data will -- would be to get the excitement in the community to also then have a smooth enrollment and trial execution, which is important.
There's plenty of reasons not to file with the FDA. I follow a few investment newsletters and Ray Blanco has a pretty good record...but one of his recommendations was turned down by the FDA even though their P3 was successful. (See below)
Time to Exit This Play On Disappointing FDA News
The news hasn’t been so good for Actinium Pharmaceuticals (NASDAQ: ATNM). The company was gearing up to submit an application to the FDA for its Iomab-B radiotherapy.
The FDA, however, wants more data, and will not accept the company’s completed Phase 3 trial for Iomab-B acute myeloid leukemia, even though the drug was a great success in achieving its primary endpoint in preparing patients for a bone marrow transplant.
Actinium is going to have to run an entire Phase 3 trial all over again, with a head-to-head matchup against existing therapies for the FDA to consider the drug for approval.
[And yes. I realize that we can easily beat the SOC in a head-to-head match up. But I don't trust the FDA because they can come up with plenty of other excuses to protect BP mabs.]
ATNM shares got clobbered on the news. The company says it will have to seek a partner to further develop Iomab-B and get it to the FDA.
It’s time to throw in the towel on ATNM and move on to other plays with better near-term upside.
Good post, SteadyT.
I was about to gather the same material (with Dr. Sabbaugh's comments) but you posted it before me. Well done, sir!
Quote: "...the only significant complaint I have about CM's leadership is the undersizing of all their trials by ~50%"
Whoa...that's a pretty significant complaint!
In fact, that's one of the reasons Doc claims that Anavex only has a 1% chance of approval.
Quote: "...the EMA will decide and then the FDA will decide."
Yes...let's hope the Anavex team submits our NDA in that order!
Obesity Drug Slows Alzheimer's Brain Shrinkage
Data from a small clinical trial published on Tuesday showed that a drug from the GLP-1 receptor agonist class known for weight loss slowed the loss of brain volume in people with mild Alzheimer's disease.
The trial results, published at the Alzheimer's Association International Conference, provided the first glimpse of how GLP-1 drugs may act on hard-to-treat brain disorders.
The trial studied just 204 patients in Britain, half of whom received Novo Nordisk's earlier-generation GLP-1 drug liraglutide, and the other half a placebo.
The trial did not meet its primary endpoint, or main goal, which was change in the cerebral glucose metabolic rate, an assessment of brain function.
It did meet the secondary endpoints. It showed liraglutide appeared to reduce shrinking in the parts of the brain that control memory, learning, language and decision-making by nearly 50% compared to placebo.
The trial was not sponsored by Novo. However, the Danish drugmaker is testing its new-generation, more effective GLP-1 drug semaglutide — sold as diabetes drug Ozempic and obesity drug Wegovy — in thousands of patients with early Alzheimer's. Its two trials began in 2021 and results are expected in 2025.
[Yikes. That's right around the corner. C'mon Anavex!!!]
Rebecca Edelmeyer, senior director of scientific engagement at the Alzheimer's Association, told Reuters in an interview that the results published on Tuesday were "really intriguing."
"This is our first time really seeing this type of intervention readout in a clinical trial," she said.
Researchers told Reuters last year that diabetes regimens, from Ozempic to insulin and metformin, appear to address several different aspects of the metabolic system implicated in Alzheimer's, including a protein called amyloid and inflammation.
The hope is that improving glucose utilization and reducing inflammation in the body - including the brain - could slow progression of Alzheimer's.
Still, the trial published on Tuesday was not designed to measure cognitive benefits, and some scientists urged caution.
"The repurposing of drugs is an important avenue of research but there is a lot of uncertainty here," said Stephen Evans, emeritus professor at the London School of Hygiene and Tropical Medicine.
He said the shrinking in the memory and learning parts of the brain observed in the small trial "may not translate to important cognitive benefits" and the results did not demonstrate that liraglutide could protect against dementia, though pursuing a larger trial would be worthwhile.
© 2024 Thomson/Reuters. All rights reserved.
https://www.newsmax.com/health/health-news/alzheimers-obesity-medication/2024/07/30/id/1174485/?ns_mail_uid=7cb8dafc-ae3b-415e-81ce-33311f68ea21&ns_mail_job=DM661022_07312024&s=acs&dkt_nbr=01010244y2td
Again, I agree. But it's common sense to always include both entities when releasing a Press Release to the public about your intentions to submit an NDA.
To withhold one of them just because it fulfills the bare minimum requirements of a material event is just silly...and makes no sense from a marketing point of view.
Agreed. But that doesn't change the logic in my statement below.
*****************************************************************************************************
Agreed. But if my memory serves me correctly, Dr. Missling told those participants at the ASM that he was going to submit an NDA to both the EMA and the FDA in the 2H of 2024. In fact, he said something like "the FDA will process our NDA quicker" - I'm paraphrasing here.
That being the case, it makes no sense to announce a Press Release that only says it will be submitting the NDA to the EMA...and not include the FDA. (Unless of course the FDA has verbally turned you down in a face-to-face meeting)
Agreed. But if my memory serves me correctly, Dr. Missling told those participants at the ASM that he was going to submit an NDA to both the EMA and the FDA in the 2H of 2024. In fact, he said something like "the FDA will process our NDA quicker" - I'm paraphrasing here.
That being the case, it makes no sense to announce a Press Release that only says it will be submitting the NDA to the EMA...and not include the FDA. (Unless of course the FDA has verbally turned you down in a face-to-face meeting)
Information that was not included in the Press Release from the P2b/3 announcement.
As you know, I've been a strong proponent of filing our NDA with the EMA first. It is my belief that the EMA actually needs our drug because of the ease of distribution and safety profile. The FDA, on the other hand, has some requirements that may reduce our chances of an NDA approval. i.e. the need for multiple ethnic groups within the study is probably the biggest impediment.
Anyway, after reading the Press Release below it is my belief that Anavex has finally spoken with the FDA and was (verbally) turned down from submitting the P2b/3 study. I came to this conclusion because of the wording in the Press Release. See the sentence that I underlined in bold below.
This does NOT mean that Anavex will not receive approval from the FDA. It simply means that they are going to submit the NDA with the EMA first. Once approved with the EMA, they will get fast-tracked for approval with the FDA. This is my opinion, of course.
NEW YORK – July 28, 2024
Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative, neurodevelopmental, and neuropsychiatric disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome, schizophrenia, and other central nervous system (CNS) diseases, today 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). The data were presented by Marwan Noel Sabbagh, MD, Professor of Neurology at Barrow Neurological Institute and Chairman of the Scientific Advisory Board at the 2024 Alzheimer's Association International Conference (AAIC).
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. As specified in the March 2024 FDA Guidance for Early AD, a sole cognitive measure can serve as the primary endpoint for early Alzheimer’s trials.[1] The protocol was designed with ADAS-Cog13 and ADCS-ADL as co-primary endpoints. 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, also recommended as an alternative primary endpoint for early AD in the new FDA guidance, is significant at both 30 mg and 50 mg at Week 48. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aß42/40-ratio and reduction of brain atrophy. Blarcamesine significantly slowed brain atrophy in key regions of interest, including the whole brain by 37.6%, total grey matter by 63.5%, and lateral ventricles by 25.1%.
“These data are very exciting, particularly in a study that can demonstrate objective slowing of markers of neurodegeneration,” said Dr. Sabbagh. “The advantage of blarcamesine is that it is a small oral molecule that exerts clinical benefits on cognition and neurodegeneration and could be appealing because of its route of administration and good comparative safety profile. The neuroimaging evaluation performed in the Phase IIb/III study demonstrated no neurological tissue damage such as hemorrhage or Amyloid-related imaging abnormalities (ARIA), as documented with other anti-amyloid targeted therapies. We believe the scalable and convenient features of blarcamesine could reduce crucial barriers within the currently complex healthcare ecosystem for Alzheimer's disease and provide broader access to a diverse population with early Alzheimer's disease.”
Blarcamesine, a small molecule administered orally once daily, demonstrated numerically superior clinical efficacy to approved therapies while also slowing neurodegeneration in early AD patients. Blarcamesine’s safety profile indicates not requiring routine MRI monitoring, and given its differentiated mechanism of action, could represent a novel treatment that could be complementary to the currently approved anti-beta amyloid monoclonal antibody drugs.
Juan Carlos Lopez-Talavera, MD, PhD, Head of Research and Development of Anavex commented: “Anavex's precision medicine approach, tailored to improving autophagy, a key clearance mechanism that removes protein aggregates and misfolded proteins across the Alzheimer's disease continuum and uniquely positions the Company to develop innovative solutions for patients and their families.” He continued: “People living with early Alzheimer's disease have the desire to maintain their sense of self for as long as possible. The study results provide the potential for people with more time to engage in meaningful activities. Full regulatory submission of blarcamesine in Europe (EMA) is expected in Q4 2024.” [No mention of filing with the FDA?!]
For the primary endpoint ADAS-Cog13, blarcamesine is significantly better than placebo for both 50 mg (-2.149; P = 0.021) at 48 weeks and for 30 mg blarcamesine dosage groups (-1.934; P = 0.026) at 48 weeks. The key secondary endpoint CDR-SB was significantly improved vs. placebo in both 50 mg (-0.465; P = 0.045) and 30 mg (-0.502; P = 0.020) assigned dose groups. CGI-I was significantly improved in both 50 mg (-0.314; P = 0.008) and 30 mg (-0.248; P = 0.024) groups.
In the respective safety population, common treatment-emergent adverse events included dizziness, which was transient and mostly mild to moderate in severity, and occurred in 120 participants (35.8%) during titration and in 76 participants (25.2%) during maintenance with blarcamesine and 10 (6.0%) during titration and 9 (5.6%) during maintenance with placebo. These events are manageable by adjusting titration schedule to slower titration and nighttime dosing, as has been positively observed in the blarcamesine compassionate use program.
“Alzheimer’s disease is such a devastating disease that affects tens of millions worldwide. The findings from this and previous studies with blarcamesine in Alzheimer’s disease further strengthen our belief in the potential of addressing the complex pathology in Alzheimer’s disease through an upstream precision medicine compensatory process, autophagy through SIGMAR1 activation,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. “We like to thank all the people involved in the study for their invaluable contributions and we look forward to continuing our journey to address the high unmet need for Alzheimer’s disease patients with a potential new convenient orally available treatment option for Alzheimer’s disease.”
The presentation is available on the Investors section of the Company’s website at www.anavex.com.
Data from the blarcamesine Phase IIb/III ANAVEX®2-73-AD-004 trial to be published in an upcoming peer-reviewed journal.
This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that any investigational uses of such product will successfully complete clinical development or gain health authority approval.
Very encouraging. Can you share some of the names of the companies that you worked for?
Quote: "EMA already have it [brain volume] as a surrogate biomarker."
Where did you get that information? (And please provide a link to the information)
Thanks
Wouldn't patient population have something to do with it?
After all, those rare diseases that only affect a small percentage of the population can only recruit a smaller n to begin with. Whereas a more prevalent disease (e.g. Covid-19, A.D., Parkinsons, etc) may require a larger n...due to the larger population.
I'm just throwing that out there because of the correlation in disease population. I have nothing to substantiate it other than my perception.
Nice find. Link?
Good post. I would also add the numerous independent studies - including a peer-reviewed study in Nature.com - that have validated the efficacy of Anavex 2-73 (Blarcamesine) in improving CNS conditions...which eventually leads to neuronal homeostasis.
These independent studies are playing a crucial role in informing the public of our company...and, by extension, the investment opportunity of Anavex.
I also agree with your sentiment that a Trump administration would dramatically increase the odds of an FDA approval for us.
Quote: "I might also add IMO that if Trump is elected, the odds of FDA approval go even higher and would match or exceed the odds at the EMA"
Well done, sir. I hope you recoup all of your losses...and then some!
Quote: "I think that this talking point is more political than clinical. It subtly affirms that blarcamesine works differently than the monoclonal antibodies and it also positions Anavex as a less threatening actor."
Yes. Exactly. We must remember that BP owns the mabs...and the mabs have been approved by the FDA. Therefore Dr. Missling has figured out a way to appease BP by emphasizing a combination therapy...and thus, the FDA will be open to approving our drug.
Kudos to Dr. Missling for this strategy!
Masterfully done!