Letter to the EMA/CHMP

To: The members of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) responsible for regulatory opinion of Anavex Life Science’s early Alzheimer’s disease (AD) treatment, blarcamesine.

Re: The upcoming scientific opinion by the CHMP for blarcamesine Bottom-line Up Front:

● Alzheimer's disease is a devastating and deadly illness for which new therapies are desperately needed

● The overriding priority must always be what is best for the patients and their families

● The disappointing trials with semaglutide and posdinemab are only the most recent in a long sequence of setbacks, extending from decades of failed attempts to achieve meaningful clinical benefit. This further underscores the critical need for effective and safe disease modifying therapies

● Improvements in amyloid biomarkers have historically not correlated to clinical benefit in many trials

● Novel improvement to neurodegenerative processes in the ANAVEX2-73-AD-004 trial rendered unprecedented cognitive benefits

● Approximately 50% of patients could enjoy a stabilization for cognitive loss (75-85% slowing); corroborated by QoL-AD

● Millions of Europeans stand to gain years of time-saved now – delay in therapy would be harmful

● Anavex’s blarcamesine is effective, oral, safe, inexpensive, easily transportable, storable, and does not require costly monitoring

● We are struck by the fact that we have a novel, oral therapeutic with proven positive clinical endpoints at the door of regulators

● We implore the CHMP to give a positive opinion for blarcamesine 

Who are we?

We are senior intelligence analysts, physicians, caregivers, patients, and stakeholders with years of research and personal experience in the field of AD.

Defining the problem

Our motivation stems from a deeply personal space and a desire to help those burdened with this disease. As caregivers, family members, or clinicians treating these patients, we have experienced first-hand the profound toll AD inflicts on patients and their families. We have a determination to find meaningful solutions. Our experiences have solidified our beliefs that AD is a soul-robbing disease that strips away identity and dignity. We believe that AD is the ultimate universal “pandemic,” which in its pervasiveness, affects nearly every family on earth as the 7th leading cause of death globally.

Evidence that proves effectiveness

This month the CHMP will announce its decision on the scientific opinion and recommendation for blarcamesine. Unlike approved monoclonal antibodies (i.e. lecanemab and donanemab), blarcamesine would represent the first clinically meaningful, disease-modifying oral treatment for Alzheimer’s disease with a novel mechanism of action addressing pathogenesis upstream of amyloid and tau formation. Blarcamesine’s patient safety record is unmatched among approved modern therapies for AD.

At 48-weeks, the landmark ANAVEX2-73-AD-004 trial featuring early-stage mild dementia due to AD and mild cognitive impairment due to AD (MMSE of 20 to 28) met its primary cognitive endpoint (ADAS-COG13) and a key secondary global endpoint (CDR-SB) in the ITT population. The ADAS-COG13 was not only statistically significant but clinically significant, exceeding the meaningful threshold of -2 at -2.027 (p = 0.008), which was not achieved in the signature monoclonal trials. The CDR-SB saw a change of -0.483 (p = 0.010). While the functional (ADCS-ADL) co-primary endpoint was not met, the trial was a success under multiplicity control rules. These clinical results were corroborated with biomarkers, further supporting the underlying effect on the disease process. The amyloid related biomarkers included a plasma Aβ42/40 ratio assay which increased significantly in blarcamesine-treated patients compared to placebo (+0.013 with p = 0.048). The trial also showed unprecedented improvements in physical signs of neurodegeneration in brain volumetric changes on MRI, one of the first recorded signs of disease by Dr. Alois Alzheimer. In just 48 weeks, blarcamesine-treated ITT patients significantly slowed whole brain volume loss by 37.6%, grey matter volume loss by 63.5%, and the lateral ventricles by 25.1%. Monoclonal antibodies do not have this effect; in fact, they exacerbate volumetric loss. No brain bleeding or swelling (ARIA) were reported, and no deaths were as a result of treatment. The most common adverse effects were dizziness and confusion (35.8% and 14.3% in dosed patients respectively), and these were predominantly mild-to-moderate severity and transitory – decreasing in frequency and severity as the maintenance phase progressed. With a different titration schedule in the OLE, the dizziness signal was ameliorated. With the final target dose restricted to 30 mg, transient dizziness is a lesser factor as well.

Anavex conducted pre-specified and exploratory genomic testing to validate a precision medicine approach. Anavex had previously established the expectation that patients with a fully functional SIGMAR1 gene (SIGMAR1 WT) were likely to reap the best benefit from blarcamesine, since the drug works by modulating the SIGMAR1 receptor. Approximately 70.7% of the general population have SIGMAR1 WT (likely higher in Europe and lower in Asia), and this pre-specified analysis vindicated their hypothesis. ADAS-COG13 cognitive benefit was extended beyond ITT with a delta of -2.317 points (p = 0.015) and CDR-SB global benefit was also improved to -0.601 (p = 0.012). Together, these scores showcase a 49.8% and 33.7% slowing compared to placebo respectively. The prospectively defined SIGMAR1 WT cohort was eventually coined ABCLEAR1. Patients with SIGMAR1 mutation status performed well under ABCLEAR1 and ITT, with non-significant ADAS-COG13 benefit of -1.593 (p = 0.225) and CDR-SB benefit of -0.230 (p = 0.449), a 25.2% and 13.7% slowing against placebo respectively. The pre-specified genomic analysis demonstrates the fact that clinical benefit is partially dependent on SIGMAR1 status, though all patients (ITT) likely stand to benefit over no treatment.

Exploratory unbiased GWAS analysis also showed intriguing data in both prospective and retrospective genome analysis that were promising and hypothesis generating. Within this analysis Anavex identified a second significant genetic marker of blarcamesine response, in the collagen gene, COL24A1. Patients with a fully functional COL24A1 gene (COL24A1 WT, approximately 71.7% of the general population) had improved clinical and biomarker response over ITT and ABCLEAR1. The COL24A1 WT cohort was coined ABCLEAR2 and should be considered credible as there is strong biological plausibility and mechanistic reasoning into how functional collagen creates an ideal extracellular matrix (ECM) or “operating environment” for the interaction with SIGMAR1 modulation and subsequent autophagy machineries within the cell. From this analysis a further subgroup was defined, which features a combined SIGMAR1 WT and COL24A1 WT. This pooled cohort was labeled ABCLEAR3, comprising just over 50% of the general population and saw megalithic response across all endpoints including the previously missed ADCS-ADL. Further improved efficacy was noted in the lower 30 mg arm. This is logical when considering patients require less titration to ramp up to 30mg dosing. Preplanned slower titration in the open label extension trial showed improvement in the side effects.

● ABCLEAR2 (COL24A1 WT ~70% of the population):

o ADAS-COG13: -3.901 (p < 0.0001), 59.8% slowing in 48 weeks o ADCS-ADL: +3.528 (p = 0.0006), 37.1% slowing in 48 weeks

o CDR-SB: -0.986 (p < 0.0001), 47.6% slowing in 48 weeks

o Whole Brain Atrophy: 48.5% (p = 0.0003) slowing in 48 weeks

o Grey Matter Atrophy: 68.8% (p = 0.002) slowing in 48 weeks

o Lateral Ventricle Atrophy: 34.1% (p < 0.0001) slowing in 48 weeks

● ABCLEAR3 (SIGMAR1 WT & COL24A1 WT ~ 50%) (pooled arms, 30 & 50 mg):

o ADAS-COG13: -4.179 (p = 0.0005), 75.9% slowing in 48 weeks o ADCS-ADL: +3.131 (p = 0.0111), 38.8% slowing in 48 weeks

o CDR-SB: -1.076 (p = 0.0002), 57% slowing in 48 weeks

o Whole Brain Atrophy: 44.5% (p = 0.0019) slowing in 48 weeks

o Grey Matter Atrophy: 65.2% (p = 0.0013) slowing in 48 weeks

o Lateral Ventricle Atrophy: 25.6% (p = 0.0101) slowing in 48 weeks

● ABCLEAR3 (SIGMAR1 WT & COL24A1 WT) (30mg arm):

 o ADAS-COG13: -4.739 (p = 0.0004), 84.7% slowing in 48 weeks o ADCS-ADL: +4.245 (p = 0.0024), 53.2% slowing in 48 weeks

 o CDR-SB: -1.414 (p < 0.0001), 75.2% slowing in 48 weeks

o Whole Brain Atrophy: 51% (p = 0.0013) slowing in 48 weeks

o Grey Matter Atrophy: 73.1% (p = 0.0012) slowing in 48 weeks

o Lateral Ventricle Atrophy: 23.5% (p = 0.0332) slowing in 48 weeks

In addition to these endpoints [graphic below after signatures], the ABCLEAR2 and ABCLEAR3 subgroups performed exceedingly well on clinician and patient surveys (CGI-I, NPI-Q, and QoL-AD). QoL-AD in particular – a patient-assessed questionnaire – suggests a reversal in the negative trajectory for AD patients, with absolute improvement in those subgroups. The other questionnaires (CGI-I & NPI-Q) can be interpreted to show relative plateauing in disease progression. In combination, these subgroups suggest that the operating environment of the ECM (via WT COL24A1) may be more important than whether the patient has a fully functional primary target (SIGMAR1). Blarcamesine enhances autophagy through lysosomal mechanisms regardless of the SIGMAR1 status; however, combining an ideal operating environment in the ECM with an ideally functional SIGMAR1 target at manageable doses provides remarkable efficacy in this subgroup (~50% of the general population). This further supports the evidence of the effectiveness of blarcamesine.

At the conclusion of the 48-week ANAVEX2-73-AD-004 trial, patients were eligible to enroll in an open-label extension (OLE) trial of 144 or up to 192 weeks (for Australian patients). The OLE featured a delayed-start analysis and concluded that patients on intervention during the primary study with no/short interruption (less than 19 days) performed exceedingly well on the co-primary endpoints ADAS-COG13 and ADCS-ADL with a delta between early-start and late-start of -4.20 (p = 0.008) and +5.75 (p = 0.001) in those assays respectively. ABCLEAR2 OLE data is available, which showed further efficacy in ADAS-COG13 of -5.43 (p = 0.0035) and ADCS-ADL of +9.50 (p < 0.0001), and a 19.5-month time-saved over 192 weeks. Further modeling of prodromal surrogates and ADNI revealed compelling discoveries as well. ABCLEAR3 patients in the 30mg arm showed the ability to match prodromal decline despite enrolled patients starting with more advanced stage (arguably very difficult to achieve), and the pooled ITT (early-start combined with late-start) at 144-weeks had a -12.78-point delta to carefully matched ADNI control for ADAS-COG13. This correlated to a 17.8-month time-saved over 144 weeks compared to ADNI. In totality, the OLE, prodromal, and ADNI comparison analysis combined with neurodegeneration biomarkers and the QoL-AD questionnaire lend further evidence that blarcamesine significantly alters the progression of disease and potentially plateaus degeneration in certain subgroups. This “time saved” data would have a significant impact in the lives of patients and their families.

While monoclonal antibodies target downstream amyloid deposits, blarcamesine enhances autophagy as well as a host of other processes including proteostasis, the electron transport chain, mitochondria, and calcium flux. In 2022, Ju-Hyun Lee et al. described aberrant lysosome mutation and subsequent waste and leakage in five separate AD mouse models. This cascade of events is prior to the presence of abnormal amyloid or tau deposition and strongly suggests that acidification issues combined with DNA corruption within lysosomal networks disrupt normal waste processing and subsequently leads to the leakage of intraneuronal β-amyloid into extracellular spaces. Please consider the quote from that paper below:

"β-amyloid plaque formation in AD has commonly been considered to originate from extracellular deposition of β-amyloid derived from secreted Aβ, which then triggers secondary neuritic dystrophy and neuronal cell death. By contrast, our evidence in diverse AD models supports the opposite sequence—namely, extracellular plaques mainly evolve from intraneuronal build-up of β-amyloid within membrane tubules, forming a centralized amyloid ‘core’ within single intact PANTHOS neurons that subsequently degenerate to give rise to the classical senile plaque. This ‘inside-out’ process accords with and substantiates hypotheses from many investigators. In versions of this hypothesis, Aβ and its oligomeric species generated intracellularly within ALP compartments can gain access to the extracellular space by neurodegeneration, local membrane damage or unconventional secretion (exocytosis). Importantly, a few investigators have described intracellular membrane-enclosed amyloid fibrils in AD mouse models and, in AD brain, the frequent presence of amyloid surrounding DAPI-positive nuclei, and neuronal lysosomal hydrolase abundance within extracellular β-amyloid."

By targeting upstream lysosomal function and autophagy, blarcamesine can render superior cognitive, global, and neurodegenerative benefits before the abnormal waste products of amyloid and tau deposits are produced. This benefit is enhanced in the ABCLEAR1 group, which was prospectively defined. The retrospective analysis of ABCLEAR2, and ABCLEAR3 represents patients where the drug target is ideal, the extracellular matrix is ideal, or both. These effects would be most prominent in MCI or early AD patients, in disease stages where patient physiology is redeemable, as opposed to later stages where the mechanism would theoretically have a cooling effect but little ability in combating system-wide corruption that has already occurred.

The approved monoclonal antibodies in AD are an advancement in the field, proving statistically significant benefit in Alzheimer’s. They represent the most significant breakthrough in treating Alzheimer’s disease in decades. They do require brain PET or spinal tap for CSF biomarkers upfront. Both signature trials also required further brain PETs later and routine MRIs along the way to evaluate ARIA risk. Blarcamesine does not have such requirements. The toxicity of ARIA is worse for monoclonal antibodies depending on APOE4 status. Interestingly, the efficacy for blarcamesine is not dependent on APOE typing.

We strongly believe that blarcamesine should be approved in Europe for the benefit of mankind as the evidence confirms impressive cognitive benefits with limited side effects. We believe such approval would be conditional on future trials, which we would welcome to advance the care of the crushing burden this disease manifests. It has long been speculated that the final answer to AD will be a combination or “cocktail” of medications that work in a complementary fashion. We would envision future trials testing blarcamesine with monoclonal antibodies to see if efficacy can be enhanced further.

Both the FDA and EMA have recognized limitations in evaluating early-stage AD functional decline (ADL’s) due to minimal or absent cognitive and functional deficits in those patients. Regulators have acknowledged that assessment tools typically used to measure functional impairment are not sensitive enough to detect subtle functional changes in early AD. Furthermore, cognition encompasses all processes and domains and is eventually reflective of functional change. Thus, powerful cognitive benefits may represent future clinically meaningful functional change even if the stand-alone functional endpoint is missed. The EMA’s own 2018 Guideline on the Clinical Investigation of Medicines for the Treatment of Alzheimer’s Disease postulates a global endpoint is sufficient for a positive opinion (as it was with lecanemab and donanemab), but other endpoints (i.e. ADAS-COG and ADCS-ADL) should still be assayed for a “comprehensive assessment” even though it “is recognized that not all of these objectives may be achievable.” Furthermore, the OLE ADL data, which represents a much longer follow-up in the patients, is positive for blarcamesine, further adding support for its efficacy.

What we’d like?

Anavex’s blarcamesine is an oral, safe, easily transportable, inexpensive, and tremendously efficacious therapy for Alzheimer’s that would save the European Union significant direct and indirect costs in treating this terrible disease. There is strong statistical evidence to prove that the intent-to-treat intervention patients benefit from the drug, with further benefit in pre-specified ABCLEAR1 and the retrospective – but credible - exploratory groups, ABCLEAR2 and ABCLEAR3. We again note that any side effects are limited and transient, unmatched by modern therapies, and improved with tempered titration. We understand the missions of regulatory agencies, such as the EMA and FDA, are to provide effective medications to help patients, where the benefits outweigh the risk of toxicity. We know this is a difficult task, which is taken seriously by those who evaluate medicines. We do fear that delaying an effective therapeutic solution has the opportunity cost of not allowing patients to benefit from such significant advancements. We the authors, physicians, caregivers, patients, and stakeholders petition the CHMP to grant blarcamesine a positive opinion. Blarcamesine likely targets disease pathogenesis and has the potential to slow decline to keep patients in earlier, more functional disease stages, reducing caregiver burden, improving healthcare costs, and preserving memories and dignities of the afflicted.

In cross-trial comparisons, with their limitations, blarcamesine appears to show greater efficacy in a shorter length of time than lecanemab or donanemab while meeting the statistical significance in cognitive benefits as outlined. This amplifies the credibility and integrity of the ANAVEX2-73-AD-004 trial and its OLE. While ABCLEAR3 patients performed the best of all subgroups, its data should be seen as supportive. With ABCLEAR1 approval, ABCLEAR3 patients will be inherently included. We are concerned that delays in patients being treated with blarcamesine will impact their care as the data demonstrates that early treatment provides the best benefit and delay causes harm. We implore the CHMP to consider all facets of the trial, its precision medicine approach, time-saved analysis, ADNI comparisons, safety, efficacy, and cost improvements over approved therapies.

We recognize how difficult advances in this field have become, as evidenced by disappointing recent setbacks such as the EVOKE/EVOKE+ trials featuring semaglutide and the phase 2 AUTONOMY trial featuring the anti-tau therapy posdinemab. These data sets are just the most recent unsuccessful attempts to treat AD in a long history of misses in this field. In light of these concerns, we are struck that we have a novel, oral therapeutic with proven positive clinical endpoints at the door of regulators. From all of the evidence, we believe approval of blarcamesine is the best logical and scientific-based step in fighting this horrific disease and seeking benefits for patients and their caregivers.

We appreciate all of your efforts. Thank you for your time and consideration.

Sincerely,

Jesse H. Silveira – Division Manager, Combat Forces Command Intelligence

Directorate, United States Space Force; Author, Spirit of the Coast Analytics, USA

James E. Boyer – Doctor of Medicine (M.D.), USA

Signatories:

Stephen MacFarlane, M.D., Head of Clinical Services for Dementia Support

Australia & Associate Professor, The Dementia Centre, HammondCare; Principal

Investigator, Anavex Alzheimer’s Trial, AUS

John Alexander, Concerned Family Member, DNK

Alan Aliskovitz, Investor, Stakeholder, USA

Kevin Ameling, Retired, Former Caregiver, USA

Matias Vidal Andersen, Financial Controller, Stakeholder, DNK

Mie Andersen, Senior Shipping Coordinator, Concerned Family Member, DNK

Elmer Asuncion, Retiree, Caregiver, USA

Joshua Austin, Director, Philanthropy & Partnerships, Inst. For Advancements in Mental Health, Caregiver, CAN

Jason Barrett, Senior Practice Manager, Jefferson Health System, Caregiver, USA

Bill Bato, Commissioning Engineer, Stakeholder, USA

Tyler Beck, Finance, Stakeholder, USA

Jasmin Benias, Director of Finance - CPA, Caregiver, CAN

Spero Benias, Motorcycle Technician, Caregiver, CAN

Martijn Berger, Director, Caregiver, NLD

Eric Berkowitz, Project Manager, Stakeholder, USA

Daniel Bilich, Retired/Educator, Stakeholder, USA

Thomas Billiouw, Air Traffic Controller, Stakeholder, BEL

Tom Bishop, Editor, BI Research, Stakeholder, USA

Richard Bobertz, Retired, Stakeholder, USA

Arjo Bol, Retired/Civil Servant, Caregiver, NLD

Mark Bradley, Appliance Store Owner, Former Caregiver, USA

Jeff Brenner, Retired/Sales & Marketing Leader, Stakeholder, USA

Pierre Briand, Business Consultant, Former Caregiver, CHE

Kenneth Bright, Retired, Caregiver, USA

Adam Brogley, Industrial Athletic Trainer, Caregiver, USA

Sabine Brändle, Administrative Employee, Concerned Family Member, DEU

Robert Buck, Finance Manager, Caregiver, USA

Rich Buono, Retired, Caregiver, USA

Kevin Buono, Sales Manager, Mapei Corp., Stakeholder, USA

Dennis Busch, Retired Accountant, Stakeholder, USA

Doug Campbell, Retired, Caregiver, USA

Tom Carey, Retired/College Instructor, Concerned Family Member, USA

Chad Carlton, Finance & Insurance Manager, Caregiver, USA

Richard Chappell, Retired, Stakeholder, USA

David Chellel, County Mortgage Owner, Concerned Family Member, USA

Joseph A. Clark, Retired, Former Caregiver, USA

Luanne Coffee, Elementary School Principal, Caregiver, USA

Martin Coker, M.D., Retired/Physician, Physician, USA

John Cole, Retired/Computer Engineer, Stakeholder, USA

Mary Conlisk, Retired, Stakeholder, USA

John Conlisk, Retired, Stakeholder, USA

Ruth I. Connor, PhD., Associate Professor of Microbiology & Immunology, Stakeholder, USA

Michael Corrie, Exercise Physiologist, Healthcare Rehab, USA

John Cosson, Retired/U.S. Navy Investigator, Stakeholder, USA

Michael Cox, Accounting Manager, Caregiver, USA

Ronald Cross, Retired, Stakeholder, USA

Anthony Crothers, Retired/IT Manager, Stakeholder, USA

John Cunningham, Retired, Former Caregiver, USA

Kevin Cutts, Stakeholder, USA

Kim Daly, Designer, Stakeholder, USA

John Dauphinais, Graphic Designer, Caregiver, USA

Joseph S. Davidson, Attorney at Law, Stakeholder, USA

Jason Davis, Restaurant Owner, Stakeholder, USA

William Day, Retired, Caregiver, USA

JW Demyan, Manager, Caregiver, USA

Michael DiGiovanni, Stakeholder, USA

Sandra Dodd, Retired/Senior Software Engineer, Stakeholder, USA

Martha Donegan, M.D., Retired, Physician, USA

Mark Dougherty, Infectious Disease Physician, Physician, USA

David Dougherty, M.D., Physician, Physician, USA

Brian Duling, Gainey Business Bank Board of Directors, Stakeholder, USA

Michael Dunphy, RPh, MS., Retired/Hospital Director, VA Committee, Pharmacist, USA

Harold Engstrom, President of Innovative Process Solutions, Former Caregiver, USA

Mathew Erickson, Healthcare Worker, Stakeholder, USA

David Faust, Retired/Frito Lay, Stakeholder, USA

David Field, General Manager, Former Caregiver, USA

Vernon Field, CEO, Stakeholder, USA

Robert Fitzgerald, Business Owner, Caregiver, USA

Kris Fitzpatrick, BHMC, Medical Social Worker, Stakeholder & Care Coordinator, USA

Cheryl Flores, Janitorial Business Owner, Caregiver, USA

Melvin Flores, Oxygen Technician, Caregiver, USA

Tilly Florquin, Retired/Special Needs Educator, Patient, BEL

Dorin Frei, Patient, USA

Fran Gaddini, Former & Current Caregiver, USA

Dominic Gaidano, Contractor, Stakeholder, USA

Vinod Gandikota, Software Service Provider, Stakeholder, USA

Kerry Gardner, Maintenance Worker, Stakeholder, USA

Kevin Giglio, Cabinet Maker, Stakeholder, USA

W. Greg Giles, Sr. Operations Manager, Siemens Healthineers, Stakeholder, USA

Eileen Gilhooly, Marketing, Medtronic, Caregiver, USA

George Giordano, Chase Employee, Stakeholder, USA

John Goller, Retired/Steel Mill Management, Former Caregiver, USA

Bart Goossens, EMEA Customer Care Manager, Stakeholder, BEL

Michael Gordon, Software Engineer, Stakeholder, USA

Keegan Goss, Construction Project Manager, Stakeholder, USA

Andreas Grauengaard, Business Owner, Stakeholder, DNK

Jeffrey Gribbon, Director of Aviation, Chief Pilot, Stakeholder, USA

Michael Hahn, Retired/Squash Professional, Patient, USA

Colin Halliwell, Software Consultant, Banking, Caregiver, GBR

Yki Haukkaniemi, Dentist, Caregiver, FIN

Brian Hazen, Retired, Caregiver, USA

Curt Hendrix, Research Chemist, Stakeholder, USA

Jared Hess, Owner, H&W Industries LLC, Stakeholder, USA

Hanne Heymans, Clinical Neuropsychologist, Physician, BEL

Henri Heymans, Retired/Primary School Teacher, Patient, BEL

Hubert Heymans, Retired/Museum Director, Stakeholder, BEL

Dr. Kerensa Hill, Psychologist, Stakeholder, USA

James Hill, Retired, Stakeholder, USA

Jack Hill, Retired, Stakeholder, USA

Colleen Hodges, Retired, Caregiver, USA

Kristen Hogan, Educator, Stakeholder, USA

Tom Hollatz, Business Owner, Stakeholder, USA

Larry Holman, Retired, Patient, USA

Grayson W. Hooper (Dr.), Neuroradiologist, Physician, USA

Gary Horsley, Retired/Project Manager, Stakeholder, USA

Kurt Huckaby, Cattle Rancher, Former Caregiver, USA

Bo Jensen, Manager, L'Oreal, Stakeholder, FRA

Rasmus Jensen, Financial Controller, Stakeholder, DNK

Jeff Jones, Retired, Caregiver, USA

Peter Jorgensen, Retired, Caregiver, USA

Rock Jung, Attorney, Caregiver, USA

Oliver Mads Jørgensen, UPS Warehouse Worker, Caregiver, DNK

Jan Jørgensen, Owner, Car Shop, Patient, DNK

Daniel Kazado, Strategic Advisor, Concerned Family Member, FRA

Tom Kennedy, Clinical Psychologist, Former Caregiver, USA

Aejaz Khan, IT Manager, Caregiver, CAN

Scott Kienast, OHST, ASP, EMT-P, Safety & Health Director, Patient Advocate & Caregiver, USA

Mark Kilduff, Accountant & Hotel Owner, Stakeholder, USA

Seung Kim, Senior Engineer & G/S Research Manager, CA Department of Transportation, Stakeholder, USA

Gary King, Retired/Regional Manager ATT, Caregiver, USA

Mike Kinlaw, Business Owner, Caregiver, USA

Michael Kjaersgaard, Design Lead, Stakeholder, DNK

Lasse Due Kjeldgaard, Energy Engineer, Caregiver, DNK

Peter Lund Kjeldsen, Revenue Manager, Stakeholder, DNK

Uwe Klotz, President, Stakeholder, DEU

Mark Knaub, Clinical Pharmacist, Caregiver, USA

Jeff Kociak, CPA Firm Partner, Stakeholder, USA

Erik Kooijman, Supply Chain Specialist, Stakeholder, NLD

Peter Staberg Krambeck, COO, Povl Klitgaard & Co. Nordic, Stakeholder, DNK

Isaac Krasnjansky, Stakeholder, USA

Morten Kristensen, Teacher, Stakeholder, DNK

Jim Kubik, Retired, Caregiver, USA

Kendall Kubik, Retired/Physical Therapist, Caregiver & Healthcare Worker, USA

Jeff Kwok, Physician, Physician & Caregiver, USA

Peter Kyhn, Business Owner, Stakeholder, DNK

Jim Kyle, Retired, Stakeholder, USA

Craig Lacy, Retired, Caregiver, USA

John Lambert, Retired/Microsoft, Patient, USA

Stephen Lane, Retired, Caregiver, USA

Kyle Lantz, Aerospace Project Manager, Caregiver, USA

Edwin Larrivee, Retired, Stakeholder, USA

Marc LeDuc, Physician Assistant, Provider, USA

Jeanne J. LeVasseur, PhD, RN., Professor & Registered Nurse, Caregiver, USA

Dietmar Leitner, Self-employed, Stakeholder, AUT

Dr. Larry Lewis, Veterinarian, Stakeholder, USA

Jill Lewis, Medical Technician, Concerned Family Member, USA

Nate Lincoln, Senior Business Intelligence Developer, Crown Equipment Corp., Stakeholder, USA

Andy Lisk, Global Head of Customer Service, StockX, Stakeholder, USA

Barry Lloyd, Retired/Engineer, Stakeholder, USA

Gerard F. Logan, Small Business Health Insurance Specialist, Concerned Family Member, USA

Todd Luttenegger, Consultant, Concerned Family Member, USA

Thomas Lynch, Project Manager, Caregiver, USA

Mads Lynge, Structural Engineer, Stakeholder, DNK

Christian Madsen, IT Business, Stakeholder, DNK

Anastasia Maher, MBA., Sr. Software Engineer & Business Analyst, Stakeholder, USA

Frank P. Manger Jr., Retired/DMA Project Director, National Geospatial-Intelligence Agency, Former Caregiver, USA

Seyed A. Marefat, Longshoreman, Caregiver, CAN

Grant Markhart, Co-founder, Former Caregiver, USA

Samuel Marrella Jr., Wealth Manager, Stakeholder, USA

Samuel Marrella Sr., Wealth Manager, Caregiver, USA

Sue Massaad, Principal, Caregiver, CAN

Scott Mathews, Retired, Patient, USA

Kimberly J. Matson, Realtor, Caregiver, USA

Kevin McCabe, Scientist, Stakeholder, USA

Stephen McClain, Retired, Caregiver, USA

John McKee, Retired, Stakeholder, USA

Brad McLellan, Chief Operating Officer, R.G. McGroup Ltd., Caregiver, CAN

David B. Meltzer, Financial Services, Avalon Leasing Inc. President, Stakeholder, USA

Dan Mikels, Retired, Caregiver, USA

John Miksa, Retired/CEO, Stakeholder, USA

Jason Millhouse, MA., Professional Educator & Curriculum Consultant, Caregiver, USA

Peter Moeller-Hansen, IT Advisor, Stakeholder, DNK

Timon Molenaar, Driver, Stakeholder, NLD

Andrew Monahan, Associate Director Operational Excellence, Patient Advocate, USA

Robert Morris, Attorney, Caregiver, USA

Darryl Mulder, Retired, Stakeholder, USA

Wendy Mulder, Retired, Stakeholder, USA

Glenn Murray, Audit Director, Caregiver, USA

Rudy Myers, Construction PM, Stakeholder, USA

Ingo S. Nagler, CEO, Bluejene GmbH, Stakeholder, AUT

Paula Nelson, Retired/Jewelry Wholesaler, Stakeholder, USA

Morten Nielsen, Corporal, Stakeholder, DNK

Stephen Nighswander, Retired, Former Caregiver, USA

Stu Nitekman, Musician, Caregiver, USA

James Nolte, Marketing, Caregiver, USA

Lau Nyholm, Purchase Manager, Stakeholder, DNK

Harry Oberai, Retired, Caregiver, USA

Søren Olsen, CFO, Caregiver, DNK

Alex Olsen, Stakeholder, DNK

Javier Ortiz, PharmD, MBA, RPh, CPh, Clinical Pharmacist, Pharmacist & Caregiver, USA

James Orzechowski, Delta Air Lines Operations, Stakeholder, USA

Frank Palazzolo, Retired/Henry Ford Health System, Caregiver, USA

Tobias Pander, CSO, Macure Pharma, Pharma Exec, DNK

Chris Pappas, Self-employed, Stakeholder, USA

Lance Paul, Retired/Marketing, Caregiver, CAN

Randall Payne, Senior System Engineer, Stakeholder, USA

Alexander Pechey, Civil Servant, Stakeholder, GBR

Michael Howald Pedersen, Process Engineer, Novonesis, Caregiver, DNK

Carl-Peter Pedersen, Retired, Stakeholder, DNK

Anthony Percha, Consulting Engineer, Stakeholder, USA

Clay Pereson, Retired, Caregiver, USA

Anders Højer Petersen, Self-employed, Caregiver, DNK

Andrew La Pietra, Medical Device Engineer, Stakeholder, USA

James Pooley, Retired, Caretaker, USA

David Priddy, PhD, Rehabilitation Psychologist, Clinical Psychologist, USA

Jim Rabe, Retired/Uber Driver, Concerned Family Member, USA

Mark Renard, Owner & CEO, MAR Financial, Stakeholder, USA

Jake Repovsch, Flight Attendant, Stakeholder, USA

Luis E. Reyes, PA, Physician Assistant, Physician, USA

Michael Rice, President, Bolder Brands, Stakeholder, USA

David Richmond, Mechanical Engineer & Patent Holder, Caregiver, USA

Richard Rieger, Stakeholder, USA

Mark Riley, Retired, Stakeholder & Friend of Patient, USA

Tyler Roebuck, Real Estate Developer, Stakeholder, USA

Robert Rogozin, Director of Channel Sales East, Stakeholder, USA

Jon Rokeh, President, Rokeh Consulting, Stakeholder, USA

Jason Romer, Business Owner, Caregiver, USA

Mike Ross, Military Officer, Stakeholder, USA

Nelson Rueda, Computer Engineer & Entrepreneur, Stakeholder, USA

John Runland, General Contractor, Stakeholder, USA

Kevin Ryder, PhD, Contractor, Medical Communications, Former Caregiver, USA

Julee Ryu, Retired/R.N., Former Caregiver, USA

Sehee Ryu, Designer, Stakeholder, USA

Tom Samuelson, Retired, Caregiver, USA

Richard J. Sasges, Aircraft Engineer, Caregiver, USA

Stelene Sattler, Medical Device Regulatory Consultant, Stakeholder, USA

Dominick Savaiano, Healthcare Attorney, Caregiver, USA

Bradley Scatterday, USPS Supervisor, Stakeholder, USA

Tim Schneider, Retired, Caregiver, USA

Jennifer Schneiderman, Cardiologist, Physician, USA

Gary Schneiderman, Retired, Stakeholder, USA

Beth Schneiderman, Retired, Stakeholder, USA

Robert Schoeber, Retired, Caregiver, USA

Ralf Schroeder (Dr.), Government Official (rtd), Stakeholder, DEU

Jami Schweers, Stay-at-home Mom, Stakeholder, USA

Robert Seip, Retired/Engineer, Stakeholder, USA

Ron Seliga, Retired, Caregiver, USA

Alexander Shadid M.D., Physician, Physician, USA

Brain Shuman, Periodontist, Surgeon, USA

Prince Sidhu, Physician, Physician, USA

Earl Siegel, PharmD, Professor Emeritus University of Cincinnati, Director Emeritus Drug & Poison Info. Center, Professor & Stakeholder, USA

Hannah Silveira, Retired, Stakeholder, USA

Don Simmons, Real Estate Brokerage & Development, Former Caregiver, USA

Mark Singleton, Security Manager, Stakeholder, IRL

Josef Sladkovsky, Customs Officer, Stakeholder, CZE

Ed Snodgrass, PE., Civil Engineer / Owner of Engineering Firm, Stakeholder, USA

Nicholas Sotis, Caregiver, USA

Edward Spelde, CPA/CVA., President-SB Associates PC CPA's, Stakeholder, USA

Jacob Spilberg, Wix Website Designer, Stakeholder, USA

Tim Sprenger, Retired/Stockbroker, Stakeholder, USA

Harry Strang, PhD., Retired/Senior VP Research & Development, Bayer Corp Science, Former Caregiver, USA

Pete Stresser, President, Laser Pharmaceuticals, Pharma Exec, USA

Jasbir Sunner, Senior Healthcare Executive, Stakeholder, CAN

Irwin Tang, Licensed Professional Counselor, Caregiver, USA

Michael Tavares, Healthcare Communications Creative Director, Stakeholder, USA

Gilbert Taylor, Marine Engineer, Edison Chouest Offshore, Caregiver, USA

Dave Tentis, PGA Golf Professional, Caregiver, USA

Grethe Thomassen, Silkeborg, Stakeholder, DNK

Anne-Sofie Thomassen, Attorney at Law, Stakeholder, DNK

Ted Thornton, Retired/Financial Executive, Stakeholder, CAN

CD Tvetenstrand, M.D., Surgeon, Caregiver, USA

Kenneth Vermillion, Automotive Technician, Stakeholder, USA

Philippe Verschueren, ExxonMobil - Mobil Brand Manager, Stakeholder, BEL

Judith Volders, Retired/Speech Pathologist, Stakeholder & Therapist, BEL

Greg Wagner, Process Manager, Stakeholder, USA

Donald E. Waldecker, Retired/IBM Engineering Manager, Caregiver, USA

Doug Waroinski, Retired/Hospitality Executive, Stakeholder, USA

Edgar Watson, Retired, Stakeholder, USA

Debbie Weaver, MBA., Retired, Stakeholder, USA

Theodore J. Weber, PsyD., Clinical Psychologist, USA

Eric Weinstein, Podiatrist, Caregiver, USA

Chris Welch, Automotive Technician, Stakeholder, USA

Leland Wilder, Stakeholder, USA

James Willson, Herpetologist, Concerned Family Member, USA

David Wilson, Field Engineer, Caregiver, USA

Bob Wilson, Retired/CPA, Stakeholder, USA

John Witshork, Retired, Stakeholder, USA

Steve Woelfel, Retired/Operations Manager, Caregiver, USA

David Young, Retired/Chief Tech Officer, Caregiver, USA

Disclosures: While the authors are shareholders in Anavex, they have no other financial relationship with the company. There is no collaboration, direction, or involvement in any way between Anavex and this letter. We speak for ourselves and not for the company. Furthermore, Jesse Silveira is an employee of the United States Space Force under the United States Government (USG), his views are not a reflection of his employers or the USG.