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Many thanks W, learning as much as possible over past couple days. The results reported in the P/R were obviously impressive, I’m in.
Gernee, what’s up, good to see you’re here as well, I’m new into ipix as of yesterday around 20 cents; here’s to continued success for our 2 common holdings.
This one was a flyer for me.
Yes good point Xena, and the immunology reference in the new job posting could also relate to Multiple Sclerosis as posted by Jimmy Mcswag.
We did just receive a patent issuance in January for this MS indication, as well as an important preclinical publication in February from leading MS researcher, Dr Lisak at WSU, with positive and promising preclinical MS validation for our 2-73 compound.
***SPECULATION ALERT***
Perhaps an MS trial is in the cards.
https://multiplesclerosisnewstoday.com/news-posts/2020/02/24/anavex-life-sciences-announces-publication-of-foundational-data-for-anavex2-73-blarcamesine-in-multiple-sclerosis-ms
And
https://www.anavex.com/anavex-life-sciences-issued-new-u-s-patent-for-anavex2-73-treatment-of-neurodevelopmental-disorders-including-rett-syndrome-and-multiple-sclerosis/
https://www.tga.gov.au/publication/pharmacovigilance-responsibilities-medicine-sponsors
Interesting. Thanks for the heads up DFRAI. So in Australia this pharmacovigilance reporting is for medicines available for purchase, withdrawn, or supplied in a company-sponsored post-registration study (post approval).
From TGA’s 2018 guidance link:
“ You MUST meet your pharmacovigilance reporting responsibilities for all the medicines you have registered or listed on the Australian Register of Therapeutic Goods (ARTG). This is regardless of their Australian marketing status - that is, whether they are currently available for purchase, withdrawn from sale or otherwise supplied e.g. in a company-sponsored post-registration study.
Unapproved medicines used in Clinical trials or supplied under the Special Access Scheme (SAS) or Authorised Prescriber are subject to separate reporting requirements and are not covered by these guidelines.
You, as a sponsor of medicines approved for supply in Australia, are legally responsible for meeting pharmacovigilance reporting requirements for your medicine. You MUST:
let us know who your Australian pharmacovigilance contact person is
submit any serious adverse reaction reportsto us
notify us of any significant safety issues you identify
keep records pertaining to the reporting requirements and safety for your medicine (under Subsection 28(5)(ca) of the Therapeutic Goods Act 1989 (the Act))
answer any request from us for additional information fully and within the specified timeframe (under Subsection 31(1) of the Act).”
“Strong experience in the conduct and management of clinical trials, especially phase II and phase III oncology or Immunology clinical trials”
Falconer it could also be an Anavex 3-71 trial for diabetes, which i believe is considered an immunological disease?
https://iibr.gov.il/Research_Development/PatentsAndApplications/Pages/AF710B.aspx
“A. Fisher, N. Bar-Ner, Victoria Nahum Bicyclic heterocyclic spiro compounds, US 8,673,931 B2 Mar. 18, 2014.The composition and method Patent covers AF710B for treating Alzheimer’s disease, type 2 diabetes and insulin resistance. The Patent has a term that expires no earlier than April 29, 2030.“
Very interesting, nice catch falconer, oncology and immunology could possibly imply an Anavex 1037 trial for pancreatic or prostate cancer.
New job posting tonight.
Sr.Manager/A.Director, Pharmacovigilance 5yrs+ Req
Anavex Life Sciences
New York, NY 10036
https://www.indeed.com/m/viewjob?jk=37085c048c7e0c83&from=serp&prevUrl=https%3A%2F%2Fwww.indeed.com%2Fm%2Fjobs%3FsameL%3D1%26q%3Danavex%26l%3D%26from%3DsearchOnSerp
Sr.Manager/A.Director, Pharmacovigilance 5yrs+ Req
Anavex Life Sciences
New York, NY 10036
Job details
Job Type
Full-time
Benefits
Pulled from the full job description
Competitive salary and yearly target bonusStock options (LTI and STI)Medical, dental, vision, life and disability insuranceEmployer-matched 401(k) plan
The Company:
Anavex Life Sciences Corp.
Health insurance
Dental insurance
Vision insurance
Retirement plan
Paid time off
Schedule:
Qualifications
Experience:
Biotechnology or Pharma, 5 years (Required)
Pharmacovigiance, 5 years (Required)
Education:
Bachelor's (Required)
Full Job Description
Job Title – Sr.Manager/A.Director, Pharmacovigilance
Young NASDAQ-listed biotech company in CNS based in NYC is looking to recruit a Pharmacovigilance Manager who will infuse the Clinical Team with their talent, energy, tactical and leadership skills. This is an exceptional opportunity to join a small company culture driven by innovation, problem-solving and fast growth vision.
Responsibilities include, but not limited to:
The Pharmacovigilance Manager is responsible for Drug Safety activities for assigned projects in clinical trials. This includes meeting internal and external sponsor requirements according to time, quality, scope, and budget parameters. The Pharmacovigilance Manager is the primary point of contact for Drug Safety on a project, for internal project team members, sponsors, investigators, and vendors. This role encompasses the coordination of a variety of Drug Safety activities such as the collection, detection, assessment, monitoring, and prevention of adverse events and effects with pharmaceutical products. The role requires a careful and precision-based mindset that looks ahead to predict and prevent safety problems before they occur in clinical trials and other pharmaceutical related projects.
The Primary Responsibilities of this position are:
Act as the both the Local Pharmacovigilance manager and key contact point for regulatory authorities on PV related issues
Build GPV leadership to set up and maintain an efficient PV system in compliance with national regulations
Track and report to the Regional Head any regulatory authorities or business changes impacting pharmacovigilance and support the development and implementation of procedures as a result of the changes
Serve as a key liaison between the Global Clinical Team, Global Pharmacovigilance, and third-party vendors for the management of adverse event reports from company sponsored clinical studies.
Lead safety operations activities related to clinical trials, and closely interact with Research & Development stakeholders to ensure an appropriate safety monitoring of clinical trials subjects
Work in collaboration Global Clinical Operations to maintain the pharmacovigilance section of the Trial Master File/Sponsor Oversight Files to ensure sections related to clinical safety are accurate and up to date.
Contribute to the authoring and review of important study documents such as Informed Consent Forms, Clinical Study Protocols, Investigators Brochures, Safety Management Plans, and Clinical Study Reports.
Represent pharmacovigilance at a variety of business meetings, including project team meeting, vendor evaluation meetings, vendor oversight meetings, and other ad hoc meetings as assigned. Support audit/regulatory inspections and work closely with GPV leadership in the implementation and management of CAPAs following the audits/inspections
Ensure direct reports training records are up to date, including SOPs and yearly Pharmacovigilance refresher training.
Responsible for receipt, timely forwarding, collection, and follow-up of individual case safety reports (ICSRs) as well as monthly reconciliation activities including maintenance of local site file/trackers when required.
Participate and support activities related to company sponsored clinical trials by attending regular scheduled clinical team meetings, act as a back-up for the Regional Head of Americas in his absence to provide required pharmacovigilance contributions such the drafting of Safety Management Plan (SMP), and the review of protocols, investigator brochures (IBs), inform consent forms (ICF), and other clinical documents as required.
Lead Global Pharmacovigilance and work with Global Clinical Operations, Regulatory Affairs, and Clinical Research Organization to ensure a timely submission of pharmacovigilance reports (SUSARs, DSURs, REMS, and other safety communications, etc.) to regulatory authorities and IRBs/ECs
Provide the needed support in the scheduling compilation and timely submissions of Periodic Adverse Drug Experience Reports (PADERS) and other aggregate safety reports to the FDA.
Forward all requests for safety information from the FDA and any other authorities in the region to Global PV and participate in the response strategy when required.
Have oversight of other programs like non-interventional studies, safety studies and local registries and websites.
Provide relevant information as needed for the compilation of the Pharmacovigilance Master File (PSMF),
Support the development and maintenance of Safety Data Exchange Agreements
Represent the US site in discussion of safety operation issues at global functional team meetings
Help in generating and tracking KPIs in monitoring site/regional compliance.
Ensure appropriate filing and archiving of Pharmacovigilance related documents is performed
Provide input into study related documents as required
Requirements
Registered Nurse (BSN, MSN), Pharmacists (RPh or PharmD), or Medical Doctor (MD, DO)
5 to 10 years’ related experience in a biotechnology or pharmaceutical company or CRO environment.
5 to 8 years’ experience in Pharmacovigilance and quality assurance - tactical, operational and strategic capacities is preferred
Strong experience in the conduct and management of clinical trials, especially phase II and phase III oncology or Immunology clinical trials
Personnel management and supervisory experience is required
Excellent verbal and written communication skills, proof reading and organization skills
Comprehensive and working knowledge of Microsoft Outlook, Microsoft WORD, Excel and PowerPoint. Electronic document management experience a plus
Ability to handle sensitive material in a confidential manner
Strong attention to detail and follow-up skills
Maintain a high level of diplomacy, discretion, maturity and sound judgement
Must be flexible and willing to take on significant administrative responsibilities
Must take initiative and have ability to work independently and as a team member, offering assistance wherever needed
Must be able to create contingency plans to deal with possible challenges and roadblocks
Location: New York, NY
Job Type: Full-time
What we offer:
Competitive salary and yearly target bonus
Stock options (LTI and STI)
Medical, dental, vision, life and disability insurance
Employer-matched 401(k) plan
The Company:
Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental diseases including Alzheimer’s disease, other central nervous system (CNS) diseases, pain and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73, recently completed a successful Phase 2a clinical trial for Alzheimer’s disease. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer’s disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson’s Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson’s disease. ANAVEX®3-71, which targets sigma-1 and M1 muscarinic receptors, is a promising preclinical drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer’s disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on neuroinflammation and mitochondrial dysfunction. Further information is available at www.anavex.com. You can also connect with the company on Twitter,Facebook and LinkedIn.
Job Type: Full-time
Experience:
Biotechnology or Pharma: 5 years (Required)
Pharmacovigiance: 5 years (Required)
Education:
Bachelor's (Required)
Additional Compensation:
Bonuses
Other forms
Work Location:
One location
Benefits:
Health insurance
Dental insurance
Vision insurance
Retirement plan
Paid time off
Schedule:
Monday to Friday
- Just postedreport job
If you require alternative methods of application or screening, you must approach the employer directly to request this as Indeed is not responsible for the employer's application process.
You can freely decide for yourself as to whether Anavex could currently apply for AU provisional approval.
I’m sorry to see that you feel somehow offended by the speculation.
“The provisional approval pathway, in contrast to the priority review pathway,enables a time-limited registration of a promising drug, based on preliminary (usually phase II) clinical data.3 If approved, the drug will be available for two years and the drug’s sponsor can apply for extensions up to a total of six years. Typically, the final stages of clinical trials (phase III) that address the safety, quality and efficacy of a medicine can take several years.”
It does not say pivotal, rather “preliminary (usually phase II)”.
Personally I believe we have phase II results that the TGA could potentially review.
I’m personally choosing to be optimistic; based on the plain language quoted directly from the TGA.
Do we have phase II data available?
Is it promising?
https://www.tga.gov.au/provisional-approval-pathway-prescription-medicines
I guess we all have to decide whether to place value on enigmatic and consistently-negative OPINIONS, or on the actual positive reports coming from many Anavex press releases and accelerated pathway decisions from regulators and positive reports directly from our own AD trial PI (who’s been involved with our Australian patients for 5 years as well as our Rett Syndrome PI) & from worldwide scientific experts for numerous CNS disease indications as it pertains to Anavex’s compounds and MOA.
My original comment stands.
Yes indeed and I recall your pointing out the Biogen MS failed ph2 trial back in 2017; and as you said back then and today, it’s difficult to overstate the import of this indication to that company in particular.
Have a good weekend T38
https://multiplesclerosisnewstoday.com/2017/05/02/ms-remyelination-therapy-opicinumab-fails-phase2-trial-biogen-wont-give-up/
Agreed
Good question not that I’m aware of
Marries up nicely with the recently announced Anavex 2-73 (blarcamesine) Multiple Sclerosis patent in January 2020 as well, great news TTTAV66.
Will there come a day when the National MS Society will step forward and help fund and progress the blarcamesine research and trial to benefit MS patients?
Dr Lisak is one of the world’s leading MS researchers and he has now presented and published numerous times over 3-4 years about the very promising and positive preclinical benefits of our compound.
I don’t know about the quarterly call, but what I do know is that if we receive an approval for just one indication, then physicians and patients will be writing and filling off-label prescriptions for blarcamesine around the world for dementia-related diseases in short order.
Especially if they are made aware of the below and if their physicians also compare the safety profiles of blarcamesine and current SOC drugs or aducanumab.
“Change in MMSE score from baseline at week 104 of matched cohorts was assessed. It showed that ANAVEX®2-73 (blarcamesine) high dose cohort had a significantly lower MMSE decline (-1.1) compared to the ADNI control cohort (-4.4) at week 104 (p < 0.01).”
So, regulators in the US have already granted 2-73 (blarcamesine) ODD Designation and Rare Pediatric Disease Designation and now this week, Fast Track Designation, for Rett Syndrome disorder.
That’s no guarantee of success, but someone appears to like what they see.
And it’s not just our CMO and RS trial PI Dr Walter Kaufmann. The same gentleman who literally wrote the book on Rett Syndrome current diagnostic guidelines and the first clinical textbook on the disorder during the course of his distinguished career.
https://www.anavex.com/anavex-life-sciences-announces-the-appointment-of-walter-e-kaufmann-md-as-chief-medical-officer/
Thanks mmd and realistically speaking, once 2-73 (blarcamesine) is approved for one indication (hopefully in 2020 following Rett Syndrome or Parkinson's Disease Dementia readouts in May or June), isn’t it highly likely that other Alzheimer’s/dementia sufferers will be QUICKLY seeking off-label prescriptions for blarcamesine from their neurologists globally?
With the backdrop of the below very favorable CTAD Alzheimer’s ph2a 104 week Alzheimer’s data for 2-73 AND the below comparison of possible side effects, and if neurologists follow the ethical standards of the Hippocratic Oath, which compound should they decide to prescribe to these AD and dementia patients?
It’s not that complicated is it?
And if/when this type of large scale global push for off-label use occurs, is it rational to assume that we could see governments allow for early AD trial readouts or provisional approvals for 2-73?
These govt leaders and regulators already understand that patients want and deserve better than current SOC meds.
Might it also be understandable when sufferers of this serious and crippling disease seek (off-label) an fda-approved medication with a much more favorable safety profile AND which has purportedly been shown to halt or potentially reverse the disease course at therapeutic dosage levels?
When you combine the powerful survival instinct of the patient with the physician’s obligation to treat the sick to the best of one's ability, it allows for some logical & common sense inferences.
“Change in MMSE score from baseline at week 104 of matched cohorts was assessed. It showed that ANAVEX®2-73 (blarcamesine) high dose cohort had a significantly lower MMSE decline (-1.1) compared to the ADNI control cohort (-4.4) at week 104 (p < 0.01).”
“Why might an approved drug be used for an unapproved use?
From the FDA perspective, once the FDA approves a drug, healthcare providers generally may prescribe the drug for an unapproved use when they judge that it is medically appropriate for their patient.
You may be asking yourself why your healthcare provider would want to prescribe a drug to treat a disease or medical condition that the drug is not approved for. One reason is that there might not be an approved drug to treat your disease or medical condition. Another is that you may have tried all approved treatments without seeing any benefits. In situations like these, you and your healthcare provider may talk about using an approved drug for an unapproved use to treat your disease or medical condition.“
https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label
Comparison of Potential Side Effects:
ANAVEX 2-73 (Blarcamesine)
“Tolerability: Maximum tolerated dose (MTD) of ANAVEX 2-73 was defined as 55mg. Observed adverse events at doses above the MTD included dizziness and headache, which were moderate in severity and reversible. These side effects are often seen with drugs that target CNS conditions, including Alzheimer's disease.”
ARICEPT (Donepezil) current SOC
More common side effects:
The more common side effects that can occur with donepezil include:
nausea
diarrhea
not sleeping well
vomiting
muscle cramps
tiredness
not wanting to eat or having a poor appetite
bruising
weight loss
Serious side effects:
Slow heart rate and fainting
Stomach ulcers and bleeding, symptoms can include:
heartburn
stomach pain that won’t go away
nausea or vomiting
blood in your vomit, or dark-colored vomit that looks like coffee grounds
bowel movements that look like black tar
Worsening of lung problems in people with asthma or other lung diseases
Seizures
Trouble urinating
ADUCANUMAB
Side effects included headache, diarrhea, and dizziness. They were mild or moderate, some possibly related to the study drug but not to the dose.
“ the higher the dose of aducanumab in the trial, the more signs of brain swelling and hemorrhaging—which show up as ARIA-E, or amyloid-related imaging abnormalities-edema.
That Phase I trial started with 165 participants, 32 of which received the higher dose. Of those, 15 developed ARIA-E, and 10 patients dropped out of the study because of adverse events, a troubling sign.”
He references the Phase III trial directly for Rosie, and that Sandra is her fellow trial participant.
“Principal investigator Professor Stephen Macfarlane, head of HammondCare clinical services, said that before coming on the Phase III trial of the drug, Craven had stopping engaging in activities she previously enjoyed.
“Rosie had enjoyed watching movies and reading but as Alzheimer’s advanced she gave up reading and found it hard to engage with movies, often falling asleep,” Macfarlane said. “Now after being on the trial, Rosie is reading again and loves watching movies and discussing them afterwards.”
The trial also helped Craven more confidently take walks, use her phone and write greetings on cards.
Fellow trial participant Sandra Rozanic also reported finding it easier to engage in hobbies. “I’m feeling a lot better, God yes,” said Sandra.”
Straight from horses’ mouths in Australia. Published today, nice work tttav66. Grateful for your contributions.
And these ladies are from the blinded controlled phase 3 (48 week) trial, and must be on the open label extension now.
“I’m back to who I am.”
Craven has said she’s “back to her happy, easy going self” after joining the trial of Anavex 2-73 in Melbourne.
“Rosie had enjoyed watching movies and reading but as Alzheimer’s advanced she gave up reading and found it hard to engage with movies, often falling asleep,” Macfarlane said. “Now after being on the trial, Rosie is reading again and loves watching movies and discussing them afterwards.”
The trial also helped Craven more confidently take walks, use her phone and write greetings on cards.
Fellow trial participant Sandra Rozanic also reported finding it easier to engage in hobbies. “I’m feeling a lot better, God yes,” said Sandra.
“HammondCare said an earlier Phase II trial saw most participants experience no decline in their cognitive capacity and others improve their mini mental state exam”
https://www.agedcareinsite.com.au/2020/01/hammondcare-alzheimers-drug-trial-shows-promising-results/?fbclid=IwAR22J52hyD7xy81vllZWIcey78pkbXRzbKjk-7rS6WC2IeJi9FolMo70h1s
HammondCare Alzheimer’s drug trial shows promising results
By: Dallas Bastian in News, Top Stories January 30, 2020
Excellent summary Sokol, and if I might tack on another “possible” opportunity for 2020 approval to your list:
AU’s provisional approval guidelines state:
“The provisional approval pathway, in contrast to the priority review pathway,enables a time-limited registration of a promising drug, based on preliminary (usually phase II) clinical data.3 If approved, the drug will be available for two years and the drug’s sponsor can apply for extensions up to a total of six years. Typically, the final stages of clinical trials (phase III) that address the safety, quality and efficacy of a medicine can take several years.”
Doesn’t seem to require the results from
a phase 3 readout, rather “preliminary (usually phase II)”.
We’ve already completed and transitioned from phase II to a phase III in AD in Australia. The pipeline chart on Anavex’s website indicates same.
It would seem that we have phase II results that the TGA could potentially review? Whether it’s the new 2b or the multiple years of available phase 2a extension results, which were analyzed and presented at December CTAD by Ariana’s Dr Mohammad Afshar.
This morning’s news from Australia may add some fuel to the proverbial fire, assuming a safe and seemingly-effective disease modifying treatment is indeed desired by patients and global leaders.
https://www.tga.gov.au/provisional-approval-pathway-prescription-medicines
Tttav66 nice work!!! Thunder from Down Under (right McMag?), thanks for posting. Perhaps Michele Sullivan will report on this as well, or do a follow up interview with Dr M or Prof Macfarlane.
One would think the journalists and researchers and advocacy groups (regulators??) for dementia-related illnesses might view this Australian news and patient/caregiver interviews as highly RELEVANT and IMPORTANT.
Curious also if these are patients in our continuing ph2a, or the new OLE extension after the ph3 48 weeks.
Thank you again tttav66
Agree completely, thank you Nidan for your valuable analysis, as per usual.
Thanks and yes I agree that it would make little to no sense for our PDD participants to be left high and dry for up to a year without access.
Post Trial Access (“PTA”)
Article regarding same for the EMA
[It would appear to me that the international ethical guidelines such as the Declaration of Helsinki and the Council for International Organizations of Medical Sciences (CIOMS) guidelines would provide ample authority for Anavex to continue providing blarcamesine access to the PDD participants immediately after their trial period ended under the Compassionate Use Program or Expanded Access Programme as long as it was disclosed to participants during the informed consent process, irrespective of whether Spain/EMA posted an official OLE start date on their website.]
https://www.somo.nl/wp-content/uploads/2015/02/Post-trial-access-to-treatment.pdf
Excerpts:
“Medicines for the European market are increasingly being tested on clinical trial participants in low- and middle-income countries (LMICs), where most participants are poor and have limited access to health care. Against this backdrop, the entitlement to Post-Trial Access to Treatment (PTA) after the trial has ended becomes increas- ingly important to avoid the exploitation of vulnerable participants. The problem is that patients are being enrolled onto clinical trials in the full knowledge of
the trial sponsors that they will not have access to the continuing treatment they may need once the trial has finished. This practice is unethical.
“Because I will get into this trial, I get better, and
then afterwards I am going to die. You have promised me life and then you take it back; that’s not fair.” HIV/AIDS Clinical Trial Participant, Kenya 2006
The Good Clinical Practice Guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH),1 which have been integrated into European legislation,2 comprehensively describe the responsibilities and expecta tions of those involved in the conduct of clinical trials. However, these guidelines do not describe any responsi bilities for continuing treatment after the trial. Leading international ethical guidelines such as the Declaration of Helsinki and the Council for International Organizations of Medical Sciences (CIOMS) guidelines include the right to PTA, but they use different wording and still raise many questions. This lack of firm guidance is fuelling a heated academic debate about fundamental ethical questions regarding the treatment of patients after clinical trials.
“In advance of a clinical trial, sponsors, researchers
and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial.
This information must also be disclosed to participants during the informed consent process.”
(Article 34, Declaration of Helsinki 2013.”
“ PTA should be ensured for all participants in the trials (Nuffield, CIOMS/WHO), and undoubtedly for those who still need an intervention identified as beneficial (DoH).”
“The principle of nonmalfeasance (do no harm) is undisputed in medicine, and most arguments in favour of PTA refer to it. A drug that has proven to be beneficial to someone cannot be withdrawn. Moreover, when it comes to LMICs, the principles of justice and global ethical standards are evoked and contribute to an increasing consensus on the desirability of PTA.”
“ 2013 Declaration of Helsinki, article 34:12
“In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for posttrial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.”
“ CIOMS/WHO Guidelines, guideline 10:14
“Before undertaking research in a population or community with limited resources, the sponsor and the investigator must make every effort to ensure that: (...) any intervention or product developed, orknowledge generated, will be made reasonably available for the benefit of that population
or community.”
CIOMS/WHO Guidelines, commentary to guideline 10:15 “If an investigational drug has been shown to be beneficial, the sponsor should continue to provide it to the subjects after the conclusion
of the study, and pending its approval by a drug regulatory authority.”
“ Commitments to PTA
There is a definite lack of clear company commitments in reference to the right to PTA. There was one clear statement on Novo Nordisk’s website: “Clinical trial participants should have access to best proven and available treatment after a trial has stopped”.43 Although not comprehensive, PTA is mentioned in various company policy documents.
All nine companies analysed for this research have included the Declaration of Helsinki (DoH) in policy documents on their websites. Either as a reference instrument for human rights (Sanofi44) or as an international ethical guideline
the company “follows” (GSK45) or “adheres to” (Gilead,46 Eli Lilly,47 Novartis48) or “complies with” (AstraZeneca,49 Pfizer50), or operates “in accordance with” (Bayer51),
or “in full conformance” (Roche52). Including the DoH unreservedly can be seen as a commitment by companies to acknowledge the entitlement to PTA.”
“ The preferred routes for PTA
The emerging standard practice for providing an unlicensed investigational drug until marketing approval is:
1 By enrolling the participants into a study extension
(an Open Label Extension Study (OLE) or LongTerm
Extension Study (LTE).
2 Through one of the forms of Early Access Programmes
(EAP), depending on the national regulatory framework in place.
Related to point 2, in the US, the Food and Drug Admini stration (FDA) regulation67 allows access through “Expanded Access Programs”, while EU regulation68 allows such access through Compassionate Use Programmes (CUPs). There
are Cohort CUPs (CUPs made available for groups of patients or hospitals on the basis of requests from physicians or companies69) and Named Patient CUPs (CUPs made available for individual patients on the basis of the physician’s request70).”
“ Characteristics of the most common PTA practices
OLE
Description: An extension of a clinical trial on the basis of a new study protocol in which the participant, healthcare professional and others know the drug and dose being given (not blinded).
Aim: It is conducted to assess the longterm safety and tolerability of an Investigational New Drug but is also used for continued prescribing of unlicensed medicines after a randomised trial to patients with medical need of the investigational medicine.
Compassionate Use Programs (CUP) or Expanded Access Programmes (EAP)
Description: An early access programme is a way of making
a promising medicine available to patients when it has not yet been authorised (licensed) for their condition.71
Aim: To make available unlicensed medicines on the basis of compassion but also used to provide a PTA. Compassionate Use Programmes and Expanded Access Programs can be considered substantially equivalent on the basis of the following characteristics: a) the compassionbased drug provision;
b) the drug is not yet authorised; c) no alternative therapy is available; and d) there is no research objective or study protocol involved.”
“Although considering Open Label Studies as their current standard, GSK seem to be in the process of considering
a transition to a different practice. A spokesman said that,
if an OLE is based only on the ethical need to supply the drug to the trial participants who benefited from the drug, then the drug should be provided with more clinical freedom and without the limitations of clinical trial protocols and
the requirements for clinical data collection. Therefore the company’s standard may shift from an OLE to an Expanded Access Program. GSK has produced a new protocol on
this topic, which is expected to be rolled out soon.75”
There are two charts on this 31 week presentation which appear to illustrate 2-73 alone providing better results at that time frame.
http://anavex.com/wp-content/uploads/2016-07-27_Poster_AVXL_Wednesday_AAIC_July_2016_Final.pdf
Excellent mmd, that Cells publication is a game changer.
Original 9/4/19 Excellence pediatric study p/r didn’t mention that other global sites would be added for this 69 person pediatric Rett study. Appeared to be only Australia, but per today’s RS news article, that has changed.
Would seem odd for the leading RS researcher Dr Kaufmann to name this pediatric Rett Syndrome trial “EXCELLENCE” without significant internal confidence IN MY OPINION.
[Sorry I take it back; that type of opinion and logic could only illustrate naivety on my part. As according to some, common sense has no place here!!]
https://www.anavex.com/anavex-life-sciences-announces-initiation-of-the-excellence-anavex2-73-rs-003-clinical-study-in-pediatric-patients-with-rett-syndrome/
https://rettsyndromenews.com/2020/01/10/anavex-2-73-earns-u-s-patent-for-neurodevelopmental-disorders-including-rett-syndrome/
Nice article today. I didn’t recall that the Excellence study in RS children would have additional global sites outside Australia. Excerpted below:
https://rettsyndromenews.com/2020/01/10/anavex-2-73-earns-u-s-patent-for-neurodevelopmental-disorders-including-rett-syndrome/
”Preliminary results from the first six participants in this trial showed that the therapy was well-tolerated and eased symptoms of Rett syndrome significantly. These benefits were associated with meaningful changes in blood levels of Rett’s biomarkers.
In addition, an international clinical trial called EXCELLENCE — designed to compare the safety and effectiveness of Anavex 2-73 to a placebo in about 69 children and adolescents (ages 5–18) with Rett – also is scheduled to begin early this year.
EXCELLENCE is expected to open in Australia in the coming months, followed by additional sites globally. More information is available here.
The U.S. Food and Drug Administration (FDA) granted orphan drug and rare pediatric disease designations to Anavex 2-73 for treating Rett syndrome.
In Europe, the Committee for Orphan Medicinal Products, an arm of the European Medicines Agency, has recommended orphan drug status from the European Commission.
These designations are intended to accelerate Anavex-2-73’s development and review, by providing regulatory support and financial benefits, and to ensure marketing exclusivity for a period of time upon approval.
Anavex also is exploring the therapy’s potential in Parkinson’sand Alzheimer’s diseases and has received a U.S. patent (No. 10,426,754) covering treatment of Alzheimer’s with Anavex 2-73.
Studies in animal models of other diseases suggest, according to the company, that the experimental therapy also may have neuroprotective, anticonvulsant, anti-amnesic, and anti-depressant effects, supporting its therapeutic potential beyond Rett.“
It’s clear that you have no way of knowing that.
Rett Syndrome Association of Australia - RSAA posted this morning on Facebook:
“Another step closer.......
https://www.anavex.com/anavex-life-sciences-issued-new-u-s-patent-for-anavex2-73-treatment-of-neurodevelopmental-disorders-including-rett-syndrome-and-multiple-sclerosis/?fbclid=IwAR3IJAx2cm4tWMWMGOqvYgFdV1Nc6jzK6KL6-7n_bj7-BzD0PRcZufLK4D0
“
GAB I’ll also say that, upon further review, I wouldn’t be surprised if ALS was someday on our pipeline chart.
It’s not the ph2a data intensive peer reviewed paper, but the authors only mention one company and compound by name in the article, which you and I share a common interest in... And there’s various references to our other recent RS and autophagy publications in describing the novel MOA and different target indications.
I found it an enjoyable read.
Can you access this new paper steadyt? New peer reviewed pub, released today, many references to 2-73.
Published January 6, 2020
The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy
https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(19)30224-3?rss=yes
Article Info
Publication History
Published online: January 06, 2020
Publication stage
In Press Corrected Proof
Identification
DOI: https://doi.org/10.1016/j.tins.2019.12.002
Copyright
© 2019 Elsevier Ltd. All rights reserved.
ScienceDirect
Access this article on ScienceDirect
Your quote: “Reading the table and the words in the paper, it seems as though +/- 55% of the patients were unchanged or improved.”
Yes and if you’re referring to the 57 week chart, a point of clarification: the 55% includes 5 of 9 participants at the high blood concentration. 4 of them were improved from baseline and only 1 was unchanged.
As a “doctor” I can only imagine how encouraged you must be on behalf of Alzheimer’s Disease sufferers.
ESPECIALLY since the FDA-endorsed data analysis firm Ariana, and its CEO Dr Afshar, presented in-depth analysis (linked below) that using Ariana technology they demonstrated a “strong drug concentration / response relationship” with 2-73, AND that the same applied for the brain activity biomarker ERP in their 2-73 PK/PD analysis.
That was at 57 weeks.
And logic tells me that Dr Afshar would not have presented our 2-73 400% improved cognitive results over the ADNI control cohort data through 104 weeks at CTAD last month UNLESS the data continued to be similarly positive internally to date.
But wait, that could be considered naive to use logic and common sense, right???
http://www.arianapharma.com/about/our-leadership/management-team/
[cited from the October 2017 PK/PD presentation outlining Ariana’s & Anavex’s representations regarding dose/concentration relationships (from our 57 week ph2a AD participants):
http://www.anavex.com/my_uploads/ANAVEX2-73-PKPD-Phase-2a-2017.pdf
· Slide 3: in depth analysis using Ariana technology demonstrates “relationship between Anavex2-73 measured exposure and dose (PK) are consistent across study periods”
Slide 3: in depth analysis using Ariana technology demonstrates “strong drug concentration / response relationship revealed for key Alzheimer’s disease trial endpoints cognition and function, MMSE and ADCS-ADL (PK/PD). This relationship is consistent across multiple time periods”
· Slide 3: “same applies for the brain activity biomarker ERP (PK/PD)”
· Slide 6: across the 5 weeks and the 52 weeks their slides say that the achieved (check mark) “dose-effect relationship”
Slide 12: Ariana indicates “confirmed reliable inter-individual variability (dispersion) for the Anavex2-73 phase 2a study with 32 patient cohort” and that “this is confirmation that the sample of 32 patients of the Phase 2a provides reliable information regarding dispersion and as such allows for meaningful predictions for larger populations”
· Slide 13: Ariana indicates “relation between Anavex2-73 exposure and dose (PK) are consistent across administrations”
· Slide 14: “High Dose of Anavex2-73 correlates with exposure”
Slide 19: “ERP Biomarker Shows Significant Drug Response: P3a Amplitude Increases with Anavex2-73”
· Slide 24: through Ariana’s KEM Systematic Analysis, they found 83 rules (possible relations across variables, endpoints, PK parameters and time) and “97% of them showing coherent dose-response relation”
Slide 25: entitled “Robust Dose (Concentration) / Response Effect of Anavex2-73” and their KEM analysis provided “consistency for 6 main exploratory endpoints cognition, function and biomarker (MMSE, ADCS-ADL & EEG/ERPs) demonstrated through systemic exploration of the full data matrix”
· Slide 25: “97% consistency: MMSE, ADCS-ADL and EEG/ERPs: Identified relations show that high dose (concentration) is linked to improved response and low dose (concentration) to poor response”
Slide 26: chart shows that for our participants that achieved >4ng/mL blood concentration level (9 total) during the 57 week study, that 4 improved on the MMSE tests and 1 remained at baseline (5 out of 9 is a majority)
· Slide 28: “an increase of MMSE is a rare event.” And “a patient receiving a higher concentration of Anavex2-73 has a +110% (2.1 fold) chance of improving its MMSE during 57 weeks”
Slide 29: “KEM identifies strong non linear relations linking concentration with response for both MMSE and ADCS-ADL”
· Slide 30: High Anavex2-73 concentration linked to improved response consistently across all analytes and periods” and “both Anavex2-73 and metabolite show a consistent response across the 3 different time frames”
Slide 32: “KEM analysis has identified exclusion / inclusion criteria. Each criteria has the potential to improve MMSE / ADAS-Cog for mild to moderate Alzheimer’s patients treated with Anavex2-73” and “these criteria will be incorporated into the upcoming Anavex2-73 phase 2/3 trial”]
I realize you’re likely discussing trial patients, but regarding titration in the real world:
If I’m diagnosed with dementia, and this blarcamesine medication becomes available, am I willing to risk some headaches and dizziness (most of which were resolved) in order to achieve a therapeutic blood concentration at the higher dosages and potentially significantly reduce my cognitive decline over (at least) 2 years (400% better than ADNI control cohort as presented at CTAD in December), or will I instead choose the much more severe natural history decline of the disease with today’s SOC drugs?
[SOC drugs that have a less favorable safety and side effect profile by comparison.]
What will such a patient choose? Will survival instincts kick in?
When current drugs are not effective and have worse side effects, wouldn’t titrating up my blarcamesine dosage ultimately make the most sense?
https://alzheimersnewstoday.com/anavex-2-73/
“The results showed a favorable safety profile for Anavex 2-73, which was important for further studies. The most common adverse side effects were minor, such as dizziness and or headache, and most were resolved. The researchers noted that “unexpected” therapeutic responses also were seen, including improved alertness and mood, and better engagement with family and friends.”
Seems we should be careful and diligent to recognize false prophets when they reappear as well.
That’s your enervated opinion based upon your own personal view of one graph, and your opinion happens to run contrary to the leading Rett Syndrome researcher’s statement and commentary on the subject.
The same RS researcher who is our CMO and is in possession of all of the data regarding the trial and its participants and their open label extension data.
Personally I’ll stick with Dr Kaufmann.
Yes, thanks for the reminder and indeed everything we’re doing may or may not work, may or may not be approved, all of the multitudes of positive developments and results and supportive peer reviewed support may or may not generate a product to sell.
But what is for sure is that the global Rett Syndrome researcher and our Anavex CMO has ALL of the data internally (including RS open-label extension data since 6/25/19) and he recently said:
“This is a remarkable first strong signal for patients with Rett syndrome especially given that the strong effects were seen in adult patients, and we look forward to discussing these results with the FDA and the European regulatory agency as we continue our Rett Syndrome Program including pediatric patients,” said Walter E Kaufmann, MD, Principal Investigator of the study and Chief Medical Officer of Anavex. “Importantly, we’ve now observed that the ANAVEX®2-73 (blarcamesine) effect is correlated with changes of Glutamate and GABA levels, objective measures and biomarkers in several neurodevelopmental disorders.”
[The last sentence in particular is quite powerful, especially when read slowly and deliberately.]
https://www.anavex.com/anavex-life-sciences-announces-preliminary-clinical-efficacy-data-of-its-u-s-phase-2-clinical-trial-of-anavex2-73-in-patients-with-rett-syndrome/
There are numerous scientific articles available that explain the typical inverse relationship between glutamate and GABA levels in various CNS and autism-related disorders.
As xena indicated the 2-73 MOA (restoration of neural cell homeostasis) could very well help to explain why Dr Kaufmann’s presentation and conclusions referenced the reduction in glutamate and correlated change in GABA levels in our preliminary RS 7 week results.
I’ll continue to value the conclusions of our RS expert and CMO over your opinion; for all the reasons I’ve already stated and referenced, and due to the fact that Dr Kaufmann has ALL OF THE DATA in his possession, unlike yourself.
“Additionally, the magnitude of GABA change was inversely correlated with the magnitude of decrease in RSBQ Total scores (2-tailed Spearman’s rho = -0.812, p = 0.050) and GABA changes demonstrated an inverse correlation of the magnitude of Glutamate changes (2-tailed Spearman’s rho = -0.829, p = 0.042). GABA is the main inhibitory neurotransmitter in the brain, known to be deficient in animal models of Rett syndrome. Excitatory-inhibitory imbalances postulated in many neurologic disorders, including Rett
syndrome, have been linked to imbalances between Glutamate and GABA 1,2.”
1 Kaufmann et al. Expert Opin Orphan Drugs 4:1043-1055, 2016
2 Banerjee et al. Brain 142:239-248, 2019
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-014-0189-0
http://www.bioline.org.br/pdf?zr12088
https://www.grc.com/health/research/Rhodiola/Glutamate%20and%20GABA%20synthesis,%20release,%20transport%20and%20metabolism%20as%20targets%20for%20seizure%20control.pdf
https://www.frontiersin.org/articles/10.3389/fphys.2017.00030/full
I will allow the conclusions and presentations of Dr Walter Kaufmann to speak for themselves.
By the way did you ever figure out what you would attribute the positive glutamate, GABA and behavioral changes to, if not the 5mg 7 week administration of blarcamesine?
“Additionally, the magnitude of GABA change was inversely correlated with the magnitude of decrease in RSBQ Total scores (2-tailed Spearman’s rho = -0.812, p = 0.050) and GABA changes demonstrated an inverse correlation of the magnitude of Glutamate changes (2-tailed Spearman’s rho = -0.829, p = 0.042). GABA is the main inhibitory neurotransmitter in the brain, known to be deficient in animal models of Rett syndrome. Excitatory-inhibitory imbalances postulated in many neurologic disorders, including Rett
syndrome, have been linked to imbalances between Glutamate and GABA 1,2.”
1 Kaufmann et al. Expert Opin Orphan Drugs 4:1043-1055, 2016
2 Banerjee et al. Brain 142:239-248, 2019
https://www.globenewswire.com/news-release/2019/09/16/1915810/0/en/Anavex-Life-Sciences-Announces-Preliminary-Clinical-Efficacy-Data-of-its-U-S-Phase-2-Clinical-Trial-of-ANAVEX-2-73-in-Patients-with-Rett-Syndrome.html
Frooool, if you expect me to place more value on your OPINION than on the conclusions and representations of Dr Kaufmann, then you’re sadly mistaken.
Dr M co-wrote the the current diagnostic guidelines for the RS disorder, edited the first RS textbook, founded and led RettSearch internationally, and leads the Rett Syndrome Molecular Biomarkers Working Group for the Rettsyndrome.org foundation and the Rett Syndrome Behaviour Questionnaire Working Group, among many other distinguished roles and professorships.
SMH.
http://genetics.emory.edu/faculty/adjunct/kaufmann-walter.html
https://www.anavex.com/anavex-life-sciences-announces-the-appointment-of-walter-e-kaufmann-md-as-chief-medical-officer/
“Dr. Walter Kaufmann’s clinical focus is on developing novel therapies for genetic disorders associated with intellectual disability. Until recently, he was the Director of the Center for Translational Research at the Greenwood Genetic Center, where he also held the Ravenel Boykin Curry Chair in Genetic Therapeutics. He holds adjunct appointments at Emory University School of Medicine, where he is an Adjunct Professor of Human Genetics, and at the MIND Institute/University of California Davis School of Medicine, where he is a Visiting Scholar in the Department of Neurology. Dr. Kaufmann is also a Simons Investigator at the Massachusetts Institute of Technology’s Simons Center for the Social Brain. Before these academic appointments, Dr. Kaufmann was a Professor of Neurology at Harvard Medical School and a Professor of Pathology, Neurology, Pediatrics, Psychiatry, and Radiology at the Johns Hopkins University School of Medicine.
A major focus of Dr. Kaufmann’s research has been Rett syndrome, a field where he has published extensively on neurobiology and clinical aspects. He served as founder and leader of RettSearch, the international consortium of Rett syndrome clinical researchers. As such, he co-authored the current diagnostic guidelines for the disorder. He also edited the first clinical textbook on Rett syndrome, published in late 2017. Dr. Kaufmann has also served as Co-Principal Investigator of the NIH-funded Natural History Study of Rett syndrome (RDCRN program). Currently, he leads the Rett Syndrome Molecular Biomarkers Working Group for the Rettsyndrome.org foundation and the Rett Syndrome Behaviour Questionnaire Working Group. Dr. Kaufmann has played different roles, including site investigator, Principal Investigator, and DSMB member/chair, in almost 20 drug trials for neurodevelopmental disorders. In this context, he has been involved in virtually all neurobiologically-based drug trials for Rett syndrome.
Dr. Kaufmann has published more than 220 journal articles, most of them original publications. He has also served on several editorial boards and as reviewer for over 100 scientific journals.”