Lecanemab approved!

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
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Julie G
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Re: Lecanemab approved!

Post by Julie G »

Pretty brutal, but honest assessment. Thanks for sharing that. I think amyloid may have a role in disease, but not at the near exclusion of all other theories. I was a huge proponent of anti-amyloid therapeutics in the mid-2000's when the company that I worked for was developing an amyloid antibody. But there have been so many failures in the theory. For me, the final nail in the coffin was the BACE inhibitors. These block a protease that produces beta-amyloid from a precursor protein. They are tremendously effective at drastically reducing beta-amyloid burden. But, in clinical trials not only did they not reduce cognitive decline, it actually accelerated! So a drastic reduction in brain amyloid cause more decline. That was it for me.
This is very impactful coming from somebody on the "inside." I'm disappointed with the lack of real investigative journalism surrounding Alzheimer's research and the failure to question the overly broad reach of large pharmaceuticals. Between the impropriety that occurred with the fast-tracking of Aduhelm and the financial ties between it's manufacturers and other stakeholders such as the Alzheimer's Association ($1.4 million since 2018), the FDA (75% of annual budget for the drug division), the consulting fees paid to prestigious journal editors and other key opinion leaders, etc, you can clearly see the conflict of interest that leaves patients without a voice or an effective treatment.
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Re: Lecanemab approved!

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Julie G wrote: Wed Jan 11, 2023 7:03 am This is very impactful coming from somebody on the "inside." I'm disappointed with the lack of real investigative journalism surrounding Alzheimer's research and the failure to question the overly broad reach of large pharmaceuticals. Between the impropriety that occurred with the fast-tracking of Aduhelm and the financial ties between it's manufacturers and other stakeholders such as the Alzheimer's Association ($1.4 million since 2018), the FDA (75% of annual budget for the drug division), the consulting fees paid to prestigious journal editors and other key opinion leaders, etc, you can clearly see the conflict of interest that leaves patients without a voice or an effective treatment.
Julie,

These are serious allegations and deserve due consideration. While patients may not yet have an effective treatment for all stages or all complex variations of AD and related causes of dementia (tau, TDP-43, alpha-synuclein, vascular dementia and CAA, neuro-inflammation, synapse loss and microglial activation, etc.) that does not mean patients do not have a voice. Clearly many people have a voice when they choose to follow the Bredesen protocol, or recommendations from Dr. Richard Isaacson or Dr. Gundry or others and to do that in lieu of or in conjunction with participation in clinical trials.

I think it's important to use current data, not information from what happened in the mid-2000's.
The National Institute on Aging (NIA) is currently supporting 442 active clinical trials on Alzheimer’s disease and related dementias (AD/ADRD). These trials reflect diverse drug and mechanistic targets, as well as diversity in the stages of AD/ADRD they address. NIA’s active trials include: early stage clinical drug development (57), late stage clinical drug development (8), non-pharmacological interventions (139), dementia care and caregiver interventions (212), and other types of trials (26), including trials for clinical therapy development for neuropsychiatric symptoms of dementia and trials for evaluating diagnostic tools.
It is true that 5 of 8 late stage drug trials (Phase2/3 and 3) are amyloid trials; the other 3 are tau, synaptic plasticity and metabolism/bioenergetics.

More recently funded Phase 1 and 2 human clinical trials trials include 7 each on multiple targets and on inflammation, 6 on growth factors/hormones, 4 each on vasculature and metabolism/bioenergetics, 3 on oxidative stress, 2 on circadian rhythm. Non-pharmacological interventions trials range from 27 on exercise and 21 on cognitive training, to 14 on sleep, 10 on diet/supplements and even 3 on music.

The NIA has specific policies which researchers must follow--and most AD research has both public (NIA) and private (drug companies or biotech companies) partnerships:
Ensuring safety of participants enrolled in NIA-funded clinical trials is the highest NIA priority. This goal applies to any trial regardless of a study's phase, stage, size or intervention type.

I have not read any claim of fraud or distortion of the actual results of the multi-year studies of lecanemab in thousands of people in Phase 1, 2 and 3 randomized, quadruple-blind trials (participant, study site doctor, site raters, central cognitive/functional skills raters and MRI radiologists. All MRIs are read first by the radiologist at the facility and then by specialized radiologists at the Mayo Clinic, with results communicated back to the sites within two weeks.

Instead, it appears that the central focus of discussion is with how to assess both safety and efficacy of this drug. This interview from 12/29/22, with a practicing neurologist at Washington University in St. Louis is sponsored by the journal Neurology, and seems to me to be a well-balanced view of the pros and cons of lecanemab. https://podcasts.apple.com/us/podcast/n ... d266288159

In the 11/29/22 NEJM article, Lecanemab in Early Alzheimer’s Disease, the 19 authors have detailed disclosure forms in 34 pages of a PDF.
nejmoa2212948_disclosures.pdf
The amounts are not listed, but the subjects include advising on the design and recruitment of DIAN-TU--a long-running study of Dominantly Inherited AZ (Randall Baeman) and co-leading the design and coordination of the AHEAD study. The NEJM does not allow authors to pay to publish, nor does it pay them, and a team of five editors approves all submissions, with reportedly only 5% of papers accepted.

Both of those studies, which are ongoing and include studying tau, and numerous biomarkers, went through a rigorous screening process to support centralized coordination through the Alzheimer's Clinical Research Center (ACTC), which is funded through the NIA, has a Research Participant Advisory Board. I have been an active member since 2020, with frequent access to both conferences, conversations and feedback with researchers.. Both I and another member (who has ApoE 4/4 and is a caregiver to multiple generations of her family, including multiple clinical trial participants), often speak of the importance of ApoE4 in research. Given the prevalence of ApoE 4/4 at 2% of the population, we have an oversized voice on this board of less than two dozen, especially given that others also carry a copy of ApoE4.

The ACTC's Advisory Board's stated aims are to:
Provide guidance on study design including the following areas: ethical considerations, disclosure of personal and study research results, privacy, recruitment approaches that engage diverse communities and increase trial generalizability, burden for participants and study partners, and selection of therapeutics, balancing risk and potential benefit
Provide feedback on network conduct: data sharing, reporting topline results, sharing results and assignments with participants, and network priorities.
ACTC also has a Non-Pharmacological Intervention Committee to
encourage and facilitate standardization of methods used to deliver and assess success of non-pharmacological interventions to support harmonization and data sharing across studies whenever possible.
All grants are also reviewed and approved by the Internal Ethics Committee, co-directed by Dr. Jason Karlawish, Professor of Medicine, Medical Ethics and Health Policy, and Neurology at the University of Pennsylvania and Co-Director of the Penn Memory Center. He has written and spoken extensively about the ethics of supporting and listening to the voices of people living with, caring for or at risk of AD and other dementias.

We all have voices and while we may use those in many disparate ways, as shown by the vast array of topics on this forum, I choose to believe that many of those working in the field are ethical and motivated by seeking to make a difference.
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Re: Lecanemab approved!

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These are serious allegations and deserve due consideration.
Which allegation? That we need more investigative journalism? I stand by that. The enthusiasm behind mainstream media's reporting of lecanamab has been unprecedented. And, all of this for a drug that shows less cognitive benefit than olive oil per CDR SOB. See this recent study.

That patients are left without a voice? The largest patient advocacy group for Alzheimer's is accepting large sums of money from the manufacture's of the drugs they endorse. This feels like a conflict of interest to me. Read more here.
In October, the Alzheimer’s Association endorsed aducanumab in a letter to the FDA advisory committee ahead of its meeting. Biogen and Eisen had donated $1.4 million to the group between 2018 and 2020, which the group did not disclose. A spokesperson for the Alzheimer’s Association defended the group, noting that the funding from Biogen and Eisen comprised only 1.09% of all donations it had received from pharmaceutical companies during that time.
That impropriety occurred with Aduhelm? See the congressional report here.

That 75% of the FDA's drug division funding comes from pharmaceuticals themselves? That's a fact. See here.

Everything in my post is well documented and I certainly stand behind it. That said, I'm really glad that you brought up the idea that current research studies are now focused on more than amyloid. Agreed and thank goodness, but the legacy and far reaching effects of the exclusive focus in amyloid for decades still remains and is widely spoken about within the Alzheimer's research community.
I choose to believe that many of those working in the field are ethical and motivated by seeking to make a difference.
I agree that the researchers who stood behind the amyloid hypothesis for so long (and still do) are good people who firmly believe their hypothesis. I never suggested otherwise.
We all have voices and while we may use those in many disparate ways, as shown by the vast array of topics on this forum.
Amen! I love that our community exists to advocate for E4 carriers. I especially love that we can respectfully share our opinions. I love you for your strong defense of what you believe. And, as I've always said, when there is a "pill" that will do what diet and lifestyle have done for me, I will gladly take it.
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Julie G
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Re: Lecanemab approved!

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Doctors for America’s FDA Task Force recently put out a press release re. the FDA’s decision to expedite the approval of lecanamab. See below:
The FDA Task Force is committed to increasing transparency at the FDA and ensuring patient safety is at the heart of all therapeutic approvals. The recent FDA decision to expeditiously approve lecanemab despite reported patients deaths associated with the drug illustrates why the FDA Task Force’s work is desperately needed. Questions also remain about whether the surrogate endpoint used as the basis for accelerated approval, beta amyloid, is indeed “reasonably predictive” of clinical benefit despite over two dozen studies not finding such an association. Moreover, FDA has yet to review the published confirmatory trial as part of the accelerated approval and it remains unclear whether the statistically significant changes seen among patients receiving the drug correspond with meaningful clinical benefit. 

In light of the recent expedited approval and the sponsor’s subsequent application for traditional approval, the Doctors for America FDA Task Force is asking the FDA to convene a group of independent advisors for a formal advisory committee meeting to address the many unanswered questions surrounding this therapy. The FDA and its advisory committee should consider the following:
1. whether the surrogate endpoint used as the basis of approval is indeed reasonably predictive of clinical benefit;
2. if the confirmatory trial results from Clarity-AD showing changes in cognitive scores are indeed clinically meaningful;
3. if the drug does show evidence of harm that outweigh its benefits in light of the deaths reported;
4. whether the clinical trials have adequate representation of patients who would be prescribed this treatment in the real-world including older adults with comorbidities and communities of color disproportionately impacted by the disease; and
5. if FDA took steps in its review of lecanemab to address irregularities in its approval of aducanumab including managing conflicts of interests.

Patient safety is the primary concern of the FDA Task Force. The approval of lecanemab is based on a secondary, unvalidated surrogate endpoint, but critical questions remain as to whether the benefits outweigh the risks reported of brain swelling, brain bleeding, and death among patients who received this drug. As a group of physicians, the FDA Task Force understands the difficult challenge clinicians across the country will face when considering prescribing this treatment. As physicians, we vow to “do no harm” in treating our patients and look to the FDA to provide unbiased, independent guidance to signal through their approval decisions that the authorized treatment’s benefits truly outweigh its risks. Like our patients, we eagerly await a future when there is a clinically meaningful and safe treatment for this debilitating, progressive neurological disease. However, ambition must not cloud our or the FDA’s judgment of the data submitted – doing so may put patients in harm’s way. 

Lecanemab’s approval comes just weeks after the House Committee on Oversight and the House Energy and Commerce Committee released an investigative report on “The High Price of Aduhelm’s Approval” and its atypical review process. The Task Force is grateful for the oversight work being done by congressional leaders, and FDA must recognize the public need for greater transparency and scrutiny around its dealings with pharmaceutical companies and interest groups. Despite widespread concern over the approval of aducanumab (Aduhelm) we are frustrated to see that no apparent changes have been made in the review and approval process. Instead, FDA within their approval documents for lecanemab has repeatedly referenced aducanumab as a precedent for this approval, misleadingly stating that it is settled science despite overwhelming evidence otherwise that an unvalidated surrogate endpoint can be used as the basis of expedited review and approval. Patients and doctors across the country want and need a cure for Alzheimer’s disease, not a false hope with a twenty-six thousand dollar price tag.

Last week, we joined other patient, public health, and physician groups in sending a letter to the Centers for Medicare and Medicaid Services (CMS) Administrator Brooks-LaSure urging that CMS uphold its sound National Coverage Determination (NCD) for FDA-approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease such as aducanumab and lecanemab. Under this policy, Medicare coverage for such therapies approved by the FDA based on a surrogate endpoint would appropriately only be available for patients enrolled in clinical trials, allowing for important data to be collected on clinical efficacy and safety. As lecanemab received accelerated approval by the FDA based on a surrogate endpoint and FDA has yet to complete its review of additional confirmatory clinical trial data, we agree with the NCD in providing coverage only through clinical trials and thus, protecting patients.
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Re: Lecanemab approved!

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Perhaps a bit too newsy, here it is:

https://www.prnewswire.com/news-release ... 32125.html

Wasn't sure what to make of this at first.

Has Europe approved Lecanemab?
NO! They accepted the application for marketing authorization.

Now they have to think about it for a while.
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