PAA science updates: all neurodegenerative diseases, research etc., page-5

Alzheimer’s review — what’s currently happening in the AD space …

5 October 2024

—- long weekend read —-

AD is a devastating neurodegenerative disorder characterised by the accumulation of tau tangles and amyloid beta (Aβ) plaques in the brain. Aβ is a protein that is said to be the primary cause of the cognitive decline associated with this disease.

· INDIANAPOLIS , July 2, 2024 / ...

Lilly's Kisunla™ (donanemab-azbt) Approved by the FDA ...

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FDA approval is just the beginning. Now Lilly’s Kisunla faces the tough Alzheimer’s market.

https://www.pharmavoice.com/news/fda-lilly-kisunla-alzheimers-market-biogen/720768/

If drugmakers have learned anything in the last few years about the Alzheimer’s market, it’s that an FDA approval is by no means a guarantee of success.

So as Eli Lilly celebrates the July approval last week’s green light for the amyloid-plaque clearing Kisunla — formerly known as donanemab — there’s still work to be done to ensure patients who qualify can access the drug.

Predecessors in the space have had mixed success.

From the outright disastrous launch of Biogen and Eisai’s Aduhelm, which payers declined to offer on the basis of muddy efficacy and safety, to the same duo’s Leqembi, which was met more positively, but has been slow to meet market expectations, Alzheimer’s has been a tough nut to crack.

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Recent history

The silver lining around Lilly’s Alzheimer’s delay could be a future with better drugs

https://www.pharmavoice.com/news/alzheimers-lilly-donanemab-fda-delay-amyloid/709940/

DELAY from FDA

In January 2023, the FDA denied approval of donanemab.

Although donanemab and its amyloid-targeting predecessors Aduhelm (pulled from market) and Leqembi — both from partners Biogen and Eisai — are the first drugs shown to potentially slow disease progression, regulators and payers have taken extra precautions to ensure the benefits outweigh the risk.

In a phase 3 trial, almost half of participants receiving donanemab showed no decline on one of the key cognitive rating scales of Alzheimer’s after one year compared to less than a third on placebo. Looks impressive. So the story goes…

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2 July 2024 — Lilly's Kisunla™ (donanemab-azbt) Approved by the FDA for the Treatment of Early Symptomatic Alzheimer's Disease

25 Sept 2024 — Eli Lilly Secures Approval for Alzheimer's Drug Kisunla in Japan

https://finance.yahoo.com/news/eli-lilly-secures-approval-alzheimers-154500244.html

Japan is the second major market where LLY's Kisunla has been approved. The drug was first approved in the United States in July 2024.

Both these Kisunla approvals are based on data from the TRAILBLAZER-ALZ 2 phase III study, which showed that treatment with Kisunla slowed cognitive and functional decline by up to 35% in patients with less advanced disease compared to placebo at 18 months. It also showed that Kisunla reduced participants' risk of progressing to the next clinical stage of disease by up to 39%.

A monthly intravenous infusion of Kisunla reduced amyloid plaques on average by 84% at 18 months compared with the start of the study in the overall population of participants.

Year to date, Eli Lilly’s shares have surged 58.6% compared with the industry’s 22.4% rise.

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But experts this time around are optimistic the delayed review process will help — not hinder — Lilly’s donanemab in the long run by establishing concrete safety and efficacy data, as well as a renewed confidence in drugmakers’ ability to design trials in innovative ways.

“Generally speaking, it’s unusual for the FDA to arrange an Adcomm meeting this late in the review cycle — that being said, I don’t think it’s necessarily a negative,” said Dr. Howard Fillit, co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation.

“One of the things the FDA probably realized is that the clinical trial had two innovative features.”

Fillit pointed to a limited dosing regimen, in which patients with a negative amyloid PET scan could stop taking donanemab, to reflect how diagnosis and treatment would work in the real world.

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Eli Lilly Secures Approval for Alzheimer's Drug Kisunla in Japan

https://finance.yahoo.com/news/eli-lilly-secures-approval-alzheimers-154500244.html

Kisunla is the only amyloid-targeting therapy that can be discontinued when amyloid plaques clear up, as shown by a PET scan.

This will lower treatment costs and burden for patients. In the TRAILBLAZER-ALZ 2 phase III study, around 47% of participants completed treatment at 12 months and 17% completed treatment at six months.

Treatment with the Lilly drug requires the intravenous (IV) administration of a single dose once every four weeks compared with Biogen/Eisai’s Leqembi, which requires IV dosing once every two weeks (forever)

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Can Lilly make a bigger splash?

Some market watchers think it’s possible despite clinical results that showed a risk of brain swelling called ARIA in a subset of patients.

Like Aduhelm and Leqembi, the drug’s label is limited to patients in early stages of the disease and with confirmed amyloid plaques in the brain.

For one reason in particular, though, Kisunla stands out in the crowd.

“Kisunla has Lilly behind it,” said Jayne Hornung, chief clinical officer at MMIT, a market access consultancy.

“That’s a powerhouse that literally knows how to bring a drug to market in the face of [adverse drug reaction] information.”

Kisunla (donanemab)carries a slightly higher price tag than Leqembi at $32,000 for a year’s worth of 13 infusions, compared to Leqembi’s $26,500. However, Kisunla can be stopped once plaques have cleared, whereas Leqembi is infused every two weeks indefinitely.

Kisunla is estimated to reach $2 billion in annual sales by 2029, according to a July 2 note from Cantor Fitzgerald analyst Louise Chen. That’s similar to Cantor’s Leqembi estimates of about $2.2 billion in the same time frame despite hitting shelves more than a year earlier than Kisunla.

Kisunla’s approval was met with enthusiasm from patient groups and medical organizations that support the entry of medications to help ease the burden of Alzheimer’s disease. Among them, the Alzheimer’s Association, Voices of Alzheimer’s and the Alzheimer’s Drug Discovery Foundation voiced support for the decision.

“Any new treatment in the Alzheimer’s area is providing some hope to that community,” Hornung said. “There’s definitely a market for it — it might not be the perfect drug today, but cancer drugs when we first developed those weren’t perfect either.”

Among critics of the FDA’s approval, however, was the consumer advocacy group Public Citizen, which cited “modest” efficacy and “substantial” safety risks that should have led to a rejection. For these reasons, access to Kisunla is appropriately limited to a specific set of patients who will benefit, Hornung said, pointing to three deaths in the late-stage study as a result of the brain swelling complications.

“It’s not the best drug for everyone, and we’ll have to pick patients appropriately, but we do that for every drug,” Hornung said. “The benefits do outweigh the risks for this medicine, like the FDA committee suggested.”

And payers are likely to provide access to drugs like Kisunla and Leqembi as long as patients qualify, Hornung said.

“Payers aren’t limiting access the way they did with Aduhelm,” Hornung said. “They’re finding ways to get this product to the right patients, and not freely handing it out to anyone with Alzheimer’s.”

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The second innovation came about as a “goldilocks” measure, using tau imaging (i.e. negative PET scan) to determine whether a patient fits in the window for donanemab’s effective range — not too early and not too late.

“I think what you’re seeing now with these approvals is a maturation of the field — in 40 years we’ve been doing this, we finally have the kind of neuroimaging and spinal fluid and blood tests that are so critical to precision drug development,”

“These trials set the groundwork for future trials … that can give us reliable answers, and that’s a real breakthrough.”

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Beyond amyloid

But could there be a silver lining for the future of Alzheimer’s treatment beyond the recent wave of amyloid-beta targeting drugs?

Amyloid-targeting drugs have demonstrated clinical advances in Alzheimer’s treatment, but many researchers in the field, including Fillit, see these therapies targeting only beta amyloid as a stepping stone to more precise understanding of the disease down the road.

“We are redefining Alzheimer’s disease,” Fillit said, pointing to the origins of diagnosis among elderly people with dementia whose brains showed evidence of plaques and tangles in an autopsy.

“It turns out that looking at the brain of an older person is like the parable of a blind man touching an elephant and trying to describe it.”

For example, brain inflammation often accompanies Alzheimer’s and is a hallmark of aging, Fillit said. That has driven a good deal of interest in reducing inflammation to slow progression of the disease.

More novel treatments with new targets are being studied each year. About a decade ago, about three-quarters of all Alzheimer’s drugs in development were anti-amyloid or anti-tau, Fillit saif — now, researchers have flipped the script, and “75% of the drugs in development today are non-amyloid, non-tau,” he said.

Like cancer, Alzheimer’s comes about as the result of many different factors, and researchers don’t yet know all of them.

While some might benefit from anti-amyloid or anti-tau drugs, others might see improvement from drugs that employ autophagy to remove mis-folded, toxic proteins from the brain.

Managing diabetes and hypertension could also play a role in Alzheimer’s treatment, as well as epigenetic changes to protein structure, Fillit said.

“We have proof of concept that aggregates of beta amyloid plaques play a role in the disease, but it’s also clear that it’s not 100%,” Fillit said. “

All other diseases of old age require a combination approach with multiple biomarkers and combination products that address multiple pathways of illness. The next generation of Alzheimer’s drugs will be precision medicine with combination therapy.”

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Other Players in the AD Space

https://finance.yahoo.com/news/eli-lilly-secures-approval-alzheimers-154500244.html

The AD target market is highly competitive as several other pharma companies like Cassava Sciences SAVA and Prothena PRTA are developing their antibody candidates targeting the AD indication.

Prothena is evaluating multiple AD candidates in early-stage studies targeting AD indication. PRTA is evaluating AD drug PRX012, also an amyloid-targeting therapy, in an early-stage study.

Prothena is also developing a dual Aβ-tau vaccine, PRX123, a potential prevention and treatment for AD.

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Cassava Sciences is conducting a phase III program consisting of two global studies on its orally-administered drug simufilam in patients with mild-to-moderate AD dementia.

While SAVA expects top-line data from the 52-week RETHINK-ALZ study before 2024-end, it expects to report data from the 76-week REFOCUS-ALZ study by mid-2025.

But there have been some massive issues with Cassava data.

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An Alzheimer’s drugmaker is accused of data ‘manipulation.’ Should its trials be stopped?

https://www.pharmavoice.com/news/alzheimers-cassava-sec-fda-doj-matthew-schrag/728863/?utm_source=Sailthru&utm_medium=email&utm_campaign=Issue:%202024-10-04%20PharmaVoice%20%5Bissue:66530%5D&utm_term=PharmaVoice

Cassava Sciences’ beleaguered investigational Alzheimer’s therapy is in two phase 3 studies.

Cassava Sciences has faced a barrage of regulator scrutiny over alleged clinical impropriety in studies of an experimental Alzheimer’s candidate.

Most recently, Cassava shelled out millions to fend off corporate misconduct allegations from the U.S. Securities and Exchange Commission, against allegations that Cassava manipulated the data “to create the appearance that the drug had caused dramatic improvements in biomarkers associated with Alzheimer’s … such as total tau,” the SEC stated.

Now, some experts want Cassava to get more heat from the FDA and have its clinical programs ground to a halt.

Dr. Matthew Schrag was thrust into the Cassava controversy in 2021. Because of his position as a vascular neurologist and assistant professor of neurology at Vanderbilt University along with his image analysis skills, a colleague who needed to find an expert in Alzheimer’s trial results gave him a call.

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Two new Alzheimer’s disease treatments — Eli Lilly’s Kisunla and Leqembi from Biogen and Eisai — are on the market, but Dr. Matthew Schrag isn’t prescribing them.

“When you talk to most patients about the risks and the cost of those drugs, they are not interested,” Schrag, a vascular neurologist at Vanderbilt University, said, adding that when patients are “determined,” he finds another doctor who can help.

Schrag’s opinion isn’t surprising, given his history of challenging the prevailing science in Alzheimer’s.

In 2021, he criticized the FDA’s approval of Biogen’s Aduhelm, which was eventually pulled from the market.

Schrag’s image analysis acumen has also made him a shrewd detective of clinical trial fraud, allowing him to expose instances of potential misconduct by Alzheimer’s researchers — including work conducted by his undergraduate mentor.

This role as an Alzheimer’s research whistleblower goes back to 2021 when he was asked to weigh in on clinical misconduct allegations levied against Cassava Sciences.

Schrag ultimately concluded that Cassava indeed appeared to have manipulated trial results.

And although Schrag has since pulled away from the controversy, the fallout for Cassava hasn’t abated.

Cassava’s facing ongoing scrutiny, including more claims of fraud, multiple regulatory investigations and settlements, and calls for its phase 3 trials of an Alzheimer’s drug to be stopped.

“I don’t think any data coming out of Cassava can possibly be trusted,” Schrag said, expressing dismay that the FDA hasn’t stopped the trials already.

“These trials [should] have never been permitted to start, so I’m astonished by the direction this has gone,” he said. “There is a moral obligation not to experiment on patients in this context.”

Cassava’s phase 3 trials are fully enrolled with 1,900 participants.

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Back to Eli Lilly.

The safety and effectiveness of donanemab - an Alzheimer's drug recently approved by the US Food & Drug Administration (FDA) - is called into question in an investigation published by The BMJ last week, Sept. 25.

Journalists Jeanne Lenzer and Shannon Brownlee explored concerns not only about its effectiveness and the number of deaths among patients taking the drug, but also about financial ties to drug makers among the "independent" advisory panelists who recommended approval.

In January 2023, the FDA denied approval of donanemab, citing a "high rate" of missing data and questioning the drug's long term safety.

The agency noted a higher rate of treatment discontinuation due to adverse events (frequently brain hemorrhage and swelling) among patients on donanemab compared with placebo, and an "imbalance" in overall deaths.

Lilly acknowledged three deaths in patients on donanemab, and an outside company it hired to obtain the missing data, found two additional deaths among patients in the donanemab arm and five deaths in the placebo arm.

But Steven Goodman, an expert in clinical trial design at Stanford University, says it is not possible to assess the reliability of the new data without more details of the outside company's methods.

"There was also no information on health outcomes in those patients other than death, nor the causes of the deaths," he says, adding that the "failure to formally follow patients who stopped treatment was a significant design flaw, particularly when that discontinuation was partly due to adverse drug effects."

The investigation also reveals that seven of the eight doctors appointed by the FDA to review donanemab received direct payments from drug companies. Three had financial ties to Lilly, two had ties to Roche, Lilly's development partner in creating a new blood test for Alzheimer's disease, and two others have patents on amyloid antibodies, and the eighth doctor had research funding from Janssen for another Alzheimer's drug.

Using the public database OpenPayments, members' CVs, disclosures in published articles, and the Google patent ownership database, The BMJ found that individual advisers received up to $62 000 (£47 000; €56 000) for consulting and speaking fees and up to $10.5m in research grants from 2017 through 2023.

Asked about the extensive financial conflicts among the physician advisors found by The BMJ, the agency stated, "The FDA does not comment on matters related to individual members of an advisory committee."

Lenzer and Brownlee also describe how the main (primary) outcome of the donanemab trials was changed during the trial from the widely accepted "clinical dementia rating scale-;sum of boxes" (CDR-SB) to Lilly's own integrated Alzheimer's disease rating scale (iADRS).

And despite results failing to show a clinically meaningful difference between patients on the drug and placebo, Lilly stated that donanemab slowed progression of Alzheimer's by 22%.

The company has also promoted donanemab as "slowing decline by 35%."

"That is a misleading statement," says Alberto J Espay, a neurologist and specialist in clinical epidemiology and healthcare research at the University of Cincinnati.

"That's a relative difference that transforms a very tiny absolute difference into a number that seems impressive."

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So that’s just looking at AD.

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There’s a science update coming: perhaps pre-AGM: at AGM: post-AGM

With one or more pre-clinical reports on:

Alzheimer’s, Parkinson’s, Huntington’s and/or ALS

When there is cell disruption resulting in rare disease, whether it presents as:

• beta-amyloid proteins that accumulate into plaque deposits - Alzheimer’s
• TDP-43 aggregates - MND/ALS
• toxic neurofibrillary tau tangles - Alzheimer’s
• cytokine storms - AD + multiple diseases
• alpha-synuclein protein accumulation - - Parkinson's
• neuro-inflammations - Parkinson's, MND/ALS, Alzheimer's and Huntington's ++
• heparan sulfate-modified protein flare-ups - Alzheimer’s
• reactive oxidation stress / reactive oxygen species (ROS) - multiple diseases
• hyper-activated integrated system response (ISR)

# the first order of priority, is to grab the fire hose and blast the entire cellular firestorm into a relative level of calm submission, regulate the process, settle the inflammation, remove toxic proteins — all autophagy-based procedures — that’s where monepantel comes into action — and then work out the next best step, for that patient, and that time.

Have a great week,

cheers,

Ice