Drugging RNA with pills: small molecules for a big frontier

 Infused or injectable medicines that interfere with RNA, the messenger molecules that turn genetic instructions into proteins, have taken the spotlight in recent years, winning approvals for several rare diseases. A group of biotechnology startups are trying to find similar success by targeting RNA with pills instead.

History shows they face a daunting task. It’s long been considered futile to use chemical-based compounds to go after RNA because of its shifty nature. When scientists have succeeded, it’s typically been by accident. Last decade, for instance, Merck & Co. discovered an experimental antibiotic it was developing blocked a type of bacterial RNA. Pfizer inadvertently found one of its drug prospects affected translation of a protein that regulates cholesterol.

Now, drugmakers are doing it intentionally. Helped by better sequencing technologies, screening methods and a broader understanding of RNA, researchers can more easily capture how the information molecules look and design drugs that attach to them.

If successful, they could help unlock disease targets that small molecules can’t currently reach, bringing forward new ways to treat neurodegenerative disorders, cancer and other diseases.

At least eight startups are developing small molecules that target RNA. Large pharmaceutical companies including Sanofi, AstraZeneca, Amgen and Roche have shown interest in their research, promising hundreds of millions of dollars in a string of deals. Here’s where things stand.

What are RNA-targeting small molecules, and how do they work?

Small molecules are chemical-based drugs that usually target proteins and block or change the way they work.

Due to their size, they can reach most tissues in the human body, slip into cells and bind to the craggy parts of their targets. They are the bedrock of the pharmaceutical industry, making up a large majority of drugs on the market.

But small molecules have limited reach. About 3,000 of the roughly 20,000 known genes are considered “druggable,” meaning they can be targeted by a medicine. Of the proteins they produce, only a few hundred are targeted by available drugs. Many of the others don’t have the well-defined pockets that small molecules can nestle into, making them more challenging to reach.

Targeting the RNA molecules that help make disease-associated proteins could give drugmakers an alternate route. In theory, such a drug could stop production of a potentially harmful protein, or make more of a helpful one.

For example, Arrakis Therapeutics is working on a medicine that would block the body from making a well-known, but long thought “undruggable,” cancer protein called Myc. An experimental Expansion Therapeutics drug destroys RNA implicated in a type of muscular dystrophy. Accent Therapeutics and Storm Therapeutics, meanwhile, aim to target the special proteins involved in transcribing and modifying RNA.

They and others in the field face significant challenges, such as finding the right RNA sequences and, within them, the correct locations to target. They also need to ensure their small molecules only stick to their intended targets and not other RNA, which could lead to side effects or other health risks.

What advantages would RNA-targeting small molecules have over existing technologies?

Drugs that interfere with RNA have proven to be powerfully effective tools to treat a range of diseases.

One method, pioneered by Alnylam Pharmaceuticals and known as RNA interference, involves using small, synthetic RNA molecules to “silence” genes and prevent them from creating harmful proteins. Another, similar method, used by Ionis Pharmaceuticals and others, uses strips of nucleic acid called antisense oligonucleotides to adjust or shut off protein production.

Both have advanced RNA drug research, leading to medicines for rare genetic diseases such as spinal muscular atrophy and transthyretin amyloidosis, as well as more common conditions like high cholesterol. The effects of the medicines can last up to months at a time.

While significant progress has been made in delivering these kinds of RNA therapies into the body, they’re still largely restricted to disease targets in the liver, meaning there are many diseases they can’t yet treat.

Research has also noted their propensity to trigger immune responses and, in some cases, difficulty in crossing the blood-brain barrier or entering cells.

Small molecules could help solve these problems. They’re a better known quantity to drugmakers, easier to deliver than nucleic acid-based therapies and, because they’re taken orally, are more convenient for patients.

Small molecules might also be better at permeating cell walls and are more easily absorbed and taken up by the body. They’re cheaper to manufacture, too.

Which companies are working on small molecules that target RNA?

At least eight startups have formed to develop oral RNA-targeting drugs. Half have already caught the eye of bigger pharmaceutical companies looking to invest in the field.

The most richly funded, Skyhawk Therapeutics, has raised at least $181 million in private funding and equity, and more than $400 million in upfront cash from partnerships, according to the company. In July, Sanofi partnered with Skyhawk to develop drugs for cancer and research programs for oncology and immune diseases. Skyhawk also has deals in place with Merck, Biogen and Vertex Pharmaceuticals.

Arrakis, launched in 2015 by a team of Biogen veterans, has raised $113 million to date. Its research has drawn the attention of first Roche and then Amgen, which handed the company a combined $265 million through deals to develop medicines aimed at a variety of disease targets.

Accent has also been successful in luring big pharma, having signed partnerships with AstraZeneca and Ipsen. The company, which is focusing on cancer research, has also raised more than $100 million in venture funding.

Select companies developing RNA-targeting small molecules

Company	Top Investors	Total funding
Accent Therapeutics	EcoR1 Capital, Atlas Venture, The Column Group	$103 million
Arrakis Therapeutics	Canaan Partners, venBio Partners, NexTech Invest	$113 million
Expansion Therapeutics	5AM Ventures, Cormorant Asset Management	$135 million
Gotham Therapeutics (now 858 Therapeutics)	Versant Ventures, Forbion, S.R. One	$54 million
Remix Therapeutics	Foresite Capital	$151 million
Skyhawk Therapeutics	Fidelity Management and Research, Alexandria Venture	$181 million
Storm Therapeutics	Cambridge Innovation Capital, Pfizer Ventures, Merck Ventures	$38 million
Twentyeight-seven	MPM Capital, Sofinnova Partners, Novartis Venture Fund	$83 million

SOURCE: Company press releases

Remix Therapeutics joined the field more recently, launching late in 2020 with $81 million in funding. The company added another $70 million this May, a few months after it teamed up with Johnson & Johnson.

Expansion, formed by pioneering RNA researchers at the Scripps Research Institute, has secured $135 million in funding and is backed by a wide range of investors including the venture arms of Sanofi and Novartis.

Storm, Gotham Therapeutics (which was folded last year into another private biotech called 858 Therapeutics) and Twentyeight-Seven Therapeutics are also researching RNA-targeting small molecules. Storm formed a cancer drug collaboration with Exelixis in 2021.

What is the status of the technology?

While several drugs built on other RNA technologies have made it to market in recent years, small molecules capable of targeting RNA are just beginning to show their potential.

The first to do so was Evrysdi, a drug from Roche and PTC Therapeutics that was approved in 2020 and helps produce a protein that people with spinal muscular atrophy lack. An experimental Huntington’s disease drug from Novartis, known as branaplam, is also in human testing, though recent safety concerns could derail its progress.

So far, none of the startups developing RNA-targeting small molecules have brought a drug prospect into clinical testing. The pipelines for some are beginning to take shape, however.

Skyhawk Therapeutics appears on the cusp of entering clinical trials, previously indicating plans to begin to advance its first drug into human testing sometime this year.

has previously said it expected to test its two lead therapies, both neurodegenerative disease treatments, in humans by the end of 2021. Storm plans to launch a clinical trial for a cancer drug by the end of this year and Accent is working to push forward a cancer medicine with Ipsen. Both candidates target METTL3, an enzyme that affects RNA function.

Arrakis lists early research programs for cancer, dyslipidemia and a COVID-19 antiviral as its most advanced targets. Expansion, meanwhile, is pursuing drugs for muscular dystrophy and ALS.

https://www.biopharmadive.com/news/rna-small-molecule-pill-biotech-startups/630788/

How a top FDA official’s words helped push closely watched ALS drug toward approval

 The meeting was already unusual. Convened by the Food and Drug Administration Wednesday, a group of independent experts were, for a rare second time, gathering to review an experimental drug for ALS that has become the latest litmus test of the agency’s approval standards.

While the drug’s developer, Amylyx Pharmaceuticals, had positive clinical trial results in hand, FDA scientists had raised red flags about how that data was analyzed and, in March, the same expert panel voted against recommending it for approval.

Yet the agency had acknowledged the urgency of getting new medicines to ALS patients, who have few treatment options and face a fast-moving and fatal disease. Documents released ahead of Wednesday’s meeting also emphasized the FDA’s flexibility when considering drugs in this context.

The FDA’s position was made clearest by a 34-minute speech given at the start of the meeting by Billy Dunn, director of the regulator’s Office of Neuroscience and a key player in the agency’s controversial approval of another neurological disease drug, Biogen’s Alzheimer’s treatment Aduhelm.

“Our underlying legal authority is clear in not only allowing, but also endorsing and encouraging the application of regulatory flexibility in the setting of serious and life threatening diseases,” Dunn said at the meeting. “It is unquestionably relevant to ALS drug development in general and to our specific consideration of the data before us.”

Dunn noted how “regulatory flexibility played a direct role” in the past approvals for the two other drugs currently used to treat ALS. He then encouraged the committee members to consider, alongside the available data, a larger, currently enrolling trial of Amylyx’s drug that could provide confirmatory evidence of its benefit in just a few year’s time.

And, in a break for usual practice, he directly called on Amylyx to commit to withdrawing the drug from market should the FDA approve it and that confirmatory study fail.

Surprisingly, Amylyx’s founders did. “To be clear, if [the trial] is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” said Justin Klee, Amylyx’s co-CEO and co-founder.

In a lengthy meeting that involved detailed discussion of clinical trial data, that commitment had an impact, helping shift the vote of at least one panelist and leading to a positive 7-2 recommendation that makes an FDA approval look more likely.

Bryan Traynor, a committee member and senior investigator at the National Institute on Aging, said he was “struck by the public statements” from Amylyx committing to withdraw the drug if that confirmatory study turns out negative. Traynor voted against Amylyx’s drug at the committee’s previous meeting in March, but voted in favor on Wednesday.

Liana Apostolova, a panelist and professor at the Indiana University School of Medicine, noted she was “reassured” by the possibility of a market withdrawal in that event.

Dunn’s comments also carried weight more broadly. Thomas Montine, the panel’s chair and a professor at Stanford University’s School of Medicine, cited them in justifying his decision to vote in favor, while Amylyx’s co-CEOs noted their impact as well.

“The commentary from Billy Dunn — really sharing the regulatory flexibility and applicable standards here for ALS — was also very important and was missing from the first panel,” said Justin Klee, in an interview with BioPharma Dive after the meeting.

Not everyone agreed, though, and one of the panelists who voted no, G. Caleb Alexander of Johns Hopkins Bloomberg School of Public Health, raised doubts about how effectively the FDA could enforce a drug’s withdrawal.

“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” he said.

The agency is set to rule on approval of Amylyx’s drug, called AMX0035, by Sept. 29. Its decision will be closely watched by ALS patients and their families, who have urged the agency to live up to past commitments to take a more flexible approach in reviewing medicines for the neurological disease.

It will also be followed by the pharmaceutical industry, which is trying to divine the FDA’s standards for approving new drugs for brain disorders, especially after the intense debate surrounding the agency’s clearance of Aduhelm in Alzheimer’s.

Wall Street analysts who follow the sector took particular note of Dunn’s speech Wednesday. “We believe his risk-on tone and emphasis on considering the context of data, coupled with what appears to be more openness and flexibility, are likely to create a more favorable overall environment across relevant FDA divisions,” wrote Brian Abrahams, an analyst at RBC Capital Markets, in a note to clients.

https://www.biopharmadive.com/news/amylyx-fda-als-meeting-dunn-flexibility-withdrawal/631533/

Can biotech IPOs bounce back? Third Harmonic to test investor appetite with planned offering

 As recently as last year, a biotechnology startup planning a lucrative initial public offering was the norm, not the exception. Now, Third Harmonic Bio finds itself in lonelier company.

This week, the Cambridge, Massachusetts-based biotech aims to sell 9 million shares at an expected price of between $16 to $18 each. At the high end of that range, Third Harmonic could raise as much as $162 million, a sum that would make its IPO the largest for the sector since May, according to data from BioPharma Dive.

Third Harmonic’s plans represent a test of investors’ appetite for emerging biotech companies. After two record-breaking years in which biotech IPOs raised nearly $30 billion combined, new offerings have ground to a halt in 2022, stunted by macroeconomic forces and a sector-wide stock market slide. By this time a year ago, 82 biotech companies had gone public on U.S. exchanges. This year, only 17 have priced an offering, and the majority have raised less than $40 million.

The more challenging environment has led many venture firms and the companies they back to wait out the market rather than test the waters. Investors interviewed by BioPharma Dive in recent months have said they are building companies more conservatively and expect to keep companies private for longer. Some have suggested a shift away from platform biotechs — drugmakers built around technologies meant to support several medicines — and towards companies focused more narrowly on specific products.

Biotechs that have gone public in 2022 have largely done so at significantly lower values, extending a steady decline in the size of stock offerings over the last two years. Median IPO values have fallen in six of the eight full quarters since the second quarter of 2020, when the median biotech IPO reached a recent peak of $183 million.

So far this quarter, by comparison, three biotechs have priced IPOs, raising $10 million, $8 million and $10 million, respectively.

Amid IPO slump, new stock offerings are getting smaller

Median proceeds raised in biotech IPOs, in millions of dollars and by quarter

Yet good biotech news has flowed over the past few months, prompting some industry watchers to forecast a turnaround. Positive data readouts from companies like Alnylam Pharmaceuticals, Regeneron Pharmaceuticals and Karuna Therapeutics, among others, led to large share price surges and helped boost a widely followed stock index for the sector.

The pace of dealmaking has also picked up, headlined by the recent multibillion dollar buyouts of Biohaven Pharmaceuticals, Global Blood Therapeutics and ChemoCentryx.

Strong interest in Third Harmonic’s IPO could add to the momentum. The company was formed and seeded by Atlas Venture in 2019. It’s run by Natalie Holles, the former CEO of gene therapy biotech Audentes Therapeutics, and emerged from stealth in February with $155 million in funding.

The company fits the profile of a “product”-focused biotech as it is built around an inflammatory disease drug, THB001, that it licensed from Novartis and is developing for a chronic form of skin hives known as urticarias. The drug works by blocking a receptor called KIT that regulates immune cells called mast cells. It’s the same approach Celldex Therapeutics is pursuing with an experimental medicine that’s shown early promise in testing. Celldex’s drug is an injectable antibody, while THB001 is an oral small molecule.

Like most biotechs to go public over the last few years, Third Harmonic doesn’t have much proof yet that its drug works. An early trial in Europe showed the drug lowered levels of a protein associated with an effect on urticarias. It began a Phase 1b trial in Europe this month, and expects to report data next year. A Phase 2 study in the U.S. should follow in 2024. It’s also studying the drug in asthma and plans to evaluate it in a range of other allergic and inflammatory diseases, according to its IPO prospectus.

Third Harmonic paid Novartis $350,000 and issued the Swiss drugmaker roughly 6 million shares of preferred stock — equivalent to a pre-IPO stake of about 9.5% — for rights to THB001. Novartis could get another $232 million in milestone payments if the drug progresses, gets to market and hits certain sales targets.

https://www.biopharmadive.com/news/third-harmonic-biotech-ipo-downturn/631589/

Evidence lacking for screening children for prediabetes, T2D: US Task Force

 The U.S. Preventive Services Task Force (USPSTF) concludes that evidence is insufficient to recommend for or against screening children or adolescents for prediabetes or type 2 diabetes. These findings form the basis of a final recommendation statement published in the Sept. 13 issue of the Journal of the American Medical Association.

Daniel E. Jonas, M.D., M.P.H., from RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center, and colleagues reviewed the evidence on the benefits and harms of screening children and adolescents for prediabetes and type 2 diabetes. Data were included from eight publications, with 856 participants; six publications were from the Treatment Options for Type 2 Diabetes in Adolescents and Youth study. The researchers found that none of the studies directly examined the benefits or harms of screening.

Based on these findings, the USPSTF concludes that the evidence is insufficient for assessing the benefits and harms of type 2 diabetes screening in children and adolescents (I statement).

"The rate of prediabetes and type 2 diabetes in youth is increasing," a task force member said in a statement. "It is important that health care professionals be aware of the signs and symptoms of prediabetes and type 2 diabetes and use their judgment when determining whether or not to screen youth."

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Explore further

USPSTF: Evidence lacking for T2DM screening in children

More information: Evidence Report
Final Recommendation Statement
Editorial 1
Editorial 2

https://medicalxpress.com/news/2022-09-task-evidence-lacking-screening-children.html

How the U.S. drug pricing law affects Medicare and its members

 U.S. President Joe Biden last month signed the $430 billion Inflation Reduction Act, authorizing the federal government to negotiate prices on some prescription drugs and cap costs for the government’s Medicare health program.

In 2024, the government will start negotiating what it will pay for 10 drugs, with the new prices taking effect in 2026. They will be chosen from among some of the 50 medicines responsible for the highest Medicare spending that have no cheaper generic or biosimilar alternatives.

The first group of medicines would include those sold mostly in pharmacies to treat diseases such as diabetes, cancer and arthritis. They will be announced in 2023.

The law does not include the newer medicines, only those that have been on the market for at least nine years.

It also excludes generic drugs, such as most statins and blood pressure medicines, or less expensive versions of pricey biologic drugs known as biosimilars. Many rare disease drugs – typically some of the priciest on the market – also are excluded.

The government has said it will negotiate prices on 15 drugs for 2028 and 20 for the year 2029, expanding the pool to include those administered in hospitals and by doctors, such as infusions and injectables.

According to a Kaiser Family Foundation analysis based on 2019 prices, if the 2029 parameters took effect this year, Medicare could negotiate the prices of 20 drugs that cost it $25.7 billion in 2019 and were used by about 7 million people, or 1-in-7 of those enrolled in the program that year.

WHAT ELSE DOES THE LAW DO?

Beginning in 2025, everyone enrolled in Medicare will have out-of-pocket pharmacy drug costs capped at $2,000 per year.

Other changes come into play next year, when Medicare enrollees will no longer have co-pays on vaccines and price increases on drugs will be limited to below the rate of inflation. Price increases for half of all drugs covered by Medicare outpaced inflation from 2019 to 2020, which averaged 1% that year. A third of those had price jumps of over 7.5%.

In 2024, people enrolled in Medicare plans managed by insurers, called Medicare Advantage, may benefit from a cap on premium increases of 6% until 2030.

In addition, the law eliminates the so-called prescription drug donut hole – a 5% coinsurance payment on drugs that can amount to thousands of dollars a year for more than 1 million people.

CAN DRUG COMPANIES OPT OUT?

Companies that refuse to negotiate drug prices will be subject to an excise tax on sales of up to 95%. Companies can opt to not have their drugs covered by Medicare and Medicaid, the low-income U.S. health program, but Medicare is an enormous source of revenue for drugmakers.

Companies that end up charging more than the negotiated price will face penalties up to 10 times the difference between what was negotiated and the price they actually charge. Those that raise prices beyond the inflation rate also will pay a penalty fee.

https://leaderpost.com/pmn/business-pmn/how-the-u-s-drug-pricing-law-affects-medicare-and-its-members

Court Rehears Fight Over Vaccine Mandate for Federal Workers

President Joe Biden has the same authority to impose a COVID-19 vaccine requirement on federal workers that private employers have for their employees, an administration lawyer told a federal appeals court Tuesday.

A lawyer for opponents of the vaccine requirement, which has been blocked nationwide by a federal judge in Texas, said the requirement imposes an "unconstitutionally intolerable choice" for executive branch workers — taking a vaccine they don't want or losing their jobs.

Judges on the appeals court meanwhile questioned how far the chief executive's authority goes, asking, theoretically, whether the president could require employees to meet certain healthy body weights or forbid them from smoking at home.

It was the second time arguments on the issue were heard before the 5th U.S. Circuit Court of Appeals. A three-judge panel of the same court had upheld the Biden requirement for executive branch workers, overturning the Texas judge.

But the full appeals court, currently with 16 active members, vacated the panel ruling and agreed to rehear the case. There was no indication when the court would rule.

Administration lawyers argue that the employees opposing the mandate should have taken their objections not to federal court but to a federal review board, in accordance with the Civil Service Reform Act. The administration also argues that the president has the same authority, under the Constitution, as the CEO of a private corporation to require that employees be vaccinated.

Arguing for the government, Charles Scarborough of the Department of Justice, said the statute provides employees with "robust" remedies if they successfully challenge the requirement through the review board, including back pay if they are dismissed for not complying.

Addressing whether the president could impose body weight requirements on federal employees, Scarborough said the vaccine requirement is part of a mainstream effort to reduce the incidence of serious COVID-19 cases in the workplace, while a body weight requirement would be among "hypotheticals at the extremes."

Opponents say the policy is an encroachment on federal workers' lives that neither the Constitution nor federal statutes authorize. And they argued that a case involving a policy that could cost some workers their jobs if they don't agree to a medical procedure is not the type of work policy that belongs before a civil service review board.

Biden issued an executive order Sept. 9 ordering vaccinations for all executive branch agency employees, with exceptions for medical and religious reasons. U.S. District Judge Jeffrey Brown, who was appointed to the District Court for the Southern District of Texas by then-President Donald Trump, issued a nationwide injunction against the requirement in January.

There came a series of varying rulings at the 5th Circuit.

One three-judge panel refused to immediately block the law.

But, a 2-1 ruling on the merits of the case by a different panel upheld Biden's position. Judges Carl Stewart and James Dennis, both nominated to the court by President Bill Clinton, were in the majority. Judge Rhesa Barksdale, a senior judge nominated by President George H.W. Bush, dissented, saying the relief the challengers sought does not fall under the Civil Service Reform Act cited by the administration.

A majority of the full court voted to vacate that ruling and reconsider the case, resulting in Tuesday's hearing.

Twelve of 16 active judges at the 5th Circuit were nominated to the court by Republicans, including six Trump appointees. Senior judges do not routinely take part in full-court hearings but Barksdale participated in the hearing Tuesday because he had been on the earlier panel.

https://www.medscape.com/viewarticle/980724

Donanemab Analyses Suggest Benefits for Select Alzheimer's Patients

 Baseline amyloid levels predicted amyloid plaque response with donanemab, an investigational drug targeting N-terminal pyroglutamate beta-amyloid in early Alzheimer's disease, a post hoc review of phase II TRAILBLAZER-ALZ data found.

The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (r −0.54, P<0.001). On average, people with a greater baseline amyloid plaque level had greater amyloid plaque removal.

Clearing amyloid plaques with donanemab was associated with less clinical decline, but exploratory analyses indicated the benefit may emerge only in certain patients, reported John Sims, MD, and co-authors, all employees of drug developer Eli Lilly in Indianapolis, writing in JAMA Neurology.

A disease-progression model showed a significant association between the percentage of amyloid reduction and changes on the integrated Alzheimer Disease Rating Scale (iARDS) in people who carried an APOE4 risk allele, but not in others.

Modeling also suggested a hypothesis that amyloid plaques might remain below the amyloid-positivity threshold for about 4 years after discontinuing donanemab. No substantial treatment effect on global tau load emerged, but neocortical and regional standardized uptake value ratios showed donanemab slowed tau accumulation in a region-dependent manner.

"These results underscore the importance of amyloid plaques in Alzheimer's disease and understanding amyloid status for treatment decisions," Sims and colleagues wrote.

The findings "predict that those with lower baseline amyloid levels are more likely to be able to stop donanemab treatment sooner," they added. "Once complete amyloid clearance was achieved and participants switched to placebo infusions, plaques did not regrow substantially over 1 year without treatment."

The previously reported TRAILBLAZER-ALZ study of 257 early symptomatic Alzheimer's patients -- 131 randomly assigned to donanemab and 126 to placebo -- showed donanemab met its primary endpoint on the iADRS, a composite measure developed by Lilly that combines the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL).

Baseline iADRS scores in TRAILBLAZER-ALZ were 106 out of a possible 144 in both groups (lower values indicate greater cognitive and functional impairment). Change from baseline at 76 weeks was −6.86 with donanemab and −10.06 with placebo, a difference of 3.20 points (95% CI 0.12-6.27, P=0.04).

In TRAILBLAZER-ALZ, overall reductions in amyloid plaque levels and global tau load on PET were 85.06 centiloids greater and 0.01 greater, respectively, with donanemab than with placebo at 76 weeks. Participants were considered to achieve complete plaque clearance if their post-treatment amyloid level was below 24.1 centiloids, the same threshold consistent with an Alzheimer's disease diagnosis.

Almost three-quarters of study participants carried APOE4. Amyloid-related cerebral edema or effusions, mostly asymptomatic, occurred in 26.7% of the donanemab group and 0.8% of the placebo group.

Using correlations, regressions, and modeling to examine possible relationships between amyloid reduction and either tau pathology or clinical outcomes, post-hoc analyses suggested:

• Once it reached 11 centiloids or less, amyloid might not re-accumulate to the 24.1-centiloid level for 3.9 years (95% prediction interval, 1.9-8.3 years) after stopping treatment.
• Participants with complete plaque clearance at 24 weeks showed a greater slowing of tau accumulation over 18 months than those who didn't reach the 24.1 centiloid threshold by that point.
• Relationships between amyloid reduction and iADRS scores were significant in APOE4 carriers, but not in participants without APOE4, which may be due to the relatively few noncarriers in TRAILBLAZER-ALZ or pharmacogenomic differences in treatment response, the researchers noted.

Interpretation of these exploratory analyses should be with caution, Sims and co-authors warned. The results did not control for multiplicity, and inflated type I error likely exists, they acknowledged. Ongoing donanemab trials -- TRAILBLAZER-EXT, TRAILBLAZER-ALZ2, and TRAILBLAZER-ALZ4 -- may confirm findings.

Lilly initiated a submission for donanemab for accelerated approval. The FDA accepted donanemab for priority review, the drug maker announced in August.

Disclosures

This study was sponsored by Eli Lilly and Company.

All researchers received stock options and a salary from Eli Lilly and Company.

Primary Source

Neurology

Source Reference: Shcherbini S, et al "Association of amyloid reduction after donanemab treatment with tau pathology and clinical outcomes: The TRAILBLAZER-ALZ randomized clinical trial" JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2022.2793.

https://www.medpagetoday.com/neurology/alzheimersdisease/100667