In unanimous votes, FDA advisory committee favors approval of Lilly’s donanemab
Eli Lilly gained serious momentum last week in its quest for FDA approval of donanemab, an investigational treatment for early Alzheimer’s disease.
Lilly had hoped to receive accelerated approval of donanemab earlier this year, but the FDA declined to grant it.
The regulatory agency was scheduled to decide on the drug’s fate in March but extended the decision deadline to allow time for input from a panel of independent experts. The Peripheral and Central Nervous System Drugs Advisory Committee met last Monday to discuss specific topics pertaining to the design of the drug’s pivotal trial and the outcomes.
In the Phase III TRAILBLAZER-ALZ 2 trial, enrollees underwent PET imaging to evaluate the presence and level of tau in their brains. Tau, a protein that forms after amyloid accumulates, appears to correlate with the severity of cognitive impairment. Those with no or very low tau were excluded, and Lilly focused primarily on participants with low to medium levels of tau (indicating an earlier stage of the disease).
While those with higher tau levels (indicating more advanced disease) were included in the overall study population, Lilly said it would likely be more difficult to determine a treatment effect in these participants. Slightly more than two-thirds of the 1,736 participants were in the low/medium tau group and the remaining participants were in the high tau group.
The FDA asked the panel of experts to weigh in on Lilly’s use of tau imaging in the trial, the exclusion of enrollees with no or low tau, and the fact that Lilly did not request that tau imaging be used to screen potential patients before starting treatment with donanemab in routine clinical practice.
The committee’s chairperson, Dr. Thomas Montine, said most of the panel members believed that requiring tau imaging would present an unnecessary barrier that would restrict access to the drug.
The trial results demonstrated that participants with intermediate tau levels experienced a significantly slower decline during treatment — measured using two different scales — as compared with those having higher levels of tau (and compared with placebo).
In separate votes, the committee voted 11-0 that 1) the available data supports the effectiveness of donanemab in individuals with mild cognitive impairment and mild dementia, and 2) the drug’s benefits outweigh its risks in these same individuals.
Dr. Kathleen Poston, also a member of the panel, said the biomarker data “were convincing of the effect,” adding, “the benefits outweigh the risks, as long as the risks are being monitored.”
Like other drugs in its class, donanemab appears to increase the risk for amyloid-related imaging abnormalities (ARIA), particularly ARIA with edema or effusion (ARIA-E; brain swelling) and ARIA with microhemorrhages and hemosiderin deposits (ARIA-H; brain bleeding). In most cases, ARIA is asymptomatic and resolves with time, though it can be severe and sometimes fatal. Individuals with a certain genetic form of Alzheimer’s are at higher risk of developing ARIA.
In the TRAILBLAZER-ALZ 2 trial, 24% of the participants in the donanemab group experienced ARIA-E and 31.4% experienced ARIA-H. Three ARIA-related deaths were attributed to treatment with donanemab.
In documents Lilly provided ahead of the committee meeting, the company wrote, “Beyond the known class-risk of ARIA with a low frequency of fatal events (0.03%), there is no evidence of an increase in risk of mortality or excess death related to donanemab.”
Dr. Cynthia Carlsson, another panel member, said steps to manage ARIA could be implemented, and risks could be “safely clarified with a proposed MRI program and training.”
Advocates for patients with Alzheimer’s had the opportunity to provide comments during the committee meeting. Several noted that people living with the disease face certain decline and death, and that even modest benefits are worth the risks associated with treatment.
The FDA also asked the panel members for their opinions on a unique aspect of TRAILBLAZER-ALZ 2: Trial participants stopped taking donanemab when scans showed they had achieved clearance of amyloid.
Overall, the committee members thought that stopping treatment would be beneficial for patients who no longer need to be on the drug, but they questioned how clinicians would be able to determine when patients should undergo additional PET scans to assess the absence of amyloid.
Dr. Montine, the committee chair, said the trial design prompts questions about the duration of the drug’s benefit, how to monitor patients between the time they stop and resume treatment, and what kind of side effects patients might experience during the cessation period or when they restart treatment.
“We just don’t know the answer to any of these things,” he said, noting that his feeling after listening to comments during the hearing “is the committee feels that this is an innovative and positive outcome of the way the trial was designed.”
The panel suggested that additional testing might provide answers to some of the questions. Some committee members also urged Lilly to study the drug in a more diverse population, including more Black patients, Hispanic patients, and patients with Down syndrome or autosomal dominance Alzheimer’s disease.
However, the committee members did not think a lack of evidence for these subgroups of the population should delay making the drug available to the public.
The FDA has not set a date for deciding whether to approve donanemab. The agency usually follows the recommendations of its advisory committees.
Our Take: If the FDA approves donanemab, which we expect to happen fairly quickly now, then Eisai and Biogen will have a rival for their approved Alzheimer’s treatment, Leqembi (lecanemab-irmb), which, like donanemab, is an anti amyloid antibody.
Leqembi was approved in January 2023 on an accelerated basis, and the drug received traditional approval last July.
No head-to-head trials have been conducted to compare Leqembi and donanemab, but the results of trials that have been conducted seem to suggest that Leqembi may have a preferable safety profile.
Paul Matteis, an analyst with Stifel, wrote in a client note that Leqembi’s “clear safety advantage is a huge deal for risk-averse neurologists, especially for a drug class where the magnitude of efficacy continues to be debated,” Biopharma Dive reported.
But some physicians may choose to initiate treatment with donanemab because of its dosing schedule. It requires infusions once every four weeks, whereas Leqembi is infused every two weeks.
Although additional studies may reveal more distinctive differences between the two drugs, in the interim, some industry analysts believe donanemab’s approval could increase sales of Leqembi.
“A rising tide lifts all boats, in our view,” wrote Myles Minter, an analyst as William Blair, according to Biopharma Dive.
Marc Goodman, an analyst at Leerink Partners, wrote that donanemab’s approval could “accelerate the uptake of this class by helping build the commercial infrastructure” the drugs need.
And Michael Yee, with Jefferies, noted that having a choice of two drugs would serve to raise awareness among physicians and patients.
What else you need to know
Alphabet’s Verily introduced an AI-powered chronic care platform called Lightpath, which it plans to pair with health coaches and a team of clinicians to serve “multiple tiers of acuity” as members’ needs change between intensive management and maintenance phases. The first Lightpath programs will focus on cardiometabolic conditions, including type 1 and type 2 diabetes, hypertension, comorbid obesity, and hyperlipidemia. Lightpath Metabolic will also include a clinically guided weight-loss program that will offer approved anti-obesity medications such as, presumably, the popular GLP-1s. The platform will apply integrated data to personalize members’ experience and provide rapid feedback loops to help drive changes in behavior. Members will have the option to connect with the clinical team via telehealth and communicate with “an AI helper.” Verily is planning to have the Lightpath platform available for open enrollment in 2026.
Ascension announced on Friday that access to its core electronic health record system and patient portals has been restored, following the cyberattack that occurred on May 8. Earlier in the week, Ascension said evidence indicates that hackers took files that may contain protected health information and personally identifiable information for some individuals. The St. Louis-based health system also said it identified how the attackers gained access to its systems — someone working in one of its facilities accidentally downloaded a malicious file. “We have no reason to believe this was anything but an honest mistake,” the organization stated. While Ascension conducts a full review of the files it believes were affected, the health system is offering complimentary credit monitoring and identity theft protection to its patients and associates who request the services. The investigation into the cyberattack is ongoing.
The Department of Veterans Affairs renewed its EHR contract with Oracle, even though a recent internal survey found that users of the electronic health record system are not happy with it. Bloomberg reported on the survey, noting that VA researchers wrote in the survey report: “There is a trend toward improvement; however, most users still indicate a negative experience.” Additionally, fewer than 20% of physicians, nurses, and other employees thought the EHR system allowed them to provide high-quality care, and only about 22% of the survey respondents indicated that their training on the new system was beneficial. A VA spokesman acknowledged that the EHR system “is not yet meeting expectations,” and said the agency is holding both itself and Oracle accountable “to get this right.” Originally, the VA entered into a $10 billion agreement with Cerner in 2018 to modernize the EHR system. Multiple delays and problems ensued, escalating the cost to $16 billion, and Oracle acquired Cerner in 2022. A year ago, the VA halted additional deployment of the system to work on correcting the known problems. It also renegotiated the contract with Oracle, switching from a five-year term to five one-year terms. The VA laid out in a press release the objectives it negotiated for the upcoming second term.
The FDA granted accelerated approval to Ipsen and Genfit’s Iqirvo (elafibranor) for use in adults with primary biliary cholangitis, a rare, autoimmune liver disease. The drug, a first-in-class oral, once-daily PPAR agonist, is approved for use in combination with ursodeoxycholic acid (UDCA) for patients who have an inadequate response to UDCA and as monotherapy for those who cannot tolerate UDCA. Ipsen noted in a press release that primary biliary cholangitis causes irreversible fibrosis and can lead to liver failure and premature death if left unmanaged. In some cases, a liver transplant may be necessary. Iqirvo is the first new drug to be approved for the condition in nearly a decade, according to Ipsen. The drug has an estimated list price of $11,500 for a month’s supply, Reuters reported. A confirmatory trial will need to be conducted before the drug can be given traditional FDA approval.
CivicaScript’s first generic drug has generated nearly $3 million in savings for Highmark, its members, and its group customers (e.g., employers) since the drug became available last September, the insurer said in a press release. Plan members who take the drug, abiraterone acetate, which is used to treat prostate cancer, save an average of $90 per month in out-of-pocket expenses, Highmark said. Founded in 2020 by Highmark, the Blue Cross Blue Shield Association, and other Blues health plans, CivicaScript is a subsidiary of Civica Rx. CivicaScript said it will continue to expand its portfolio of lower-cost drugs, with a focus on generic outpatient drugs that treat specialty and other chronic health conditions such as cancer and diabetes.
A bipartisan group of 32 state attorneys general have asked the Supreme Court to rule on states’ authority to regulate pharmacy benefit managers. In an amicus brief, the group asked the high court to review a decision from the 10th U.S. Circuit Court of Appeals; that decision blocked Oklahoma laws regulating PBMs. In the amicus brief, the AGs said the circuit court’s broad approach to preemption would “severely and unduly impede states’ abilities to protect their residents and regulate businesses,” according to a news release from the office of Minnesota AG Keith Ellison.
What we’re reading
CMS Should Create Clinician Workforce Quality Metrics. Health Affairs, 6.11.24
Mass General Brigham’s Patient-Reported Outcomes Measurement System: A Decade of Learnings. NEJM Catalyst, 6.12.24
Trends in Private Equity Consolidation in Cardiovascular Care. JAMA Forum, 6.14.24
