The clinical benefits previously reported for Eli Lilly’s donanemab were borne out by full data from a Phase 3 trial of the monoclonal antibody, the drugmaker said Monday, presaging a two-way battle between drugs that clear brain amyloid plaque in patients with early Alzheimer’s disease.
The detailed results from the Phase 3 TRAILBLAZER-ALZ 2 study — shared both during the Alzheimer’s Association International Conference (AAIC) and in parallel in the Journal of the American Medical Association (JAMA) — were largely in line with a May topline release.
They showed that donanemab “significantly slowed” cognitive and functional decline in people with mild cognitive impairment (MCI) or early dementia.
An approval decision by the Food and Drug Administration is expected by year’s end, based on a submission filed with the regulator earlier this year, Lilly said.
The findings further bolstered donanemab’s strong profile, analysts said. The results also foreshadowed a market showdown pitting the relative merits of donanemab’s finite treatment regimen against the cleaner safety profile of Leqembi, the anti-amyloid drug developed jointly by Eisai and Biogen which was approved earlier this month by the FDA.
“If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease and the possibility of completing their course of treatment as early as six months once their amyloid plaque is cleared,” stated Anne White, EVP of Lilly and president of its neuroscience unit, in an announcement.
In the earlier readout, donanemab showed a 29% benefit versus placebo on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the largest clinical benefit to date shown on the rating scale. That compared with a 27% benefit seen in Eisai’s Clarity-AD study of Leqembi.
One takeaway from Monday’s detailed data drop was support for the notion that “earlier is better” when it comes to patient intervention. Among subjects with low-to-medium levels of tau (a biomarker for the presence of amyloid plaque in the brain), donanemab slowed decline by 36% on the CDR-SB, versus 20% to 30% for the total population.
That equates to a 0.67 improvement on the CDR-SB, versus a maximum benefit of 1.88, which was the decline seen in the placebo group.
In that context, “0.67 is highly meaningful,” observed Dan Skovronsky, Lilly’s chief scientific and medical officer, on a call with investors Monday. “An analysis showed that this translates to 7.5 months of time savings for patients.”
As further proof of an early dosing benefit, Lilly noted that nearly half of participants at the earlier stage of disease on donanemab had no clinical progression at the one-year mark. Additional subpopulation analyses presented at AAIC showed that those study participants at the earliest stage of disease had an even greater benefit, with 60% slowing of decline versus placebo.
In addition, the study showed greater benefits for patients diagnosed with MCI at baseline as compared to those with mild Alzheimer’s. These MCI patients saw a 46% CDR-SB at 76 weeks while patients under 75 years of age also saw a benefit of 45% to 50%.
Continued efficacy for patients
Lilly, in fact, has said it believes AB-antibodies will show even greater efficacy in the prevention setting.
“These data points appear to support a view that earlier intervention could be associated with very meaningful reductions in patient progression — something Lilly will be studying in the TRAILBLAZER 3 trial, which looks at an asymptomatic preclinical population,” pointed out J.P. Morgan analyst Chris Schott in a note to investors Monday.
“We anticipate Lilly will receive a broad label for donanemab given the benefit in the broader population and with all efficacy datapoints trending in a positive direction,” the analyst wrote.
Another big takeaway from the data release was a validation of Lilly’s “finite-dosing” approach. Donanemab’s treatment effect expanded over time, with the effect continuing to grow even for those patients who stopped dosing early.
This held true for those patients who stopped dosing early due to their amyloid burden being brought back into the normal range. In other words, discontinuing dosing once plaque clearance had been achieved did not appear to impact efficacy.
“We see this data as well as earlier extension data from the phase 2 study as further validating Lilly’s finite-dosing approach for donanemab (which should alleviate some of the burdens associated with continuous dosing for Leqembi),” added Schott.
Addressing adverse events
A third takeaway from the in-depth readout involved adverse events. Hemorrhaging and edema have so far been the main side effects plaguing these drugs.
Donanemab’s rate of amyloid related imaging abnormalities (ARIA) was largely in line with expectations, with Leqembi maintaining a slight safety edge. About 6% of patients on the donanemab cohort experienced symptomatic ARIA, which is above the roughly 2.8% seen with Leqembi, Schott observed, although differences in study baseline populations likely played some role in this difference.
Similar to Leqembi, ARIA rates were far higher in those with the ApoE4 allele, specifically in those with identical copies of the gene from both parents.
In the donanemab trials, three deaths were determined to be drug-related among participants who developed serious ARIA. During the Leqembi trials, two patient deaths due to hemorrhage were seen, although the difference in mortality between the treatment and placebo arms was nowhere near statistically significant.
Safety issues are one reason the Centers for Medicare and Medicaid Services is requiring patients to be enrolled in a registry for traditionally approved antibody Alzheimer’s treatments to be covered under Medicare. The portal is designed to gather evidence about the effectiveness and safety of the drugs in real-world practice.
Such data will also help assess value. In an accompanying JAMA editorial, Meredith Rosenthal of the Harvard School of Public Health noted that, at a projected launch price of $28,000, donanemab would not be cost-effective. In an earlier analysis by an influential drug pricing watchdog, Leqembi was found to be cost-effective at 19% less than its $26,500 sticker cost.
From a health system point of view, both drugs raise affordability issues. Lilly estimated the prevalence of early symptomatic Alzheimer’s with amyloid plaque at between 6 million to 7 million people in the U.S., only 30% of whom get diagnosed. It follows that reimbursement for these pricey therapies could “quickly swell public and private healthcare budgets,” Rosenthal cautioned.
“Moreover, Black patients, who are disproportionately diagnosed with AD, are 1.5 times more likely to be uninsured than White patients, which could make treatment with donanemab inaccessible given the overall cost of treatment noted above,” Rosenthal wrote.
Speaking of which, another editorial criticized the Lilly trial for a lack of diversity in the study population.
“I wish we had better diversity,” acknowledged Skovronsky, when asked about the topic during the call.
He cited the difficulty in recruiting from minority populations during the study’s enrollment period, which overlapped with the COVID-19 pandemic, and added that he expects the larger safety database to better reflect the diversity of the Alzheimer’s patient base.
Meanwhile, analysts were busy handicapping a looming donanemab-Leqembi faceoff. Raymond James analyst Danielle Brill asserted in a research note that donanemab’s more convenient dosing schedule will be alluring to clinicians and patients upon approval.
“While lecanemab has a slight first-mover advantage, we ultimately expect a relatively equitable split of the market between the two anti-AB agents,” Brill wrote.
That said, “In all, we still view the safety/efficacy profile of donanemab as relatively similar to lecanemab, with a slight edge on efficacy, but a slightly higher risk of ARIA,” the analyst wrote.
Schott also doesn’t expect the donanemab safety data to “meaningfully shift” the coming showdown with Leqembi.
“We continue to see donanemab having a favorable dosing profile while Leqembi continues to have a slight safety advantage leading to a market split between the two drugs and expect identifying/managing ARIA to remain a top area of focus for the class,” he concluded.
Schott reiterated that he sees a slow sales ramp in the near-term for both drugs, due to data-collection requirements and limitations in the diagnostic infrastructure, and a 60-40 Alzheimer’s market split in favor of Lilly.
Some physicians, he explained, will prefer the brisk plaque clearance and finite regimen of donanemab, while others may lean toward Leqembi for its relatively cleaner safety profile.
On the call, Lilly execs were also asked about the hurdle of educating physicians to properly identify candidates for the medications, as well as manage the safety risk.
“You’ll see us continue those efforts around education,” said White.
