The benefit-risk balance is tipping more in favor of Eli Lilly’s Kisunla in early Alzheimer’s disease as the FDA approves a new dosing regimen of the drug with an improved safety profile.

The new recommended regimen for Kisunla features a more gradual titration and a significantly lower rate of brain swelling known as amyloid-related imaging abnormalities with edema and effusion (ARIA-E) when compared to the original regimen.

ARIA is a class-wide side effect that has impeded broader adoption of anti-amyloid antibody drugs, including Kisunla, in early Alzheimer’s disease.

“Anything we can do to advance the science in that space should have an impact on the benefit-risk discussions that clinicians are having with patients,” Brandy Matthews, M.D., Lilly’s VP of global & U.S. medical affairs for Alzheimer’s disease, said in an interview with Fierce Pharma.

The original Kisunla regimen would give patients two 350 mg vials of the drug for each of the first three infusions before increasing to four vials from the fourth dose. The updated dosing instead starts with one vial for the first infusion, followed by two vials and then three vials in the next two infusions, and four vials per dose thereafter. The drug is still administered every four weeks.

In a phase 3b study coded Trailblazer-Alz6, the modified Kisunla regimen significantly lowered the incidence of any ARIA-E to 14%, compared with 24% for those receiving the original regimen, by week 24. This translates into a 41% lower risk for the new dosing regimen.

At one year, the rate of ARIA-E was 16% and 25% for the two regimens, respectively, with the tweaked version linked to a 35% lower risk.

The modified titration group also experienced fewer severe ARIA-E events. Among patients who received the modified regimen, no one developed radiographically severe ARIA-E. That’s compared with two cases of such severity for the original regimen in the phase 3 Trailblazer-Alz2 study that underpinned Kisunla's FDA nod in early symptomatic Alzheimer’s, Matthews noted.

The new dosing regimen pared down ARIA-E incidents without compromising the drug’s amyloid-lowering ability. At 24 weeks, patients on the modified titration regimen had on average 67% reduced amyloid plaques versus baseline, compared with 69% for those on the original dosing regimen, Trailblazer-Alz6 showed.

“The results of the study can have really significant and positive implications for both healthcare professionals and patients as they’re engaging in these benefit-risk discussions related to the initiation of [Kisunla],” she said.

The study, however, didn’t observe a significant difference on another type of ARIA, brain bleeding known as ARIA-H. The trial investigators argued that the study would need to enroll a much larger population to be able to detect a significant lowering of ARIA-H because this phenomenon often occurs spontaneously, including in patients who are not receiving amyloid-targeting therapies.

Lilly’s effort to make Kisunla safer comes as anti-amyloid drugs have struggled to gain traction, partly because of questions surrounding their benefit-risk profiles. In March, drug reviewers at the European Medicines Agency rejected Kisunla while specifically highlighting the risk of ARIA. European regulators are currently re-evaluating Kisunla’s case.

After Eisai and Biogen’s Leqembi, industry watchers were hoping that Kisunla's entry in 2024 would expand the Alzheimer’s market. But that didn’t happen. In the first quarter of 2025, Lilly only recorded $21.5 million in Kisunla sales globally. Leqembi’s sales were $96 million during the same period.

Besides safety profiles that need to be carefully assessed, limitations with cumbersome diagnostic methods have also hindered the rollout of anti-amyloid drugs. The FDA recently approved the first blood-based test to help diagnose Alzheimer’s, but analysts figured its potential positive impact on treatment uptake will take time.

Now, industry watchers await results from the Trailblazer-Alz3 trial, which is evaluating Kisunla in cognitively unimpaired patients with evidence of Alzheimer’s disease pathology. The treatment setting is referred to as preclinical Alzheimer’s, given that patients have not shown any symptoms.

Trailblazer-Alz3 “could be THE most important trial in terms of changing the treatment paradigm for Alzheimer’s,” Jefferies analysts wrote in a May note.

The study currently bears a primary completion date for 2027, although Jefferies noted that the study could read out earlier since it’s an event-driven trial using a time-to-progression primary endpoint.