Donanemab (Kisunla): Eli Lilly's Alzheimer's Treatment and What Sets It Apart

Donanemab (brand name Kisunla) is a monoclonal antibody developed by Eli Lilly that targets a modified form of amyloid-beta called pyroglutamate amyloid-beta (N3pG). This particular form is found almost exclusively in established amyloid plaques rather than in the soluble forms of amyloid circulating in the brain. This targeting strategy means donanemab acts very specifically on existing plaque deposits.

The drug is administered by intravenous infusion every four weeks — less frequently than lecanemab's every-two-week schedule. In clinical trials, donanemab produced very aggressive amyloid clearance: by around six months of treatment, a substantial proportion of patients had amyloid levels on PET scan fall below the threshold used to define amyloid positivity.

One distinctive feature of donanemab's development program is that the trials allowed for treatment discontinuation when amyloid was fully cleared. Because the drug specifically targets plaque deposits, once those deposits are gone, the drug has nothing left to bind. Patients who achieved amyloid clearance were switched to placebo — and their outcomes were compared to those who continued active treatment, allowing researchers to assess whether durable benefit remained after stopping.

The pivotal TRAILBLAZER-ALZ 2 trial enrolled 1,736 participants with early symptomatic Alzheimer's disease and confirmed amyloid and tau pathology. Results were published in JAMA in July 2023. The trial is notable for stratifying participants by tau level — those with low-to-medium tau (earlier-stage disease) versus those with high tau (more advanced disease).

In the overall population, donanemab reduced decline on the integrated Alzheimer's Disease Rating Scale (iADRS) by 22% compared to placebo. In the low-to-medium tau group — those with earlier disease — the benefit was substantially larger: 35% slower decline. This stage-specific benefit underscores the importance of early intervention: the earlier the treatment, the greater the slowing effect.

FDA approval was granted in July 2024. Like lecanemab, donanemab carries significant ARIA risk — about 24% of participants developed ARIA-E (brain swelling) and 31% developed ARIA-H (microhemorrhages), with higher rates than seen in the lecanemab trial. Three deaths in the TRAILBLAZER-ALZ 2 trial were considered possibly related to ARIA.

The amyloid clearance rates were impressive: roughly 40% of donanemab-treated patients had amyloid cleared below the positivity threshold by six months, and 76% by twelve months. Whether patients who stopped after achieving clearance maintained their benefit over longer follow-up remains an important ongoing research question.

Like lecanemab, donanemab is specifically for early Alzheimer's disease with confirmed amyloid pathology. The potential for a finite treatment course — rather than indefinite ongoing infusions — is clinically meaningful for patients and healthcare systems. If amyloid can be cleared and patients can then discontinue treatment while retaining benefit, the overall burden and cost of therapy could be substantially reduced.

The stage-dependency of the benefit is an important clinical signal. In the low-to-medium tau subgroup, 35% slowing represents a real-world difference in how long someone remains independent and functional. In the high-tau group, the benefit was not statistically significant. This means donanemab appears most useful when started before tau pathology has advanced significantly.

For people currently in the early stages of Alzheimer's or approaching eligibility, the choice between lecanemab and donanemab will depend on individual factors: ARIA risk profile, APOE4 status, logistical preferences around infusion frequency, and clinician experience. Neither drug is obviously superior — they are both meaningful advances.

The ARIA risk profile with donanemab is somewhat higher than with lecanemab in trial data, which may influence prescribing decisions. APOE4 homozygotes face substantially elevated ARIA risk with both drugs and require careful counseling.

Donanemab's approval in 2024, following lecanemab's in 2023, establishes anti-amyloid immunotherapy as a genuine treatment category in early Alzheimer's care. Having two approved options creates clinical experience, competitive pressure that may improve access, and an evidence base that will grow as more patients are treated in real-world settings.

The possibility of treatment discontinuation after amyloid clearance is a conceptually important development. If validated in longer-term follow-up, it suggests that amyloid clearance itself may produce durable neuroprotective changes — not just a temporary suppression of pathology. This would strengthen the argument that early detection and early treatment is not just slowing an inevitable decline but actually modifying the disease course.

Both donanemab and lecanemab reinforce the same strategic implication for the broader field: early detection matters more than it ever has. These drugs work best in the earliest stages, which means identifying who is in those stages — and monitoring who is approaching them — has direct therapeutic relevance.

Researchers are now exploring combination approaches that pair amyloid clearance with tau-targeting therapies, neuroprotective agents, and lifestyle interventions. The next decade of Alzheimer's treatment research is likely to look very different from the previous one: not single-drug trials, but combination strategies in carefully selected, carefully monitored early-stage patients.