After EU setback, Eisai/Biogen build case for Leqembi

Eisai and Biogen have reported data showing that the benefit of treatment with their Alzheimer's disease therapy Leqembi appears to build over time, with no increase in safety risks.

The results come from a cohort of patients with three years of follow-up in the pivotal Clarity AD trial of anti-amyloid antibody Leqembi (lecanemab), which supported the drug's approval in the US, China, Japan, and other countries.

At the primary endpoint after 18 months, Clarity AD showed that Leqembi reduced cognitive decline by 27% compared to placebo. Now, data reported at the Alzheimer's Association International Conference (AAIC) showed that the gap between the drug and control widened after three years of continuous treatment.

The study and open-label extension (OLE) has three groups – one on Leqembi for 36 months, another that switched to the drug from placebo at 18 months, and finally a group on no active treatment for the entire period.

More than 50% of those on continuous Leqembi treatment continued to show improvement over three years. In that group, there was a -0.95 decline on the CDR-SB cognition rating scale at 35 months, with the switch group showing a more modest result that was still better than the no-treatment arm.

According to Eisai and Biogen, that level of change on the CDR-SB can be "the difference between slight impairment and loss of independence, such as people's ability to be left alone, remember recent events, participate in daily activities, complete household chores, function independently, and engage in hobbies and intellectual interests."

The results also suggested that patients' Alzheimer's worsened more quickly if they stopped treatment, even after amyloid plaques in the brain were cleared, while there was a decrease in the risk of serious side effects like brain swelling or bleeds after the first six months, according to Christopher van Dyck of Yale University School of Medicine, who reported the results at AAIC.

These could be very important findings for Eisai and Biogen on two fronts. They are now facing the first direct competition to Leqembi from Eli Lilly's Kisunla (donanemab), which has been approved with a fixed duration of treatment until amyloid plaques in the brain resolve.

That has been held up as an advantage by Lilly – reducing patient exposure to the drug and possible side effects, as well as reducing costs – but the case could now be made that Leqembi can offer additional benefit without increased risk when given for longer. Of course, there's no long-term data yet with Kisunla to allow a direct comparison.

Eisai and Biogen maintain that, even after amyloid plaques are cleared, toxic amyloid 'protofibrils' persist in the brain and continue to cause neuronal damage and death.

The data "support[s] a disease-modifying effect [for Leqembi] and the importance of continued long-term [...] treatment," said van Dyck.

Meanwhile, the safety of Leqembi was the primary reason behind the decision by the EMA's human medicines committee not to back approval of Leqembi last week, so longer-term efficacy data – without increased risk – could tip the risk:benefit balance as the European Commission decides whether to follow its experts' advice.

Tau sub-study

A sub-study of the trial looking at patients with no or very low levels of tau protein at baseline, another biomarker for Alzheimer's, was also highlighted at AAIC. As tau begins to accumulate in the brain, cognition and function start to decline, so patients with no tau or low tau represent a very early stage of Alzheimer's.

After three years on Leqembi, 59% of this group showed no evidence of Alzheimer's progression at all, and 51% improved their cognition according to the CDR-SB scale, with a similar pattern for the ADAS-Cog14 and ADCS MCI-ADL scales. That makes the case to start treatment as early as possible, said Eisai and Biogen.

Both Leqembi and Kisunla have experimental data showing they can slow down the rate of increase in tau protein, revealing the close interaction between amyloid and tau in Alzheimer's pathology.