Eisai and Biogen Advance Lecanemab Subcutaneous Formulation Following Positive Mid-Stage Data at CTAD 2023

On October 26, Eisai/Biogen announced interim study data on the subcutaneous formulation of Aβ antibody Lecanemab (LEQEMBI) at the 16th Clinical Trials on Alzheimer's Disease (CTAD) conference. The results showed that subcutaneous administration of LEQEMBI was more effective and safer compared to intravenous administration.

Based on this positive clinical outcome, Eisai expects to submit the Biologics License Application for the LEQEMBI subcutaneous formulation to the FDA by March 31, 2024.

On July 6 this year, LEQEMBI received FDA approval. Thus, LEQEMBI has become the first Alzheimer's disease (AD) drug targeting β-amyloid to transition from accelerated approval to traditional approval. It is also the first new AD drug to gain FDA approval since 2003.

LEQEMBI Subcutaneous Injection (SC) Sub-Study Evaluated in the Open-Label Extension (OLE) of Phase 3 Clinical Study Clarity AD. In the SC sub-study, a total of 394 AD patients were enrolled, of which 72 patients received LEQEMBI subcutaneous formulation for the first time and only, while 322 patients received LEQEMBI subcutaneous formulation in the SC sub-study after receiving LEQEMBI intravenous formulation in the Clarity AD core study.

At the 6th month, the subcutaneous (SC) group showed more positive clinical data compared to the intravenous (IV) group.

In newly treated SC patients, amyloid positron emission tomography (PET) data showed that brain amyloid levels decreased by -40.3 ± 2.27 units from baseline with SC administration, compared to -35.4 ± 1.14 units with IV administration. Weekly SC dosing demonstrated a 14% higher amyloid plaque removal effect than biweekly IV dosing.

In addition, the 90% CI of SC and IV drug exposure falls within the 80%-125% bioequivalence limit, which means that SC can achieve an AUC (area under the curve) equivalent to that of IV at a certain dose. In this case, the AUC of SC is 11% higher than that of IV in this study.

Moreover, systemic injection reactions in the SC group were uncommon and mild, with no related reactions observed in patients receiving SC formulation LEQEMBI for the first time. Overall, the incidence of local injection site reactions in patients treated with SC was low (8.1%), with most being mild to moderate, including redness, irritation, or swelling, with no reports of rash or other allergic reactions.

Notably, the rate of amyloid-related imaging abnormalities (ARIA) with IV formulation in the Clarity AD core study was similar to the rate observed in LEQEMBI patients entering the SC sub-study for the first time in the Clarity AD OLE.

In the Clarity AD core study (n=898), the incidence rates of ARIA-E (vasogenic edema, effusion in brain tissue), ARIA-H (microhemorrhages or hemosiderin deposits in cerebral parenchyma, pia mater), and isolated ARIA-H (ARIA-H without ARIA-E) were 12.6%, 17.3%, and 8.9%, respectively. In newly treated patients in the SC group (n=72), the rates were 16.7%, 22.2%, and 8.3%, respectively. However, due to the smaller sample size in the SC group, an accurate comparison with the IV group could not be made.

According to Phase 2 and Phase 3 clinical studies, Cmax (maximum exposure) is the strongest predictor of ARIA-E incidence following IV administration. In SC studies, however, due to relatively stable exposure, AUCss (steady-state exposure) appears to be a better predictor of ARIA-E rates in SC.

Overall, the subcutaneous injection of LEQEMBI will offer more effective and safer outcomes. Eisai will continue to evaluate the subcutaneous formulation of LEQEMBI in the Clarity AD OLE. If the subcutaneous formulation is approved, patients will no longer need to visit hospitals for intravenous injections and can self-administer the subcutaneous injection at home.

At present, the fundamental cause of AD has not been found, and pharmaceutical companies still frequently encounter setbacks in the AD field; drugs with truly breakthrough potential have yet to arrive.

But the positive progress of Lecanemab has injected a boost into the development of new Aβ-targeting drugs, encouraging the industry's AD new drug research and development, with numerous AD new drug companies catching up.

The Cortellis database shows that, as of January 1, 2023, a total of 187 Phase 1, 2, and 3 clinical trials are ongoing, involving 141 new AD drugs. Among them, 36 drugs are in 55 Phase 3 trials, 87 drugs are in 99 Phase 2 trials, and 33 Phase 1 trials cover 31 drugs, with some drugs undergoing more than one trial.

As of now, multiple AD products have announced positive Phase 3 clinical results.

On June 29, AI pharmaceutical company BioXcel Therapeutics announced that the Phase 3 clinical trial TRANQUILITY II of BXCL501 for the treatment of AD-related agitation met the primary endpoint of 2-hour PEC score and also achieved the secondary endpoint of 1-hour PEC score. Notably, the BXCL501 60mg dose group showed significant improvement in the 2-hour PEC score. Although the data had been previously questioned, the company released the audit results of the clinical data the day before, confirming the reliability and integrity of the data.

On July 18, at the 2023 Alzheimer's Association International Conference (AAIC), Eli Lilly announced the full results of the donanemab antibody for treating AD from the Phase 3 clinical trial TRAILBLAZER-ALZ 2. Data showed that, compared with placebo, donanemab significantly slowed cognitive and functional decline in early AD patients and delayed disease progression, with a reduction in cognitive and functional decline of up to 60%.

Currently, Eli Lilly has submitted a listing application to the U.S. FDA and is expected to receive the review result by the end of this year.

Previously, although Roche's AD new drug gantenerumab failed in its Phase 3 clinical trial, Roche did not stop there. Instead, it improved upon gantenerumab and designed a new drug, trontinemab.

At this year's CTAD, Roche also announced positive data from the Phase 1b/2a trial of trontinemab for the treatment of AD. The results showed that, compared with typical amyloid-targeting antibodies, trontinemab can achieve rapid amyloid plaque clearance at significantly lower dose levels. After 28 weeks of treatment with the highest dose (1.8 mg/kg), 75% of patients had their amyloid levels reduced to below the normal detection level.

The continuously announced positive clinical results indicate that meaningful breakthroughs have been achieved in the development of new AD drugs, and more new products may bring greater therapeutic benefits to AD patients in the future.