Under-the-skin formulation seen to work better than approved Leqembi
More efficacy with experimental formulation, new Phase 3 trial data show
Weekly injections of an investigational formulation of the Alzheimer’s disease therapy Leqembi (lecanemab) worked better than the approved treatment in removing harmful amyloid beta plaques from patients’ brains over six months in a Phase 3 trial.
In fact, the subcutaneous or under-the-skin formulation cleared 14% more plaques in early Alzheimer’s patients than did Leqembi’s approved every-other-week intravenous or into-the-vein formulation.
That’s according to new interim data from the subcutaneous or SC substudy of the Clarity AD trial (NCT03887455), which will run through 2027. In the trial, patients either were switched from Leqembi to the subcutaneous formulation, or received treatment for the first time with the experimental formulation in the study’s open-label extension (OLE) portion.
These and other new Clarity AD findings were shared by Eisai in a late-breaking symposium called “Lecanemab for Early Alzheimer’s Disease: Long-Term Outcomes, Predictive Biomarkers and Novel Subcutaneous Administration.” The symposium was part of the 16th annual Clinical Trials on Alzheimer’s Disease (CTAD) conference, being held Oct. 24-27 in Boston and online.
“We believe that the subcutaneous formulation can provide substantial benefit for greater patient access, improved compliance and convenience with overall lower costs to the healthcare system,” Michael Irizarry, MD, senior vice president of clinical research at Eisai, which is developing Leqembi in collaboration with Biogen, said during the symposium.
Developer to seek FDA approval of under-the-skin formulation in 2024
Eisai plans to submit an application to the U.S. Food and Drug Administration (FDA) by March 31, 2024, seeking approval of the therapy’s subcutaneous formulation, according to a company press release.
In July of this year, the intravenous formulation became the first treatment approved by the FDA for slowing disease progression in adults with early Alzheimer’s.
The company already has also filed for Leqembi’s approval for early Alzheimer’s, as a intravenous formulation, in Australia, Canada, China, Great Britain, Israel, South Korea, and Switzerland, as well as in the European Union.
Nearly all cases of Alzheimer’s are characterized by the presence of amyloid plaques and tau clumps, or tangles. These are clumps of two proteins that build up to toxic levels in the brain and are thought to play a role in brain cell death, cognitive decline, and dementia.
Administered intravenously every two weeks, Leqembi is an antibody-based therapy designed to prevent amyloid protein buildup in the brain — with the goal of slowing cognitive decline.
Because of its demonstrated benefits, Leqembi was recently selected as one of TIME’s Best Inventions of 2023 in the medical care category.
The first part of the Phase 3 Clarity AD trial evaluated Leqembi versus a placebo in 1,795 people with early Alzheimer’s. Data after 1.5 years showed that Leqembi significantly slowed dementia progression by 27% compared with a placebo, and these findings supported the therapy’s full approval in the U.S.
Participants who completed the trial’s placebo-controlled core part could enter its OLE portion, in which all are receiving Leqembi to evaluate its long-term efficacy and safety.
The trial’s SC substudy within the OLE includes patients who received Leqembi or a placebo in the core part and switched to the experimental subcutaneous regimen in the OLE, as well as those switching to the new formulation after at least six months of Leqembi within the extension study. Additionally, it includes newly enrolled patients whose first exposure to lecanemab products was the subcutaneous formulation.
Under-the-skin formulation removed 14% more plaques than Leqembi
The newly presented interim data concerned 322 patients who switched from intravenous Leqembi to the subcutaneous formulation and 72 patients who received the medication for the first time as its subcutaneous form. The new formulation is given at a dose of 720 mg, once a week, via a vial syringe or an auto-injector, Irizarry said.
Six-month results showed that weekly subcutaneous injections led to 11% more body-wide exposure to the drug than the every-other-week intravenous infusions. Importantly, this translated into 14% greater amyloid removal.
Newly-treated patients on the subcutaneous formulation particularly saw benefits. Their brain amyloid was reduced by 40.3 centroids — a standardized assessment of amyloid using PET scans — compared with 35.5 with approved Leqembi.
While infusion reactions were the most common adverse event of Leqembi in the Clarify AD’s core portion, injection-related reactions were uncommon with subcutaneous administration, occurring in 8.1% of patients. The researchers noted that no such reactions occurred among those who had not received prior Leqembi treatment.
Most injection-related reactions were mild to moderate in severity and consisted of redness, irritation, or swelling, with no signs of skin rash or other allergic reactions.
No differences between the subcutaneous and intravenous regimens were observed in terms of rates of amyloid-related imaging abnormalities, or ARIAs. Those are a side effect specific to amyloid-clearing antibody-based therapies that can lead to temporary brain swelling and small bleeding spots.
“However, due to the [small] sample size of newly treated patients in the SC substudy, no exact comparison can be made,” Eisai stated in the release.
Clarity AD’s core part also included an optional substudy, in which PET scans were used to identify patients with a low brain accumulation of the tau protein. Given that tau also forms damaging clumps in Alzheimer’s, having low brain levels represent the early stage of the disease.
In this subgroup of patients, a greater proportion of Leqembi-treated patients relative to those on a placebo showed no cognitive decline (76% vs. 55%) or cognitive improvements (60% vs. 28%) over 1.5 years. Leqembi also showed consistent benefits across secondary measures of cognition, dementia, and activities of daily living.
In addition, Leqembi slowed the buildup of tau proteins in the temporal lobe, a region of the brain where tau accumulates in the very early stages. It also suppressed tau build-up across a broader range of brain regions in those with higher tau levels in the brain.
“This suggests that Leqembi treatment may have different effects on brain regions indexed by tau depending on the stage of the disease,” Eisai stated in the release.
The statically significant differences in cognitive function seen between the Leqembi and placebo groups in the Clarity AD’s core portion were maintained in the first six months of the OLE. This indicated a similar disease trajectory in the OLE for both patients always on Leqembi and those who switched to the therapy after 1.5 years.
Also, levels of blood biomarkers were also improved, even in the group of patients with the delayed start of Leqembi treatment.