Pivotal Phase 3 Trials of Oral Simufilam Planned for Year’s End

Cassava Sciences plans to launch two Phase 3 clinical trials evaluating the efficacy of simufilam, its investigational oral treatment for Alzheimer’s disease, in the second half of this year, the company announced.

If successful, results of these studies in patients with mild-to-moderate disease will support a request for simufilam’s approval.

“For over 10 years we’ve been doing basic research and early drug development with simufilam. We are excited to finally advance simufilam into pivotal Phase 3 clinical studies in people with Alzheimer’s disease,” Remi Barbier, president and CEO of Cassava, said in a press release.

The decision follows the successful completion of an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) for simufilam. The FDA agreed to key elements of the planned Phase 3 trials, such as the outcomes that will measure treatment effectiveness.

FDA officials also agreed that findings from these Phase 3 trials, in combination with previous trial data, would be sufficient to show evidence of clinical efficacy for simufilam as an Alzheimer’s treatment.

“We appreciate the valuable guidance and flexibility FDA has provided. We look forward to continuing a collaborative dialogue throughout the pivotal Phase 3 clinical development program,” said Jim Kupiec, MD, Cassava’s chief clinical development officer.

One Phase 3 trial will evaluate the disease-modifying effects of simufilam in Alzheimer’s disease. Specifically, it aims to determine whether simufilam’s slows the rate of decline in patients’ cognition and their ability to go about daily life activities, compared with a placebo.

It will enroll about 1,000 people with mild-to-moderate Alzheimer’s, who will be randomized to treatment with one of two doses of the investigational medication (50 or 100 mg), or to a placebo, taken by mouth twice daily for 18 months. Plans are to initiate this trial between July and September.

The other Phase 3 study will evaluate changes in symptoms — specifically, whether simufilam treatment improves cognition and participation in daily life activities, again relative to a placebo.

This trial will enroll approximately 600 mild-to-moderate Alzheimer’s patients, who will be randomized to treatment with simufilam (at a dose of 100 mg) or to a placebo, taken twice daily by mouth, for nine months to a year. The company plans to initiate this trial between October and the close of December.

Both trials will use the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) and Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) as co-primary endpoints (their main efficacy measures). ADAS-Cog measures cognition, while ADCS-ADL assesses overall abilities in such everyday tasks as dressing yourself, preparing meals, watching TV, or engaging in conversations.

The Integrated Alzheimer’s Disease Rating Scale (iADRS) — a clinical tool that combines cognitive and functional scores from ADAS-Cog and ADCS-ADL — will be assessed as a secondary endpoint. Other secondary endpoints in both trials include levels of Alzheimer’s-associated biomarkers, as well as the Neuropsychiatric Inventory (NPI), used to evaluate the presence and severity of dementia-related behavior.

The FDA agreed to review the final version of each protocol for these Phase 3 studies, and to conduct a Special Protocol Assessment for both trials. This formal procedure confirms whether certain important details of a trial’s protocol — such as the statistical analyses that will be used — meet the agency’s standards for an approval review.

Cassava also plans to expand its open-label trial of simufilam (NCT04388254) to include 50 more patients — all participants in previous simufilam studies — in addition to the 100 patients already envisioned. An open-label trial is one in which all participants get the active medication.

A pre-planned interim analysis after six months of treatment indicated that the investigational medication aided cognition and behavior in Alzheimer’s patients. Cassava is opening new clinical sites in the U.S. and Canada to accommodate this expansion; information on trial locations is available here.

A second pre-planned safety and efficacy analysis, covering about 50 patients treated for a full year in this extension study, is expected at midyear.

Cassava also plans a cognition maintenance study (CMS), in which people treated for at least one year in the open-label trial will be randomized  to either continue with simufilam or move to a placebo. The CMS will compare the effects of treatment continuation or discontinuation, respectfully, on cognition and dementia-related measures.

This CMS will run for six months, after which its participants will be allowed to return to simufilam treatment in the open-label study.

Simufilam, previously called PTI-125, is a small oral molecule designed to restore the normal shape and function of filamin A (FLNA), a protein that is misfolded in people with Alzheimer’s and believed to play a role in the accumulation of toxic protein clumps (aggregates) within nerve cells.

Top-line data from a previous Phase 2b trial (NCT04079803) in more than 60 people with mild to moderate Alzheimer’s showed that treatment with simufilam safely lowered levels of biomarkers of disease activity, neurodegeneration, and inflammation.