simufilam (PTI-125) / Cassava - LARVOL DELTA

Cassava Reports Q1 2025 Financials Results, Provides Business Update (GlobeNewswire) - "* Simufilam for Alzheimer’s disease....Research and development (R&D) expenses were $13.7 million. This compared to $16.2 million for the same period in 2024. This 16% decrease was due primarily to the discontinuation of clinical trials in Alzheimer's disease beginning the fourth quarter of 2024. This decrease was partially offset by an increase in stock-based compensation expense due to new awards granted in the third quarter of 2024."

Commercial • Alzheimer's Disease

Unraveling the Immune Puzzle: Role of Immunomodulation in Alzheimer's Disease. (PubMed, J Neuroimmune Pharmacol) - "Preclinical studies of immunomodulatory agents, including salidroside, festidinol, astragalin, sulforaphane, BM-MSC, simvastatin, Ab-T1, hTREM2, and XENP345, demonstrate promising effects. Additionally, clinical investigations of drugs such as simufilam, AL002, TB006, VGL101, DNL919, XPro1595, astragalus, and IBC-Ab002 underscore the therapeutic potential of targeting immune pathways in AD. This review emphasizes how neuroinflammation, microglial activation, and peripheral immune responses contribute to disease progression. By exploring immunomodulatory mechanisms, the article sheds light on potential therapeutic targets that could help mitigate AD pathology which may pave the way for novel interventions preventing neurodegeneration in AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Immunology • Oncology • CTNNB1 • TNFA

The potential of ARL4C and its-mediated genes in atherosclerosis and agent development. (PubMed, Front Pharmacol) - "Many agents, including ABCA1 agonists (CS-6253, IMM-H007, RG7273, and R3R-01), FLNA antagonist sumifilam, LRP6 inhibitor BI-905677 and agonist SZN-1326, and SOX2 inhibitor STEMVAC, were investigated in clinical trials. Thus, ARL4C and its regulated genes may be a potential target for drug development. Thus, we focus on the role of ARL4C and its-mediated genes in atherosclerosis and agent development, which provide insights for the identification, research, and drug development of novel targets."

Journal • Review • Atherosclerosis • Cardiovascular • Colorectal Cancer • Hepatology • Liver Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCA1 • ALDH1A3 • SNAI2 • SOX2

RETHINK -ALZ PHASE 3 CLINICAL TRIAL OF SIMUFILAM IN MILD -TO-MODERATE ALZHEIMER'S DISEASE: ENHANCING TRIAL INTERGRITY BY QUALITY REVIEW AND INDEPENDENT CHAIN OF CUSTODY (ADPD 2025) - "The RETHINK -ALZ trial was designed and executed with quality oversight of eligibility criteria and an independent chain of custody of all trial data to enhance clinical trial integrity."

Clinical • P3 data • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Aβ42

Comment on Wang et al. Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer's Disease. Int. J. Mol. Sci. 2023, 24, 13927. (PubMed, Int J Mol Sci) - "The authors have published their findings that simufilam, a small novel molecule suggested for clinical use in Alzheimer's disease (AD), restores a deleterious conformation of filamin A (FLNA), which is a large intracellular scaffolding protein, as indicated by changes in isoelectric focusing points [...]."

Journal • Alzheimer's Disease • CNS Disorders

Cassava Sciences Reports Topline Phase 3 REFOCUS-ALZ Data (Cassava Sciences Press Release) - P3 | N=1,125 | (NCT05026177) | Sponsor: Cassava Sciences, Inc | "Topline data indicate that REFOCUS-ALZ did not meet each of the prespecified co-primary, secondary and exploratory biomarker endpoints. The co-primary endpoints were the change in cognition and function from baseline to the end of the double-blind treatment period at week 76, assessed by the ADAS-COG12 and ADCS-ADL scales, comparing simufilam to placebo. REFOCUS-ALZ enrolled 1,125 patients and was discontinued on November 25, 2024, following the report that a prior 52-week Phase 3 study, RETHINK-ALZ, did not meet its co-primary endpoints. A large portion of subjects enrolled in REFOCUS-ALZ completed their final study visit prior to the termination of the trial. Simufilam continued to demonstrate an overall favorable safety profile...'Cassava will discontinue all efforts to develop simufilam for Alzheimer’s disease and we expect to phase out the program by the end of Q2 2025'..."

Discontinued • P3 data: top line • Trial termination • Alzheimer's Disease

RETHINK-ALZ PHASE 3 CLINICAL TRIAL OF SIMUFILAM IN MILD-TO-MODERATE ALZHEIMER’S DISEASE: FULL DATA ANALYSES (ADPD 2025) - "Finally, simufilam has been shown to improve insulin receptor signaling, thereby restoring mechanistic target of rapamycin (mTOR)’s responsivity to insulin. Results While top-line data exploring the slowing of decline on co-primary endpoints ADAS-Cog12 and ADCS-ADL and changes in key secondary endpoints such as NPI and CDR-SB will already have been released, we will present full clinical trial data including post hoc correlations and sensitivity analyses. Conclusions RETHINK-ALZ, a pivotal Phase 3 clinical trial in mild-to-moderate AD is expected to be submitted, along with results from the 76-week REFOCUS-ALZ trial, in a New Drug Application to FDA."

Clinical • IO biomarker • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Aβ42 • GFAP • IR • mTOR • p-tau181 • TLR4

Cassava Sciences Reports 2024 Financial Results and Provides Business Update (GlobeNewswire) - "'Cassava is preparing to report the topline results of the now-discontinued REFOCUS-ALZ, the second Phase 3 study of simufilam in Alzheimer’s disease, in late first-quarter/early second-quarter 2025.'"

P3 data: top line • Alzheimer's Disease

Open-label Extension for Phase 3 Clinical Trials of Simufilam (clinicaltrials.gov) - P3 | N=1081 | Terminated | Sponsor: Cassava Sciences, Inc. | Active, not recruiting ➔ Terminated; sponsor decision

Trial termination • Alzheimer's Disease • CNS Disorders

REFOCUS-ALZ: Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease (clinicaltrials.gov) - P3 | N=1125 | Terminated | Sponsor: Cassava Sciences, Inc. | Trial completion date: May 2025 ➔ Dec 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2025 ➔ Dec 2024; Sponsor decision

Trial completion date • Trial primary completion date • Trial termination • Alzheimer's Disease • CNS Disorders

Open-Label Extension of the PTI-125-04 Study in Mild-to-Moderate Alzheimer's Disease (clinicaltrials.gov) - P2 | N=90 | Terminated | Sponsor: Cassava Sciences, Inc. | Completed ➔ Terminated; Sponsor Decision

Trial termination • Alzheimer's Disease • CNS Disorders

Open-Label Extension of the PTI-125-04 Study in Mild-to-Moderate Alzheimer's Disease (clinicaltrials.gov) - P2 | N=90 | Completed | Sponsor: Cassava Sciences, Inc. | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders

A Pharmacokinetic Study of Simufilam in Subjects With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=27 | Completed | Sponsor: Cassava Sciences, Inc. | Recruiting ➔ Completed

Trial completion • Hepatitis C • Liver Failure

Open-label Extension for Phase 3 Clinical Trials of Simufilam (clinicaltrials.gov) - P3 | N=1081 | Active, not recruiting | Sponsor: Cassava Sciences, Inc. | Enrolling by invitation ➔ Active, not recruiting | N=1600 ➔ 1081 | Trial completion date: Jul 2026 ➔ Mar 2025 | Trial primary completion date: Jul 2026 ➔ Mar 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders

Open-Label Extension of the PTI-125-04 Study in Mild-to-Moderate Alzheimer's Disease (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Cassava Sciences, Inc. | Trial completion date: Nov 2025 ➔ Feb 2025 | Trial primary completion date: Oct 2025 ➔ Feb 2025

Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders

Cassava Sciences Topline Phase 3 Data Did Not Meet Co-Primary Endpoints (GlobeNewswire) - P3 | N=804 | RETHINK-ALZ (NCT04994483) | Sponsor: Cassava Sciences, Inc. | "Cassava Sciences, Inc...today announced that the topline results from the Phase 3 ReThink-ALZ study of simufilam in mild-to-moderate AD did not meet each of the pre-specified co-primary, secondary and exploratory biomarker endpoints...Simufilam continued to demonstrate an overall favorable safety profile. The Company will hold a webcast today at 8 AM ET...'We have made the difficult decision to discontinue ReFocus-ALZ, given the nature of today’s reported results...We will also be discontinuing the Open Label Extension study.'"

Discontinued • P3 data: top line • Alzheimer's Disease • CNS Disorders

Cassava Sciences Reports Q3 2024 Financial and Operating Results (GlobeNewswire) - "All efficacy data from our Phase 3 program remain blinded. No interim analyses on efficacy outcomes are planned. We expect to report top-line data for RETHINK-ALZ before the end of 2024. We anticipate a top-line data readout for REFOCUS-ALZ approximately mid-year 2025."

P3 data: top line • Alzheimer's Disease • CNS Disorders

RETHINK-1: Simufilam 100 Mg for Mild-to-Moderate Alzheimer's Disease (clinicaltrials.gov) - P3 | N=804 | Completed | Sponsor: Cassava Sciences, Inc. | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders

Cassava Sciences Announces Completion of an Interim Safety Review of Oral Simufilam On-going Phase 3 Trials (GlobeNewswire) - "Cassava Sciences, Inc...today announced the completion of a third interim safety review of simufilam in on-going Phase 3 clinical trials in patients with Alzheimer’s disease. A routine, scheduled meeting of a Data and Safety Monitoring Board (DSMB) resulted in a recommendation that both of Cassava Sciences’ on-going Phase 3 studies continue as planned, without modification...The first Phase 3 trial (NCT04994483) has a 52-week treatment period; 804 Alzheimer’s patients were randomized into this trial. Top-line results for the 52-week Phase 3 trial are currently expected by year-end 2024. The second Phase 3 trial (NCT05026177) has a 76-week treatment period; 1,125 Alzheimer’s patients were randomized into this trial. Top-line results for the 76-week Phase 3 trial are currently expected approximately mid-year 2025."

Biomarker • DSMB • P3 data • Alzheimer's Disease • CNS Disorders

A Pharmacokinetic Study of Simufilam in Subjects With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=34 | Recruiting | Sponsor: Cassava Sciences, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatitis C • Liver Failure

Cassava Alzheimer’s drug set for first Phase 3 readout by December 2024 (Microsoft News) - "Cassava Sciences...executive chairman and principal executive officer Rick Barry said on Monday that the company’s first Phase 3 trial of its lead drug candidate, simufilam, is expected to read out by December 2024. Simufilam, formerly known as PTI-125, is an investigational small molecule oral drug currently in Phase III clinical studies to test a new approach for the treatment and diagnosis of Alzheimer's disease...'The second Phase 3 trial of 1,125 patients (randomized 1:1:1 between two dose levels of simufilam and placebo) is expected to conclude by June 2025.'"

P3 data • Alzheimer's Disease • CNS Disorders

Scientist who worked on Cassava's Alzheimer drug simufilam charged with fraud. (PubMed, BMJ) - No abstract available

Journal • Alzheimer's Disease • CNS Disorders

Cassava Sciences Reports Q1 2024 Financial Results and Clinical Updates on Phase 3 Trials of Simufilam (GlobeNewswire) - "We anticipate top-line data readout for our 76-week study (REFOCUS-ALZ) approximately mid-year 2025....Approximately 90% of patients who’ve completed treatment in a Phase 3 study have opted to enter the open-label extension study. To date, over 655 patients have entered the open-label extension study."

Enrollment status • P3 data: top line • Alzheimer's Disease • CNS Disorders

A Pharmacokinetic Study of Simufilam in Subjects With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=34 | Not yet recruiting | Sponsor: Cassava Sciences, Inc.

New P1 trial • Hepatitis C • Liver Failure

Open-label Study of the Absorption, Metabolism, and Excretion of [14C]-Simufilam Following a Single Oral Dose in Healthy Male Subjects (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Cassava Sciences, Inc. | Not yet recruiting ➔ Completed

Trial completion