simufilam (PTI-125) / Cassava - LARVOL DELTA

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

Cassava Sciences Announces Virtual Presentation at the AD/PD 2024 International Conference (GlobeNewswire) - "Cassava Sciences, Inc...today announced plans to present a virtual oral presentation at the International Conference on Alzheimer’s and Parkison’s Disease (AD/PD 2024) taking place in Lisbon, Portugal from March 5-9, 2024."

Retrospective data • Alzheimer's Disease • CNS Disorders

RETHINK AND REFOCUS PHASE 3 CLINICAL TRIALS OF ORAL SIMUFILAM IN MILD-TO-MODERATE ALZHEIMER'S DISEASE: BASELINE CHARACTERISTICS (ADPD 2024) - "Simufilam improves insulin receptor signaling and responsivity to insulin by mechanistic target of rapamycin (mTOR), while suppressing mTOR's basal overactivation that occurs in AD. RETHINK and REFOCUS have identical entry criteria. Top-line results for RETHINK are expected approximately year-end 2024."

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

No Decline in Cognition Scores in Patients with Mild Alzheimer's Disease Who Received Simufilam Continuously For 24 Months (GlobeNewswire) - P2 | N=200 | NCT04388254 | Sponsor: Cassava Sciences, Inc | "Patients with mild Alzheimer’s disease who received simufilam treatment continuously for two years (n=47) had no decline in ADAS-Cog scores (± 1.51 SE) as a group. Patients with mild Alzheimer’s who received simufilam treatment non-continuously (n=40) declined 1 point on ADAS-Cog (± 1.65 SE) as a group. Non-continuous treatment consisted of one year on open-label drug, six months on placebo and six months back on open-label drug. In patients with mild Alzheimer's, the largest separation between the continuous and non-continuous treatment groups occurred at the end of the 6-month randomized, placebo-controlled withdrawal phase. Patients with moderate Alzheimer’s who received simufilam treatment continuously for two years (n=32) declined 11.05 points on ADAS-Cog (± 1.91 SE) as a group."

P2 data • Alzheimer's Disease • CNS Disorders

Navigating the Dementia Landscape: Biomarkers and Emerging Therapies. (PubMed, Ageing Res Rev) - "Notably, Leqembi recently received full FDA approval, marking a significant breakthrough in AD treatment. Additionally, ongoing phase 3 clinical trials are investigating novel therapies, including Masitinib and NE3107, focusing on cognitive and functional improvements in AD patients...Lastly, ongoing clinical trials in anti-amyloid therapy for AD, such as Simufilam, Solanezumab, Gantenerumab, and Remternetug, offer hope for individuals affected by this devastating disease, with the potential to alter the course of cognitive decline. These advancements collectively illuminate the evolving landscape of dementia research and the pursuit of effective treatments for these challenging conditions."

Biomarker • Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • TARDBP

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 | Not yet recruiting | Sponsor: Cassava Sciences, Inc.

New P1 trial

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. | Enrolling by invitation ➔ Active, not recruiting | N=165 ➔ 90

Enrollment change • Enrollment closed • Alzheimer's Disease • CNS Disorders

Simufilam (PTI-125), 100 mg, for Mild-to-moderate Alzheimer's Disease Patients (clinicaltrials.gov) - P2 | N=220 | Completed | Sponsor: Cassava Sciences, Inc. | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders • Aβ42 • CHI3L1 • CSF Aβ42 • CSF P-tau • CSF T-tau • HMGB1 • NEFL

New Drug Development in Alzheimers Disease (ACNP 2023) - "This year alone in the United States, there were at least 2 drugs that have been early approved by the FDA: Lecanemab, and Donanemab [5]...Also in development are anti- inflammatory drugs, such as that of Cassava Sciences, simufilam, which binds to an altered conformation of filamin A, which is related to elevated levels of beta amyloid [3] . we are entering an exciting era in new drug development in AD"

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Psychiatry

Simufilam's primary mechanism of action confirmed by time-resolved FRET (CTAD 2023) - "A robust technology designed to detect highly sensitive molecular interactions confirmed simufilam’s primary mechanism of action. Simufilam’s high potency in reducing Aβ42–α7nAChR binding, measured by time-resolved FRET, appears unprecedented for a mechanism of binding a receptor-associated protein. The picomolar IC50 in reducing this interaction corroborates previous data showing a reduced binding affinity of Aβ42 for α7nAChR as well as the picomolar IC50s for simufilam’s inhibition of the Aβ42– α7nAChR interaction, tau hyperphosphorylation, and FLNA linkages to α7nAChR and TLR4 shown by other techniques."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Aβ42 • TLR4

Interim MRI safety analysis from a 76-week Phase 3 clinical trial of simufilam in Alzheimer's Disease (CTAD 2023) - P3 | "This interim neuroradiologic evaluation of Week 40 MRIs from 181 patients enrolled in the REFOCUS-ALZ Phase 3 clinical study suggests simufilam is not associated with ARIA-E emergence. ARIA-H was a common baseline finding, occurring in 29% of patients. In this blinded dataset, new MCHs occurred predominantly in patients with pre-existing MCHs: 39% of patients with pre-existing MCHs vs."

Clinical • P3 data • P3 data: top line • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Hematological Disorders • Inflammation • Ischemic stroke • APOE • Aβ42 • TLR4

Results of a Phase 2 randomized withdrawal study of simufilam in mild-to-moderate Alzheimer's (CTAD 2023) - "In this Phase 2, randomized withdrawal study, simufilam 100 mg b.i.d for 6 months slowed cognitive decline by 38% in patients with mild-to-moderate AD versus placebo (difference not significant). Mild AD patients randomized to simufilam improved -0.6 points over 6 months, a 205% difference in favor of drug. Mild AD patients on simufilam for 18 months showed minimal decline in ADAS-Cog scores, indicating stable cognition."

Clinical • Late-breaking abstract • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Aβ42 • TLR4

Novel therapies for Alzheimer's disease (ECNP 2023) - "This year alone in the United States, there were at least 2 drugs that have been early approved by the FDA: Lecanemab, and Donanemab [5]...Current clinical trials testing anti-tau drugs include Janssen JNJ-63733657, a humanized IgG1 monoclonal antibody that binds to aggregated phosphorylated tau [1]...Also in development are anti-inflammatory drugs, such as that of Cassava Sciences, simufilam, which binds to an altered conformation of filamin A, which is related to elevated levels of beta amyloid [3] . The altered filamin A prevents various toxic signaling cascades as seen in the AD brain."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Psychiatry

Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer's Disease. (PubMed, Int J Mol Sci) - "Oral simufilam reduced both the FLNA-CCR5 linkage and the CCR5-G protein coupling in these mice, while restoring CCR5's responsivity to C-C chemokine ligand 3 (CCL3). By disrupting aberrant FLNA-receptor interactions critical to AD pathogenic pathways, simufilam may promote brain health."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • CCL3 • CD4 • CXCR4 • TLR2 • TLR4

Cassava Sciences Completes Patient Enrollment for Pivotal Phase 3 Clinical Trial of Oral Simufilam in Alzheimer’s Disease (GlobeNewswire) - "Cassava Sciences, Inc...today announced the completion of patient enrollment in a pivotal Phase 3 clinical trial. Eight hundred four (804) Alzheimer’s patients are enrolled in this 12-month trial. A second Phase 3 clinical trial with a target enrollment of approximately 1,100 patients is expected to complete patient enrollment in Q4 2023. Both on-going Phase 3 clinical trials are evaluating the safety and efficacy of oral simufilam in patients with Alzheimer's disease dementia."

Enrollment closed • Enrollment status • Alzheimer's Disease • CNS Disorders • Dementia

Cassava Sciences Announces Positive Interim Safety Review of Simufilam On-going Phase 3 Trials in Patients with Alzheimer’s Disease (GlobeNewswire) - "Cassava Sciences, Inc...today announced a positive 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) recommended that both of Cassava Sciences’ Phase 3 studies of simufilam continue as planned, without modification...'We look forward to announcing the completion of patient enrollment for both Phase 3 studies this year'....The next routine meeting of the DSMB is scheduled for March 2024."

DSMB • Enrollment status • Alzheimer's Disease • CNS Disorders