simufilam (PTI-125) / Filana Therapeutics - LARVOL DELTA

Filana Therapeutics…announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold on the Company's investigational new drug (IND) application, enabling Filana to initiate a planned Phase 2a proof-of-concept study in patients aged 12 to 55 with TSC-related epilepsy (GlobeNewswire) - "Patient screening is expected to begin by the first quarter of 2027....Filana’s Phase 2a study is a 16-week multicenter, randomized, double-blind clinical trial to evaluate two doses of simufilam in patients with refractory TSC-related seizures. The study is planned to be conducted at 13 sites in the U.S. with a target enrollment of 40 subjects aged 12 to 55. All subjects who complete the double-blind treatment phase are eligible to participate in a 48-week extension study."

FDA event • New P2a trial • CNS Disorders • Epilepsy

Progress report on new epilepsy treatments: A summary of the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII). I. Treatments in preclinical and early clinical development. (PubMed, Epilepsia) - "These include AUT00206, a positive allosteric modulator of Kv3.1 and Kv3.2 voltage-gated potassium channels in development for the treatment of rare epilepsy syndromes as well as neurodevelopmental and neuropsychiatric disorders; ION283, an antisense oligonucleotide designed to suppress the expression of glycogen synthase 1, under investigation for the treatment of Lafora disease; MSCA-7136, a selective allosteric RAS/mitogen-activated protein kinase-extracellular signal regulated kinase (MEK) inhibitor being developed for the treatment of focal seizures associated with mesial temporal lobe epilepsy and seizures associated with tuberous sclerosis complex; OV329, a selective inhibitor of γ-aminobutyric acid (GABA) aminotransferase, in development for the treatment of drug-resistant focal seizures; PTI5803 (probenecid), an uricosuric agent and a blocker of pannexin 1 channels, repurposed as a treatment for seizures associated with focal cortical dysplasia; simufilam, a..."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Psychiatry

Decoding neuroinflammation: the critical role of NLRP3 inflammasome in Alzheimer's disease. (PubMed, Inflammopharmacology) - "Furthermore, the review assesses preclinical and clinical research targeting NLRP3 and its upstream regulators, emphasizing potential treatment options as Simufilam, MCC950, OLT1177, and CY-09. This work highlights the therapeutic potential of the inflammasome and promotes the development of targeted anti-inflammatory treatments to ameliorate AD pathology by elucidating the molecular mechanisms linking NLRP3 to AD progression."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Metabolic Disorders • IL18 • IL1B • NLRP3 • TLR4

Cassava Sciences stock (US14428V1035): Clinical progress in Alzheimer's treatments (AD HOC NEWS) - "Key milestones include Phase 3 initiation expected in H2 2026 and topline data in 2028."

New P3 trial • P3 data: top line • Alzheimer's Disease

The small molecule simufilam dose-dependently attenuates the worsening of seizures in a mouse model of tuberous sclerosis complex. (PubMed, Epilepsia) - "These findings suggest that simufilam treatment in a TSC mouse model prevented the worsening of seizure activity in a dose-dependent manner and supports clinical investigation of simufilam as a potential therapeutic intervention for seizures in TSC."

Journal • Preclinical • CNS Disorders • Epilepsy

Filamin A phosphorylation at S2152: A molecular switch fueling cancer and neurodegeneration. (PubMed, Cell Commun Signal) - No abstract available

Journal • Review • Alzheimer's Disease • CNS Disorders • Oncology

Simufilam in Alzheimer's Disease: Assessment of Efficacy of a Controversial Drug in Human Neuronal Cell Culture. (PubMed, Pharmaceuticals (Basel)) - "Further, simufilam did not improve mitochondrial genes or structure. Our results align with clinical outcomes and indicate that insufficient activity across multiple tests of ability to impact processes related to neuronal health can serve as a preliminary indicator of limited clinical utility."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • APP • BDNF

Cassava Announces Publication of Peer-Reviewed Phase 3 Results for Simufilam in Alzheimer’s Disease in the Journal of Prevention of Alzheimer’s Disease (Cassava Sciences Press Release) - "The paper provides a detailed analysis of data from two Phase 3 clinical trials, RETHINK-ALZ and REFOCUS-ALZ...Mild Patients in REFOCUS-ALZ: Simufilam (100 mg) was associated with slower cognitive decline than placebo in the prespecified mild subgroup, with differences at Week 4 and Weeks 28, 40, 52, and 64 (nominally significant at p = 0.01, 0.01, 0.02, 0.02, and 0.02, respectively)...Pooled Mild Patients in REFOCUS-ALZ and RETHINK-ALZ: A prespecified pooled analysis of mild patients administered simufilam (100 mg) or placebo in both trials through week 52 showed potential treatment group differences at weeks 4 and 28 (nominally significant at p < 0.01)."

P3 data • Retrospective data • Alzheimer's Disease

Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer's disease. (PubMed, J Prev Alzheimers Dis) - P3 | "Simufilam did not meet co-primary or secondary endpoints in these Phase 3 trials. Simufilam was safe and well tolerated. Trials registered at clinicaltrials.gov: NCT04994483 and NCT05026177."

Clinical • Journal • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Aβ42 • p-tau181

Cassava Sciences receives FDA request for more information on epilepsy trial (Investing.com) - "The company indicated it will work with the FDA to provide the requested information and continues preparations to begin the proof-of-concept study in the first half of 2026."

FDA event • New trial • Epilepsy

Simufilam, a small molecule with a favorable clinical safety profile, reduced seizure activity in a mouse model of focal cortical dysplasia type II and tuberous sclerosis complex (AES 2025) - "Rationale: Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. Based on these findings, Cassava Sciences is preparing to submit an IND application to the FDA and enroll patients in a proof-of-concept trial of simufilam for the treatment of epilepsy in TSC."

Late-breaking abstract • Preclinical • Alzheimer's Disease • CNS Disorders • Epilepsy • Psychiatry • FLNA

FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer. (PubMed, Cell Mol Biol Lett) - "This study elucidates the interplay between disulfidptosis and the CRC immune landscape, highlighting FLNA as a therapeutic target. These findings suggest that modulating disulfidptosis in conjunction with immunotherapy may offer a novel treatment paradigm for CRC."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • CD8 • SLC2A1

Cassava Presents Promising Preclinical Simufilam Data at TSC Alliance Meeting (GlobeNewswire) - "These compelling preclinical data build on favorable safety findings from prior human clinical studies and support our plan to begin our first clinical study in TSC-related epilepsy in the first half of 2026....The Bordey lab showed that treating mice with simufilam, before or after seizure onset, alleviated neuronal abnormalities and reduced seizure frequency by 60% compared to vehicle-treated mice: Simufilam significantly reduced seizure frequency (p<0.0001). Significantly more mice achieved seizure freedom with simufilam (3/29 vehicle (saline) treated mice v. 11/32 simufilam treated mice, p=0.0343)....Data from two Phase 3 studies of simufilam in 1,929 patients with mild-to-moderate Alzheimer’s disease were also presented in the poster: Simufilam demonstrated a favorable safety profile. Non-serious adverse events were typically mild and not considered simufilam-related."

Clinical data • New trial • Preclinical • Epilepsy

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