Simufilam Clears FDA Hold, Advances to Phase 2 Trial of Tuberous Sclerosis Complex

The FDA has lifted a clinical hold on simufilam, clearing Filana Therapeutics, the company formerly known as Cassava Sciences, to begin a phase 2a study of the drug in tuberous sclerosis complex (TSC)-related epilepsy. The milestone marks a new chapter for simufilam, which spent years in Alzheimer disease (AD) development amid data integrity allegations and 2 failed phase 3 trials before its developer rebranded and redirected the compound toward a new disease and mechanistic rationale.

The planned phase 2a study is a 16-week, multicenter, randomized, double-blind trial with an optional 48-week extension, enrolling approximately 40 patients ages 12 to 55 with drug-resistant, TSC-related seizures across 13 U.S. sites; primary end points include safety, tolerability, pharmacokinetics, and seizure measures such as frequency, intensity, duration, and nighttime seizures, with patient screening expected to begin in the first quarter of 2027.¹

The FDA had placed the trial on clinical hold in December 2025, requesting additional preclinical data before allowing the study to proceed; Filana said it used the intervening months to complete trial-readiness activities, including engaging a clinical research organization and identifying study sites.²

“Drug-resistant epilepsy remains a challenge for a majority of individuals affected by TSC," said Rick Barry, president and chief executive officer of Filana, said in a statement.¹ Kari Luther Rosbeck, president and chief executive officer of the TSC Alliance, added, “Research investigating different molecular pathways offers hope for potential new options.”

Simufilam's history in this program traces back to Cassava Sciences, which developed the oral small molecule to target filamin A, a scaffolding protein the company said becomes abnormally altered in AD. In September 2020, Cassava reported phase 2b data claiming cognitive improvements of up to 46% versus placebo, and the company raised approximately $260 million following that announcement.³

Those results soon drew scrutiny. In 2021, neuroscientists David Bredt, MD, PhD, and Geoffrey Pitt, MD, PhD, raised concerns about the underlying data, prompting an independent analysis by Matthew Schrag, MD, a vascular neurologist at Vanderbilt University, who identified anomalies in Western blot images suggesting samples had been altered or reused. The FDA denied a citizen petition to halt Cassava's trials that year.⁴

A 2022 FDA inspection of the CUNY laboratory of Hoau-Yan Wang, PhD, a Cassava consultant and co-developer of the underlying science, found improper equipment maintenance and data security issues, prompting a formal CUNY investigation.⁴

Federal investigations and settlements

In June 2024, the U.S. Department of Justice indicted Wang on charges of defrauding the National Institutes of Health of $16 million in grant funding tied to simufilam research.⁴ The following month, Cassava publicly acknowledged that its original 2020 phase 2b analysis had excluded 40% of enrolled patients from the presented results.³

On September 26, 2024, the U.S. Securities and Exchange Commission charged Cassava Sciences, former CEO Remi Barbier, former senior vice president Lindsay Burns, PhD, and Wang with securities fraud violations, alleging that Wang had accessed unblinded trial data and manipulated biomarker results while the company misrepresented the trial as properly blinded. All parties settled without admitting or denying the allegations: Cassava agreed to pay $40 million, Barbier $175,000 with a 3-year bar from officer or director roles, Burns $85,000 with a 5-year bar, and Wang $50,000.⁵

In May 2025, CUNY's internal investigation concluded that Wang had improperly manipulated images in several studies but determined the conduct fell short of the university's formal misconduct threshold. On October 17, 2025, a federal court dismissed the DOJ's fraud case against Wang with prejudice, meaning the charges cannot be refiled; prosecutors did not publicly explain the dismissal.⁶

Two failed phase 3 trials and a pivot

Alongside the federal scrutiny, simufilam's clinical program for AD was faltering. Topline results from the phase 3 RETHINK-ALZ trial, reported November 2024, showed simufilam did not separate from placebo on either co-primary end point (ADAS-Cog12: 2.8 vs 3.2 points, P =.43; ADCS-ADL: -3.3 vs -3.8 points, P =.40).⁷ The second pivotal trial, REFOCUS-ALZ, enrolled 1,125 patients and reported topline results on March 25, 2025, that also missed both co-primary end points across the 50-mg and 100-mg doses (ADAS-Cog12 deltas of 0.56 and 0.27, respectively, versus placebo; ADCS-ADL deltas of -1.10 and -0.95).⁸

READ MORE: Xenon Submits New Drug Application for Azetukalner as Treatment for Focal Seizures

“These results were unambiguous,” Barry said at the time regarding the lack of treatment benefit in mild-to-moderate AD. Cassava announced it would discontinue all AD development for simufilam by the end of the second quarter of 2025, while beginning to explore the drug's potential in TSC-related epilepsy, marking the first public signal of the pivot that would follow.⁸

A new name and a new rationale

In March, Cassava Sciences completed a corporate rebrand to Filana Therapeutics, changing its Nasdaq ticker from SAVA to FLNA. Barry described the change as centered on filamin A biology and reflecting “our dedication to rigorous scientific discovery and to bringing new treatment options to patients.”²

The preclinical rationale for the TSC indication was published in April 2026 in Epilepsia, in a study using a Tsc1 conditional knockout mouse model described as an exceptionally severe, progressive model of TSC-related epilepsy. All told, simufilam significantly attenuated the progression of seizure activity relative to vehicle, with seizure attenuation correlating with dose and plasma drug exposure.

“These results underscore the positive correlation between seizure outcomes and plasma exposure to simufilam,” Angelique Bordey, PhD, a Yale School of Medicine neuroscientist and study co-author, said in a statement.⁹

REFERENCES
1. Filana Therapeutics announces FDA lift of clinical hold on simufilam, enabling phase 2a study in TSC-related epilepsy. News release. Published September 22, 2026. Accessed September 22, 2026. https://www.globenewswire.com/news-release/2026/09/22/3366269/8339/en/filana-therapeutics-announces-fda-lift-of-clinical-hold-on-simufilam-enabling-phase-2a-study-in-tsc-related-epilepsy.html
2. Filana leaves Cassava roots behind amid branch into epilepsy. FiercePharma. Published March 10, 2026. Accessed September 22, 2026. https://www.fiercepharma.com/marketing/filana-leaves-cassava-roots-behind-amid-branch-epilepsy-0
3. Cassava pays $40M over allegedly misleading statements about Alzheimer's data. FierceBiotech. Published September 27, 2024. Accessed September 22, 2026. https://www.fiercebiotech.com/biotech/cassava-pays-40m-over-allegedly-misleading-statements-about-alzheimers-data
4. An Alzheimer's drugmaker is accused of data manipulation. Should its trials be stopped? BioPharma Dive. Published October 4, 2024. Accessed September 22, 2026. https://www.biopharmadive.com/news/cassava-alzheimers-trials-misconduct-scrutiny-matthew-schrag/728955/
5. U.S. Securities and Exchange Commission. SEC charges Cassava Sciences, two former executives for misleading claims about Alzheimer's clinical trial. Press release 2024-151. Published September 26, 2024. Accessed September 22, 2026. https://www.sec.gov/newsroom/press-releases/2024-151
6. Cassava fraud case dismissed, closing a chapter in Alzheimer's drug saga. Being Patient. Published October 30, 2025. Accessed September 22, 2026. https://beingpatient.com/cassava-fraud-case-dismissed/
7. Cassava Sciences topline phase 3 data did not meet co-primary endpoints. News release. Published November 25, 2024. Accessed September 22, 2026. https://www.globenewswire.com/news-release/2024/11/25/2986578/8339/en/Cassava-Sciences-Topline-Phase-3-Data-Did-Not-Meet-Co-Primary-Endpoints.html
8. Cassava Sciences reports topline phase 3 REFOCUS-ALZ data. News release. Published March 25, 2025. Accessed September 22, 2026. https://www.globenewswire.com/news-release/2025/03/25/3048697/8339/en/Cassava-Sciences-Reports-Topline-Phase-3-REFOCUS-ALZ-Data.html
9. Stansley B, Islam MM, Aguiar DJ, et al. The small molecule simufilam dose-dependently attenuates the worsening of seizures in a mouse model of tuberous sclerosis complex. Epilepsia. Published online April 14, 2026. doi:10.1002/epi.70227