Background

Simufilam binds to filamin, a ubiquitous scaffolding protein and regulator of the actin cytoskeleton. Filamin has been claimed to stabilize the high-affinity interaction of soluble Aβ42 and the α7 nicotinic acetylcholine receptor (α7nAChR), which has been reported to trigger tau phosphorylation and synaptic dysfunction in some experimental systems (Wang et al., 2000; Wang et al., 2003; Snyder et al., 2005).

Preclinical studies suggest that PTI-125 prevents and reverses the binding of Aβ42 to α7nAChR. In one, daily infusions of human synthetic Aβ42 into mouse cerebral ventricles resulted in association of Aβ42 and filamin with α7 receptors in the hippocampus and prefrontal cortex. Concomitant intraperitoneal PTI-125 injections prevented this association, reduced tau phosphorylation and amyloid deposition, and normalized signaling through the α7, NDMA, and insulin receptors. PTI-125 reportedly tamped down Aβ-induced inflammatory cytokine release by blocking filamin recruitment to toll-like receptor 4. When applied to human AD postmortem brain tissue, PTI-125 was reported to cause filamin and Aβ42 to dissociate from the α7 receptor (Jul 2012 news). Subsequently, the same group reported that simufilam could inhibit Ab42-induced filamin A interactions with multiple inflammatory receptors (Wang et al., 2023). These studies used immunoprecipitation and western blotting to quantitate protein-protein interactions. One study using fluorescence resonance energy transfer in intact cells reported that simufilam reduced Aβ42 binding to α7 with picomolar potency (Wang et al., 2023).

Two months of oral PTI-125 in 3xTg AD mice reportedly reduced tau hyperphosphorylation, amyloid and tau deposition, and neuroinflammation, and restored synaptic function, nesting behavior, and spatial and working memory relative to untreated mice. The study claimed that Aβ42 induces a conformational change in filamin, which would promote its association with the α7 and toll-like receptors, enabling Aβ42 toxicity and inflammation. PTI-125 was said to preferentially bind altered filamin and normalize its conformation (Wang et al., 2017). Most research on filamin, Aβ42 and Alzheimer's comes from the same laboratory, although several independent studies have implicated filamin in AD and progressive supranuclear palsy (Levert et al., 2023; Aumont et al., 2022; Tsujikawa et al., 2022).

Findings

In 2017, Cassava Sciences started with a Phase 1 safety study of 50, 100, or 200 mg of PTI-125 in 24 healthy adults.

In early 2019, the company ran an NIH-funded Phase 2a trial in people with mild to moderate AD. This open-label, multicenter safety, pharmacokinetics, and biomarker study enrolled 13 participants with MMSE scores between 16 and 24 and a CSF total tau/Aβ42 ratio of 0.30 or higher. They took 100 mg PTI-125 capsules twice daily for 28 days. Primary outcomes were pharmacokinetic measures; secondary ones were CSF biomarkers of Alzheimer’s pathology, neurodegeneration, and neuroinflammation. The study measured levels of PTI-125DX, an experimental diagnostic biomarker to indicate altered filamin in blood.

In a September 2019 press release, Cassava claimed that drug treatment significantly decreased CSF total and phosphorylated tauT181, neurofilament light, neurogranin, YKL-40, Il-6, Il-1β, and TNFα, consistent with drug effects countering neurodegeneration and -inflammation. P-tauT181 and neurogranin fell by about a third with treatment, while the inflammatory markers decreased from 5 to 14 percent. Every participant showed changes on most markers with treatment. The ratio of phosphorylated tau to Aβ42 apparently improved. This trial did not measure cognition. At CTAD, the company presented data showing reduction in plasma levels of neurogranin, total tau, neurofilament light, and YLK-40 after treatment. Multiple forms of modified tau declined in plasma, including p-tauT181, p-tauT202, and p-tauT231, as did a nitrated form of tau, n-tauY29 (Dec 2019 conference news). The data were published after peer review (Wang et al., 2020). In a subsequent analysis, the company claimed that simufilam treatment had normalized suboptimal insulin responses in patients’ blood cells by modulating filamin A interaction with the mTOR protein (Wang et al., 2023).

From September 2019 to March 2020, the company ran an NIH-funded Phase 2b study at 10 sites across the U.S. It compared 100 or 50 mg PTI-125 with placebo, dosed twice daily for 28 days, in 64 participants with a clinical diagnosis of mild to moderate AD, confirmed by CSF biomarkers. The primary endpoint was change in CSF phosphorylated tau, neurofilament light chain, neurogranin, total tau, YKL-40, and Aβ42; secondary outcomes include cognition and plasma biomarkers. The randomized period of this trial was followed by an open-label extension for participants who completed previous Phase 2 trials, plus new enrollees to bring its participant number up to 100. This study aimed to gather one-year treatment data on the 100 mg twice-daily dose.

In top-line results announced in May 2020, the 28-day dosing phase missed its primary outcome (press release). In November 2020 at CTAD, data on reanalyzed CSF samples were presented, whereby both doses led to improvements in all CSF biomarkers tested, compared to placebo, with 10 to 40 percent decreases in total tau, p-tau181, neurogranin, NfL, HMGB1, YKL40, IL-6, sTREM2, albumin, and immunoglobulin G. CSF Aβ42 was reported to have risen by about 10 percent. Scores on episodic memory and spatial working memory tests were reported as having improved in treated groups, with effect sizes between 17 and 46 percent. No safety issues were reported (press release). In a poster at the July 2021 AAIC, the company claimed to see a significant reduction in plasma p-tau181 in both treated groups compared to placebo. 

The study confirmed target engagement as defined by reduced association of filamin-A with the α7 and TLR4 receptor in lymphocytes.

In November 2020, the drug's name was changed to simufilam, due to a potential trademark conflict with the previous name (press release).

In February 2021, the company announced interim data from the open-label extension, claiming that 50 patients who had completed six months of dosing improved by 1.6 points on the ADAS-Cog and 1.3 points on the NPI (press release). Adverse events were said to be mild and transient. At the July 2021 AAIC, the company reported on CSF biomarkers measured in 25 people after six months treatment. Aβ42 significantly increased, while total tau, p-tau181, NfL, neurogranin, sTrem2, YKL40, and HMGB1 all significantly decreased between 18 and 72 percent. At the same conference, the company claimed a continued improvement on ADAS-COG11 by 3 points in the first 50 patients who completed nine months of the open-label treatment. 

In mid-2021, Cassava expanded the open-label study from 100 to 200 patients, and added a new extension. Patients who completed one year of open-label simufilam were randomized to further treatment or placebo for six months to assess effects of withdrawal, followed by another six months of open-label treatment. The open-label portion of the study finished in December 2022. Dosing for the placebo-controlled extension was completed in May 2023.

In May 2021, a pharmacokinetic study of formulation and food effects was completed in 24 healthy volunteers.

In November 2021, the company began two Phase 3 trials. One will randomize 750 participants with AD and a clinical dementia rating of 0.5, 1, or 2 to placebo or 100 mg simufilam twice a day for one year, with co-primary outcomes of the ADAS-Cog12 and ADCS-ADL. This trial will run through October 2023. A parallel trial will enroll 1,083 similar patients to be randomized to placebo, 50, or 100 mg simufilam twice a day for 18 months, with the same primary outcomes, and run until June 2024. The company announced an agreement with the FDA on special protocol assessments for these trials of simufilam (press release). In April 2022, the company disclosed the trials had enrolled 60 patients (corporate presentation).

In August 2021, an anonymous citizen petition was filed with the FDA, requesting the agency halt ongoing simufilam trials. The complaint alleged instances of research misconduct involving the clinical trial biomarker data and previous, foundational research on the drug (Endpoint news, FDA website). Soon after, several independent scientists reported instances of apparent data manipulation in several published studies (see PubPeer and Retraction Watch) and in the blood biomarker data on the 2021 AAIC poster (Science Integrity Digest blog). On September 3, the company denied wrongdoing, admitting errors in a figure on the poster but standing by the underlying data analysis and conclusions (see statement, corrected figure). Quanterix, the biomarker testing CRO that analyzed the blood, denied any role in the disputed analysis beyond assaying blinded samples and reporting raw values to Cassava (press release). In January 2022, a New Yorker article on whistleblowers detailed the circumstances surrounding this citizen petition. In February 2022, the FDA rejected the petition on procedural grounds (FDA letter).

In September 2021, a securities fraud class action lawsuit was filed against Cassava Sciences (Yahoo Finance news). In November 2021, the company disclosed that it is the target of an SEC investigation into claims that it manipulated research results on simufilam (WSJ article).

In February, 2022, the journal Neuroscience published an editorial note to a 2005 paper, finding no evidence of data manipulation. In March 2022, the journal PlosOne retracted five papers by Cassava academic collaborator Hoau-Yan Wang at CUNY; although none were related to the AD work, two had been co-authored with a Cassava employee (Wang et al., 2008; Wang and Burns, 2009; Bakshi et al., 2011; Bakshi et al., 2014; Stucky et al., 2016). In 2021 and 2022, journals re-examined three of Wang’s papers related to simufilam; none found convincing evidence of data manipulation, according to a Cassava press release.

On 18 April 2022, the New York Times featured simufilam in a news article. On May 5, the company announced that the phase 3 program had thus far enrolled about 120 participants. On July 7, a securities class action case was opened. On July 27, Reuters news agency reported that the U.S. Department of Justice had opened a criminal investigation into whether Cassava Sciences manipulated research results (Reuters news). 

In their August 2022 earnings report, Cassava released additional results on the open-label trial. The first 100 patients to complete at least 12 months treatment reportedly improved their ADAS-COG scores by an average of 1.5 points from baseline. The company also reported that their Phase 3 trials had enrolled more than 500 patients out of an intended 1,750, evenly split between the two studies (press release; September 13 corporate presentation).

In October 2022, a person unaffiliated with Cassava asked the FDA to grant breakthrough therapy designation to simufilam. The agency rejected the request, on the grounds that only the drug sponsor can apply for this designation (FDA letter).

Also in October 2022, the company added an optional, one-year, open-label extension to their Phase 3 trials (press release).

In November 2022, Cassava announced it had filed a defamation lawsuit against the whistleblowers who originated the citizen’s complaint with the FDA, and others (press release).

In January 2023, Cassava announced final results of their open label study (press release). In 200 patients treated for one year or more, ADAS-Cog scores declined by an average of 0.5 points. This was in contrast to previous findings on the first 100 patients, where the company reported an improvement of 1.5 points after one year. The drug remained safe, with no serious adverse events reported. 

In February 2023, the company said 953 patients were enrolled in the Phase 3 trials, just over half the target (press release). In July 2023, the company reported topline results of the six-month withdrawal study involving 157 patients (press release). The primary outcome of change in the ADAS-Cog was not statistically significantly different between drug continuation and withdrawal groups.

In October 2023, Science magazine reported that the City University of New York had accused Wang of research misconduct involving 20 research papers, including work that formed the basis for simufilam’s clinical development (Science article; WSJ story). The news story was based on a confidential draft report. The leak of the report and other questions about the integrity of the investigation led the University to pause its inquiry (statement; NYT article). In a press release, Cassava denied wrongdoing. 

In November 2023, the company announced that enrollment was complete in both Phase 3 trials (press release).

For details of registered trials, see clinicaltrials.gov.

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