Synonyms: PTI-125, sumifilam
Chemical Name: 4-benzyl-8-methyl-1,4,8-triazaspiro[4.5]decan-3-one
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Cassava Sciences
PTI-125 binds to filamin, a ubiquitous scaffolding protein and regulator of the actin cytoskeleton. Filamin appears 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 (July 2012 news).
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).
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 12 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).
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 is 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 aims to gather one-year treatment data on the 100 mg twice-daily dose; it will run to March 2022.
In top-line results announced in May 2020, this trial missed its primary outcome (press release). In November 2020 at CTAD, reanalyzed CSF data 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 rose by about 10 percent. Scores on episodic memory and spatial working memory tests 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 6 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 9 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 complete one year of open-label simufilam will be randomized to further treatment or placebo for six months to assess effects of withdrawal. The study is expected to end in 2023.
In May 2021, a pharmacokinetic study of formulation and food effects was completed in 24 healthy volunteers.
In August 2021, the company registered two Phase 3 trials to begin in the fall. 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).
Also in August 2021, anonymous whistleblowers filed a citizen petition with the FDA to halt ongoing simufilam trials. The complaint alleged multiple instances of research misconduct involving the clinical trial biomarker data and previous, foundational research on the drug (Endpoint news). The FDA posted the statement of concern on its 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). The FDA has 150 days to act on the complaint.
Also in September 2021, a securities fraud class action lawsuit was filed against Cassava Sciences (Yahoo Finance news).
For details of registered trials, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 21 Sep 2021
- Fluid AD Biomarkers Link P-Tau to Synapses, Inflammation
- Novel Drug Knocks Aβ Off Synapses, Reduces Toxicity
Research Models Citations
- Wang HY, Pei Z, Lee KC, Lopez-Brignoni E, Nikolov B, Crowley CA, Marsman MR, Barbier R, Friedmann N, Burns LH. PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients. J Prev Alzheimers Dis. 2020;7(4):256-264. PubMed.
- Wang HY, Lee DH, D'Andrea MR, Peterson PA, Shank RP, Reitz AB. beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. J Biol Chem. 2000 Feb 25;275(8):5626-32. PubMed.
- Wang HY, Li W, Benedetti NJ, Lee DH. Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. J Biol Chem. 2003 Aug 22;278(34):31547-53. PubMed.
- Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.
- Wang HY, Lee KC, Pei Z, Khan A, Bakshi K, Burns LH. PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol Aging. 2017 Jul;55:99-114. Epub 2017 Mar 31 PubMed.
- Burns LM, Wang HY. Altered filamin A enables amyloid beta induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease. Neuroimmunol Neuroinflammation 2017;4:263-71.
- Zhang L, Huang T, Teaw S, Nguyen LH, Hsieh LS, Gong X, Burns LH, Bordey A. Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations. Sci Transl Med. 2020 Feb 19;12(531) PubMed.