Synonyms: PTI-125, sumifilam
Chemical Name: sumifilam
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
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 caused 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 proposed 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 subsequently published (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).
The study confirmed target engagement as defined by reduced association of filamin-A with the α7 and TLR4 receptor in lymphocytes.
Also in November 2020, Cassava Sciences changed the drug's name 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. The company reportedly plans to expand the open-label study from 100 to 150 patients, and add 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 (press release).
The company held an end-of-Phase-2 meeting with the FDA in January 2021, and plans to start two Phase 3 trials later this year (press release),
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 Apr 2021
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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.