Simufilam
From Wikipedia, the free encyclopedia
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| Other names | PTI-125, PTI-910 |
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| Elimination half-life | 4.5 hours[1] |
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| Formula | C15H21N3O |
| Molar mass | 259.353 g·mol−1 |
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Simufilam (PTI-125) is an experimental medication for the treatment of Alzheimer's disease[2][3] that was being developed by the American pharmaceutical firm Cassava Sciences. Its development was discontinued in November 2024 after it failed to show clinical benefit during phase III clinical trials.[4]
From research funded by Cassava Sciences (then Pain Therapeutics), Lindsay Burns (Cassava's senior vice president of neuroscience), Hoau-Yan Wang (a CUNY professor and Cassava advisor),[5] and Maya Frankfurt (CUNY) reported in PLOS One the binding of a 300-kDa protein called filamin A (FLNA) with naloxone to prevent opioid tolerance and drug dependence.[6] The authors claimed this was a critical discovery of the binding of certain opioid antagonists (naloxone and naltrexone) to FLNA, a cytoskeletal protein that is critical in maintaining cell shape and division.[7] Burns and Wang reported the pentapeptide binding site on FLNA the next year.[8] Both of these papers were retracted by PLOS One in 2022.[9]
Wang separately identified a large protein associating with the alpha 7 nicotinic receptor when Abeta42 bound and signaled through this receptor in Alzheimer's disease models. He identified it as FLNA, and Wang and Burns tested the hypothesis that it was critical to the toxic signaling of soluble amyloid. In 2012, they stated in The Journal of Neuroscience that the compound PTI-125 disrupted FLNA linkage with the alpha 7 nicotinic receptor as well as the toxic signaling of Abeta42, presenting PTI-125 as a novel therapeutic strategy for Alzheimer's disease.[7][10] The Journal of Neuroscience issued an expression of concern in 2022.[9]
Wang, Burns and co-authors reported in Neurobiology of Aging in 2017 that PTI-125 induced improvements in Alzheimer's disease pathology as it binds, and restores to normal, an altered conformation of FLNA in a transgenic mouse model of Alzheimer's disease.[11][12] Neurobiology of Aging issued an expression of concern for this paper in 2022.[9]
In 2018, the National Institutes of Health granted the company a research award for early clinical trials of PTI-125 as an Alzheimer's drug.[13][14] In August 2020, the United States Adopted Names (USAN) assigned the drug chemical name as simufilam.[15]
Open-label studies started in March 2020,[9] and Cassava Sciences reported in May 2020 that initial biomarker analysis of cerebrospinal fluid (CSF) samples from its phase IIb clinical trials of PTI-125 had failed, but reported in September 2020 that a new analysis by an "outside lab" showed improvements in biomarkers, adding that individuals with Alzheimer's also showed improvements in cognition with simufilam.[9][16][17] It was later revealed that the outside lab was Wang's CUNY lab.[16][9]
In October 2021, larger trials were initiated;[9] Cassava Sciences announced in December 2021 that the first phase III trial of simufilam would enroll about 750 participants, and the second 1,000.[9][18] In the first quarter of 2022, 60 participants were enrolled;[9] Stat stated that enrollment had slowed as of April 2022, as people were deterred from enlisting due to the prevailing controversies.[19] In August 2022, Cassava stated that over 400 patients had enrolled in the trials.[20]
On 25 November 2024, development of simufilam was discontinued after it failed to show clinical benefit during its phase III clinical trials.[4]
Pharmacology
The publishing journals have issued expressions of concern for studies related to the pharmacology.[6][10][11]
Burns and Wang reported in 2008 that FLNA contains the high-affinity binding site of naloxone and naltrexone in preventing opioid tolerance and dependence,[6] and in 2020 that by disrupting that simufilam reduces the ultra-tight binding of amyloid beta 42 to the alpha-7 nicotinic receptor.[1][10] Burns and Wang say that the FLNA linkage to the alpha-7 nicotinic receptor is critical to amyloid's toxic signaling through this receptor and that simufilam disrupts FLNA's linkage to this receptor to stop this toxic signaling.[10] They later demonstrated, by isoelectric focusing, that simufilam restores to normal an altered conformation of FLNA in Alzheimer's disease models or postmortem human brain tissue.[11][12]
A 2020 study found simufilam improved epilepsy in a mouse model where FLNA was overexpressed.[21]
