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Simufilam

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Simufilam
Clinical data
Other namesPTI-125, PTI-910
ATC code
  • None
Pharmacokinetic data
Elimination half-life4.5 hrs[1]
Identifiers
  • 1-benzyl-8-methyl-1,4,8-triazaspiro(4.5)decan-2-one
CAS Number
PubChem CID
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC15H21N3O
Molar mass259.353 g·mol−1
3D model (JSmol)
  • CN1CCC2(CC1)NCC(=O)N2Cc1ccccc1
  • InChI=1S/C15H21N3O/c1-17-9-7-15(8-10-17)16-11-14(19)18(15)12-13-5-3-2-4-6-13/h2-6,16H,7-12H2,1H3
  • Key:BSQPTZYKCAULBH-UHFFFAOYSA-N

Simufilam is an Investigational New Drug for the treatment of Alzheimer's disease in phase III clinical trials expected to finish in 2023 or 2024.[2][3] It is being developed by the American pharmaceutical firm Cassava Sciences.

History

From research funded by Cassava Sciences (then Pain Therapeutics), Lindsay Burns (Cassava's senior vice president of neuroscience) and Hoau-Yan Wang (a CUNY professor and Cassava advisor)[4] 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.[5][6]

Wang, Burns and co-authors reported in Neurobiology of Aging in 2017 showed that PTI-125 induced improvements in Alzheimer's disease pathology as it binds, and restores to normal, an altered conformation of FLNA in experimental Alzheimer's disease transgenic mice.[7][8]

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.[9][10] In August 2020, the United States Adopted Names (USAN) assigned the drug chemical name as simufilam.[11]

Open-label studies started in March 2020,[12] 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 to show significant difference from placebo[13]. Additional analysis revealed substantial fluctuations in biomarker levels in the placebo group, which likely caused the lack of difference from placebo[14]. Cassava reported in September 2020 that a new analysis by Wang's CUNY lab showed improvements in biomarkers, adding that individuals with Alzheimer's also showed improvements in cognition with simufilam.[12][15]

In October 2021, larger trials were initiated;[12] Cassava Sciences announced in December 2021 that the first phase III trial of simufilam would enroll about 750 participants, and the second 1,000.[12][16] In the first quarter of 2022, 60 participants were enrolled;[12] In August 2022, Cassava stated that over 400 patients had enrolled in the trials.[17] In September 2022, Cassava reported over 500 patients are enrolled. [18]

Pharmacology

Further information: Cassava Sciences § Allegations of research fraud

Burns and Wang reported in 2008 that FLNA contains the high-affinity binding site of naloxone and naltrexone in preventing opioid tolerance and dependence,[19] and in 2020 that by disrupting that simufilam reduces the ultra-tight binding of amyloid beta 42 to the alpha-7 nicotinic receptor.[1][6] 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.[6] 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.[7][8]

No other researchers have examined simufilam binding to FLNA[6] or simufilam's restoration of altered filamin A.[7][8] One independent study found that simufilam improved epilepsy in a mouse model.[20] Research papers demonstrating the mechanism of action of simufilam contained an error of units in methods (one instance of milligrams noted as micrograms) and erroneous duplication of images, but neither journal found evidence of data manipulation that was previously alleged.[21][22] Two papers unrelated to Alzheimer's disease that reported FLNA binding by certain opioid antagonists and FLNA's role in opioid tolerance and dependence were retracted for "similarities in background pixels" in western blot images without evidence of data manipulation.[23][24]

Lawrence Sterling Honig, professor of neurology at Columbia University Irving Medical Center, had remarked on Burns and Wang's claims: "But in fact, all the evidence seems to be from this [Wang's] lab."[12] Robert Howard, professor of psychiatry at the University College London, is concerned on the lack of placebo and small sample size and said that the research "at the very least is implausible". Thomas C. Südhof, Nobel laureate neuroscientist at Stanford University, also commented: "The overall conclusions with regard to Alzheimer's disease make no sense to me whatsoever... [The findings of Burns and Wang] are not in the mainstream of the field, and to me they seem implausible and contrived."[12]

Allegations of research irregularities

Further information: Cassava Sciences § Allegations of research fraud

As of July 2022, Cassava Sciences and papers published by Burns and Wang are under investigation by the U.S. Justice Department; Cassava denies any wrongdoing.[25][4] Two papers were retracted by journals and expressions of concern were issued for other papers.[26] The U.S. Securities and Exchange Commission (SEC), the U.S. National Institutes of Health (NIH), and City University of New York (CUNY) were also investigating allegations of manipulated data.[4]

References

  1. ^ a b Wang HY, Pei Z, Lee KC, Lopez-Brignoni E, Nikolov B, Crowley CA, et al. (2020). "PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients". The Journal of Prevention of Alzheimer's Disease. 7 (4): 256–264. doi:10.14283/jpad.2020.6. PMID 32920628. S2CID 211039039.
  2. ^ "A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Study Evaluating the Safety and Efficacy of Simufilam 100 mg Tablets in Subjects with Mild-to-Moderate Alzheimer's Disease". May 25, 2022.
  3. ^ "A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 76-week Study Evaluating the Safety and Efficacy of Two Doses of Simufilam in Subjects with Mild-to-Moderate Alzheimer's Disease". June 2, 2022.
  4. ^ a b c Michaels, Dave; Walker, Joseph (November 17, 2021). "SEC Investigating Cassava Sciences, Developer of Experimental Alzheimer's Drug". Wall Street Journal. ISSN 0099-9660. Retrieved April 29, 2022.
  5. ^ Burns LH, Wang HY (2017). "Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease". Neuroimmunology and Neuroinflammation. 4 (12): 263–271. doi:10.20517/2347-8659.2017.50. PMC 8294116. PMID 34295950.
  6. ^ a b c d Wang HY, Bakshi K, Frankfurt M, Stucky A, Goberdhan M, Shah SM, et al. (July 2012). "Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A". The Journal of Neuroscience. 32 (29): 9773–9784. doi:10.1523/JNEUROSCI.0354-12.2012. PMC 6621293. PMID 22815492.
  7. ^ a b c Wang HY, Lee KC, Pei Z, Khan A, Bakshi K, Burns LH (July 2017). "PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis". Neurobiology of Aging. 55: 99–114. doi:10.1016/j.neurobiolaging.2017.03.016. PMID 28438486. S2CID 207163555.
  8. ^ a b c Toniolo S, Sen A, Husain M (December 2020). "Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer's Disease". International Journal of Molecular Sciences. 21 (23): 9318. doi:10.3390/ijms21239318. PMC 7730926. PMID 33297460.
  9. ^ "Multiple Ascending Dose clinical trial of PTI-125, a novel AD therapeutic candidate". nih.gov. 2018. Retrieved April 29, 2022.
  10. ^ Cassava Sciences, Inc. (September 7, 2021). "A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multiple Dose, Biomarker and Safety Study of PTI-125 in Mild-to-moderate Alzheimer's Disease Patients". National Institute on Aging (NIA).
  11. ^ "Cassava Sciences Announces Lead Drug Candidate PTI-125 Is Assigned the Chemical Drug Name 'sumifilam' by USAN" (Press release). Cassava Sciences. August 24, 2020. Retrieved May 3, 2022 – via GlobeNewswire.
  12. ^ a b c d e f g Mandavilli A (April 18, 2022). "Scientists Question Data Behind an Experimental Alzheimer's Drug". The New York Times. Retrieved April 28, 2022.
  13. ^ MS, Marisa Wexler; MS, Marisa Wexler. "PTI-125 Fails to Lower Alzheimer's Protein Levels in Phase 2 Trial". Retrieved October 12, 2022.
  14. ^ Staff, B. N. S. "Simufilam (PTI-125)". Retrieved October 12, 2022.
  15. ^ Keefe, Patrick Radden (January 15, 2022). "Jordan Thomas's Army of Whistle-Blowers". The New Yorker. Archived from the original on July 22, 2022. Retrieved April 29, 2022.
  16. ^ "Cassava Sciences Launches Clinical Website to Support Phase 3 Studies of Oral Simufilam in Alzheimer's Disease". GlobeNewswire News Room (Press release). Cassava Sciences, Inc. December 23, 2021. Retrieved April 30, 2022.
  17. ^ Cassava Sciences, Inc. (August 3, 2022). "Cassava Sciences Reports Second Quarter Financial Results for 2022, Mid-year Corporate Update and Interim Analysis of Open-label Study".
  18. ^ "Simufilam | ALZFORUM". www.alzforum.org. Retrieved October 12, 2022.
  19. ^ Wang HY, Frankfurt M, Burns LH (February 2008). "High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence". PLOS ONE. 3 (2): e1554. Bibcode:2008PLoSO...3.1554W. doi:10.1371/journal.pone.0001554. PMC 2212716. PMID 18253501.
  20. ^ Zhang L, Huang T, Teaw S, Nguyen LH, Hsieh LS, Gong X, et al. (February 2020). "Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations". Science Translational Medicine. 12 (531). doi:10.1126/scitranslmed.aay0289. PMID 32075941. S2CID 211213874.
  21. ^ "Expression of Concern: Wang et al., "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A"". The Journal of Neuroscience. 42 (3): 529. January 2022. doi:10.1523/JNEUROSCI.2306-21.2021. PMC 8802929. PMID 34921050.
  22. ^ "Expression of Concern: Wang et al., (2017) PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol. Aging, 55:99-114". Neurobiology of Aging. 113: 152. 2022. doi:10.1016/j.neurobiolaging.2022.03.012. S2CID 247586479.
  23. ^ "Retraction: High-Affinity Naloxone Binding to Filamin A Prevents Mu Opioid Receptor-Gs Coupling Underlying Opioid Tolerance and Dependence". PLOS ONE. 17 (3): e0266627. March 30, 2022. Bibcode:2022PLoSO..1766627.. doi:10.1371/journal.pone.0266627. PMC 8967022. PMID 35353861.
  24. ^ "Retraction: Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor-Gs Coupling and CREB Activation of Acute Morphine". PLOS ONE. 17 (3): e0266629. 2022. Bibcode:2022PLoSO..1766629.. doi:10.1371/journal.pone.0266629. PMC 8967007. PMID 35353864.
  25. ^ Taylor, Marisa; Spector, Mike (July 27, 2022). "Exclusive: Cassava Sciences faces U.S. criminal probe tied to Alzheimer's drug, sources say". Reuters. Retrieved July 31, 2022.
  26. ^ Piller, Charles (July 21, 2022). "Blots on a field?". Science. 377 (6604): 358–363. doi:10.1126/science.add9993. PMID 35862524. S2CID 250953611. Archived from the original on August 28, 2022.
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