Simufilam

Last updated

Simufilam
Simufilam skeletal.svg
Clinical data
Other namesPTI-125, PTI-910
ATC code
  • None
Pharmacokinetic data
Elimination half-life 4.5 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
Formula C15H21N3O
Molar mass 259.353 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 (PTI-125) is an experimental medication for the treatment of Alzheimer's disease. [2] [3] It is being developed by the American pharmaceutical firm Cassava Sciences. The drug is in phase III clinical trials as of October 2023. There are two phase III clinical studies: RETHINK-ALZ, a 52-week trial, is set to complete in 2024, [4] and REFOCUS-ALZ, spanning 76 weeks, is projected to finish in 2025. [5]

Contents

The US Food and Drug Administration (FDA) received a citizen petition in August 2021 to stop the clinical trials and investigate simufilam. Other scientists have questioned the preclinical results, citing the small sample size, alleged methodological flaws in an in vitro technique, alleged manipulations of western blot images and potential conflict of interest. [6] [7] [8]

After the FDA said that the citizen petition was the improper procedure to request an investigation, Reuters reported in July 2022 that a criminal investigation of Cassava Sciences was started by the United States Department of Justice (DOJ) over research results related to the experimental drug. [9] 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 whether Cassava or individuals manipulated data. [10] In June 2024, Wang was indicted by the United States Department of Justice (DOJ) for fraud and charged with falsifying data on $16 million in grant applications to the NIH related to simufilam. [11] [12] [13] [14]

History

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), [10] 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. [15] 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. [16] Burns and Wang reported the pentapeptide binding site on FLNA the next year. [17] Both of these papers were retracted by PLOS One in 2022. [6]

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. [16] [18] The Journal of Neuroscience issued an expression of concern in 2022. [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. [19] [20] Neurobiology of Aging issued an expression of concern for this paper in 2022. [6]

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. [21] [22] In August 2020, the United States Adopted Names (USAN) assigned the drug chemical name as simufilam. [23]

Open-label studies started in March 2020, [6] 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. [6] [24] [25] It was later revealed that the outside lab was Wang's CUNY lab. [24] [6]

In October 2021, larger trials were initiated; [6] Cassava Sciences announced in December 2021 that the first phase III trial of simufilam would enroll about 750 participants, and the second 1,000. [6] [26] In the first quarter of 2022, 60 participants were enrolled; [6] Stat stated that enrollment had slowed as of April 2022, as people were deterred from enlisting due to the prevailing controversies. [27] In August 2022, Cassava stated that over 400 patients had enrolled in the trials. [28]

Pharmacology

The publishing journals have issued expressions of concern for studies related to the pharmacology. [15] [18] [19]

Burns and Wang reported in 2008 that FLNA contains the high-affinity binding site of naloxone and naltrexone in preventing opioid tolerance and dependence, [15] and in 2020 that by disrupting that simufilam reduces the ultra-tight binding of amyloid beta 42 to the alpha-7 nicotinic receptor. [1] [18] 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. [18] 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. [19] [20]

A 2020 study found simufilam improved epilepsy in a mouse model where FLNA was overexpressed. [29]

Allegations of research irregularities

In June 2024, a grand jury indicted Wang on charges of falsifying data to obtain grants. [30]

As of July 2022, Cassava Sciences and papers published by Burns and Wang were under investigation by the U.S. Justice Department; Cassava denies any wrongdoing. [31] [10] Two papers were retracted by journals and expressions of concern were issued for other papers. [32] 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. [10]

In October 2023, a leaked CUNY report indicated that they could obtain none of Wang's original data, which meant that they were unable to either prove or disprove allegations that the images were improperly manipulated; [7] [33] they paused the investigation a few weeks later over concerns about confidentiality and integrity of the process. [34]

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. [35] [36] 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. [37] [38]

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." [6] 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." [6]

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References

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  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. Archived from the original on June 6, 2022. Retrieved June 6, 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 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 | Alzheimers.gov". www.nia.nih.gov.
  5. ↑ "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 | Alzheimers.gov". www.nia.nih.gov.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 Mandavilli A (April 18, 2022). "Scientists Question Data Behind an Experimental Alzheimer's Drug". The New York Times . Archived from the original on April 27, 2022. Retrieved April 28, 2022.
  7. 1 2 Piller C (October 12, 2023). Co-developer of Cassava's potential Alzheimer's drug cited for 'egregious misconduct' (Report). Science. doi:10.1126/science.adl3444.
  8. ↑ Mandavilli A (October 14, 2023). "Scientists Investigating Alzheimer's Drug Faulted in Leaked Report". The New York Times . Archived from the original on October 15, 2023. Retrieved October 15, 2023.
  9. ↑ Taylor M, Spector M (July 27, 2022). "Exclusive: Cassava Sciences faces U.S. criminal probe tied to Alzheimer's drug, sources say". Reuters. Archived from the original on July 30, 2022. Retrieved July 31, 2022.
  10. 1 2 3 4 Michaels D, Walker J (November 17, 2021). "SEC Investigating Cassava Sciences, Developer of Experimental Alzheimer's Drug". The Wall Street Journal . ISSN   0099-9660. Archived from the original on May 3, 2022. Retrieved April 29, 2022.
  11. ↑ "Cassava Sciences Issues Statement on Former Science Advisor" (Press release). Cassava Sciences. June 28, 2024. Retrieved June 29, 2024.
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  13. ↑ Wosen J (June 28, 2024). "Cassava Sciences collaborator charged with defrauding NIH in grants supporting its Alzheimer's drug". Stat News. Retrieved June 29, 2024.
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  17. ↑ Wang HY, Burns LH (2009). "Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine". PLOS ONE. 4 (1): e4282. Bibcode:2009PLoSO...4.4282W. doi: 10.1371/journal.pone.0004282 . PMC   2628740 . PMID   19172190. (Retracted, see doi:10.1371/journal.pone.0266629, PMID   35353864,  Retraction Watch)
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  19. 1 2 3 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. (This paper currently has an expression of concern, see doi:10.1016/j.neurobiolaging.2022.03.012)
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  21. ↑ "Multiple Ascending Dose clinical trial of PTI-125, a novel AD therapeutic candidate". nih.gov. 2018. Archived from the original on June 2, 2022. Retrieved April 29, 2022.
  22. ↑ 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).
  23. ↑ "Cassava Sciences Announces Lead Drug Candidate PTI-125 Is Assigned the Chemical Drug Name 'sumifilam' by USAN" (Press release). Cassava Sciences. August 24, 2020. Archived from the original on May 3, 2022. Retrieved May 3, 2022– via GlobeNewswire.
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  26. ↑ "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. Archived from the original on December 23, 2021. Retrieved April 30, 2022.
  27. ↑ Feuerstein A (April 5, 2022). "Troubles mount for Cassava Sciences, as patient enrollment lags for Alzheimer's drug studies". Stat . Retrieved April 30, 2022.
  28. ↑ 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". Archived from the original on August 9, 2022. Retrieved August 5, 2022.
  29. ↑ 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 . ISSN   1946-6234. PMID   32075941.
  30. ↑ Mandavilli A (June 28, 2024). "Embattled Alzheimer's Researcher Is Charged With Fraud". The New York Times . Archived from the original on June 29, 2024. Retrieved July 8, 2024.}}
  31. ↑ Taylor M, Spector M (July 27, 2022). "Exclusive: Cassava Sciences faces U.S. criminal probe tied to Alzheimer's drug, sources say". Reuters. Archived from the original on July 30, 2022. Retrieved July 31, 2022.
  32. ↑ Piller C (July 21, 2022). "Blots on a field?". Science . 377 (6604): 358–363. Bibcode:2022Sci...377..358P. doi:10.1126/science.add9993. PMID   35862524. S2CID   250953611. Archived from the original on August 28, 2022.
  33. ↑ Subbaraman N, Walker J (October 13, 2023). "Cassava Sciences Adviser Found to Have Committed 'Egregious Misconduct'; Scientist, who is a City University of New York professor, didn't provide school investigators with data or records supporting his research". The Wall Street Journal . ProQuest   2876611078.
  34. ↑ Mandavilli A (October 28, 2023). "CUNY Halts Investigation of Alzheimer's Researcher". The New York Times . Retrieved October 29, 2023.
  35. ↑ "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.
  36. ↑ "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.
  37. ↑ PLOS ONE Editors (March 30, 2022). "Retraction: High-Affinity Naloxone Binding to Filamin A Prevents Mu Opioid Receptor-Gs Coupling Underlying Opioid Tolerance and Dependence". PLOS ONE. 17 (3): e0266627. Bibcode:2022PLoSO..1766627.. doi: 10.1371/journal.pone.0266627 . PMC   8967022 . PMID   35353861.
  38. ↑ PLOS ONE Editors (2022). "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. Bibcode:2022PLoSO..1766629.. doi: 10.1371/journal.pone.0266629 . PMC   8967007 . PMID   35353864.
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