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Simufilam

Clinical data
Other names	PTI-125, PTI-910
Routes of administration	Oral administration (tablets)
ATC code	None
Legal status
Legal status	Experimental
Pharmacokinetic data
Elimination half-life	4.5 hrs
Identifiers
IUPAC name 1-benzyl-8-methyl-1,4,8-triazaspiro(4.5)decan-2-one
CAS Number	1224591-33-6
PubChem CID	46195331
UNII	6NV440YIO0
KEGG	D12003
ChEMBL	ChEMBL4650230
Chemical and physical data
Formula	C15H21N3O
Molar mass	259.353 g·mol
3D model (JSmol)	Interactive image
SMILES CN1CCC2(CC1)NCC(=O)N2Cc1ccccc1
InChI 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. Developed by an American pharmaceutical firm Cassava Sciences (previously Pain Therapeutics), based in Austin, Texas, it is an oral tablet that was reported to restore impaired function of neurons and improve cognition in mice. Lindsay Burns (Senior Vice President and wife of Remi Barbier, founder and President of Cassava Sciences) and Hoau-Yan Wang of the City University of New York (science advisor to the company) are the main scientists who led the research on the discovery and development of the drug.

Promising results from Phase II trial were reported in 2020, based on a small, non–placebo-controlled study in 13 Alzheimer subjects. Reductions of biomarkers from cerebrospinal fluid that are associated with Alzheimer's (for the disease itself, as well as neurodegeneration and inflammation) were an indication of the effectiveness. The research on the drug and its funding company were brought to the limelight when the Food and Drug Administration received a citizen petition in August 2021 to stop the clinical trials as there were possible research misconducts in the development of the drug and clinical trials. Submitted by Jordan A. Thomas of the law firm Labaton Sucharow, the petition represented technical criticisms from two scientists David Bredt and Geoffrey Pitt. Upon the publicity of the allegations, other scientists have also questioned these results, citing the size of the study, methodological and follow-up flaws, data manipulations and potential conflict of interest.

In the early 2022, the FDA rejected the petition. The Journal of Neuroscience and Neurobiology of Aging reexamined the papers they published on simufilam discovery and development, found no apparent data manipulation, but noted several errors, and issued expressions of concern. The Quintessential Capital Management had called simufilam "a worthless compound."

History

From a research funded by Cassava Sciences (then Pain Therapeutics), Lindsay Burns (later Senior Vice President and wife of Remi Barbier, founder and President of Cassava Sciences) with Hoau-Yan Wang and Maya Frankfurt of the City University of New York, reported in PLOS One the binding of a 300-kDa protein called filamin A (FLNA) with naloxone to prevent drug dependence. This report, the authors claimed, was a critical discovery of the binding of opioid antagonists (naloxone and naltrexone) to FLNA, a cytoskeletal protein that is critical in maintaining cell shape and division. Burns and Wang reported the confirmation of the molecular binding the next year. In 2010, they identified a new compound describing it as "a novel analgesic" and named it PTI-609 (PTI for Pain Therapeutics, Inc.). The molecule could also bind to FLNA as those of opioid antagonists. In 2012, their research team redescribed it (its analogue) as PTI-125 and reported it as "a novel compound" in The Journal of Neuroscience. Their report showed PTI-125 similarly binding to FLNA and claimed that this binding was of medical relevance since filamin A is malformed in brain disease condition such as Alzheimer's disease. Their report in Neurobiology of Aging in 2017 showed that PTI-125 induced improvements in the symptoms of brain damage as it binds to FLNA in experimental Alzheimer mice .

In 2018, the National Institutes of Health granted the company a research fund of $260,585 for the clinical trials of PTI-125 as an Alzheimer's drug. As fully focused on Alzheimer's disease, the company was renamed Cassava Sciences, Inc. the next year. In August 2020, the United States Adopted Names (USAN) assigned the drug chemical name as simufilam, and Barbier announced it as "an absolutely new type of drug therapy for Alzheimer’s disease." In 2020, it was announced that the initial biomarker analysis of the Phase II trial had failed. The follow-up studies showed good results, to which Barbier declared: "the first drug—to our knowledge—that can restore cognition."

The final stage, Phase III trials started in February 2021. The first phase would require 750 participants, and the second, 1000. Due to mounting controversies, people are deterred to enlist in the trial. As of May 2022, over 120 people were enrolled in the study.

Pharmacology and controversies

The nature and effects of simufilam are not yet fully understood. All the knowledge on FLNA binding and simufilam came from Burns and Wang's research. The original discovery paper claimed that FLNA is the binding site of opioid antagonists in reducing and preventing drug dependence; and likewise simufilam. They predicted that simufilam binds to FLNA and prevents the association of complexes that include amyloid beta 42 and the alpha-7 nicotinic receptor. Such complex otherwise is hypothesised to have cytotoxic effects on neurons and their accumulation is considered as the cause of Alzheimer at the molecular level. Preventing or lowering the amounts of these molecules in the blood and cerebrospinal fluid is believed to be the key focus in Alzheimer drug development. It is based on this presumption that Burns and Wang claimed that by binding simufilan to FLNA, amyloid beta and nicotinic receptor molecules were reduced, and such reducing effect could be used in the treatment of Alzheimer.

No other research have shown simufilan binding to FLNA and simulifan restoration of distorted filamin A. The research results showing such effects contain critical errors, and thus, remain doubtful. The papers that reported the discovery of FLNA binding with opioid antagonists had been retracted for lack "reliability of results."

The link between FLNA and Alzheimer's disease is still unknown as the evidences remain under scrutiny. 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 lab." The placebo effect, a beneficial non-drug treatment, is an important parameter in clinical trials involving brain diseases as it can have beneficial effects as the drugs. 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... are not in the mainstream of the field, and to me they seem implausible and contrived."

Research issues

In March 2021, David C. Burrow, Director of the Office of Scientific Investigations, Food and Drug Administration, sent a warning letter to Evelyn Lopez-Brignoni, one of the lead scientists in the simufilam clinical trials, regarding violation of the FDA regulations on the clinical trials. He remarked:

You failed to ensure that the investigation was conducted according to the investigational plan . As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan... Your failure to ensure that subjects adhered to the dosing regimen (b)(4) for the pediatric clinical studies raises concerns about the validity and integrity of the data collected at your site. In addition, considering that pediatric subjects are a vulnerable population, we are concerned about the severity of the violations and their potential impact on subjects’ rights, safety, and welfare, given that according to the investigational plan, study subjects were inadequately dosed.

In August 2021, Jordan A. Thomas of the law firm Labaton Sucharow in New York City, submitted a citizen petition to the FDA to investigate simufilam research. The petition "raises grave concerns about the quality and integrity of the laboratory-based studies surrounding this drug candidate and supporting the claims for its efficacy," and made four key points:

1. Claims that filamin A is associated with Alzheimer's disease and that simufilam binds to filamin A are not supported by any independent research;
2. Images of western blots in Burns and Wang's papers that described simufilam activities data anomalies and manipulations;
3. The biomarker data in clinical trials were questionable; and
4. "Remarkable" molecular experiments were said to be suspicious.

Thomas expressed that "The volume of problematic material uncovered in publicly available sources indicates a thorough audit would likely unveil significant additional scientific misconduct and data manipulation," and that "the methodology allegedly used in these experiments defies logic." Cassava Sciences publicly defended against each claim asserting that "the claims made in this post regarding scientific integrity are false and misleading. The Company stands behind its science, its scientists and its scientific collaborators, and is responding to ensure the facts are known and respected."Barbier maintained that the research data were genuine, and said, "As a science company, we champion facts that can be evaluated and verified."

Cassava Sciences further stated: "Cassava Sciences' plasma p-tau data from Alzheimer's patients was generated by Quanterix Corp., an independent company, and presented at the recent Alzheimer’s Association International Conference." Quanterix immediately made a public disclaimer that although its facilities were used for the specific analysis, it was not involved in making the experimental results, stating: "Quanterix or its employees did not interpret the test results or prepare the data charts presented by Cassava."

In November 2021, David Bredt, a neuroscientist at Johnson & Johnson, was revealed as the lead whistleblower in The Wall Street Journal. Early in 2021, Bredt became aware of the drug as the shares of Cassava Sciences reached a notable height. Examining the clinical trials, he was concerned with the lack of placebos. Further scrutiny of all the research papers made him conclude that, "They were making statements that were incompatible with biology and with pharmacology," and such important discoveries deserved to "win five Nobel Prizes." Teaming up with a childhood friend Geoffrey Pitt, a cardiologist and a professor at Weill Cornell Medical College, he directed Thomas for the petition.

The petition, however, was rejected by Patrizia Cavazzoni, Director of the Center for Drug Evaluation and Research, in February 2022. The letter concluded:

We take the issues you raise seriously. Please note that your Petitions are being denied solely on the grounds that your requests are not the appropriate subject of a citizen petition. This response does not represent a decision by the Agency to take or refrain from taking any action relating to the subject matter of your Petitions.

Reactions from the journals

The 2012 paper in The Journal of Neuroscience was the one which reported that simufilam could bind to filamin A,the key claim for the potential use of the drug in Alzheimer's disease. The study relies on the western blot images and data. After reassessment, Marina R. Picciotto, the editor-in-chief, reported in November 2021 that although data manipulation was not detected, there were duplications of images were duplicated. The authors were allowed to publish an erratum mentioning the correct information along with the original images in December 2021. The journal declared that the "error does not affect the conclusions of the article." However, the journal received further information that the original images created further problems on the overall results, and it issued an expression of concernon 19 January 2022:

The editors have been made aware of concerns about Western blots in this study, including those published with the article's erratum (Wang et al., 2021). These and other concerns are currently under investigation by the academic authorities at the City University of New York (CUNY). JNeurosci will await the outcome of that investigation before taking further action.

PLOS One re-examined all the Burns and Wang's research papers and came to conclusion in March 2020 that there were several manipulations in the western blot data. It retracted five of Wang's papers, two of which were co-authored with Burns, which were the foundations for the development of simufilam. The retraction note on the original discovery paper states:

The data and comments provided did not resolve the concerns about the integrity and reliability of data presented in this article. In light of these issues, the PLOS ONE Editors retract this article. HYW and LB did not agree with the retraction. MF either did not respond directly or could not be reached. HYW stands by the article’s findings.

Neurobiology of Aging, which published the 2017 paper reporting the ability of simufilam to restore distorted filamin A in mice, also reassessed the paper, making a notification that there were no "compelling evidence of data manipulation intended to misrepresent the results," but there were at least eight errors in different data. It issued and expression of concern:

The authors have requested a corrigendum to correct these issues. However, Neurobiology of Aging is aware of an ongoing inquiry of these and other concerns by the sponsoring institution, the City University of New York (CUNY), and will make a final decision as to appropriate corrective action once that inquiry has been concluded.

References

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