Lindsay Burns: Difference between revisions

Lindsay Burns
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Born	January 6, 1965 (age 59); Big Timber, Montana, U.S.
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Women's rowing
Representing United States
Olympic Games
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Lindsay H. Burns ^[1] is an American neuroscientist and rower who won a silver medal at the 1996 Summer Olympics.^[2] As of 2022, she is a Senior Vice President at a pharmaceutical company Cassava Sciences based in Austin, Texas.^[3] The company largely relies on her research and one of her major works, the discovery and development of simufilam (a drug candidate for Alzheimer's disease). Due to its novel mechanism of action and unprecedented early data, simufilam has been a focus of short-sellers of Cassava Sciences stock and other accusers mired in conflicts of interest since 2021.^[4]^[5] The controversies initiated by short sellers of Cassava Sciences stock were intended to damage the company.^[6] Burns graduated magna cum laude from Harvard University, Cambridge, Massachusetts, and earned a neuroscience PhD from the University of Cambridge, England.

Biography

Burns was born in Big Timber, Montana. She studied neuroscience at Harvard University from 1983^[7] and graduated with an AB degree in 1987.^[1] She went to England for a PhD research at the University of Cambridge. Supervised by Barry Everitt and Trevor Robbins,^[8]^[9] she obtained her doctoral degree on the thesis Functional interactions of limbic afferents to the striatum and mesolimbic dopamine in reward-related processes in 1991.^[10]

She worked as a research fellow in psychobiology at McLean Hospital in Belmont, Massachusetts.^[7] She later joined Cassava Sciences and became Senior Vice President of Neuroscience in 2021.^[11]

Rowing career

Burns started competitive rowing soon after joining Harvard.^[7] In 1987, she rowed in the Radcliffe varsity crew and won the Eastern Association of Women's Rowing Colleges (EAWRC) championship that gave her the Ivy title and the EAWRC League title.^[12] She was included the US rowing team from 1987 and from 1990-1996. Having competed at six World Rowing Championships, she had won four medals such as gold in the four in 1987, silvers in the double in 1990 and 1991, and a bronze in the double in 1994, all in the lightweight category. She also won a silver medal at the 1995 Pan American Games competing in the quad sculls (heavyweight) category.^[2] She was an alternate rower at the 1992 Summer Olympics in Barcelona, Spain. ^[1]

She teamed up with Teresa Bell at the 1996 Summer Olympics in Atlanta, Canada, and won the second prize (silver medal) in the Lightweight Double Sculls.^[2] In 2006, she was inducted into the Harvard Sports Hall of Fame.^[12] In 2016, she was inducted into the National Rowing Foundation Hall of Fame. ^[13]

Scientific works

Burns' first research was on the effect of neurokinin A on brain functions in rats. Her first paper in 1988, written with Ann E. Kelley, reported that neurokinin A in the ventral tegmental area modifies dopamine circuits to induce behavioral changes.^[14] She continued her PhD research on the role of dopamine and the limbic system.^[8]^[9]^[10]^[15]^[16] Durinbg her post-doc at McLean Hospital, she focused on neurodegenerative diseases, specifically, transplantation of pig neural cells into rat brain as a possible treatment of Parkinson's or Huntington's disease.^[17] Further research indicated possible use in humans.^[18] While working for a biotech company later acquired by Elan Pharmaceuticals, she published the effects of ziconotide in a rat model of spinal cord ischemia.^[19]

Cassava Sciences (as Pain Therapeutics) was established in 1998 with projects on the development of three drug candidates: Oxytrex, Remoxy and PTI-901.^[20]^[21] Burns joined the company as a scientist in 2002. In 2005, she published a series of papers on Oxytrex and related research with ultra-low doses of certain (opioid antagonists) to enhance analgesia and prevent opioid-induced hyperalgesia, opioid tolerance and substance dependence.^[22]^[23]^[24]^[25]

Since 2006, Burns collaborated with Hoau-Yan Wang, an Associate Medical Professor at the City University of New York,^[26] who had been investigating Alzheimer's disease. Wang is the researcher who discovered that Amyloid beta42 binds the alpha 7 nicotinic acetylcholine receptor to hyperphosphorylate tau.^[27]^[28]^[29] Previously identifying filamin A (FLNA) for its role in regulating opioid receptor signaling, Burns and Wang then identified FLNA as a critical protein in enabling Abeta42's signaling through the alpha 7 nicotinic acetylcholine receptor to induce Alzheimer's disease pathology.^[30]^[31]^[32]

Discovery of simufilam and research controversies

In 2008, Burns, Wang and Maya Frankfurt published in PLOS One a discovery that the opioid antagonists naloxone and naltrexone bind with ultra-high affinity to FLNA to prevent mu opioid receptor excitatory signaling.^[33] Burns and Wang identified the binding site on FLNA and the activation of CREB by opioid receptor - Gs coupling in the same journal the next year.^[34] FLNA is a cytoplasmic protein that maintains normal cell shape and division. In 2010, Burns and Wang announced the discovery of "a novel analgesic" which they named PTI-609 (PTI for Pain Therapeutics, Inc.) and showed that the molecule binds to FLNA as well as activating mu opioid receptors. They stated: "PTI-609 was designed after discovering filamin A as the high-affinity target of naltrexone or naloxone."^[35]

In 2012, they published in The Journal of Neuroscience a novel compound PTI-125 that binds to FLNA similarly to naloxone and naltrexone.^[36] With PTI-125, they revealed that FLNA has important implications in Alzheimer's disease: FLNA aberrantly links to the alpha 7 nicotinic receptor, enabling signaling of Abeta42 to hyperphosphorylate tau.^[31]^[36] PTI-125 disrupted both the FLNA linkage to the alpha 7 nicotinic receptor and Abeta42's signaling through this receptor, evidenced by reduced tau hyperphosphorylation and Alzheimer's disease pathology in the mouse model.

In 2017, they reported in Neurobiology of Aging that the FLNA in Alzheimer's disease transgenic mice and human postmortem brain tissue has an altered conformation (based on a shift in isoelectric focusing) and that PTI-125 binding to altered FLNA restores its normal shape, thereby reducing tau hyperphosphorylation, amyloid deposits and tau-containing lesions in the brains of the mice.^[37]^[38]

In 2018, the National Institutes of Health granted Pain Therapeutics a grant award for a clinical trial of PTI-125 in Alzheimer's patients.^[39]^[40] The company name was changed to Cassava Sciences, Inc.^[41] The United States Adopted Names (USAN) gave the drug name for PTI-125 as simufilam in 2020.^[42] In 2020, it was announced that the initial biomarker analysis of the second clinical trial had failed due to high variability in CSF biomarker changes seen even in placebo subjects over this 28-day trial. It was later determined that this initial biomarker analysis showed no correlation between biomarkers in change from baseline (mean pearson's r=0.06), which is unexpected because biomarkers generally move together. This lack of correlation was especially evident in individual placebo subjects' data that showed huge improvements in one biomarker coincident with worsening in another.^[43] Back-up CSF samples were analyzed at a different lab and showed good results, confirming results from the earlier Phase 2a trial.^[44] The Phase III trials started in February 2021.^[45]

David Bredt, a former neuroscientist at Johnson & Johnson,^[46] who mysteriously left venture capital firm MPM after a 4-month stint in August when the petition was filed, became suspicious of the research methods and findings on FLNA binding and simufilam trials in the early 2021. Bredt was previously presented the simufilam program under CDA while at J&J. As he examined the research papers, he came to the conclusion, saying, "They [Burns and Wang's papers] were making statements that were incompatible with biology and with pharmacology," and such important discoveries deserved to "win five Nobel Prizes."^[4] With Geoffrey Pitt, a cardiologist and a professor at Weill Cornell Medical College, they discussed the issue with Jordan A. Thomas of the law firm Labaton Sucharow.^[47] In August 2021, Thomas submitted a citizen petition to the Food and Drug Administration expressing concerns of unreliable research and misuse of scientific data and requesting investigation into the Cassava Sciences works.^[43] Three days later (after the stock plummeted, providing a financial windfall for short sellers), Thomas disclosed that his clients were short sellers of Cassava stock.^[48] Others have noted that the petition was "Gaming the FDA" for financial gain.^[49] FDA denied the petition, saying:

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.^[50]

Other scientists linked to Bredt also started to make public comments that the research on simufilam is unreliable. To the link between filamin A and Alzheimer's disease, Lawrence Sterling Honig, professor of neurology at Columbia University Irving Medical Center, noted: "But in fact, all the evidence seems to be from this [Wang's] lab." This statement is not true: FLNA overexpression has been noted as a result of PS1 mutation in familial AD.^[51] FLNA overexpression has also been linked to tau hyperphosphorylation and aggregation in another neurodegenerative disease, Progressive Supranuclear Palsy (PSP).^[52] Robert Howard, professor of psychiatry at the University College London, remarked on the lack of placebo and small sample size that making such research conclusion "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 Cassava Sciences] are not in the mainstream of the field, and to me they seem implausible and contrived."^[4] Many of these critics were involved with the original petition, are linked to Bredt and/or have their own conflicts of interest. The FDA denied the petition. Unrelatedly, PLOS One retracted five of Wang's papers in March 2022, none of which are about Alzheimer's disease and two of which were published with Burns ^[53] that reported the discovery of naloxone and naltrexone binding to FLNA and FLNA's role in opioid receptor signaling.^[33]^[34] Without evidence of data manipulation, and relating to "similarities in background pixels" of Western blot images, the retraction reads:

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.^[54]^[55] The authors [Hoau-Yan Wang and Lindsay Burns] did not agree with the retraction. HYW stands by the article’s findings.^[54]

In December 2021, Neuroscience found "no evidence of data manipulation" in a paper that was alleged to be fraudulent by short-sellers.

In January 2022, The Journal of Neuroscience did not find evidence of data manipulation but issued an expression of concern on the 2017 paper,^[36] saying that "[It] will await the outcome of that investigation [by the City University of New York] before taking further action.^[56] Neuroscience also found no evidence of data manipulation.^[57]In May 2022, Neurobiology of Aging "did not find compelling evidence of data manipulation but issued an expression of concern on the 2017 paper,^[37] saying that it "will make a final decision as to appropriate corrective action once that inquiry has been concluded."^[58]

References

^ ^a ^b ^c "Olympedia – Lindsay Burns". www.olympedia.org. Retrieved May 2, 2022.
^ ^a ^b ^c "Biography: Lindsay Burns". Olympics. International Olympic Committee. Retrieved May 2, 2022.
^ Keown, Alex (April 19, 2022). "Cassava Faces Renewed Speculation Over Experimental Alzheimer's Drug". BioSpace. Retrieved May 9, 2022.
^ ^a ^b ^c Mandavilli, Apoorva (April 18, 2022). "Scientists Question Data Behind an Experimental Alzheimer's Drug". The New York Times. ISSN 0362-4331. Retrieved April 28, 2022.
^ "Retractions of a Key Collaborator's Papers Set Up a Big April for Cassava Sciences". Seeking Alpha. March 31, 2022. Retrieved May 2, 2022.
^ "The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects".
^ ^a ^b ^c "Harvard at the Olympics". Harvard Magazine. Retrieved May 3, 2022.
^ ^a ^b Burns, L; Robbins, T; Everitt, B (1993). "Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions ofd-amphetamine". Behavioural Brain Research. 55 (2): 167–183. doi:10.1016/0166-4328(93)90113-5. PMID 8357526. S2CID 4032314.
^ ^a ^b Burns, Lindsay H.; Everitt, Barry J.; Kelley, Ann E.; Robbins, Trevor W. (1994). "Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement". Psychopharmacology. 115 (4): 516–528. doi:10.1007/BF02245576. PMID 7871097. S2CID 28351013.
^ ^a ^b Burns, Lindsay H. (1991). Functional interactions of limbic afferents to the striatum and mesolimbic dopamine in reward-related processes (Ph.D. thesis). University of Cambridge. OCLC 556753196.
^ "Lindsay H Burns, Cassava Sciences Inc: Profile and Biography". Bloomberg.com. Retrieved May 3, 2022.
^ ^a ^b "Lindsay Burns Barbier '87". www.harvardvarsityclub.org. Retrieved May 2, 2022.
^ "The National Rowing Foundation Announces the 2016 Inductees to the National Rowing Hall of Fame". January 26, 2016.
^ Burns, Lindsay H.; Kelley, Ann E. (1988). "Neurokinin-α injected into the ventral tegmental area elicits a dopamine-dependent behavioral activation in the rat". Pharmacology Biochemistry and Behavior. 31 (2): 255–263. doi:10.1016/0091-3057(88)90343-7. PMID 2469085. S2CID 20941335.
^ Burns, Lindsay H.; Annett, Lucy; Kelly, Ann E.; Everitt, Barry J.; Robbins, Trevor W. (1996). "Effects of lesions to amygdala, ventral subiculum, medial prefrontal cortex, and nucleus accumbens on the reaction to novelty: Implications for limbic—striatal interactions". Behavioral Neuroscience. 110 (1): 60–73. doi:10.1037/0735-7044.110.1.60. ISSN 1939-0084. PMID 8652073.
^ Parkinson, John A.; Olmstead, Mary C.; Burns, Lindsay H.; Robbins, Trevor W.; Everitt, Barry J. (1999). "Dissociation in Effects of Lesions of the Nucleus Accumbens Core and Shell on Appetitive Pavlovian Approach Behavior and the Potentiation of Conditioned Reinforcement and Locomotor Activity byd-Amphetamine". Journal of Neuroscience. 19 (6): 2401–2411. doi:10.1523/JNEUROSCI.19-06-02401.1999. PMC 6782569. PMID 10066290.
^ Isacson, Ole; Deacon, Terrence W.; Pakzaban, Peyman; Galpern, Wendy R.; Dinsmore, Jonathan; Burns, Lindsay H. (1995). "Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres". Nature Medicine. 1 (11): 1189–1194. doi:10.1038/nm1195-1189. PMID 7584993. S2CID 7344970.
^ Galpern, Wendy R.; Burns, Lindsay H.; Deacon, Terrence W.; Dinsmore, Jonathan; Isacson, Ole (1996). "Xenotransplantation of Porcine Fetal Ventral Mesencephalon in a Rat Model of Parkinson's Disease: Functional Recovery and Graft Morphology". Experimental Neurology. 140 (1): 1–13. doi:10.1006/exnr.1996.0109. PMID 8682173. S2CID 23945411.
^ Burns, Lindsay H.; Jin, Zhen; Bowersox, S.Scott (1999). "The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia". Journal of Vascular Surgery. 30 (2): 334–343. doi:10.1016/S0741-5214(99)70145-X. PMID 10436454.
^ Jacobs, Tom (2005). "No pain, no gain?". Nature Biotechnology. 23 (8): 934. doi:10.1038/nbt0805-934. PMID 16082357. S2CID 20266178.
^ Wolfson, Wendy (2005). "Janus-Faced Drugs: The Double-Edged Synthetic Opiate Trade". Chemistry & Biology. 12 (10): 1055–1056. doi:10.1016/j.chembiol.2005.10.003. PMID 16242645.
^ Chindalore, Vishala L.; Craven, Richard A.; Yu, K. Peony; Butera, Peter G.; Burns, Lindsay H.; Friedmann, Nadav (2005). "Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia: A Randomized, Controlled Trial of Oxytrex". The Journal of Pain. 6 (6): 392–399. doi:10.1016/j.jpain.2005.01.356. PMID 15943961.
^ Olmstead, Mary C.; Burns, Lindsay H. (2005). "Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats". Psychopharmacology. 181 (3): 576–581. doi:10.1007/s00213-005-0022-7. PMID 16010543. S2CID 13270740.
^ Leri, Francesco; Burns, Lindsay H. (2005). "Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats". Pharmacology Biochemistry and Behavior. 82 (2): 252–262. doi:10.1016/j.pbb.2005.08.008. PMID 16182352. S2CID 25513761.
^ Burns, Lindsay H.; Vanderah, Todd W.; Wang, Hoau-Yan (2009), Dean, Reginald L.; Bilsky, Edward J.; Negus, S. Stevens (eds.), "Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance", Opiate Receptors and Antagonists, Totowa, NJ: Humana Press, pp. 3–17, doi:10.1007/978-1-59745-197-0_1, ISBN 978-1-58829-881-2, retrieved May 3, 2022
^ Wang, Hoau-Yan; Burns, Lindsay H. (2006). "Gβγ that interacts with adenylyl cyclase in opioid tolerance originates from a Gs protein". Journal of Neurobiology. 66 (12): 1302–1310. doi:10.1002/neu.20286. PMID 16967511.
^ Wang, H. Y.; Lee, D. H.; Davis, C. B.; Shank, R. P. (2000). "Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors". Journal of Neurochemistry. 75 (3): 1155–1161. doi:10.1046/j.1471-4159.2000.0751155.x. PMID 10936198. S2CID 85190431.
^ Wang, Hoau-Yan; Lee, Daniel H.S.; D'Andrea, Michael R.; Peterson, Per A.; Shank, Richard P.; Reitz, Allen B. (2000). "β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity". Journal of Biological Chemistry. 275 (8): 5626–5632. doi:10.1074/jbc.275.8.5626. PMID 10681545.
^ Gopalan (May 24, 2007). "Magnets to the rescue of Alzheimer's patients". Medindia. Retrieved May 3, 2022.
^ Wang, Hoau-Yan; Bakshi, Kalindi; Frankfurt, Maya; Stucky, Andres; Goberdhan, Marissa; Shah, Sanket M.; Burns, Lindsay H. (2012). "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A". J Neurosci. 32 (29): 9773–9784. doi:10.1523/JNEUROSCI.0354-12.2012. PMC 6621293. PMID 22815492. S2CID 9933756.
^ ^a ^b Burns, Lindsay H.; Wang, Hoau-Yan (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.
^ Wang, Hoau‐Yan; Pei, Zhe; Xu, Qiang; Brunelle, Lynn A; Burns, Lindsay H.; Thornton, George Ben (2021). "SavaDx, a novel plasma biomarker to detect Alzheimer's disease, confirms mechanism of action of simufilam". Alzheimer's & Dementia. 17 (S5): online. doi:10.1002/alz.054385. S2CID 245570217.
^ ^a ^b Wang, Hoau-Yan; Frankfurt, Maya; Burns, Lindsay H. (February 6, 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.
^ ^a ^b Wang, Hoau-Yan; Burns, Lindsay H. (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. ISSN 1932-6203. PMC 2628740. PMID 19172190.
^ Burns, Lindsay H.; Wang, Hoau-Yan (2010). "PTI-609: A Novel Analgesic that Binds Filamin A to Control Opioid Signaling". Recent Patents on CNS Drug Discovery (Discontinued). 5 (3): 210–220. doi:10.2174/157488910793362386. PMID 20726836.
^ ^a ^b ^c Wang, H.-Y.; Bakshi, K.; Frankfurt, M.; Stucky, A.; Goberdhan, M.; Shah, S. M.; Burns, L. H. (2012). "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A". Journal of Neuroscience. 32 (29): 9773–9784. doi:10.1523/JNEUROSCI.0354-12.2012. PMC 6621293. PMID 22815492.
^ ^a ^b Wang, Hoau-Yan; Lee, Kuo-Chieh; Pei, Zhe; Khan, Amber; Bakshi, Kalindi; Burns, Lindsay H. (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.
^ Toniolo, Sofia; Sen, Arjune; Husain, Masud (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.
^ "Multiple Ascending Dose clinical trial of PTI-125, a novel AD therapeutic candidate". nih.gov. 2018. Retrieved April 29, 2022.
^ 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).
^ Schoen, Eric (March 27, 2019). "Pain Therapeutics Announces Name Change to Cassava Sciences, Inc". GlobeNewswire. Retrieved April 28, 2022.
^ Inc, Cassava Sciences (August 24, 2020). "Cassava Sciences Announces Lead Drug Candidate PTI-125 Is Assigned the Chemical Drug Name 'sumifilam' by USAN". GlobeNewswire News Room. Retrieved May 3, 2022. {{cite web}}: |last= has generic name (help)
^ ^a ^b Keefe, Patrick Radden (January 15, 2022). "Jordan Thomas's Army of Whistle-Blowers". The New Yorker. Retrieved April 29, 2022.
^ Wang, H.-Y.; Pei, Z.; Lee, K.-C.; Lopez-Brignoni, E.; Nikolov, B.; Crowley, C.A.; Marsman, M.R.; Barbier, R.; Friedmann, N.; Burns, L.H. (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.
^ Owusu, Tony (February 28, 2021). "Cassava Jumps on Plan for Phase 3 Trial of Alzheimer's Drug". TheStreet. Retrieved April 30, 2022.
^ Rockoff, Jonathan D. (March 3, 2011). "J&J Poaches Lilly's Neurological Research Chief". Wall Street Journal. ISSN 0099-9660. Retrieved April 29, 2022.
^ 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.
^ https://www.regulations.gov/comment/FDA-2021-P-0930-0021
^ "The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects".
^ Cavazzoni, P. (February 10, 2022). "Response Letter from FDA CDER to Labaton Sucharow". www.regulations.gov. Retrieved April 29, 2022.
^ Lu, Q.; Ding, K.; Frosch, M. P.; Jones, S.; Wolfe, M.; Xia, W.; Lanford, G. W. (2010). "Alzheimer's disease-linked presenilin mutation (PS1M146L) induces filamin expression and γ-secretase independent redistribution". Journal of Alzheimer's Disease : Jad. 22 (1): 235–245. doi:10.3233/JAD-2010-100585. PMC 3813954. PMID 20847418.
^ Tsujikawa, Koyo; et al. (2022). "Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology". Science Advances. 8 (21): eabm5029. doi:10.1126/sciadv.abm5029. PMC 9132466. PMID 35613261. S2CID 249065715.
^ Akst, Jef (March 31, 2022). "PLOS ONE Pulls Five Papers Tied to Alzheimer's Drug Controversy". The Scientist. Retrieved April 28, 2022.
^ ^a ^b 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. ISSN 1932-6203. PMC 8967022. PMID 35353861. {{cite journal}}: |author1= has generic name (help)
^ 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. {{cite journal}}: |author1= has generic name (help)
^ "Expression of Concern: Wang et al., "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A"". Journal of Neuroscience. 42 (3): 529. January 19, 2022. doi:10.1523/JNEUROSCI.2306-21.2021. ISSN 0270-6474. PMC 8802929. PMID 34921050.
^ "Science Journal Finds No Evidence to Support Claims of Data Manipulation in 2005 Publication | Cassava Sciences, Inc".
^ "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.

External links

Lindsay Burns at World Rowing
Evans, Hilary; Gjerde, Arild; Heijmans, Jeroen; Mallon, Bill; et al. "Lindsay Burns". Olympics at Sports-Reference.com. Sports Reference LLC. Archived from the original on June 12, 2018. Retrieved March 28, 2018.
Profile at Cassava Sciences
Profile at Encyclopedia.com

[:0-1] "Olympedia – Lindsay Burns". www.olympedia.org. Retrieved May 2, 2022.

[:1-2] "Biography: Lindsay Burns". Olympics. International Olympic Committee. Retrieved May 2, 2022.

[3] Keown, Alex (April 19, 2022). "Cassava Faces Renewed Speculation Over Experimental Alzheimer's Drug". BioSpace. Retrieved May 9, 2022.

[:16-4] Mandavilli, Apoorva (April 18, 2022). "Scientists Question Data Behind an Experimental Alzheimer's Drug". The New York Times. ISSN 0362-4331. Retrieved April 28, 2022.

[:2-5] "Retractions of a Key Collaborator's Papers Set Up a Big April for Cassava Sciences". Seeking Alpha. March 31, 2022. Retrieved May 2, 2022.

[6] "The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects".

[:5-7] "Harvard at the Olympics". Harvard Magazine. Retrieved May 3, 2022.

[:6-8] Burns, L; Robbins, T; Everitt, B (1993). "Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions ofd-amphetamine". Behavioural Brain Research. 55 (2): 167–183. doi:10.1016/0166-4328(93)90113-5. PMID 8357526. S2CID 4032314.

[:10-9] Burns, Lindsay H.; Everitt, Barry J.; Kelley, Ann E.; Robbins, Trevor W. (1994). "Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement". Psychopharmacology. 115 (4): 516–528. doi:10.1007/BF02245576. PMID 7871097. S2CID 28351013.

[:11-10] Burns, Lindsay H. (1991). Functional interactions of limbic afferents to the striatum and mesolimbic dopamine in reward-related processes (Ph.D. thesis). University of Cambridge. OCLC 556753196.

[11] "Lindsay H Burns, Cassava Sciences Inc: Profile and Biography". Bloomberg.com. Retrieved May 3, 2022.

[:13-12] "Lindsay Burns Barbier '87". www.harvardvarsityclub.org. Retrieved May 2, 2022.

[13] "The National Rowing Foundation Announces the 2016 Inductees to the National Rowing Hall of Fame". January 26, 2016.

[14] Burns, Lindsay H.; Kelley, Ann E. (1988). "Neurokinin-α injected into the ventral tegmental area elicits a dopamine-dependent behavioral activation in the rat". Pharmacology Biochemistry and Behavior. 31 (2): 255–263. doi:10.1016/0091-3057(88)90343-7. PMID 2469085. S2CID 20941335.

[15] Burns, Lindsay H.; Annett, Lucy; Kelly, Ann E.; Everitt, Barry J.; Robbins, Trevor W. (1996). "Effects of lesions to amygdala, ventral subiculum, medial prefrontal cortex, and nucleus accumbens on the reaction to novelty: Implications for limbic—striatal interactions". Behavioral Neuroscience. 110 (1): 60–73. doi:10.1037/0735-7044.110.1.60. ISSN 1939-0084. PMID 8652073.

[16] Parkinson, John A.; Olmstead, Mary C.; Burns, Lindsay H.; Robbins, Trevor W.; Everitt, Barry J. (1999). "Dissociation in Effects of Lesions of the Nucleus Accumbens Core and Shell on Appetitive Pavlovian Approach Behavior and the Potentiation of Conditioned Reinforcement and Locomotor Activity byd-Amphetamine". Journal of Neuroscience. 19 (6): 2401–2411. doi:10.1523/JNEUROSCI.19-06-02401.1999. PMC 6782569. PMID 10066290.

[17] Isacson, Ole; Deacon, Terrence W.; Pakzaban, Peyman; Galpern, Wendy R.; Dinsmore, Jonathan; Burns, Lindsay H. (1995). "Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres". Nature Medicine. 1 (11): 1189–1194. doi:10.1038/nm1195-1189. PMID 7584993. S2CID 7344970.

[18] Galpern, Wendy R.; Burns, Lindsay H.; Deacon, Terrence W.; Dinsmore, Jonathan; Isacson, Ole (1996). "Xenotransplantation of Porcine Fetal Ventral Mesencephalon in a Rat Model of Parkinson's Disease: Functional Recovery and Graft Morphology". Experimental Neurology. 140 (1): 1–13. doi:10.1006/exnr.1996.0109. PMID 8682173. S2CID 23945411.

[19] Burns, Lindsay H.; Jin, Zhen; Bowersox, S.Scott (1999). "The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia". Journal of Vascular Surgery. 30 (2): 334–343. doi:10.1016/S0741-5214(99)70145-X. PMID 10436454.

[:12-20] Jacobs, Tom (2005). "No pain, no gain?". Nature Biotechnology. 23 (8): 934. doi:10.1038/nbt0805-934. PMID 16082357. S2CID 20266178.

[:02-21] Wolfson, Wendy (2005). "Janus-Faced Drugs: The Double-Edged Synthetic Opiate Trade". Chemistry & Biology. 12 (10): 1055–1056. doi:10.1016/j.chembiol.2005.10.003. PMID 16242645.

[22] Chindalore, Vishala L.; Craven, Richard A.; Yu, K. Peony; Butera, Peter G.; Burns, Lindsay H.; Friedmann, Nadav (2005). "Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia: A Randomized, Controlled Trial of Oxytrex". The Journal of Pain. 6 (6): 392–399. doi:10.1016/j.jpain.2005.01.356. PMID 15943961.

[23] Olmstead, Mary C.; Burns, Lindsay H. (2005). "Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats". Psychopharmacology. 181 (3): 576–581. doi:10.1007/s00213-005-0022-7. PMID 16010543. S2CID 13270740.

[24] Leri, Francesco; Burns, Lindsay H. (2005). "Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats". Pharmacology Biochemistry and Behavior. 82 (2): 252–262. doi:10.1016/j.pbb.2005.08.008. PMID 16182352. S2CID 25513761.

[25] Burns, Lindsay H.; Vanderah, Todd W.; Wang, Hoau-Yan (2009), Dean, Reginald L.; Bilsky, Edward J.; Negus, S. Stevens (eds.), "Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance", Opiate Receptors and Antagonists, Totowa, NJ: Humana Press, pp. 3–17, doi:10.1007/978-1-59745-197-0_1, ISBN 978-1-58829-881-2, retrieved May 3, 2022

[26] Wang, Hoau-Yan; Burns, Lindsay H. (2006). "Gβγ that interacts with adenylyl cyclase in opioid tolerance originates from a Gs protein". Journal of Neurobiology. 66 (12): 1302–1310. doi:10.1002/neu.20286. PMID 16967511.

[27] Wang, H. Y.; Lee, D. H.; Davis, C. B.; Shank, R. P. (2000). "Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors". Journal of Neurochemistry. 75 (3): 1155–1161. doi:10.1046/j.1471-4159.2000.0751155.x. PMID 10936198. S2CID 85190431.

[28] Wang, Hoau-Yan; Lee, Daniel H.S.; D'Andrea, Michael R.; Peterson, Per A.; Shank, Richard P.; Reitz, Allen B. (2000). "β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity". Journal of Biological Chemistry. 275 (8): 5626–5632. doi:10.1074/jbc.275.8.5626. PMID 10681545.

[29] Gopalan (May 24, 2007). "Magnets to the rescue of Alzheimer's patients". Medindia. Retrieved May 3, 2022.

[30] Wang, Hoau-Yan; Bakshi, Kalindi; Frankfurt, Maya; Stucky, Andres; Goberdhan, Marissa; Shah, Sanket M.; Burns, Lindsay H. (2012). "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A". J Neurosci. 32 (29): 9773–9784. doi:10.1523/JNEUROSCI.0354-12.2012. PMC 6621293. PMID 22815492. S2CID 9933756.

[Burns_2017_263–271-31] Burns, Lindsay H.; Wang, Hoau-Yan (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.

[32] Wang, Hoau‐Yan; Pei, Zhe; Xu, Qiang; Brunelle, Lynn A; Burns, Lindsay H.; Thornton, George Ben (2021). "SavaDx, a novel plasma biomarker to detect Alzheimer's disease, confirms mechanism of action of simufilam". Alzheimer's & Dementia. 17 (S5): online. doi:10.1002/alz.054385. S2CID 245570217.

[:14-33] Wang, Hoau-Yan; Frankfurt, Maya; Burns, Lindsay H. (February 6, 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.

[:15-34] Wang, Hoau-Yan; Burns, Lindsay H. (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. ISSN 1932-6203. PMC 2628740. PMID 19172190.

[35] Burns, Lindsay H.; Wang, Hoau-Yan (2010). "PTI-609: A Novel Analgesic that Binds Filamin A to Control Opioid Signaling". Recent Patents on CNS Drug Discovery (Discontinued). 5 (3): 210–220. doi:10.2174/157488910793362386. PMID 20726836.

[:72-36] Wang, H.-Y.; Bakshi, K.; Frankfurt, M.; Stucky, A.; Goberdhan, M.; Shah, S. M.; Burns, L. H. (2012). "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A". Journal of Neuroscience. 32 (29): 9773–9784. doi:10.1523/JNEUROSCI.0354-12.2012. PMC 6621293. PMID 22815492.

[:92-37] Wang, Hoau-Yan; Lee, Kuo-Chieh; Pei, Zhe; Khan, Amber; Bakshi, Kalindi; Burns, Lindsay H. (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.

[38] Toniolo, Sofia; Sen, Arjune; Husain, Masud (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.

[39] "Multiple Ascending Dose clinical trial of PTI-125, a novel AD therapeutic candidate". nih.gov. 2018. Retrieved April 29, 2022.

[40] 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).

[41] Schoen, Eric (March 27, 2019). "Pain Therapeutics Announces Name Change to Cassava Sciences, Inc". GlobeNewswire. Retrieved April 28, 2022.

[42] Inc, Cassava Sciences (August 24, 2020). "Cassava Sciences Announces Lead Drug Candidate PTI-125 Is Assigned the Chemical Drug Name 'sumifilam' by USAN". GlobeNewswire News Room. Retrieved May 3, 2022. {{cite web}}: |last= has generic name (help)

[:43-43] Keefe, Patrick Radden (January 15, 2022). "Jordan Thomas's Army of Whistle-Blowers". The New Yorker. Retrieved April 29, 2022.

[44] Wang, H.-Y.; Pei, Z.; Lee, K.-C.; Lopez-Brignoni, E.; Nikolov, B.; Crowley, C.A.; Marsman, M.R.; Barbier, R.; Friedmann, N.; Burns, L.H. (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.

[45] Owusu, Tony (February 28, 2021). "Cassava Jumps on Plan for Phase 3 Trial of Alzheimer's Drug". TheStreet. Retrieved April 30, 2022.

[46] Rockoff, Jonathan D. (March 3, 2011). "J&J Poaches Lilly's Neurological Research Chief". Wall Street Journal. ISSN 0099-9660. Retrieved April 29, 2022.

[:8-47] 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.

[48] ttps://www.regulations.gov/comment/FDA-2021-P-0930-0021

[49] "The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects".

[50] Cavazzoni, P. (February 10, 2022). "Response Letter from FDA CDER to Labaton Sucharow". www.regulations.gov. Retrieved April 29, 2022.

[51] Lu, Q.; Ding, K.; Frosch, M. P.; Jones, S.; Wolfe, M.; Xia, W.; Lanford, G. W. (2010). "Alzheimer's disease-linked presenilin mutation (PS1M146L) induces filamin expression and γ-secretase independent redistribution". Journal of Alzheimer's Disease : Jad. 22 (1): 235–245. doi:10.3233/JAD-2010-100585. PMC 3813954. PMID 20847418.

[52] Tsujikawa, Koyo; et al. (2022). "Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology". Science Advances. 8 (21): eabm5029. doi:10.1126/sciadv.abm5029. PMC 9132466. PMID 35613261. S2CID 249065715.

[:62-53] Akst, Jef (March 31, 2022). "PLOS ONE Pulls Five Papers Tied to Alzheimer's Drug Controversy". The Scientist. Retrieved April 28, 2022.

[:4-54] 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. ISSN 1932-6203. PMC 8967022. PMID 35353861. {{cite journal}}: |author1= has generic name (help)

[55] 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. {{cite journal}}: |author1= has generic name (help)

[56] "Expression of Concern: Wang et al., "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A"". Journal of Neuroscience. 42 (3): 529. January 19, 2022. doi:10.1523/JNEUROSCI.2306-21.2021. ISSN 0270-6474. PMC 8802929. PMID 34921050.

[57] "Science Journal Finds No Evidence to Support Claims of Data Manipulation in 2005 Publication | Cassava Sciences, Inc".

[58] "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.

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 In 2018, the [[National Institutes of Health]] granted Pain Therapeutics a grant award for a [[clinical trial]] of PTI-125 in Alzheimer's patients.<ref>{{Cite web |date=2018 |title=Multiple Ascending Dose clinical trial of PTI-125, a novel AD therapeutic candidate |url=https://reporter.nih.gov/search/YoRzhIftw0iqVqfMEI3yPg/project-details/9625278 |access-date=2022-04-29 |website=nih.gov}}</ref><ref>{{Cite web |last=Cassava Sciences, Inc. |date=2021-09-07 |others=National Institute on Aging (NIA) |title=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 |url=https://clinicaltrials.gov/ct2/show/NCT04079803}}</ref> The company name was changed to Cassava Sciences, Inc.<ref>{{Cite web |last=Schoen |first=Eric |date=2019-03-27 |title=Pain Therapeutics Announces Name Change to Cassava Sciences, Inc. |url=https://www.globenewswire.com/news-release/2019/03/27/1773930/8339/en/Pain-Therapeutics-Announces-Name-Change-to-Cassava-Sciences-Inc.html |access-date=2022-04-28 |website=[[GlobeNewswire]] |language=en}}</ref> The [[United States Adopted Names]] (USAN) gave the drug name for PTI-125 as simufilam in 2020.<ref>{{Cite web |last=Inc |first=Cassava Sciences |date=2020-08-24 |title=Cassava Sciences Announces Lead Drug Candidate PTI-125 Is Assigned the Chemical Drug Name 'sumifilam' by USAN |url=https://www.globenewswire.com/news-release/2020/08/24/2082591/8339/en/Cassava-Sciences-Announces-Lead-Drug-Candidate-PTI-125-Is-Assigned-the-Chemical-Drug-Name-sumifilam-by-USAN.html |access-date=2022-05-03 |website=GlobeNewswire News Room |language=en}}</ref> In 2020, it was announced that the initial biomarker analysis of the second clinical trial had failed due to high variability in CSF biomarker changes seen even in placebo subjects over this 28-day trial. It was later determined that this initial biomarker analysis showed no correlation between biomarkers in change from baseline (mean pearson's r=0.06), which is unexpected because biomarkers generally move together. This lack of correlation was especially evident in individual placebo subjects' data that showed huge improvements in one biomarker coincident with worsening in another.<ref name=":43">{{Cite magazine |last=Keefe |first=Patrick Radden |date=2022-01-15 |title=Jordan Thomas's Army of Whistle-Blowers |url=https://www.newyorker.com/magazine/2022/01/24/jordan-thomas-army-of-whistle-blowers |access-date=2022-04-29 |magazine=The New Yorker |language=en-US}}</ref> Back-up CSF samples were analyzed at a different lab and showed good results, confirming results from the earlier Phase 2a trial.<ref>{{Cite journal |last1=Wang |first1=H.-Y. |last2=Pei |first2=Z. |last3=Lee |first3=K.-C. |last4=Lopez-Brignoni |first4=E. |last5=Nikolov |first5=B. |last6=Crowley |first6=C.A. |last7=Marsman |first7=M.R. |last8=Barbier |first8=R. |last9=Friedmann |first9=N. |last10=Burns |first10=L.H. |date=2020 |title=PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients |url=https://link.springer.com/article/10.14283/jpad.2020.6 |journal=The Journal of Prevention of Alzheimer's Disease |volume=7 |issue=4 |pages=256–264 |doi=10.14283/jpad.2020.6|pmid=32920628 |s2cid=211039039 }}</ref> The [[Phases of clinical research|Phase III]] trials started in February 2021.<ref>{{Cite web |last=Owusu |first=Tony |date=2021-02-28 |title=Cassava Jumps on Plan for Phase 3 Trial of Alzheimer's Drug |url=https://www.thestreet.com/investing/cassava-sciences-climbs-on-planned-phase-3-alzheimers-drug-trial |access-date=2022-04-30 |website=TheStreet |language=en-us}}</ref>
-[[David Bredt]], a former neuroscientist at [[Johnson & Johnson]],<ref>{{Cite news |last=Rockoff |first=Jonathan D. |date=2011-03-03 |title=J&J Poaches Lilly's Neurological Research Chief |language=en-US |work=Wall Street Journal |url=https://www.wsj.com/articles/BL-HEB-47822 |url-access=subscription |access-date=2022-04-29 |issn=0099-9660}}</ref> who mysteriously left venture capital firm MPM after a 4-month stint in August when the petition was filed, became suspicious of the research methods and findings on FLNA binding and simufilam trials in the early 2021. Bredt was previously presented the simufilam program [https://www.cassavasciences.com/node/15906/html under CDA while at J&J]. As he examined the research papers, he came to the conclusion, saying, "They [Burns and Wang's papers] were making statements that were incompatible with biology and with pharmacology," and such important discoveries deserved to "win five Nobel Prizes."<ref name=":16" /> With Geoffrey Pitt, a cardiologist and a professor at [[Weill Cornell Medical College]], they discussed the issue with [[Jordan A. Thomas]] of the law firm [[Labaton Sucharow]].<ref name=":8">{{Cite news |last1=Michaels |first1=Dave |last2=Walker |first2=Joseph |date=2021-11-17 |title=SEC Investigating Cassava Sciences, Developer of Experimental Alzheimer's Drug |language=en-US |work=Wall Street Journal |url=https://www.wsj.com/articles/cassava-sciences-alzheimers-sec-investigation-11637154199 |access-date=2022-04-29 |issn=0099-9660}}</ref> In August 2021, Thomas submitted a [[citizen petition]] to the [[Food and Drug Administration]] expressing concerns of unreliable research and misuse of scientific data and requesting investigation into the Cassava Sciences works.<ref name=":43"/> Three days later (after the stock plummeted, providing a financial windfall for short sellers), Thomas disclosed that his clients were short sellers of Cassava stock.<ref>https://www.regulations.gov/comment/FDA-2021-P-0930-0021</ref> Others have noted that the petition was "Gaming the FDA" for financial gain.<ref>{{cite web | url=https://www.complianceweek.com/risk-management/the-cassava-sciences-saga-short-sellers-gaming-the-fda-and-the-damaging-ripple-effects/31416.article | title=The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects }}</ref> FDA denied the petition, saying:<blockquote>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.<ref>{{Cite web |last=Cavazzoni |first=P. |date=2022-02-10 |title=Response Letter from FDA CDER to Labaton Sucharow |url=https://www.regulations.gov/document/FDA-2021-P-0930-0228 |access-date=2022-04-29 |website=www.regulations.gov}}</ref></blockquote>Other scientists also started to make public comments that the research on simufilam is unreliable. To the link between filamin A and Alzheimer's disease, Lawrence Sterling Honig, professor of neurology at [[Columbia University Irving Medical Center]], noted: "But in fact, all the evidence seems to be from this [Wang's] lab." However, FLNA has recently been linked to tau hyperphosphorylation and aggregation in another neurodegenerative disease, [[Progressive Supranuclear Palsy]] (PSP).<ref>{{cite journal | doi=10.1126/sciadv.abm5029 | title=Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology | year=2022 | last1=Tsujikawa | first1=Koyo | last2=Hamanaka | first2=Kohei | last3=Riku | first3=Yuichi | last4=Hattori | first4=Yuki | last5=Hara | first5=Norikazu | last6=Iguchi | first6=Yohei | last7=Ishigaki | first7=Shinsuke | last8=Hashizume | first8=Atsushi | last9=Miyatake | first9=Satoko | last10=Mitsuhashi | first10=Satomi | last11=Miyazaki | first11=Yu | last12=Kataoka | first12=Mayumi | last13=Jiayi | first13=Li | last14=Yasui | first14=Keizo | last15=Kuru | first15=Satoshi | last16=Koike | first16=Haruki | last17=Kobayashi | first17=Kenta | last18=Sahara | first18=Naruhiko | last19=Ozaki | first19=Norio | last20=Yoshida | first20=Mari | last21=Kakita | first21=Akiyoshi | last22=Saito | first22=Yuko | last23=Iwasaki | first23=Yasushi | last24=Miyashita | first24=Akinori | last25=Iwatsubo | first25=Takeshi | last26=Ikeuchi | first26=Takeshi | last27=Miyata | first27=Takaki | last28=Sobue | first28=Gen | last29=Matsumoto | first29=Naomichi | last30=Sahashi | first30=Kentaro | journal=Science Advances | volume=8 | issue=21 | pages=eabm5029 | pmid=35613261 | pmc=9132466 | s2cid=249065715 | display-authors=1 }}</ref> Robert Howard, professor of psychiatry at the University College London, remarked on the lack of [[placebo]] and small sample size that making such research conclusion "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 Cassava Sciences] are not in the mainstream of the field, and to me they seem implausible and contrived."<ref name=":16" /> Many of these critics were involved with the original petition, are linked to Bredt and/or have their own [https://www.cassavasciences.com/node/15906/html conflicts of interest].
+[[David Bredt]], a former neuroscientist at [[Johnson & Johnson]],<ref>{{Cite news |last=Rockoff |first=Jonathan D. |date=2011-03-03 |title=J&J Poaches Lilly's Neurological Research Chief |language=en-US |work=Wall Street Journal |url=https://www.wsj.com/articles/BL-HEB-47822 |url-access=subscription |access-date=2022-04-29 |issn=0099-9660}}</ref> who mysteriously left venture capital firm MPM after a 4-month stint in August when the petition was filed, became suspicious of the research methods and findings on FLNA binding and simufilam trials in the early 2021. Bredt was previously presented the simufilam program [https://www.cassavasciences.com/node/15906/html under CDA while at J&J]. As he examined the research papers, he came to the conclusion, saying, "They [Burns and Wang's papers] were making statements that were incompatible with biology and with pharmacology," and such important discoveries deserved to "win five Nobel Prizes."<ref name=":16" /> With Geoffrey Pitt, a cardiologist and a professor at [[Weill Cornell Medical College]], they discussed the issue with [[Jordan A. Thomas]] of the law firm [[Labaton Sucharow]].<ref name=":8">{{Cite news |last1=Michaels |first1=Dave |last2=Walker |first2=Joseph |date=2021-11-17 |title=SEC Investigating Cassava Sciences, Developer of Experimental Alzheimer's Drug |language=en-US |work=Wall Street Journal |url=https://www.wsj.com/articles/cassava-sciences-alzheimers-sec-investigation-11637154199 |access-date=2022-04-29 |issn=0099-9660}}</ref> In August 2021, Thomas submitted a [[citizen petition]] to the [[Food and Drug Administration]] expressing concerns of unreliable research and misuse of scientific data and requesting investigation into the Cassava Sciences works.<ref name=":43"/> Three days later (after the stock plummeted, providing a financial windfall for short sellers), Thomas disclosed that his clients were short sellers of Cassava stock.<ref>https://www.regulations.gov/comment/FDA-2021-P-0930-0021</ref> Others have noted that the petition was "Gaming the FDA" for financial gain.<ref>{{cite web | url=https://www.complianceweek.com/risk-management/the-cassava-sciences-saga-short-sellers-gaming-the-fda-and-the-damaging-ripple-effects/31416.article | title=The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects }}</ref> FDA denied the petition, saying:<blockquote>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.<ref>{{Cite web |last=Cavazzoni |first=P. |date=2022-02-10 |title=Response Letter from FDA CDER to Labaton Sucharow |url=https://www.regulations.gov/document/FDA-2021-P-0930-0228 |access-date=2022-04-29 |website=www.regulations.gov}}</ref></blockquote>Other scientists linked to Bredt also started to make public comments that the research on simufilam is unreliable. To the link between filamin A and Alzheimer's disease, Lawrence Sterling Honig, professor of neurology at [[Columbia University Irving Medical Center]], noted: "But in fact, all the evidence seems to be from this [Wang's] lab." This statement is not true: FLNA overexpression has been noted as a result of PS1 mutation in familial AD.<ref>{{cite journal |pmid=20847418 |year=2010 |last1=Lu |first1=Q. |last2=Ding |first2=K. |last3=Frosch |first3=M. P. |last4=Jones |first4=S. |last5=Wolfe |first5=M. |last6=Xia |first6=W. |last7=Lanford |first7=G. W. |title=Alzheimer's disease-linked presenilin mutation (PS1M146L) induces filamin expression and γ-secretase independent redistribution |journal=Journal of Alzheimer's Disease : Jad |volume=22 |issue=1 |pages=235–245 |doi=10.3233/JAD-2010-100585 |pmc=3813954 }}</ref> FLNA overexpression has also been linked to tau hyperphosphorylation and aggregation in another neurodegenerative disease, [[Progressive Supranuclear Palsy]] (PSP).<ref>{{cite journal | doi=10.1126/sciadv.abm5029 | title=Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology | year=2022 | last1=Tsujikawa | first1=Koyo | last2=Hamanaka | first2=Kohei | last3=Riku | first3=Yuichi | last4=Hattori | first4=Yuki | last5=Hara | first5=Norikazu | last6=Iguchi | first6=Yohei | last7=Ishigaki | first7=Shinsuke | last8=Hashizume | first8=Atsushi | last9=Miyatake | first9=Satoko | last10=Mitsuhashi | first10=Satomi | last11=Miyazaki | first11=Yu | last12=Kataoka | first12=Mayumi | last13=Jiayi | first13=Li | last14=Yasui | first14=Keizo | last15=Kuru | first15=Satoshi | last16=Koike | first16=Haruki | last17=Kobayashi | first17=Kenta | last18=Sahara | first18=Naruhiko | last19=Ozaki | first19=Norio | last20=Yoshida | first20=Mari | last21=Kakita | first21=Akiyoshi | last22=Saito | first22=Yuko | last23=Iwasaki | first23=Yasushi | last24=Miyashita | first24=Akinori | last25=Iwatsubo | first25=Takeshi | last26=Ikeuchi | first26=Takeshi | last27=Miyata | first27=Takaki | last28=Sobue | first28=Gen | last29=Matsumoto | first29=Naomichi | last30=Sahashi | first30=Kentaro | journal=Science Advances | volume=8 | issue=21 | pages=eabm5029 | pmid=35613261 | pmc=9132466 | s2cid=249065715 | display-authors=1 }}</ref> Robert Howard, professor of psychiatry at the University College London, remarked on the lack of [[placebo]] and small sample size that making such research conclusion "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 Cassava Sciences] are not in the mainstream of the field, and to me they seem implausible and contrived."<ref name=":16" /> Many of these critics were involved with the original petition, are linked to Bredt and/or have their own [https://www.cassavasciences.com/node/15906/html conflicts of interest].
 The FDA denied the petition. Unrelatedly, ''PLOS One'' retracted five of Wang's papers in March 2022, none of which are about Alzheimer's disease and two of which were published with Burns <ref name=":62">{{Cite web |last=Akst |first=Jef |date=2022-03-31 |title=PLOS ONE Pulls Five Papers Tied to Alzheimer's Drug Controversy |url=https://www.the-scientist.com/news-opinion/plos-one-pulls-five-papers-tied-to-alzheimer-s-drug-controversy-69860 |access-date=2022-04-28 |website=The Scientist |language=en}}</ref> that reported the discovery of naloxone and naltrexone binding to FLNA and FLNA's role in opioid receptor signaling.<ref name=":14" /><ref name=":15" /> Without evidence of data manipulation, and relating to "similarities in background pixels" of Western blot images, the retraction reads:<blockquote>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.<ref name=":4" /><ref>{{Cite journal |date=2022 |title=Retraction: Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor–Gs Coupling and CREB Activation of Acute Morphine |journal=PLOS ONE |language=en |volume=17 |issue=3 |pages=e0266629 |doi=10.1371/journal.pone.0266629 |pmc=8967007 |pmid=35353864|doi-access=free |author1=PLOS ONE Editors |bibcode=2022PLoSO..1766629. }}</ref> The authors  [Hoau-Yan Wang and Lindsay Burns] did not agree with the retraction. HYW stands by the article’s findings.<ref name=":4">{{Cite journal |date=2022-03-30 |title=Retraction: High-Affinity Naloxone Binding to Filamin A Prevents Mu Opioid Receptor–Gs Coupling Underlying Opioid Tolerance and Dependence |journal=PLOS ONE |language=en |volume=17 |issue=3 |pages=e0266627 |doi=10.1371/journal.pone.0266627 |issn=1932-6203 |pmc=8967022 |pmid=35353861|doi-access= free|author1= PLOS ONE Editors|bibcode= 2022PLoSO..1766627.}}</ref></blockquote>In December 2021, ''Neuroscience'' found "[https://www.cassavasciences.com/news-releases/news-release-details/science-journal-finds-no-evidence-support-claims-data no evidence of data manipulation]" in a paper that was alleged to be fraudulent by short-sellers.