Therapeutics

PU-AD

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Overview

Name: PU-AD
Synonyms: PU-HZ151, icapamespib
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Samus Therapeutics

Background

A member of a new class of drugs called epichaperome inhibitors, PU-AD is an oral, brain-permeable inhibitor of the molecular chaperone heat shock protein 90. HSP90 stabilizes mutant or aberrantly modified proteins associated with cancer and multiple neurodegenerative diseases. 

HSP90 inhibitors enhance degradation of pathogenic proteins and promote cell survival in animal models of tau pathology, and of Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis/frontotemporal dementia, Huntington’s disease, and spinal and bulbar muscular atrophy (reviewed in Carman et al., 2013). Brain-penetrant HSP90 inhibitors were reported to enhance the degradation of mutated or hyperphosphorylated tau in mouse models (May 2007 news). Another brain-penetrant inhibitor enhanced working memory and spatial learning/memory in Tg2576 AD mice, and improved conditioned fear memory after infusion of Aβ into the brain (Wang et al., 2016).

Although all cells express HSP90 at high levels, PU-AD and some other HSP90 inhibitors bind with high affinity to HSP90 from cancer cells and AD tissue, but not from normal tissue, suggesting the possibility of selective inhibition in disease states (Moulick et al., 2011; Dickey et al., 2007).

Affinity purification using PU-AD, and proteomic analyses, have identified HSP90-centered, stable chaperone complexes that emerge in cells under stress, including in cancer, Parkinson’s, and Alzheimer’s diseases (Rodina et al., 2016; Kishinevsky et al., 2018; Joshi et al., 2018). In AD tissues and mouse models, these complexes, dubbed epichaperomes, incorporate cell proteins not normally associated with HSP90, including some involved in synaptic function, learning, and memory. PU-AD treatment dissociates the epichaperome, and restores HSP90’s normal protein associations (Inda et al., 2020).

PU-AD has been tested in the PS19 tau mouse and the 3xTg mouse. After 6 to 12 weeks of thrice-weekly dosing, 3-month-old or 8- to 9-month-old PS19 mice performed better on learning and memory trials in a Barnes maze, compared to untreated animals (Inda et al., 2020). Treatment also normalized deficits in synaptic long-term potentiation, extended life span, and decreased phospho-tau and tau oligomers in multiple brain regions. PU-AD had similar effects on tau and on memory and learning in 3XTg mice.

Findings

Between June and December 2019, Samus Therapeutics ran a Phase 1 study of PU-AD in 40 healthy volunteers, who received single or multiple doses of an oral solution of drug or placebo. At the CTAD 2019 conference, the company reported that single doses of 10, 20, or 30 mg were well-tolerated, with mild adverse events and linear pharmacokinetics. Healthy elderly volunteers completed one week of 20 mg per day doses, with no events resulting in interruption of dosing (see Dec 2019 press release). 

A second Phase 1 study, at Memorial Sloan Kettering Cancer Center, New York, evaluated a radioactively labeled form of PU-AD (1241-PU-AD) as a diagnostic reagent in five people with cancer and/or AD. Participants received a low dose of 1241-PU-AD, followed by PET-CT. This study was completed in June 2019. The investigators reported low binding of the PET ligand in the brain of a cognitively normal 58-year-old, but elevated retention in a 71-year-old person with AD (Inda et al., 2020). Accumulation of the tracer in peripheral tumors in cancer patients was also reported (Pillarsetty et al., 2019). 1241-PU-AD was shown to cross the blood-brain barrier and accumulate in glioblastoma tumors in humans (Bolaender et al., 2021).

In June 2020, a Phase 2 trial began recruiting 150 people with mild Alzheimer’s dementia and a positive tau-PET scan to evaluate safety and pharmacological effects of PU-AD. Participants receive 30 mg PU-AD daily or placebo for six months. Primary outcomes are changes in brain glucose uptake by FDG-PET, and the incidence and severity of adverse events. Secondary outcomes include tau-PET, CSF tau, and p-tau, multiple measures of cognition and function, and pharmacokinetics. The trial is slated to end in December 2022.

A Phase 2 trial in people with amyotrophic lateral sclerosis is registered to start in December 2021. It will enroll 30 participants for six months of PU-AD 30 mg daily or placebo, against conventional primary outcomes of function, breathing capacity, and strength. Blood and CSF biomarkers are secondary measures. The study is planned to run through December 2022.

A Phase 1 trial in people with recurrent glioblastoma is slated to begin in November 2021.

Samus is testing another epichaperome inhibitor, PU-H71, in Phase 1 for multiple forms of cancer. PU-H71 does not cross the blood brain barrier.

For details on PU-AD trials, see clinicaltrials.gov.

Last Updated: 07 Oct 2021

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References

News Citations

  1. Therapeutic Takedown: Hsp90 Inhibitors Tackle Tau

Research Models Citations

  1. Tau P301S (Line PS19)
  2. 3xTg

Paper Citations

  1. Inda MC, Joshi S, Wang T, Bolaender A, Gandu S, Koren Iii J, Che AY, Taldone T, Yan P, Sun W, Uddin M, Panchal P, Riolo M, Shah S, Barlas A, Xu K, Chan LY, Gruzinova A, Kishinevsky S, Studer L, Fossati V, Noggle SA, White JR, de Stanchina E, Sequeira S, Anthoney KH, Steele JW, Manova-Todorova K, Patil S, Dunphy MP, Pillarsetty N, Pereira AC, Erdjument-Bromage H, Neubert TA, Rodina A, Ginsberg SD, De Marco Garcia N, Luo W, Chiosis G. The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction. Nat Commun. 2020 Jan 16;11(1):319. PubMed.
  2. Pillarsetty N, Jhaveri K, Taldone T, Caldas-Lopes E, Punzalan B, Joshi S, Bolaender A, Uddin MM, Rodina A, Yan P, Ku A, Ku T, Shah SK, Lyashchenko S, Burnazi E, Wang T, Lecomte N, Janjigian Y, Younes A, Batlevi CW, Guzman ML, Roboz GJ, Koziorowski J, Zanzonico P, Alpaugh ML, Corben A, Modi S, Norton L, Larson SM, Lewis JS, Chiosis G, Gerecitano JF, Dunphy MP. Paradigms for Precision Medicine in Epichaperome Cancer Therapy. Cancer Cell. 2019 Nov 11;36(5):559-573.e7. Epub 2019 Oct 24 PubMed.
  3. Bolaender A, Zatorska D, He H, Joshi S, Sharma S, Digwal CS, Patel HJ, Sun W, Imber BS, Ochiana SO, Patel MR, Shrestha L, Shah SK, Wang S, Karimov R, Tao H, Patel PD, Martin AR, Yan P, Panchal P, Almodovar J, Corben A, Rimner A, Ginsberg SD, Lyashchenko S, Burnazi E, Ku A, Kalidindi T, Lee SG, Grkovski M, Beattie BJ, Zanzonico P, Lewis JS, Larson S, Rodina A, Pillarsetty N, Tabar V, Dunphy MP, Taldone T, Shimizu F, Chiosis G. Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system. Nat Commun. 2021 Aug 3;12(1):4669. PubMed.
  4. Carman A, Kishinevsky S, Koren J 3rd, Lou W, Chiosis G. Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention. J Alzheimers Dis Parkinsonism. 2013 Apr;2013(Suppl 10) PubMed.
  5. Wang B, Liu Y, Huang L, Chen J, Li JJ, Wang R, Kim E, Chen Y, Justicia C, Sakata K, Chen H, Planas A, Ostrom RS, Li W, Yang G, McDonald MP, Chen R, Heck DH, Liao FF. A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. Mol Psychiatry. 2016 Jul 26; PubMed.
  6. Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol. 2011 Sep 25;7(11):818-26. PubMed.
  7. Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J, Ash P, Shoraka S, Zlatkovic J, Eckman CB, Patterson C, Dickson DW, Nahman NS, Hutton M, Burrows F, Petrucelli L. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest. 2007 Mar;117(3):648-58. PubMed.
  8. Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, Chiosis G. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature. 2016 Oct 20;538(7625):397-401. Epub 2016 Oct 5 PubMed.
  9. Kishinevsky S, Wang T, Rodina A, Chung SY, Xu C, Philip J, Taldone T, Joshi S, Alpaugh ML, Bolaender A, Gutbier S, Sandhu D, Fattahi F, Zimmer B, Shah SK, Chang E, Inda C, Koren J 3rd, Saurat NG, Leist M, Gross SS, Seshan VE, Klein C, Tomishima MJ, Erdjument-Bromage H, Neubert TA, Henrickson RC, Chiosis G, Studer L. HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nat Commun. 2018 Oct 19;9(1):4345. PubMed.
  10. Joshi S, Wang T, Araujo TL, Sharma S, Brodsky JL, Chiosis G. Adapting to stress - chaperome networks in cancer. Nat Rev Cancer. 2018 Sep;18(9):562-575. PubMed.

External Citations

  1. Dec 2019 press release
  2. clinicaltrials.gov

Further Reading