A Phase 2 Open-label Study of Zelavespib (PU-H71) in Subjects With Accelerated Phase Myeloproliferative Neoplasm (AP MPN) or Blast Phase Myeloproliferative Neoplasm

This is a multicenter, Phase 2 Simon 2-Stage study designed to assess the safety, tolerability, PK, and efficacy of oral zelavespib (PU-H71) administered daily in adults with accelerated phase (10% to 19% blasts in peripheral or bone marrow) myeloproliferative neoplasm, with or without ongoing concomitant treatment with ruxolitinib.

Start Date15 Jun 2022

Sponsor / Collaborator

Samus Therapeutics, Inc.

NCT03935555 / TerminatedPhase 1

Phase 1b Study of PU-H71 for the Treatment of Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), Treated With Ruxolitinib

This is a multicenter, Phase 1b study with dose escalation and expansion cohorts designed to assess the safety, tolerability, PK, and preliminary efficacy of PU-H71 in subjects with PMF, Post-PV MF, Post-ET MF, taking stable doses of ruxolitinib.

Start Date12 Aug 2019

Sponsor / Collaborator

Samus Therapeutics, Inc.

NCT03373877 / TerminatedPhase 1

A Phase Ib Study of Ruxolitinib in Combination With PU-H71 for the Treatment of Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV MF), and Post-EssentialThrombocythemia MF (Post-ET MF)

This is a multicenter 2-part, Phase 1b study designed to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of PU-H71 in subjects taking concomitant ruxolitinib. The first part (Dose Escalation) will employ a standard 3+3 dose escalation design to determine Maximum Tolerated Dose (MTD). The second part of the study (Dose Confirmation) will confirm the recommended Phase 2 dose (RP2D) in an expanded population.

Start Date24 May 2018

Sponsor / Collaborator

Samus Therapeutics, Inc.

100 Clinical Results associated with PU-H71

100 Translational Medicine associated with PU-H71

100 Patents (Medical) associated with PU-H71

Literatures (Medical) associated with PU-H71

21 Sep 2023·Blood

Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells.

Article

Author: Sobieski, Mary ; Nishida, Yuki ; Tao, Wenjing ; Mak, Po Yee ; Isgandarova, Sevinj ; Muftuoglu, Muharrem ; Ostermann, Lauren B ; Pei, Jingqi ; Shpall, Elizabeth J ; Martinez-Moczygemba, Margarita ; Boettcher, Steffen ; Moll, Ute M ; Nguyen, Nghi ; Ke, Baozhen ; Morgan, Robert A ; Powell, Reid T ; Basyal, Mahesh ; Stephan, Clifford ; Pemmaraju, Naveen ; Bedoy, Andrea D ; Ebert, Benjamin L ; Wallner, Barbara ; Karras, Georgios I ; Carter, Bing Z ; Andreeff, Michael

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. PU-H71 effectively suppressed cell intrinsic stress responses and killed AML cells, primarily by inducing apoptosis; targeted TP53-mutant stem/progenitor cells; and prolonged survival of TP53-mutant AML xenograft and patient-derived xenograft models, but it had minimal effects on healthy human BM CD34+ cells or on murine hematopoiesis. PU-H71 decreased MCL-1 and multiple signal proteins, increased proapoptotic Bcl-2-like protein 11 levels, and synergized with BCL-2 inhibitor venetoclax in TP53-mutant AML. Notably, PU-H71 effectively killed TP53-WT and -mutant cells in isogenic TP53-WT/TP53-R248W Molm13 cell mixtures, whereas MDM2 or BCL-2 inhibition only reduced TP53-WT but favored the outgrowth of TP53-mutant cells. Venetoclax enhanced the killing of both TP53-WT and -mutant cells by PU-H71 in a xenograft model. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation.

23 Aug 2023·Current issues in molecular biology

HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia.

Article

Author: Seipel, Katja ; Kohler, Scarlett ; Bacher, Ulrike ; Pabst, Thomas

Targeting the molecular chaperone HSP90 and the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The HSP90 inhibitor PU-H71, MCL1 inhibitor S63845, and BCL2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and TP53 mutant AML cell lines and a variety of patient-derived AML cells. Results: PU-H71 and combination treatments with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in susceptible AML cell lines and primary AML. The majority of the primary AML samples were responsive to PU-H71 in combination with BH3 mimetics. Elevated susceptibility to PU-H71 and S63845 was associated with FLT3 mutated AML with CD34 < 20%. Elevated susceptibility to PU-H71 and venetoclax was associated with primary AML with CD117 > 80% and CD11b < 45%. The combination of HSP90 inhibitor PU-H71 and MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity.

01 Aug 2023·bioRxiv : the preprint server for biology

Selective inhibition of hsp90 paralogs: Structure and binding studies uncover the role of helix 1 in Grp94-selective ligand binding.

Author: Gewirth, Daniel T ; Aw, Wen J ; Que, Nanette L S ; Seidler, Paul M ; Chiosis, Gabriela

Grp94 is the endoplasmic reticulum paralog of the hsp90 family of chaperones, which have been targeted for therapeutic intervention via their highly conserved ATP binding sites. The design of paralog-selective inhibitors relies on understanding the structural elements that mediate each paralog's response to inhibitor binding. Here, we determined the structures of Grp94 and Hsp90 in complex with the Grp94-selective inhibitor PU-H36, and of Grp94 with the non-selective inhibitor PU-H71. In Grp94, the 8-aryl moiety of PU-H36 is inserted into Site 2, a conditionally available side pocket, but in Hsp90 it occupies Site 1, a non-selective side pocket that is accessible in all hsp90 paralogs. The structure of Grp94 in complex with the non-selective PU-H71 shows only Site 1 binding. Large conformational shifts involving helices 1, 4 and 5 of the N-terminal domain of Grp94 are associated with the engagement of the Site 2 pocket for ligand binding. To understand the origins of Site 2 pocket engagement, we tested the binding of Grp94-selective ligands to chimeric Grp94/Hsp90 constructs. These studies show that helix 1 of the Grp94 N-terminal domain is the discriminating element that allows for remodeling of the ATP binding pocket and exposure of the Site 2 selective pocket.

News (Medical) associated with PU-H71

03 Apr 2023

·endpts.com

Vertex and CRISPR send exa-cell for FDA approval; Aridis Therapeutics axes 20% of its workforce

Vertex and CRISPR Therapeutics have finished the BLA for its treatment exagamglogene autotemcel, or exa-cel, and will be going toward the FDA for approval. Exa-cell is intended to treat sickle cell disease and transfusion-dependent beta-thalassemia. The BLA also has a priority review attached and, if given, could bring down the FDAs review of the application to eight months instead of 12 months. Vertex and CRISPR are backing the submission with data from two Phase III trials and a follow-up study. “Within a decade, we have progressed from the discovery of the CRISPR platform to the first regulatory filings for a CRISPR-based therapy, which speaks to the transformative nature of CRISPR technology,” said Phuong Khanh Morrow, CRISPR Therapeutics CMO in a release . — Tyler Patchen Aridis Pharmaceuticals laid off seven of 33 employees after AstraZeneca terminated a license for its drug candidate being studied to prevent ventilator-acquired pneumonia. “While we seek a remedy to the license dispute, we want to assure our shareholders that we remain steadfastly committed to developing our pipeline products as potential breakthrough therapies to fight antimicrobial resistance,” Aridis CEO Vu Truong said in a statement Friday night. With AstraZeneca scrapping the agreement, Aridis’ European-funded Phase III went back onto the shelf. The monoclonal antibody, known as AR-320, entered the late-stage clinical trial last fall. — Kyle LaHucik Arrowhead Pharmaceuticals has roped in a further $30 million in a milestone payment from GSK. What triggered the payment was the pharma kicking off the Phase IIb trial of the GSK4532990, formerly known as ARO-HSD, an RNAi therapeutic to treat NASH. The drug is being developed between GSK and Arrowhead since both signed an exclusive license to develop and commercialize the candidate in all territories except Greater China, where Arrowhead retains the rights. GSK is responsible for the development and commercialization of areas outside of China. The trial itself will look at the safety and efficacy of the drug in adults and plans to enroll up to 246 participants. — Tyler Patchen A Boston biotech recently joined the growing list of shuttered startups in drug development. Samus Therapeutics closed shop, per updates to two clinical studies on the US federal trials database. Based on work out of Memorial Sloan Kettering Cancer Center, Rockefeller University and Weill Cornell Medicine, Samus was trying to go after the epichaperome. The protein complex is thought to be involved in cancers, neurological disorders and chronic traumatic encephalopathy, or CTE, the brain condition that became a focus of attention after many former NFL players were found to have it. Samus axed a Phase II study of its oral drug candidate zelavespib, or PU-H71, for adults with myeloproliferative neoplasm. The company also terminated a Phase I testing icapamespib, or PU-AD, in patients with recurrent brain lesions. The private startup had also set out to make diagnostics to go along with its investigational therapeutics. CEO Dick Bagley declined to comment. The company was previously led by Jonathan Lewis. Both executives formerly held leadership roles at Ziopharm Oncology, now known as Alaunos Therapeutics . — Kyle LaHucik The Swiss biotech Covis Finco Sarl has entered an agreement to recapitalize itself and reduce its debt by an estimated $450 million, with 95% of its first lien lenders and 100% of its second lien lenders. The release stated that the move will boost Covis’s balance sheet and its liquidity. Once the recapitalization is finished, the funds will be managed by an affiliate of Apollo Global Management, who will remain the majority owners, and the first lien lenders will be handed a minority stake. According to Covis, this will put the biotech on a path to scale up its business, work on its existing portfolio, and grow physically. It also said it was pursuing “inorganic growth opportunities” but did not specify what those options could be. “At Covis, our paramount focus continues to be patient outcomes and improving the health of people with serious medical conditions,” said Michael Porter, CEO of Covis, in a release . — Tyler Patchen The Massachusetts-based liquid biopsy biotech Mercy BioAnalytics has closed a $41 million Series A round. The investment will be going towards development and commercialization efforts for its Mercy Halo testing platform, which plans to look for cancer-related biomarkers on the surface of cancer-derived extracellular vesicles. The platform specifically will be used for high-risk lung cancer screening. The cash will also be going towards moving along other clinical programs in other indications, such as ovarian cancer. “A simple, inexpensive blood-based screening test could be a vital new tool to significantly increase patient engagement in lung cancer screening, creating the opportunity to save lives through early detection,” said Mercy BioAnalytics CEO Dawn Mattoon in a release . The round was led by Novalis LifeSciences and had participation from the American Cancer Society BridgtEdge, Sozo Ventures, Hatteras Venture Partners, iSelect Fund and Broadway Angels. There were also investments from Bruker and Labcorp. — Tyler Patchen

Phase 2Phase 3License out/inPhase 1

11 May 2021

·www.biospace.com

Samus Therapeutics Receives IND Clearance from FDA for PU-AD for the Treatment of Recurrent Malignant Glioma

BOSTON, May 11, 2021 /PRNewswire/ -- Samus Therapeutics, Inc. ("Samus Therapeutics" or the "Company"), a privately held, Boston-based biopharmaceutical company developing epichaperome inhibitors to treat CNS diseases and hematologic malignancies, today announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application to develop PU-AD for the treatment of recurrent malignant glioma. Under this IND, Samus will proceed with its Phase 1b study addressing the safety, tolerability and pharmacokinetics of PU-AD (icapamespib) in patients with recurrent malignant glioma. Icapamespib is an orally administered small molecule that is a specific inhibitor of epichaperomes. Under the leadership of Dr. John de Groot, at the University of Texas M.D. Anderson Cancer Center and Dr. Howard Colman at the Huntsman Cancer Institute at the University of Utah, the multicenter Phase 1b study will be conducted in two stages at multiple sites across the U.S. The dose escalation will address daily administration of icapamespib in patients with a first, second or third recurrence of isocitrate dehydrogenase (IDH) wild type glioblastoma, or grade 3 or 4 IDH mutant astrocytoma. "The expansion stage of this trial will not only confirm safety of the Phase 2 dose, but also investigate the biology of recurrent disease through biomarker analysis and evidence of target engagement," said Dick Bagley, President and CEO of Samus Therapeutics. Malignant glioma is a characterization of Stage 3 and 4 glioblastoma/astrocytoma diagnoses. Standard of care at outset is varied but predominantly includes surgery, chemotherapy, and radiation therapy. According to the American Cancer Society, glioblastoma is the most common and most aggressive form of the primary brain tumors in adults, accounting for half of all primary brain cancers. Despite extensive research, available treatments have not improved the median survival of 14-16 months. "Through the work of our scientific founder Gabriela Chiosis, PhD and her collaborators, we have established that glioblastomas express high levels of epichaperomes as evidenced in explants, primary and secondary neurospheres, and glial stem cells. Epichaperome driven glioblastoma cells respond well to icapamespib treatment in xenograft mouse models and ex vivo studies even when resistant to Temodar® (temozolomide) and Avastin® (bevacizumab), giving us a signal that icapamespib could have a clinical impact on this devastating disease," commented Barbara Wallner, PhD, Chief Scientific Officer. About Samus Therapeutics Samus Therapeutics is a privately held Boston-based biopharmaceutical company developing orally administered PU-AD (icapamespib) and PU-H71 (zelavespib) that target the epichaperome, also termed the stress chaperome, to address the breakdown of regulatory pathways that normally prevent aggregation and accumulation of disease associated aberrant proteins in CNS diseases and oncogenic protein signaling pathways in cancer. This press release contains certain forward-looking information about Samus Therapeutics, Inc. that is intended to be covered by the safe harbor for "forward-looking statements" provided by the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts, and in some cases can be identified by terms such as "may," "will," "could," "expects," "plans," "anticipates," "forecasts," and "believes." These statements include, but are not limited to, statements regarding the progress, timing and results of preclinical and clinical trials involving the Company's drug candidates, and the progress of the Company's research and development programs. All such statements are subject to certain risks and uncertainties, many of which are difficult to predict and generally beyond the control of the Company, that could cause actual results to differ materially from those expressed in, or implied by, the forward-looking statements. These risks and uncertainties include, but are not limited to whether any of our therapeutic candidates will advance further in the preclinical or clinical trials process and whether and when, if at all, they will receive final approval from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies, whether our products will be successfully marketed if approved; the strength and enforceability of our intellectual property rights; and competition from other pharmaceutical and biotechnology companies. While Samus Therapeutics may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to update or revise any forward-looking-statements contained in this press release whether as a result of new information or future events, except as may be required by law. View original content to download multimedia: SOURCE Samus Therapeutics, Inc.

Radiation TherapySmall molecular drug

100 Deals associated with PU-H71

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Blast Phase Chronic Granulocytic Leukemia	Phase 2	-	Samus Therapeutics, Inc.	15 Jun 2022
Myeloproliferative Disorders	Phase 2	-	Samus Therapeutics, Inc.	15 Jun 2022
Post-essential thrombocythemia myelofibrosis	Phase 1	US	Samus Therapeutics, Inc.	24 May 2018
Post-polycythemia vera myelofibrosis	Phase 1	US	Samus Therapeutics, Inc.	24 May 2018
Primary Myelofibrosis	Phase 1	US	Samus Therapeutics, Inc.	24 May 2018
Metastatic breast cancer	Phase 1	US	Samus Therapeutics, Inc.	23 May 2017
Advanced cancer	Phase 1	US	Memorial Sloan Kettering Cancer Center	06 Jul 2011
Lymphoma	Phase 1	US	Memorial Sloan Kettering Cancer Center	06 Jul 2011
Metastatic Solid Tumor	Phase 1	US	Memorial Sloan Kettering Cancer Center	06 Jul 2011
Low Grade B-Cell Non-Hodgkin's Lymphoma	Phase 1	US	National Cancer Institute	26 Apr 2011

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03935555 (ASH2022) Manual	Phase 1	Recurrent Myelofibrosis	11	Zelavespib+Ruxolitinib	vztyhrvjot(bcsxujtbtn) = Most AEs were Gr 1 and 2 and the most frequent were abdominal pain, diarrhea and fatigue. vxfasmqrtl (gvureuymzm ) View more	Positive	15 Nov 2022
NCT01393509 (Pubmed \| Invest New Drugs) Manual	Phase 1	Solid tumor	17	PU-H71	jcvsivznfv(tksynmcrqz) = uycrktmriy feihtlhxoj (ytxlveeuxh ) View more	Negative	01 Apr 2018

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