icapamespib (PU-AD) / Samus Therap - LARVOL DELTA

Systems-Level Interactome Mapping Reveals Actionable Protein Network Dysregulation Across the Alzheimer's Disease Spectrum. (PubMed, Res Sq) - "Notably, pharmacological disruption of epichaperomes with PU-AD restores PPI network integrity and reverses synaptic and cognitive deficits, directly linking epichaperome-driven network dysfunction to AD pathology. These findings establish epichaperomes as key mediators of molecular collapse in AD and identify network-centric intervention strategies as a promising avenue for disease-modifying therapies."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Shifting from Epigenetics to the Epichaperome: HSP90 as a therapeutic target for H3K27M Diffuse Midline Glioma (DMG) (SNO 2024) - "HSP90 inhibitors, PU-H71 and PU-HZ151, effectively reduced viability of DMG lines in vitro in the low nanomolar range and result in caspase mediated cell death (p<0.0001 1 uM, p<0.05 500 nM, n=6). To enhance the therapeutic efficacy of epichaperome inhibition, we employed the CSNK2A1 kinase inhibitor, CX-4945, in combination with PU-HZ151, resulting in the effective ablation of DMG patient cells in vitro. These data highlight the potential of epichaperome inhibitors for DMG treatment, as they target multiple DMG oncogenic pathways."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CDC37 • HSF1 • HSP90AA1

Alzheimer's Disease Stressors Induce Epichaperome Formation within Glutamatergic Neurons (Neuroscience 2023) - "We showed synaptic protein network connectivity, and in turn cognitive function, revert to normal levels upon treatment with small molecules, including PU-AD, that dismantle epichaperomes into individual, normal, folding chaperones, providing a therapeutic channel not optimally exploited to date...We tested the hypothesis that this well-known AD-related stressor results in epichaperome formation which can be rigorously and reproducibly visualized using this new chemical probe for understanding AD biology in the context of presynaptic and postsynaptic neural markers. We posit the newly developed probe will be an indispensable tool to understand epichaperome formation, composition, and localization in different biological scenarios, including the pathogenesis of AD, with mechanistic and therapeutic implications."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action. (PubMed, Biomedicines) - "In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases."

Journal • CNS Disorders • Oncology

PET Imaging of Subjects Using 124I-PU-AD (clinicaltrials.gov) - P1 | N=5 | Terminated | Sponsor: Samus Therapeutics, Inc. | Completed ➔ Terminated; Company has ceased operations

Trial termination • Alzheimer's Disease • CNS Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor

A Single and Multiple Ascending Dose Study to Evaluate the Safety and Pharmacokinetics of PU-AD in Healthy Subjects (clinicaltrials.gov) - P1 | N=40 | Terminated | Sponsor: Samus Therapeutics, Inc. | Completed ➔ Terminated; Company ceased operations

Trial termination • Alzheimer's Disease • CNS Disorders

Epichaperomes: an emerging target for precision medicine approach to proteostasis defects in Alzheimer’s disease (Neuroscience 2022) - "Epichaperomes therefore provides unique proteostasis-related precision medicine opportunities for detection and reversal of functional imbalances associated with AD. The discovery and clinical translation of the epichaperome agent PU-AD, currently in Phase 2 studies in AD (https://www.alzforum.org/therapeutics/pu-ad), and of a companion diagnostic, including recent developments are presented."

Alzheimer's Disease • CNS Disorders

Illuminating epichaperomes: tools and methods to study epichaperomes in cells and tissues (Neuroscience 2022) - "Indeed, as proof-of-principle we showed synaptic protein network connectivity and in turn cognitive function revert to normal levels upon treatment with small molecules, such as PU-AD, that dismantle epichaperomes into individual, normal, folding chaperones, providing a therapeutic channel not optimally exploited to date...We provide examples in the use of these probes on cellular models as well as in human brain tissues and provide proof-of-principle in how these probes can be utilized to address key questions related to the context-dependent composition of the epichaperomes, their cellular localization and localization change in response to and during distinct intra- and extra-cellular events and/or stressors. In sum, these preliminary studies propose our imaging probes as unique and important reagents to study the biology of an emerging AD target."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders

To Evaluate Safety, Tolerability and Pharmacological Effects of PU AD in Subjects With Mild AD Dementia (clinicaltrials.gov) - P2a | N=4 | Terminated | Sponsor: Samus Therapeutics, Inc. | Trial completion date: Dec 2023 ➔ Nov 2022 | Suspended ➔ Terminated; Samus Therapeutics company closure

Trial completion date • Trial termination • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • APOE

HSP90 inhibition as a novel therapy for Diffuse Intrinsic Pontine Glioma (DIPG) (SNO 2022) - "Treating DIPG with PU-H71 successfully reduced tumor cell viability but PU-H71 has poor brain penetration. To overcome this, a molecular isoform of PU-H71 has been developed, PU-HZ151, which will be used to test the in vivo efficacy of HSP90 inhibition for DIPG."

Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CASP3 • CASP7 • HSP90AA1 • MAPK3

ALS: Evaluate PU-AD in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Samus Therapeutics, Inc. | Trial completion date: Sep 2020 ➔ Jan 2025 | Trial primary completion date: Sep 2020 ➔ Dec 2024

Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders • GFAP • NEFL • SOD1 • TARDBP

Study of Icapamespib (PU-AD) in Patients With Recurrent Malignant Glioma (clinicaltrials.gov) - P1b | N=7 | Terminated | Sponsor: Samus Therapeutics, Inc. | N=48 ➔ 7 | Trial completion date: Aug 2023 ➔ Nov 2022 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2023 ➔ Nov 2022; Samus Therapeutics Closure

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults. (PubMed, J Prev Alzheimers Dis) - "The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer's Disease and other neurodegenerative diseases."

Clinical • Journal • PK/PD data • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Hematological Disorders • Pain

To Evaluate Safety, Tolerability and Pharmacological Effects of PU AD in Subjects With Mild AD Dementia (clinicaltrials.gov) - P2a | N=4 | Suspended | Sponsor: Samus Therapeutics, Inc. | Trial completion date: Oct 2020 ➔ Dec 2023 | Terminated ➔ Suspended

Trial completion date • Trial suspension • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • APOE

Synthesis of I-labeled epichaperome probes and assessment in visualizing pathologic protein-protein interaction networks in tumor bearing mice. (PubMed, STAR Protoc) - "This protocol describes the synthesis and characterization of two I-labeled epichaperome probes, [I]-PU-H71 and [I]-PU-AD, both which have translated to clinical studies. (2020), and Pillarsetty et al. (2019)."

Journal • Preclinical • Oncology

To Evaluate Safety, Tolerability and Pharmacological Effects of PU AD in Subjects With Mild AD Dementia (clinicaltrials.gov) - P2a | N=4 | Terminated | Sponsor: Samus Therapeutics, Inc. | N=150 ➔ 4 | Active, not recruiting ➔ Terminated; Additional nonclinical studies needed

Enrollment change • Trial termination • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • APOE

ALS: Evaluate PU-AD in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Samus Therapeutics, Inc. | N=30 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Amyotrophic Lateral Sclerosis • CNS Disorders • GFAP • TARDBP

Study of Icapamespib (PU-AD) in Patients With Recurrent Malignant Glioma (clinicaltrials.gov) - P1b; N=48; Recruiting; Sponsor: Samus Therapeutics, Inc.; Not yet recruiting ➔ Recruiting; Trial completion date: Aug 2022 ➔ Aug 2023; Trial primary completion date: Apr 2022 ➔ Apr 2023

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • MRI

Samus Therapeutics Announces First Patient Dosed in Phase 1b Study of Icapamespib in Recurrent Malignant Glioma (PRNewswire) - "Samus Therapeutics...announced the first patient was dosed in the multicenter Phase 1b study of icapamespib in patients with recurrent malignant glioma....The Phase 1b trial consists of two stages. The first stage is currently recruiting patients and will evaluate the safety, tolerability and pharmacokinetics of icapamespib. This dose escalation stage is designed to define a recommended Phase 2 dose (RP2D). The second stage, dose expansion, will confirm the safety and tolerability of the RP2D."

Trial status • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

ALS: Evaluate PU-AD in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2; N=30; Not yet recruiting; Sponsor: Samus Therapeutics, Inc.; Trial completion date: Feb 2022 ➔ Dec 2022; Trial primary completion date: Dec 2021 ➔ Dec 2022

Clinical • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders • GFAP • TARDBP

Study of Icapamespib (PU-AD) in Patients With Recurrent Malignant Glioma (clinicaltrials.gov) - P1b; N=48; Not yet recruiting; Sponsor: Samus Therapeutics, Inc.; Initiation date: Aug 2021 ➔ Nov 2021

Clinical • Trial initiation date • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • MRI

Study of Icapamespib (PU-AD) in Patients With Recurrent Malignant Glioma (clinicaltrials.gov) - P1b; N=48; Not yet recruiting; Sponsor: Samus Therapeutics, Inc.; Initiation date: Apr 2021 ➔ Aug 2021

Clinical • Trial initiation date • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

"#SamusTherapeutics Receives InvestigationalNewDrug Clearance from #FDA for PU-AD for the Treatment of Recurrent #MalignantGlioma https://t.co/BbrqZgmARC" (@1stOncology)

IND • Brain Cancer • Glioma • Oncology • Solid Tumor

Samus Therapeutics Receives IND Clearance from FDA for PU-AD for the Treatment of Recurrent Malignant Glioma (PRNewswire) - “Samus Therapeutics, Inc…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.”

IND • Glioma • Oncology

ALS: Evaluate PU-AD in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2; N=30; Not yet recruiting; Sponsor: Samus Therapeutics, Inc.; Initiation date: Jan 2021 ➔ Apr 2021

Clinical • Trial initiation date • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • GFAP • TARDBP