ARM210 / Servier, RyCarma Therapeutics - LARVOL DELTA

RyCarma Therapeutics Announces New Leadership and Company Name, Introduces Program in Heart Failure (Businesswire) - "RyCarma Therapeutics, Inc., formerly known as ARMGO Pharma...unveiled its new leadership and company name change from 'ARMGO Pharma, Inc.' to 'RyCarma Therapeutics, Inc.' and introduced a new program in heart failure. The name RyCarma references the Company’s foundational work and leadership in ryanodine receptor (RyR) biology and in establishing the therapeutic potential of Rycals, a novel class of small molecule drugs. RyCarma’s new program focuses on developing its lead candidate ARM210 in heart failure with reduced ejection fraction, which affects millions of people worldwide."

Commercial • Pipeline update • Heart Failure

Treatment of an Inherited Ventricular Arrhythmia (clinicaltrials.gov) - P2 | N=8 | Terminated | Sponsor: Armgo Pharma, Inc. | N=20 ➔ 8 | Trial completion date: Jan 2025 ➔ Apr 2024 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Apr 2024; Due to challenges in recruiting patients.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia • CYP19A1 • PVT1

Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders. (PubMed, Nat Commun) - "Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca2+ leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders."

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Treatment of an Inherited Ventricular Arrhythmia (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Armgo Pharma, Inc. | Trial completion date: Sep 2024 ➔ Jan 2025 | Trial primary completion date: Jun 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia • CYP19A1 • PVT1

Update on RYR1-related myopathies. (PubMed, Curr Opin Neurol) - "Recent advances in clinical and pathological understanding have provided new insights into RYR1-RM. Novel pathomechanisms elucidated by cryo-EM and rapid screening methods have led to the identification of several promising drug candidates. We are hopeful about the potential of Rycal, other new drugs, and gene therapy, offering a promising outlook for the future."

Journal • Fatigue • Gene Therapies • Myositis • RYR1

S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM) (clinicaltrials.gov) - P1 | N=7 | Completed | Sponsor: Armgo Pharma, Inc. | Active, not recruiting ➔ Completed | N=10 ➔ 7

Enrollment change • Trial completion • Myositis

Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial. (PubMed, EClinicalMedicine) - P1 | "These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYR1-RM. NINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017-551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier."

Clinical • Journal • Fatigue • Myositis • RYR1

Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes. (PubMed, Stem Cell Res Ther) - "By testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest."

Journal • Cardiovascular • Genetic Disorders • Ventricular Tachycardia • RYR2

Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice. (PubMed, Sci Transl Med) - "Here, we show that chemotherapy treatment with doxorubicin (DOX) in a breast cancer mouse model induced protein kinase A (PKA) phosphorylation of the neuronal ryanodine receptor/calcium (Ca) channel type 2 (RyR2), RyR2 oxidation, RyR2 nitrosylation, RyR2 calstabin2 depletion, and subsequent RyR2 Ca leakiness...RyR2 leakiness and cognitive dysfunction could be ameliorated by treatment with a small molecule Rycal drug (S107). Chemobrain was also found in noncancer mice treated with DOX or methotrexate and 5-fluorouracil and could be prevented by treatment with S107...Proteomics and Gene Ontology analysis indicated that the signaling downstream of chemotherapy-induced leaky RyR2 was linked to the dysregulation of synaptic structure-associated proteins that are involved in neurotransmission. Together, our study points to neuronal Ca dyshomeostasis via leaky RyR2 channels as a potential mechanism contributing to chemobrain, warranting further translational studies."

Journal • Preclinical • Alzheimer's Disease • Breast Cancer • Cognitive Disorders • Oncology • Solid Tumor • TNFA

Treatment of an Inherited Ventricular Arrhythmia (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Armgo Pharma, Inc. | Not yet recruiting ➔ Recruiting | Trial completion date: Mar 2024 ➔ Sep 2024 | Trial primary completion date: Jan 2024 ➔ Jun 2024

Enrollment open • Trial completion date • Trial primary completion date • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia • CYP19A1 • PVT1

Defective cerebellar ryanodine receptor type 1 and endoplasmic reticulum calcium 'leak' in tremor pathophysiology. (PubMed, Acta Neuropathol) - "Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca leak via RyR1 may contribute to tremor pathophysiology."

Journal • CNS Disorders • Essential Tremor • Movement Disorders • Parkinson's Disease • RYR1

S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM) (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Armgo Pharma, Inc. | Trial completion date: Sep 2022 ➔ Jun 2023 | Trial primary completion date: Jun 2022 ➔ Dec 2022

Trial completion date • Trial primary completion date • Myositis

Phase 1 open-label trial of Rycal S48168 (ARM210) for RYR1-related myopathies (WMS 2022) - P1 | "Other preliminary efficacy results were mixed. Given the favorable safety profile and efficacy trends, further clinical development of S48168 (ARM210) is warranted for RYR1-RM."

Clinical • P1 data • CNS Disorders • Fatigue • Muscular Dystrophy • Myositis • RYR1

The RyR-calstabin interaction stabilizer S107 protects hippocampal neurons from GABAergic synaptic alterations induced by Abeta42 oligomers. (PubMed, J Physiol) - "Amyloid beta 42 peptide (Abeta42) accumulation is a key characteristic of Alzheimer's disease (AD) and causes synaptic dysfunctions. To date, the effects of Abeta42 accumulation on GABAergic synapses are poorly understood Our findings suggest that, similarly to what observed on glutamatergic synapses, Abeta42 modifies GABAergic synapses by targeting ryanodine receptors and causing calcium dysregulation The GABAergic impairments can be restored by the RyR-calstabin interaction stabilizer S107 Based on our research, RyRs stabilization may represent a novel pharmaceutical strategy for preventing or delaying of AD."

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

Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment. (PubMed, Sci Adv) - "The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210."

Journal • Cardiovascular • Ventricular Tachycardia

S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM) (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Armgo Pharma, Inc. | Trial primary completion date: Mar 2022 ➔ Jun 2022

Trial primary completion date • Myositis

Treatment of an Inherited Ventricular Arrhythmia (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: Armgo Pharma, Inc. | Trial completion date: Dec 2023 ➔ Mar 2024 | Initiation date: May 2022 ➔ Oct 2022 | Trial primary completion date: Sep 2023 ➔ Dec 2023

Trial completion date • Trial initiation date • Trial primary completion date • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia • CYP19A1 • PVT1

It takes two to tango: Rycals and ATP snuggle up to bind ryanodine receptors. (PubMed, Structure) - "In this issue of Structure, Melville and colleagues used cryo-EM to study the binding of ryanodine receptors to Rycals, compounds with the potential to treat skeletal and cardiac muscle disorders. Unexpectedly, they found that Rycal packs against an ATP in a peripheral pocket, which stabilizes the closed channel state."

Journal

A drug and ATP binding site in type 1 ryanodine receptor. (PubMed, Structure) - "A class of therapeutics known as Rycals prevent the RyR-mediated leak, are effective in preventing disease progression and restoring function in animal models, and are in clinical trials for patients with muscle and heart disorders. Using cryogenic-electron microscopy, we present a model of RyR1 with a 2.45-Å resolution before local refinement, revealing a binding site in the RY1&2 domain (3.10 Å local resolution), where the Rycal ARM210 binds cooperatively with ATP and stabilizes the closed state of RyR1."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Muscular Dystrophy • Myositis • RYR1

Role of oxidation of excitation-contraction coupling machinery in age-dependent loss of muscle function in C. elegans. (PubMed, Elife) - "Preventing FKB-2 depletion from the UNC-68 macromolecular complex using the Rycal drug S107 improved muscle Ca transients and function. Taken together, these data suggest that UNC-68 oxidation plays a role in age-dependent loss of muscle function. Remarkably, this age-dependent loss of muscle function induced by oxidative overload, which takes ~2 years in mice and ~80 years in humans, occurs in less than 2-3 weeks in C. elegans, suggesting that reduced antioxidant capacity may contribute to the differences in life span amongst species."

Journal

S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM) (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Armgo Pharma, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2021 ➔ Jul 2022 | Trial primary completion date: Oct 2021 ➔ Mar 2022

Enrollment closed • Trial completion date • Trial primary completion date • Myositis

Treatment of an Inherited Ventricular Arrhythmia (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: Armgo Pharma, Inc. | Initiation date: Dec 2021 ➔ May 2022

Trial initiation date • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia • CYP19A1 • PVT1

Treatment of an Inherited Ventricular Arrhythmia (clinicaltrials.gov) - P2; N=20; Not yet recruiting; Sponsor: Armgo Pharma, Inc.

New P2 trial • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia • CYP19A1 • PVT1

The Ryanodine receptor stabilizer S107 fails to support motor neuronal neuritogenesis in vitro. (PubMed, Tissue Cell) - "We investigated whether S107, a RyR-stabilizing compound (Rycal), is beneficial for survival and neuritogenesis of spinal cord motor neurons in vitro...Results showed that S107 (i) had no effect on gliosis resulting from slices preparation; (ii) had no effect on motor neuronal survival and proliferation; and (iii) impaired neurite sprouting, no matter whether it was a differentiation (NSC-34 cells) or regeneration (spinal cord slices) process. The results underline the need for a flexible Cahomeostasis provided by the ER for re-initiation of neuritogenesis."

Journal • Preclinical • CNS Disorders • Orthopedics

S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM) (clinicaltrials.gov) - P1; N=10; Recruiting; Sponsor: Armgo Pharma, Inc.; Trial completion date: Aug 2021 ➔ Dec 2021; Trial primary completion date: May 2021 ➔ Oct 2021

Clinical • Trial completion date • Trial primary completion date • Myositis