copper histidinate (CUTX-101) / Fortress, Zydus Lifesci - LARVOL DELTA

Intravenous AAV9-ATP7A plus subcutaneous copper histidinate optimizes outcomes in a lethal Menkes disease mouse model. (PubMed, Sci Adv) - "In conjunction with subcutaneous injections of clinical-grade copper histidinate in the first month of life, 95% long-term survival was attained, which was correlated with improvements in serum and brain copper levels, brain neurochemical profiles, somatic growth, and neuromotor function. The notable results support a trial of this treatment combination in affected male newborns with Menkes disease."

Journal • Preclinical • CNS Disorders • Epilepsy • Gene Therapies • ATP7A

OVERCOMING BARRIERS IN MENKES DISEASE: A STANDARDIZED HIGH QUALITY AND STABLE INJECTABLE COPPER HISTIDINATE. (PubMed, J Pharm Sci) - "This study extends and optimizes the manufacturing procedure by incorporating active principles as salts or neutral substances and accommodating a broader pH range. The Cu-Hiinj 1:3 formulation not only offers enhanced stability but also shows potential for industrial production, thus improving access to Menkes disease treatment while ensuring safety and efficacy."

Journal • Rare Diseases

Fortress Biotech and Cyprium Therapeutics Announce U.S. FDA Acceptance and Priority Review of NDA for CUTX-101 for Treatment of Menkes Disease (GlobeNewswire) - "Fortress Biotech, Inc....today announced the acceptance for review of the New Drug Application ('NDA') by the U.S. Food and Drug Administration ('FDA') for CUTX-101 (Copper Histidinate) for the treatment of Menkes disease, a rare X-linked recessive pediatric disease caused by gene mutations of the copper transporter ATP7A. The NDA has been granted Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) target action date of June 30, 2025...The CUTX-101 NDA submission is supported by positive topline clinical efficacy results for CUTX-101, demonstrating statistically significant improvement in overall survival for Menkes disease subjects who received early treatment with CUTX-101...If the CUTX-101 NDA is approved, the product may be eligible for a Rare Pediatric Disease Priority Review Voucher (PRV), for which Cyprium would retain ownership...Cyprium is also eligible to receive royalties and up to $129 million in aggregate development and sales milestones from Sentynl."

Commercial • FDA filing • PDUFA • Priority review • Genetic Disorders

Huppke-Brendel syndrome: Novel cases and a therapeutic trial with ketogenic diet and N-acetylcysteine. (PubMed, JIMD Rep) - "Therapeutic trials with copper histidinate failed to achieve any clinical improvement. The overall metabolic pattern shows a trend toward lowered levels of N-acetylated amino acids in CSF and to a lesser extent in plasma. Although there are some assumptions, the function of AT-1 is still not clear and further studies are needed to better understand mechanisms underlying this complex disorder."

Journal • Pediatrics • SLC33A1

EFFICACY OF A COPPER NANOCLUSTERS TO TREAT A MOUSE MODEL OF MENKES DISEASE (SSIEM 2024) - "Copper-histidinate is the current treatment but does not improve the neurologic status of these patients... We demonstrated that CuNC, thanks to its very little size (< 1nm), is able to cross the physiological barriers (including the BBB) and to restore the copper-enzymes activities. Due to these results, we obtain the Orphan Drug Designation (ODD) by the EMA in 2023 and we hope to begin the phase I/II trial in children with MD by the end of 2024."

Preclinical • Cardiovascular • CNS Disorders • Osteoporosis • Rheumatology • Tyrosinase

Long Term Follow-up on Menkes Disease Patients (clinicaltrials.gov) - P=N/A | N=50 | Enrolling by invitation | Sponsor: Cyprium Therapeutics, Inc. | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date

LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism. (PubMed, iScience) - "Crystals of the monomeric species Cu(His) were obtained in our experimental conditions and the actual transport of the complex was evaluated by a combined strategy of bioinformatics, site-directed mutagenesis, radiolabeled transport, and mass spectrometry analysis. The LAT1-mediated transport of Cu(His) may have profound implications for both the treatment of copper dysmetabolism diseases, such as the rare Menkes disease, and of cancer as an alternative to platinum-based therapies."

Journal • Metabolic Disorders • Oncology • SLC7A5

Characterization of the Mottled-Blotchy Mouse Model of Abnormal Copper Transport (ASGCT 2023) - "We sought to quantify the amount of properly spliced Atp7a transcript in mo-blotchy mice in order to better understand its phenotype and response to AAV9-mediated gene replacement in combination with subcutaneous copper histidinate (CuHis)...We also identified one female pup with skewed X-inactivation leading to a severe phenotype and premature death. Cultured fibroblasts obtained from this mouse are under investigation for gene therapy mediated modulation of X-inactivation.The results from this study advance understanding of clinical and biochemical aspects of abnormal human copper transport and provide insight and direction for rational treatment approaches to Menkes disease and its milder variants."

Preclinical • Gene Therapies • Genetic Disorders • ATP7A

Dose Ranging Pre-Clinical Studies of Systemic AAV9 with Codon-Optimized Reduced Size ATP7A (cors-ATP7A) Plus Subcutaneous Copper Histidinate in a Menkes Disease Model (ASGCT 2023) - "Our IND-generating studies in the mo-br mouse represent important steps toward a future pilot clinical trial for individuals with this illness. In combination with newborn screening for ATP7A-related disorders, the potential impact of our results on clinical practice is high since the largest barriers to good health for patients with Menkes disease would be circumvented."

Preclinical • CNS Disorders • Epilepsy • Gene Therapies • Hepatology • ATP7A

Newly identified disorder of copper metabolism caused by variants in CTR1, a high-affinity copper transporter. (PubMed, Hum Mol Genet) - "We also assessed the effects of Copper Histidinate in the patients' cultured cells and in the patients, under a formal clinical protocol...In combination with present and prior studies, these infants' clinical, biochemical, and molecular phenotypes establish the impact of this novel variant on copper metabolism and cellular homeostasis and illuminate a crucial role for CTR1 in human brain development. CTR1 deficiency represents a newly defined inherited disorder of brain copper metabolism."

Journal • CNS Disorders • Epilepsy • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders • ATP7A • ATP7B • SLC31A1

Long Term Follow-up on Menkes Disease Patients (clinicaltrials.gov) - P=N/A | N=50 | Enrolling by invitation | Sponsor: Cyprium Therapeutics, Inc. | Trial completion date: Jul 2022 ➔ Dec 2022 | Trial primary completion date: Jul 2022 ➔ Dec 2022

Trial completion date • Trial primary completion date

Systemic Administration of Recombinant AAV9 with a Codon-Optimized, Reduced Size Version of the Human ATP7A Transgene Plus Subcutaneous Copper-Histininate Rescues 100% of Menkes Disease Mice (ASGCT 2022) - "We previously documented 22% and 53% rescue of this model with CSF-directed AAV5 and AAV9 transfer of a reduced size (rs) version of human ATP7A trimmed to conform to rAAV packaging limits, in combination with CSF or subcutaneous Copper Histidinate (CuHis)...The synergistic effect of AAV9-corsATP7A plus CuHis could further enhance survival and overall quality of life, including attainment of independent ambulation (walking) by 18 months of age. These latest breakthrough findings in the mo/br mouse model help establish the safety of this combination treatment approach and represents an important step toward a pilot clinical trial for individuals with this illness."

Preclinical • CNS Disorders • Epilepsy • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • ATP7A

Tracking Labile Copper Fluctuation In Vivo/Ex Vivo: Design and Application of a Ratiometric Near-Infrared Fluorophore Derived from 4-Aminostyrene-Conjugated Boron Dipyrromethene. (PubMed, Inorg Chem) - "The ex vivo imaging of the resected viscera of mice revealed that CUTX-101 injection enhanced the labile copper level in the liver, intestine, lung, and gall bladder in sequence, yet the kidney, heart, and spleen showed almost no response. This study indicated that modifying BODIPY as an extended ICT fluorophore, with its electron-donating group being derived as a metal chelator, is an effective design rationale of NIR ratiometric sensors for copper tracking in vivo/ex vivo."

Journal • Preclinical

[VIRTUAL] Copper Histidinate Treatment for Menkes Disease (Kinky Hair Syndrome) (AAP-NCE 2021) - "CUTX-101 was safe and well tolerated. In pre-specified primary and secondary efficacy analyses, OS was significantly improved in Menkes disease subjects treated with CUTX-101 compared to untreated subjects. Clinical benefit for CuHis-ET was greater than for CuHis-LT, underscoring the importance of early identification, including newborn screening, and prompt initiation of treatment."

CNS Disorders • Epilepsy • Infectious Disease • Pneumonia • Respiratory Diseases • ATP7A

Long Term Follow-up on Menkes Disease Patients (clinicaltrials.gov) - P=N/A; N=50; Enrolling by invitation; Sponsor: Cyprium Therapeutics, Inc.; Trial completion date: Mar 2021 ➔ Jul 2022; Trial primary completion date: Mar 2021 ➔ Jul 2022

Clinical • Trial completion date • Trial primary completion date

[VIRTUAL] Progress toward Complete Treatment of ATP7A-Related Copper Transport Disorders (ASGCT 2021) - "While patients with Menkes disease treated with subcutaneous Copper Histidinate (CuHis) injections often show improved survival and neurodevelopmental outcomes, combining CuHis with adeno-associated virus (AAV)-mediated gene therapy to provide some working copies of the ATP7A gene represents an even more promising approach...Similarly, characterization and treatment of a mouse model of ATP7A-related distal motor neuropathy will help further illuminate the role of this copper transporter in motor neuron biology. Taken together, potential advances in newborn screening for ATP7A-related disorders by DNA sequencing and progress in small molecule (CuHis) and AAV gene therapies augur well for improved life expectancy and outcomes for affected individuals and their families."

Chronic Obstructive Pulmonary Disease • Gene Therapies • Pain • Pulmonary Disease • Pulmonary Emphysema • Respiratory Diseases • ATP7A

Copper Toxicity Associated With an ATP7A-Related Complex Phenotype. (PubMed, Pediatr Neurol) - "Our findings broaden the clinical spectrum of ATP7A-related disorders and demonstrate that two clinical phenotypes can occur in the same patient. The copper-induced toxicity and low levels of both ATP7A and ATP7B in our patient suggest that copper accumulation in motor neurons is the pathogenic mechanism in ATP7A-related dHMN."

Adverse events • Journal • Pain • ATP7A • ATP7B

Long Term Follow-up on Menkes Disease Patients (clinicaltrials.gov) - P=N/A; N=50; Enrolling by invitation; Sponsor: Cyprium Therapeutics, Inc.; Trial completion date: Oct 2020 ➔ Mar 2021; Trial primary completion date: Oct 2020 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date

Long Term Follow-up on Menkes Disease Patients (clinicaltrials.gov) - P=N/A; N=50; Enrolling by invitation; Sponsor: Cyprium Therapeutics, Inc.; Trial completion date: May 2020 ➔ Oct 2020; Trial primary completion date: May 2020 ➔ Oct 2020

Clinical • Trial completion date • Trial primary completion date