dm+d

Unassigned

New Medicines

Ornithine carbamoyltransferase (OTC) deficiency

Information

New molecular entity
Ultragenyx
Ultragenyx

Development and Regulatory status

Phase II Clinical Trials
Phase II Clinical Trials
Phase II Clinical Trials
Yes
Yes
Feb 20Following discussions with the FDA regarding the potential PIII study design, ammonia is expected to be a primary endpoint, with ureagenesis as a measure of biologic activity that supports the decision for patients to discontinue alternate pathway medications [5].
Jan 20Ultragenyx is in discussion with the US FDA for a PIII trial design of DTX 301 for the treatment of Inborn urea cycle disorder [3].
Mar 16Has orphan drug status in EU & US, plus fast track status in US [3].

Category

An AAV type 8 gene therapy. DTX 301 is designed to deliver a gene for durable expression of OTC in patients with OTC deficiency
A rare, genetic disorder of urea cycle metabolism and ammonia detoxification characterized by either a severe, neonatal-onset disease found mainly in males, or later-onset (partial) forms of the disease. Both present with episodes of hyperammonemia that can be fatal and which can lead to neurological sequelae. Ornithine transcarbamylase deficiency (OTCD) is the most common type of urea cycle disorder. Worldwide prevalence estimates range between 1 per 56,500 to 1 per 113,000 live births [1].
Ornithine carbamoyltransferase (OTC) deficiency
Intravenous infusion

Trial or other data

Jul 20Updated positive data from PI/II CAPtivate study presented at ASGCT. All three patients in the third dose cohort (1.0 x 10^13 GC/kg) are responders to DTX301 as shown by sustained meaningful increases in the rate of ureagenesis or reductions in ammonia levels. Six of nine patients across all three cohorts have now responded to the gene therapy, including three females and three males. All three complete responders, those who have discontinued all ammonia scavengers and liberalized their diets, remain clinically and metabolically stable after longer-term follow-up. A fourth cohort of three patients at the same Cohort 3 dose is planned using prophylactic steroids. Dosing is still on hold due to COVID-19 but data are expected by the end of 2020. Ultragenyx intends to hold an end-of-phase 2 meeting with the FDA based on the first three cohorts, with PIII study initiation currently expected in H1 21 [4].
Mar 20Topline data from the PI/II CAPtivate trial, demonstrates confirmed response and potential response in two and one patient, each in cohort 3, with confirmed response in three patients, in cohort 2. In cohort 3, seventh patient reported 79% change in the rate of ureagenesis, from a low of 24% of normal at baseline to the 51 to 64% range, and stayed at 44% of normal at week 52. Patient was reported to be clinically and metabolically stable without a rise in ammonia. In eight patient 90% reduction in ammonia levels, was reported with a time-normalisation over a 24 hour period, from 184umol/L at baseline to 19umol/L at week 24. Ninth patient reported 123% increase in rate of ureagenesis, from 25% of normal at baseline to 56% of normal at week 12. In Cohort 2, sixth patient reported 218% improvement in rate of ureagenesis, from 20 % 61% at Week 52 and maintained at 64% at week 78. Further 74% reduction in ammonia levels from 156umol/L at baseline to 40umol/L was reported at week 78 [3].
Mar 20A long-term follow-up study of DTX 301 following a single IV dose in adults with late-onset OTC deficiency (301OTC02; NCT03636438), that started in Aug 18, is enrolling by invitation [2].
Mar 20PI/II CAPtivate trial is ongoing but no longer recruiting [2].
Jan 17PI/II CAPtivate trial to evaluate the safety and efficacy of single ascending doses of DTX 301 in adults with late-onset OTC deficiency starts (NCT02991144; 301OTC01). The trial includes assessment of 13C-acetate to evaluate rate of ureagenesis and hepatocyte (liver) ureagenesis capacity. Eligible subjects will receive a single IV infusion of DTX301. Dose escalation will be conducted according to a model that uses the collected data to predict the safety profile of the dose in order to determine the optimal biological dose (OBD). The decision to proceed to the next dose cohort will be made after the data monitoring committee (DMC) has evaluated the safety data for all subjects in a dosing cohort. Subjects will be followed for 52 weeks after dosing. After completion of this study, subjects will be asked to enroll in a 4-year extension study to evaluate the long term (a total of 5 years) safety and efficacy of DTX301. It will enrol 15 patients in the US, Canada, Spain and the UK (sites are National Hospital for Neurology & Neurosurgery in London and Queen Elizabeth Hospital in Birmingham). The trial is due to complete Feb 21 [2].