New Medicines

Ornithine carbamoyltransferase (OTC) deficiency


New molecular entity

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Apr 21Ultragenyx announces successful completion of an end-of-PII meeting with the FDA. It has finalised the PIII study design, which will include a 64-week primary efficacy analysis period and enrol approximately 50 patients 12 years of age and older, randomised 1:1 to DTX 301 (1.7 x 10^13 GC/kg dose) or placebo. The co-primary endpoints will be change in 24-hour plasma ammonia levels and the percent of patients who achieve a response as measured by discontinuation or reduction in baseline disease management [6].
Jan 21Ultragenyx completes the initial Scientific Advice process with the EMA regarding the PIII trial development plan [6].
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].


An in vivo gene therapy using an adeno-associated virus serotype 8 (AAV8) capsid and a codon-optimised version of the ornithine carbamoyltransferase (OTC) gene. Designed to deliver a gene for durable expression of OTC. Given as a single dose.
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

Sep 22PIII trial sites include the US, Argentina, Australia, Brazil, Canada, France, Germany, Italy, Japan, Netherlands, Portugal, Spain and the UK (University Hospitals Birmingham) [10].
Sep 22PIII trial to evaluate the efficacy of DTX301 on the improvement of ornithine transcarbamylase (OTC) function by maintaining safe plasma ammonia levels with removal of dietary protein restriction and alternative pathway medication starts (NCT05345171). Participants will receive a single peripheral IV infusion of DTX301 in solution (or placebo), and at week 64, a single peripheral IV infusion of placebo (or DTX301). Collection of primary outcome data is expected to complete Dec 24 [10].
Jul 22Ultragenyx expects to initiate the PIII study of DTX301 in patients with OTC in H2 2022. The 64-week study will include approximately 50 patients, randomised 1:1 to DTX301 or placebo. The primary endpoints are response as measured by removal of ammonia-scavenger medications and protein-restricted diet and change in 24-hour ammonia levels [9].
Nov 21Ultragenyx is currently in the process of initiating the PIII study with the first patients in the US expected to enter an approximate 4-to 8-week baseline screening period around the end of 2021, after which they would receive a single dose of DTX301 or placebo [8].
Sep 21Long-term follow-up study (NCT03636438) is still enrolling by invitation and due to complete collection of primary outcome data Dec 25 [7].
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].