Ultragenyx Announces Progress Across Broad Gene Therapy Portfolio and Positive Longer-Term Data from Multiple Phase 1/2 Gene Therapy Studies

Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel products for rare and ultra-rare diseases, today announced positive longer-term safety and efficacy data from the first three cohorts of the ongoing Phase 1/2 studies of DTX401, an investigational adeno-associated virus (AAV) gene therapy for Glycogen Storage Disease Type Ia (GSDIa), and DTX301, an AAV gene therapy for ornithine transcarbamylase (OTC) deficiency. In addition, dosing is nearing completion for the prophylactic steroid cohorts in both studies. Discussions with regulatory agencies continue to progress for both programs, and Ultragenyx expects to initiate Phase 3 studies for DTX401 in the first half of 2021 and for DTX301 in the second half of 2021. The company also plans to start a seamless single-protocol Phase 1/2/3 study for UX701, an AAV gene therapy for Wilson disease.

We continue to see durable and clinically meaningful responses in patients in both the DTX401 and DTX301 programs. GSDIa patients treated with DTX401 demonstrate continually improved glucose metabolism with reduction or elimination of cornstarch dependence over time. OTC patients treated with DTX301 show good metabolic control after tapering or discontinuation of alternate pathway medications and protein restricted diet, saidEric Crombez, M.D., Chief Medical Officer of the Ultragenyx Gene Therapy development unit. With the initiation of the UX701 program in Wilson disease and progression of DTX401 and DTX301 to Phase 3 as well as progress in our preclinical stage programs, we are leveraging our proprietary platforms to advance one of the broadest portfolios of gene therapy programs in the industry.

DTX401 (GSDIa) Program

Phase 1/2 data update: All patients (n=9) responding and demonstrating continued improvement of glucose control while reducing or eliminating cornstarch therapy

All nine patients continue to demonstrate improved glucose control while tapering or discontinuing oral glucose replacement with cornstarch and improvements in energy metabolism pathways over the long term. Patients continue to taper the amount and frequency of cornstarch dosing with progress in eliminating overnight and daytime cornstarch doses. At the primary evaluation timepoint at Week 52, the overall mean reduction in cornstarch was 77% across all three cohorts, including two patients in Cohort 3 showing a reduction of greater than 75%. Longer term follow-up for more than two years for the three patients in Cohort 1 have shown sustained and continued cornstarch reductions with a mean reduction of 91% through weeks 104 and 120. Two patients (one each from Cohort 1 and 3) are completely off cornstarch therapy at weeks 127 and 60, respectively.

Data collected from continuous glucose monitoring (CGM) implemented in Cohort 3 indicate that glycemic control was maintained and even improved despite the reductions in cornstarch dependence. Through Week 48, these patients had decreased cornstarch use by between 30% and 92%. Even with these substantial cornstarch reductions, the patients had a mean 10% increase in the percent of time spent in euglycemia, defined by blood glucose levels in the normal range of 60 to 120 mg/dL.

Additionally, these reductions in cornstarch dosing have had an impact on energy metabolism and body weight. Seven of nine treated patients had decreases of 5% (5.6 kg) to 21% (10.5 kg) in bodyweight following DTX401 treatment, with a mean decrease of 12% from the mean baseline weight of 82.8 kg in these seven patients. The notable weight loss is attributed to improved glycemic control and potentially increased physical activity reported by patients.

Interviews with patients following their Week 24 and/or Week 52 visits provide support for the study results seen to date. Patients reported improvements in both their physical and mental health. This includes increased energy and strength, supporting normalization of daily activities and weight loss, as well as greater mental acuity and reduced stress, with the latter in part noted as related to diminished fears of missing a cornstarch dose. No negative patient feedback has been received to date on their experiences with DTX401.

The safety profile of DTX401 remains favorable; there have been no infusion-related adverse events and no treatment-related serious adverse events reported. All adverse events have been Grade 1 or 2.

All three GSDIa patients dosed in prophylactic steroid cohort doing well with no safety issues

All three patients in a fourth and final Phase 1/2 cohort, which utilizes prophylactic steroids, have been dosed at the same dose as Cohorts 2 and 3. There have been no safety issues through up to 11 weeks post-dosing, and all three patients are doing well and have demonstrated early reduction in daily cornstarch intake.

Phase 3 study of DTX401 in GSDIa expected to initiate in first half 2021

The company has completed Scientific Advice with the European Medicines Agency (EMA) and an End of Phase 2 (EOP2) meeting with the U.S. Food and Drug Administration (FDA) to discuss the Phase 2 data, the Phase 3 design, and endpoints. Based in part on this feedback, Ultragenyx plans to conduct a 48-week Phase 3 study in approximately 50 patients, randomized 1:1 to DTX401 or placebo. All patients in the study will cross over to the therapeutic arm and receive therapy at the end of the initial 48-week follow-up period.

Based on the regulatory discussion and pending finalization, Ultragenyx intends to study as primary endpoints glycemic control by assessing the maintenance of glucose control by CGM and the reduction in cornstarch requirements. These primary endpoints will be supported by key secondary endpoints of improvement in percent of time spent in normal glucose control (60-120 mg/dL), time to hypoglycemia in controlled fasting challenge, and the GSDIa functional assessment diary signs and symptom scale. The durability of the treatment will be supported by the longer-term Phase 1/2 data and early treated Phase 3 patients. Based on the results to date, the therapeutic benefit appears to increase over time during the second year after treatment. Ultragenyx expects to initiate the study in the first half of 2021.

DTX301 (OTC) Program

Phase 1/2 data update: All six previous responders demonstrate durable metabolic control, including greater than two-year sustained responses

As previously reported, six out of nine treated patients responded to DTX301 on a dose-dependent basis, including all three treated at the highest dose. The three complete responders have now been stable through 104, 130, and 156 weeks post-treatment with good ammonia control despite discontinuation of their alternative pathway medications and protein-restricted diets. The three other responders also remain stable through Weeks 52 and 130 and are either continuing to taper medications and diet or intend to continue tapering once COVID-19 restrictions are lifted and patients can be more closely followed in clinic. All responders remain in excellent clinical condition with no significant adverse events, hospitalizations, or other events related to OTC deficiency.

There have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study. All treatment-related adverse events have been Grade 1 or 2.

Prophylactic steroid cohort: Two OTC patients dosed with no safety issues; third patient to be dosed this month

Two of three patients have been dosed in the prophylactic steroid cohort, the final cohort in the Phase 1/2 study, at the same dose as in Cohort 3. Through up to 18 weeks post-dosing, both patients are doing well clinically with good metabolic control and without any safety issues. The third patient in the cohort, who has not yet been dosed due to delays related to COVID-19, is expected to be dosed this month.

Phase 3 study of DTX301 in OTC expected to initiate in second half 2021

Ultragenyx completed the initial Scientific Advice process with the EMA regarding the Phase 3 development plan and continues to have discussions with the FDA regarding the Phase 3 study of DTX301. The EOP2 meeting with the FDA had been delayed and is now scheduled to occur late in the first quarter of 2021.

Based on regulatory feedback to date, the proposed Phase 3 study design will include approximately 50 patients, randomized 1:1 to DTX301 or placebo and followed for 48 weeks initially. The change in 24-hour ammonia levels is expected as the primary endpoint. The entry criteria will allow patients with higher baseline ammonia levels than in the Phase 1/2 study to allow sufficient power to assess the change in ammonia. The primary endpoint will be supported by the change in the rate of ureagenesis as a key secondary endpoint that evaluates the capacity to generate urea from ammonia. Additional secondary endpoints include reduction or discontinuation of scavenger medications and normalization of protein-restricted diet.

The Phase 3 study is expected to begin dosing in the second half of 2021. Placebo patients participating in the study will receive DTX301 at the end of the initial 48-week follow-up period. The company will continue to follow patients in the ongoing Phase 1/2 study during the Phase 3 in order to augment the overall long-term data package supporting the durability of DTX301.

Update on Dose Level Determination Method for DTX301 and DTX401

A new droplet digital PCR (ddPCR) test method has been implemented to determine the level of genome copy (GC) titers for Ultragenyxs gene therapy candidates. This new process improves the accuracy, precision, and specificity compared to the prior quantitative PCR (qPCR) approach. As a result, the actual highest Phase 1/2 dose and planned Phase 3 dose for DTX301 is 1.7 x 10^13 GC/kg (from 1.0 x 10^13 GC/kg) and for DTX40 2021 Global Data Point.