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 study of DTX301, an investigational adeno-associated virus (AAV) gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency. Six of nine patients in the study have responded to the gene therapy (three female, three male), including all three patients in Cohort 3 who are now confirmed responders. The three previously disclosed complete responders, who have discontinued all ammonia scavengers and liberalized their diet, remain clinically and metabolically stable after longer-term follow-up. Data from the Phase 1/2 study were presented today at the American Society of Gene & Cell Therapy (ASGCT) virtual 2020 Annual Meeting.
“We are seeing durable and clinically meaningful responses to DTX301. We are extremely encouraged that the patients who have stopped alternate pathway medications and liberalized dietary restrictions continue to do very well over these longer periods of time,” said Eric Crombez, M.D., Chief Medical Officer of the Ultragenyx Gene Therapy development unit. “The recent data also reinforces the higher response rate seen with the Cohort 3 dose of 1x10^13 GC/kg. All three patients in Cohort 3 have responded to DTX301 and the treating physician of one of these patients reported that this is the best she has been health wise. This dose has been selected for the Phase 3 study, which is currently expected to initiate in the first half of 2021.”
Cohort 3 Updated Data: All three patients at 1x1013 GC/kg dose now confirmed responders
Patient 9 (newly confirmed responder, male):
Patient 9 showed a 188 percent increase in rate of ureagenesis, from 25 percent of normal at baseline to 73 percent of normal at Week 24. He now has shown two significantly increased ureagenesis measures and is confirmed as a responder. His ammonia levels have remained in the normal range since treatment. He has not yet discontinued alternate pathway medications or liberalized his diet.
Patient 8 (previously disclosed responder, female):
As previously disclosed, Patient 8 has experienced a significant and sustained reduction in her elevated baseline ammonia levels. This patient has now increased protein intake and has discontinued one of her two ammonia scavenger medications. She continues to do well clinically and the plan is to begin to taper her second alternate pathway medication once she is able to return to clinic post COVID-19 restrictions.
Patient 7 (previously disclosed complete responder, female):
As previously disclosed, Patient 7 demonstrated a meaningful change in rate of ureagenesis and has maintained normal ammonia levels since treatment. She continues to be clinically and metabolically stable after liberalizing diet and discontinuing ammonia scavenger medications.
Cohorts 1 and 2 Long-term Data Show Sustained Efficacy
The two complete responders in Cohorts 1 and 2 (Patients 1 and 4) have shown ongoing durable responses for 2 years and 1.5 years, respectively. Their ureagenesis rates remain above 100% of normal. Both patients have discontinued alternate pathway medications and liberalized restricted protein diets for more than one year, and remain stable with ammonia levels maintained in the normal range. They remain in excellent clinical condition with no significant adverse events, hospitalizations, or other events related to OTC deficiency. The third responder from the earlier cohorts (Patient 6) continues to do well, and is currently tapering her medications and liberalizing her diet. Her increase in ureagenesis and normalization of ammonia have been maintained.
As of the data cutoff date, there have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study. All adverse events have been Grade 1 or 2. As previously reported, six patients experienced mild, clinically asymptomatic elevations in ALT levels, similar to what has been observed in other programs using AAV-based gene therapy. All six of these patients have responded to reactive tapering courses of steroids, and all patients remain clinically stable.
Prophylactic Steroid Cohort Planned
A fourth cohort of three patients at the Cohort 3 dose (1.0 × 10^13 GC/kg) is planned, using prophylactic steroids. Dosing in this cohort is currently on hold due to the COVID-19 pandemic, but data are still expected in the second half of 2020, barring further delays related to clinical site closures due to COVID-19.
Phase 3 Study Planning Underway
Ultragenyx is currently planning the Phase 3 study of DTX301 in parallel to conducting the prophylactic steroid cohort. The Company intends to hold an end of Phase 2 meeting with the U.S. Food and Drug Administration (FDA) in the second half of 2020, based on data from the first three cohorts of the Phase 1/2 study. The use of prophylactic steroids in the Phase 3 study is anticipated, and will be confirmed by the Phase 1/2 fourth cohort data once available. For the Phase 3 study, ammonia is expected to be a primary endpoint based on direct FDA feedback to date. The Phase 3 study is currently expected to begin enrollment in the first half of 2021, barring any significant delays due to COVID-19.
Conference Call and Webcast Information
Ultragenyx will host a conference call on Friday, May 15, 2020, at 8:30 a.m. ET/ 5:30 a.m. PT during which Emil D. Kakkis, M.D., Ph.D., the company's Chief Executive Officer and President, will discuss the new data from the DTX301 and DTX401 studies presented at ASGCT. The live and replayed webcast of the call and slides will be available through the company’s website at http://ir.ultragenyx.com/events.cfm. To participate in the live call by phone, dial (855) 797-6910 (USA) or (262) 912-6260 (international) and enter the passcode 2366186. The replay of the call will be available for one year.