Abstract: TH-PO449
PHYOX: A Safety and Tolerability Study of DCR-PHXC in Primary Hyperoxaluria Types 1 and 2
Session Information
- CKD: Clinical, Outcomes, Trials - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2102 CKD (Non-Dialysis): Clinical, Outcomes, and Trials
Authors
- Hoppe, Bernd, University Hospital Bonn, Bonn, Germany
- Cochat, Pierre, Université ClaudeBernard Lyon1-, Bron, France
- Lemoine, Sandrine, Edouard Herriot Hospital, Lyon, France
- Lipkin, Graham W., Queen Elizabeth Hospital, Bimingham, UK, Birmingham, United Kingdom
- Gentile, Amanda M., Dicerna Pharmaceuticals, Cambridge, Massachusetts, United States
- Brown, Bob D., Dicerna Pharmaceuticals, Cambridge, Massachusetts, United States
- Rosskamp, Ralf, Dicerna Pharmaceuticals, Cambridge, Massachusetts, United States
- Hulton, Sally, Birmingham Childrens'' Hospital, Birmingham, United Kingdom
- Groothoff, Jaap, Amsterdam UMC (Academic Medical Center), Amsterdam, Netherlands
- Baum, Michelle Amy, Boston Children Hospital, Wareham, Massachusetts, United States
Background
Primary Hyperoxaluria (PH) is characterized by hepatic overproduction of oxalate due to three distinct genetic mutations. DCR-PHXC is an investigational RNAi therapeutic targeting the LDHA enzyme, which is involved in the final step of hepatic oxalate production.
Methods
Preliminary data from the ongoing PHYOX study (ClinicalTrials.gov: NCT03392896), a two-part, single-ascending dose study conducted in 25 Healthy Volunteers (HVs, Group A) and 18 PH patients (Group B, reported here). Eligible PH patients have PH1 or PH2, urinary oxalate (Uox) ≥0.7mmol/24Hr, and eGFR ≥30 mL/min/1.73m2. Group B is open label and has three PH1 Cohorts dosed at 1.5, 3, and 6 mg/kg DCR-PHXC and a 4th PH1/PH2 cohort (1.5 and 3 mg/kg DCR-PHXC). The primary objective is safety. Change in 24Hr Uox from baseline (the mean of two screening 24Hr urine collections) was assessed.
Results
Safety Results: Group A is complete with no clinical meaningful safety signals and no serious adverse events (SAEs). Two mild injection site reactions (ISRs) occurred.
Group B: Fifteen adult and three adolescent participants have been dosed. Four SAEs have occurred in three participants. Two SAEs of reoccurring fever, both unrelated to study drug, occurred in one participant. An SAE of ureteral stone occurred in a different participant and was unrelated to study drug. A fourth SAE of appendicitis was reported in another patient, also unrelated to study drug. All four SAEs are resolved. Seven participants experienced mild or moderate ISRs and all resolved within 96 hours.
Efficacy Results: Group B: Preliminary results following a single administration of DCR-PHXC are captured in table 1. At 6mg/kg one participant experienced undetectable levels of Uox at Days 57 and 85.
Conclusion
Observed reduction of 24Hr Uox following a single administration of DCR-PHXC in both PH1 and PH2 participants is a promising sign of DCR-PHXC’s potential potency and duration of action.
Table 1
| Dose | N | Day 57 Reached | Max Reduction. Mean (range) | Max Reduction Time. Mean (range) | Near-normalization (> 0.46 and < 0.6 mmol/24Hr) N (%) | Normalization (< 0.46 mmol/24Hr) N (%) | Follow-up in Weeks. Mean (range) |
| 1.5 mg/kg | 6 (1 PH2) | 6 | 47 (28-59%) | 57 (Day 43 –85) | 2 (33.3) | 1 (16.7) | 10.8 (8.1-14.1) |
| 3.0 mg/kg | 8 (2 PH2) | 8 | 64 (22-80%) | 60.5 (Day 29 – 141) | 1 (12.5) | 5 (62.5) | Ongoing |
| 6.0 mg/kg | 4 (4 PH1) | 4 | 66 (35-100%) | 46.5 (Day 43 – 113) | 2 (50) | 1 (25) | Ongoing |
Funding
- Commercial Support – Dicerna Pharmaceuticals