Kidney Week

Abstract: TH-PO1167

PHYOX: A Safety and Tolerability Study of DCR-PHXC in Primary Hyperoxaluria Types 1 and 2

Session Information

• Late-Breaking Clinical Trials Posters
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• No subcategory defined

Authors

• Hoppe, Bernd, University Hospital Bonn, Bonn, Germany

Bernd Hoppe,

• Cochat, Pierre, Université ClaudeBernard Lyon1-, Bron, France

Pierre Cochat,

• Lipkin, Graham, Queen Elizabeth Hospital, Birmingham, United Kingdom

Graham Lipkin,

• Gentile, Amanda M., Dicerna Pharmaceuticals, Cambridge, Massachusetts, United States

Amanda M. Gentile,

• Brown, Bob D., Dicerna Pharmaceuticals, Cambridge, Massachusetts, United States

Bob D. Brown,

• Rosskamp, Ralf, Dicerna Pharmaceuticals, Cambridge, Massachusetts, United States

Ralf Rosskamp,

• Hulton, Sally, Birmingham Children's Hospital, Birmingham, United Kingdom

Sally Hulton,

• Groothoff, Jaap Willem, Emma Children's Hospital AMC, Amsterdam, Netherlands

Jaap Willem Groothoff,

• Baum, Michelle Amy, Boston Children's Hospital , Boston, Massachusetts, United States

Michelle Amy Baum,

Background

Primary Hyperoxaluria (PH) is a family of rare diseases characterized by hepatic overproduction of oxalate due to 3 distinct genetic mutations. Clinical manifestations include nephrocalcinosis, recurrent kidney stones, progressive renal impairment, and systemic oxalosis (primarily PH1). DCR-PHXC is an investigational RNAi therapeutic targeting LDHA enzyme, which is involved in the ultimate step of hepatic oxalate production and has the potential to treat all 3 known genetic forms of PH.

Methods

This abstract includes preliminary data from the ongoing PHYOX study (ClinicalTrials.gov: NCT03392896), a two-part, single-ascending dose study conducted in 25 normal healthy volunteers (NHVs, Group A) and 16 PH patients (Group B). Eligible PH patients have PH1 or PH2, urinary oxalate (Uox) ≥0.7 mmol/24Hr, and eGFR ≥30 mL/min/1.73m². Group A is randomized including placebo with 5 cohorts dosed at 0.3, 1.5, 3, 6, and 12 mg/kg DCR-PHXC or placebo. Group B is open label and has 3 PH1 Cohorts dosed at 1.5, 3, and 6 mg/kg DCR-PHXC and a 4^th PH2-only cohort. The primary objective is safety and secondary endpoints include change in 24Hr Uox from baseline defined as the mean of two 24Hr urine collections during screening.

Results

Group A is complete with no observed safety or tolerability issues and no serious adverse events (SAEs). Two mild injection site reactions (ISRs) occurred and resolved within 48Hrs. Dosing is complete in Group B Cohorts 1 (1.5 mg/kg, n=4) and 2 (3.0 mg/kg, n=4) and in the Cohort 4 sentinel PH2 subject (1.5 mg/kg). To date, only adults have been dosed. No SAEs have occurred in Group B. Two mild ISRs resolved within 48Hrs. Preliminary results following a single administration of 1.5 mg/kg DCR-PHXC in Cohorts 1 and 4 shows maximum 24Hr Uox reductions from baseline between 39%-57% between postdose Days 43 and 95. Cohort 2 has shown 40-62% reductions in Uox between Days 15 and 43 and 2/4 patients have 24Hr Uox values in the normal range. Follow-up in all Cohorts is ongoing.

Conclusion

Preliminary PHYOX data show DCR-PHXC is safe and well-tolerated in this ongoing study. Observed reduction of 24Hr Uox following a single administration of DCR-PHXC in both PH1 and PH2 patients is a promising sign of DCR-PHXC’s potential potency and duration of action.

Funding

• Commercial Support – Dicerna Pharmaceuticals