RNAi Digest - August 2020

RNAi Digest - August 2020

Dicerna announced positive Phase 3 (PHYOX3) multidose open-label extension trial interim analysis data for nedosiran for primary hyperoxaluria (PH)

06 Aug 2020

Nedosiran (siRNA targeting LDHA) – PHYOX3 Phase 3 data:

  • Efficacy: 11 patients (8 PH1 and 3 PH2 reached by day 120 receiving once-monthly nedosiran 9/11 (82%) had achieved normal or near-normal urinary oxalate (Uox) levels, defined as below 0.46 mmol/1.73 m2 body surface area adjusted (BSA)/24 hr (laboratory assay upper limit of normal [ULN]) and from 0.46 to 0.6 mmol/1.73 m2 BSA/24 hr (1.3xULN, defined per protocol as near-normal), respectively
  • Safety: No drug-related severe adverse events; 3 injection-site reactions and 1 serious AE that was unrelated to Nedosiran); AE profile comparable to that of PHYOX1 (Phase 1)
  • Based on the cumulative number of days, total patient exposure to monthly dosing of nedosiran delivered subcutaneously has reached 5.8 years

Dicerna reported Phase 3 positive results for ultra-rare disease primary hyperoxaluria

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CI Scientists Remarks: 

  • Dicerna has created a first-in-class molecule Nedosiran (silencing lactate dehydrogenase A (LDHA)) to treat PH1 (AGXT gene mutation), PH2 (GRHPR gene mutation) and PH3 (HOGA1 gene mutation)
  • Nedosiran has been granted orphan drug designation for PH (2018), breakthrough therapy for PH1 (2019), rare pediatric disease designation for PH (2020) by FDA; Is in discussion for a potential expansion of the Breakthrough Therapy Designation to include PH2
  • With PHYOX3 showing positive signals, Dicerna is one step closer to NDA submission of Nedosiran for the treatment of PH1 and PH2
  • Results from patients with PH1 are very encouraging, but only 1/3 patients with PH2 achieved normalization at day 120
  • Due to COVID-19, Dicerna changed its guidance of enrollment completion for its registrational PHYOX2 trial (for PH1 and PH2) from Q2 to Q4 2020; Any further delays will be detrimental to trial enrolment because Alnylam’s Lumasiran’s (PH1) PDUFA date is scheduled for Dec 3, 2020
  • To support its submission package of PHYOX2 and PHYXO3, Dicerna has planned additional supportive studies:
    • PHYOX4: In patients with PH3; Enrollment initiation expected in Q3 2020
    • PHYOX7: In patients with PH1, PH2; Enrollment initiation expected in Q4 2020
    • PHYOX8: In patients with PH1, PH2; Enrollment initiation expected in Q1 2021
    • PHYOXOBX: In patients with PH3; Study initiation expected in Q3 2020
  • An NDA in US by Q3’21 and subsequent filings are expected in Europe and then Japan; Nedosiran market approval is expected in 2022

– Tarun Raisinghani, CI Scientists

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