CAMBRIDGE, Mass.—Dicerna Pharmaceuticals, Inc., a leading developer of ribonucleic acid interference (RNAi) therapies, announced today that the U.S. Food and Drug Administration (FDA) has granted a Breakthrough Therapy designation (BTD) to DCR-PHXC for the treatment of patients with primary hyperoxaluria type 1 (PH1).
Primary hyperoxaluria (PH) is a family of severe, rare, genetic liver disorders characterized by overproduction of oxalate. In patients with PH, the kidneys are unable to eliminate the large amount of oxalate that is produced. The accumulation of oxalate can result in severe damage to the kidneys and other organs.
There are three known genetic types of PH, each of which results from a mutation in a specific gene. In each type, the mutation decreases the activity of an enzyme in the liver, leading to an increase in the production of oxalate. PH1 is caused by a mutation in the AGXT gene. This causes a deficiency of the enzyme alanine:glyoxylate-aminotransferase.
Dicerna’s DCR-PHXC is reportedly the only RNAi investigational drug in development for the treatment of all types of primary hyperoxaluria, and the most advanced product candidate utilizing Dicerna’s GalXC technology. In animal models of PH, DCR-PHXC selectively silences lactate dehydrogenase A enzyme, or LDHA, in the liver, blocking the excess production of oxalate.
In preclinical studies DCR-PHXC was well tolerated, with no adverse effects in the liver. LDHA deficiency in the liver may be beneficial for patients with PH, as the LDHA enzyme is implicated in the abnormal production of oxalate in PH, which in turn is responsible for the severe damage to kidneys and other organs. Studies have shown that people who are completely deficient in LDHA show no liver dysfunction and can lead normal lives.
In its communication to Dicerna, the FDA also conveyed its determination that PH type 2 (PH2) and PH type 3 (PH3) meet the criteria for a serious or life-threatening disease or condition, based on the agency’s standards. Dicerna will continue its ongoing dialogue with the FDA regarding endpoints for studies of DCR-PHXC in patients with PH2 and PH3, as part of the PHYOX clinical development program.
Interim results from the ongoing PHYOX1 Phase 1 study have demonstrated normalization or near-normalization of urinary oxalate levels in a majority of participants receiving DCR-PHXC, as well as a favorable tolerability profile. Dicerna recently presented updated data from the PHYOX1 clinical trial, which reported substantial post-dose reductions in 24-hour urinary oxalate levels in adult and adolescent study participants with PH1 and PH2. The updated PHYOX1 data, presented at the Oxalosis and Hyperoxaluria Foundation’s International Workshop on June 22, also showed that a single dose of DCR-PHXC led to normalization or near-normalization of urinary oxalate levels in a majority of patients and was generally well-tolerated.
“By granting Breakthrough Therapy Designation, the FDA recognizes both the urgent need to develop a therapy for primary hyperoxaluria type 1 and the encouraging preliminary data from the PHYOX1 clinical trial of DCR-PHXC in these patients,” said Ralf Rosskamp, M.D., Dicerna’s chief medical officer. “We look forward to continuing our dialogue with the FDA as we advance DCR-PHXC as quickly as possible as a potential therapeutic option for all persons living with primary hyperoxaluria.”