Clinical Trial Application Filed for Potential Primary Hyperoxaluria Treatment

Mathew Shanley

The first clinical trial application (CTA) has been submitted by Dicerna Pharmaceuticals, Inc. to the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom for the potential initiation of a Phase 1 study of DCR-PHXC.

DCR-PHXC is the company’s most advanced GalXC product candidate for the potential treatment of primary hyperoxaluria (PH). Assuming the CTA is authorized by the MHRA and local ethics committees, Dicerna will aim to start its Phase 1 clinical study in up to 25 healthy volunteers and up to 16 patients with PH types 1 and 2 at trial sites in the UK.

PH is a group of rare, genetic liver disorders characterized by the overproduction and buildup of oxalate, often resulting in complete liver failure. In healthy persons, oxalate is filtered through the kidneys and excreted through the urine, while in patients with PH, the accumulation deposits into the urinary tract and groups together with calcium to form kidney and bladder stones.

PH type 1 is caused by a mutation in the AGXT gene, resulting in a deficiency of the enzyme alanine:glyoxylate-aminotransferase (AGT). PH type 2 is the byproduct of a mutation in the GRHPR gene, which leads to a deficiency of the enzyme glyoxylate/hydroxypyruvate reductase (GR/HPR). Current treatment options for the condition include both liver and kidney transplants, followed by the lifelong intake of immunosuppressant drugs.

“The filing of this CTA marks an important milestone for Dicerna, for our GalXC technology platform, and most importantly, for our pipeline of GalXC product candidates,” said Douglas Fambrough, Ph.D., president and chief executive officer of Dicerna in a press release. “Specifically, the filing signals our readiness to begin GalXC-based clinical efforts as we further investigate a needed pharmaceutical treatment option for patients with PH, a family of severe disorders with a high unmet medical need. I want to thank the many Dicerna employees, external collaborators and the primary hyperoxaluria community, who have been instrumental in advancing our GalXC-based program for PH to this point. Pending CTA approval, we look forward to dosing the first person with DCR-PHXC and moving this program through clinical trials. We expect to present initial data from our Phase 1 proof-of-concept study in 2018.”

The anticipated Phase 1 trial will be a randomized, single-blind, placebo-controlled, single-ascending dose study with the primary objective of evaluating the safety and tolerability of single doses of DCR-PHXC, which is intended to target the lactate dehydrogenase A (LDHA) gene, which is a potentially optimal therapeutic target in patients with PH.

Participants being enrolled into the study will be divided into as many as 5 sequential cohorts of increasing doses. Secondary endpoints include the pharmacokinetics of DCR-PHXC and its pharmacodynamics effects on oxalate biomarkers in plasma and urine.

“Based on pre-clinical data, LDHA has the potential to be an ideal therapeutic target in patients with PH and we hope to replicate the inhibitory effect on oxalate production in human clinical studies,” said Ralf Rosskamp, M.D., chief medical officer of Dicerna Pharmaceuticals. “Our research findings to date, along with the findings from our PHYOS observational study, have been instrumental in our understanding of PH and informing our clinical development plan. Preclinical studies have shown that DCR-PHXC results in the potent, durable, and consistent knockdown of LDHA and reduces oxalate in multiple animal models of PH. We are committed to investigating a treatment option for patients with all forms of PH and are excited to begin the Phase 1 trial.”

Craig B. Langman, M.D., The Isaac A Abt MD Professor of Kidney Diseases at the Feinberg School of Medicine at Northwestern University commented: “With this CTA filing, and the expected initiation of a first-in-human, proof-of-concept Phase 1 trial of DCR-PHXC once the MHRA authorizes the CTA, Dicerna is pursuing an exciting and important approach that may address a high unmet medical need in primary hyperoxaluria. Given the lack of curative treatment options for individuals with this devastating family of diseases, a medication that suppressed oxalate production would be a welcome therapeutic solution for these patients.”

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