In an October 19 news release from biopharmaceutical company Dicerna Pharmaceuticals, Inc. (“Dicerna”), the company shared results from the Phase 1 PHYOX4 clinical trial. During the trial, researchers sought to understand the safety and tolerability of subcutaneously administered nedosiran for patients with primary hyperoxaluria (PH). Altogether, the entire PHYOX development program is seeking to understand how nedosiran could impact patients with PH. In this particular PHYOX4 clinical trial, however, researchers specifically explored nedosiran as compared to a placebo for patients with primary hyperoxaluria type 3 (PH3).
Nedosiran
So what exactly is nedosiran? According to Dicerna, nedosiran works to prevent hepatic lactate dehydrogenase (LDH) enzyme production. Normally, this enzyme helps convert glyoxylate to oxalate. Since oxalate is overproduced in patients with PH3, inhibiting the LDH enzyme can stop too much glyoxylate from turning into oxalate. The therapy, administered in a single subcutaneous dose, was created using Dicerna’s GalXC RNAi technology.
Within the Phase 1 PHYOX4 clinical trial, researchers compared nedosiran to a placebo in patients with PH3. Altogether, 6 patients enrolled. 4 patients (66%) received nedosiran while the remaining 2 patients (33%) received the placebo. To participate, patients with PH3 must have experienced at least one kidney stone within the past year. Researchers found that nedosiran reduced urinary oxalate, though the trial did not meet its overall efficacy endpoint. However, the treatment was found to be relatively safe and well-tolerated, with back pain occurring as the most common side effect.
Currently, Dicerna is looking to continue evaluating nedosiran for primary hyperoxaluria, and will submit a New Drug Application (NDA) for PH1 by the end of the year.
Primary Hyperoxaluria Type 3 (PH3)
Altogether, there are 3 types of primary hyperoxaluria (PH), a rare genetic disorder characterized by frequent and recurrent kidney and bladder stones. AGXT gene mutations cause primary hyperoxaluria type 1 (PH1), GRHPR mutations type 2 (PH2), and HOGA1 mutations type 3 (PH3). In each case, the mutations result in enzyme deficiencies and oxalate overproduction. As a result, oxalate accumulates, causing a number of health-related issues. Right now, therapeutic options for patients are extremely limited.
According to Myriad Genetics, PH3 is:
an inherited disease in which a lack of a particular liver enzyme causes the body to accumulate a substance called oxalate. Excess oxalate leads to a buildup of insoluble calcium salts in the kidneys, which may cause kidney stones and progressive kidney damage.
An estimated 10% of primary hyperoxaluria diagnoses are PH3. Unlike the other two forms, PH3 oxalate accumulation only occurs in the kidneys. An estimated 50% of patients develop kidney stones by age 5, although the amount of kidney stones sometimes falls in adulthood. Other symptoms include nephrocalcinosis and impaired kidney function. However, PH3 is often milder than the other forms.
