Dicerna's stock sinks after its Alnylam rival shows mixed data, stymieing approval filing

After finding success with one RNAi candidate for a rare metabolic disorder that impacts the kidneys called primary hyperoxaluria 1, Dicerna Pharmaceuticals was hopeful that a second RNAi candidate would be able to tackle other types of PH. However, the company released mixed results from what was meant to be a pivotal study for nedosiran, sending its shares down some 13% when the markets opened today.

The phase 2 trial showed efficacy in one PH type but not another, meaning Dicerna will not be able to seek approval in PH2 for now. There are three forms of the disease, all of which are closely related and characterized by high urinary oxalate levels that cause frequent kidney stones and progression to end-stage renal disease. Dicerna designed nedosiran to silence a gene involved in what it believes to be the ultimate step in the oxalate production pathway, thereby enabling it to treat PH1, PH2 and PH3 with the drug.

The pivotal data raise significant doubts about the use of nedosiran in PH2. Across the mix of 34 PH1 and PH2 patients with at least one efficacy assessment, nedosiran drove a statistically significant drop in urinary oxalate. However, the overall result masks variation between PH1 and PH2 patients. 

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Urinary oxalate levels fell sharply in the cohort of 17 PH1 patients who received nedosiran, while the average rose in the 11 subjects on placebo. In the PH2 group, urinary oxalate levels rose slightly in the five patients who received nedosiran and fell in the one subject on placebo. Having seen strong effects in a PH2 mouse model, Dicerna was taken back by the results.  

“This was a surprise, and at this point we do not have a hypothesis that's not in the realm of rank speculation for what happened,” Dicerna CEO Douglas Fambrough, Ph.D., told investors on a conference call to go over the results. 

Dicerna has gone back and looked at data from another study, and “it does appear that those three patients are deriving benefit as shown by reductions in urinary oxalate levels sustained over time,” Fambrough said. Work is underway to assess whether something happening outside the liver is affecting the PH2 patients, but, for now, Dicerna is in the dark.

The impact on Dicerna’s go-to-market plans is clearer. Fambrough said the results don’t support including the PH2 indication in the NDA Dicerna plans to submit to the FDA in the fourth quarter. As it stands, Dicerna plans to focus on PH1 in the submission, although it may adjust its strategy based on the results of a PH3 trial that is due to read out early in the fourth quarter.

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Alnylam won FDA approval for Oxlumo in PH1 late last year, but that RNAi drug has a mechanism of action that isn't expected to work in PH2 or PH3. Dicerna, by targeting a later step common to all PH types, sought to secure a broader label. The failure to generate the data to support such broad use leaves Dicerna facing the prospect of going head-to-head with Alnylam for PH1 patients.