Alnylam's Primary Hyperoxaluria RNAi Drug Clears Patient Hurdle

Alnylam today provided an update on its clinical program of Lumasiran for primary hyperoxaluria (PH), an ultra-rare disease of organ damage and failure due to elevated levels oxalate (here for OxalEurope presentation slides).

The new data include safety and efficacy from all three studied dose cohorts (1 and 3mg/kg monthly, 3mg/kg quarterly) and involved early-stage PH type 1 (PH1) patients without end-stage renal disease and systemic oxalosis.  Accordingly, RNAi knockdown of the target glycolate oxidase (GO) enzyme reduced (urinary) oxalate by ~2/3.

Importantly, this was uniformly achieved across all dosing cohorts, perhaps with somewhat less inter-patient variability for the 3mg/kg cohorts.  Accordingly, oxalate levels were reduced in all patients below a threshold where natural history studies point to an almost complete protection from progression to ESRD. 

Of note, despite the caution that RNAi competitor Dicerna Pharmaceuticals had voiced that GO as a target might be prone to a rebound effect- based on the preclinical observations that oxalate reductions only kick in after profound, ~85% GO gene knockdown is achieved- the new data provide no evidence for this.  Instead, quarterly dosing with 3mg/kg was as good as with monthly dosing of the same dose, consistent with the sustained target-gene knockdown profiles seen with most current GalNAc-RNAi candidates.

The safety profile was unremarkable for a disease like this.  The only obvious drug-related side effect were transient injection site reactions in 2 out of the 9 patients receiving the investigational agent.

With these data in hand, Alnylam is about to embark on a registrational study of Lumasiran in ~25 PH1 patients.  This study will further include younger patients and those with more advanced disease than in the present study.  Given the similarity of the oxalate knockdowns across the cohorts, it is difficult to predict what the dose and dosing schedule will be, but testing both 1mg/kg and 3mg/kg quarterly could be a good idea.

Dicerna competition

Lumasiran is not the only gene knockdown agent in the clinic.  Its closest competitor, ~1.5 years behind based on the May 30 announcement that the 1^st PH patient has now been dosed, is Dicerna Pharmaceuticals’ DCR-PHXC.  DCR-PHXC is differentiated from Lumasiran in that it targets LDHA instead of GO1 and is expected to have a more linear target gene knockdown-oxalate knockdown relationship.  

It is also applicable beyond the PH1 patient population, i.e. also for the less severe (and much less commonly diagnosed) PH2 and PH3 forms of primary hyperoxaluria.

Lumasiran has thus now set a high bar for the commercially currently most valuable patient population.  It will be thus be important for Dicerna to improve diagnosis rates of PH2 and 3 as it intends to embark on a pivotal study in 2019.