Review of Recent RNAi-Related Developments

The last 2 weeks have been busy ones in the lands of RNAi Therapeutics.  Here, I would therefore like to offer my take on the most important developments.

Alnylam’s Primary Hyperoxaluria Drug Breezes Through Clinic

With 20 subjects on Lumasiran, a GalNAc-RNAi targeting glycolate oxidase, for a median of 7 months, the investigational treatment for type I primary hyperoxaluria (PH1) ismore and more looking like a solid drug.  If the data presented last week at a Paediatric meeting in Turkey hold up in another 30 patients, it should fly through approval onto the market by the end of 2019.

While the relatively small numbers in each cohort has caused a bit statistical noise, it seemed like 3mg/kg monthly gives you an advantage over 1mg/kg monthly or 3mg/kg monthly in terms of the key biomarker urinary oxalate.  Interestingly, the company has chosen 3 times 3mg/kg monthly as the loading dose regimen in the now ongoing pivotal ILLUMINATE-A trial to be followed by dosing every 3 months. , the initiation of which the company has just announced.    

The core double-blind portion of the trial runs for only 6 months, so I am a bit puzzled how much the trial can inform on the value of the loading dose regimen and whether quarterly maintenance doses are sufficiently effective.   In any case, the trial design apparently was blessed by the FDA (incl. the urinary oxalate lowering primary endpoint), so surely they will know (e.g. based on preclinical animal data).

Regarding the competition with the primary hyperoxaluria drug candidate from Dicerna, the approximately 2/3 lowering of urinary oxalate and essentially all patients getting into a range considered safe and an unremarkable safety profile sets a high hurdle for the upcoming data presentation of DCR-PHXC at ASN later this month.

Arbutus HBV-RNAi Drug About to Die   

Yesterday, Arbutus provided an update on its LNP-enabled RNAi drug candidate for the treatment of chronic HBV (ARB-1467) and it does not bode well.  Similar to most other drug candidates attempted and barely tried, ARB-1467 should be canned in the not-too-distant future. 

In a combination study testing ARB-1467 in chronic HBV patients on nucleoside reverse transcriptase inhibitor tenofovir, probably only 1 in 6 patients hit a pre-defined criteria in terms of HBsAg lowering that would allow the patient to then receive immune booster PEG-Interferon.  The not very forthcoming revelation and the fact that the data was mentioned even after dropping another shoe that its small molecule HBV RNA destabilizer is also biting the dust makes it clear that not even the company sees much value in ARB-1467.

What an utter disaster this company has been since its inception as a HBV solutions entity.

Arrowhead Early HBV Deal Further Validates

Last week, shareholders in Arrowhead Pharmaceuticals got a lesson in biotech investing as it shares have given up ~1/3 of its value following a nice deal with Johnson&Johnson for the leading HBV knockdown asset in the space, ARO-HBV.

The deal gives Arrowhead a solid $250M in financing, including a $175M upfront fee and a $75M investment in company stock at a premium of ~50% to current trading.  While this avoids an imminent dilutive secondary share issuance- the company had been running low of cash- the ‘up to 15%’ in royalties from future sales of early phase II-stage ARO-HBV is clearly disappointing.  The relatively low royalty despite of it having confirmed strong HBsAg knockdown in patients can be explained with the fact that Arrowhead has avoided bearing the full risk of having to show proof-of-concept of HBV control.  This despite of having earlier paraded results obtained with an earlier DPC-based RNAi candidate (ARC-520) as strong evidence that RNAi can achieve such immune control.

While Arrowhead got punished for playing it safely, it can now focus on commercial home-run indications with highly validated targets and transition to being a broad platform company with a wholly owned attractive lead candidate in ARO-AAT.  Indeed, Arrowhead may emerge as the leading RNAi company as Alnylam, with a market cap ~8x that of Arrowhead, is still burdened by late-stage RNAi drugs with suboptimal specificity.

While humiliating, this serves Alnylam as a good reminder to also value innovation by the direct competition (note: specificity-enhancing technology now adopted by Alnylam has been available for a decade and could have been had for peanuts, e.g. from now defunct RNAi play mdRNA/Nastech).  Fittingly, today long-time archrival Silence Therapeutics issued a press release indicating that Alnylam is playing hard-ball with regard to Silence-owned IP purportedly covering ONPATTRO.

My guess is that Alnylam would rather risk an injunction and deprive patients of a very good medicine than to submit to what appear to me legitimate demands of a competitor.

Akcea’s antisense drug for TTR amyloidosis gets FDA nod

Last Friday, Akcea’s TTR drug TEGSEDI (licensed from Ionis) finally got FDA marketing approval for patients suffering from TTR-related polyneuropathy.  As expected from the delay in the approval process, TEGSEDI’s approval is accompanied by hefty black box warnings highlighting thrombocytopenia and renal risks of the (non-GalNAc) phosphorothioate oligonucleotide.  

Furthermore, the REMS program calls for frequent blood monitoring, essentially negating the claimed at-your-home convenience advantage over competing RNAi drug ONPATTRO.  Add to the poor safety profile clear efficacy disadvantages and pricing at parity with ONPATTRO, ONPATTRO should clearly win out in the marketplace.

Having said that, the TTR community is relatively small and key opinion leaders with relationships to a given drug company tend to support the drugs from the same company.

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.