Monday, September 10, 2018

Second-Tier RNAi Therapeutics Companies Starting to Deliver Clinically


Alnylam has had a 3 year head-start on the competition with GalNAc RNAi Therapeutics, but now additional companies are populating the field with actual clinical data.  While the knockdowns appear robust and the chemistries well tolerated, therapeutic utility and the potential of liver toxicity from off-targeting will have to be demonstrated in upcoming longer-term studies.

Dicerna clinically validates new target for primary hyperoxaluria

Dicerna used to be the leader in applying RNAi Therapeutics to primary hyperoxaluria (PH), an orphan genetic condition caused by dangerously high levels of oxalate in the blood.  Oxalate crystallization and deposition may then poison first the kidneys and then various organs leading to premature death.  Unfortunately, as its old LNP technology proved to be impractical, Alnylam's directly competing program targeting glycolate oxidase (GO) assumed the lead.

When Dicerna then came up with a GalNAc-based follow-up candidate (DCR-PHXC), it also chose a new target: hepatic lactate dehydrogenase (LDHA), a target which may have be applicable also for forms of PH beyond the most frequently diagnosed PH1 and for which GO is a suitable target.  Cynics may suspect that the new target was not chosen because it is the better one, but in an effort to provide differentiation over more advanced competition.  To wit, first-mover advantage can be significant in the orphan drug arena.

Perhaps due to its long-standing, deep relationship with the PH community, Dicerna has been able to recruit patients more quickly than I had suspected (in light of Alnylam's parallel recruitment efforts) in its first-in-patient study.  First data from this study (PHYOX) were revealed last week.  To their relief, LDHA knockdown resulted in oxalate lowering in all 9 subjects (8 PH1, 1 PH2) tested.

Following a single-dose of either 1.5mg/kg or 3.0mg/kg, at least 30% reductions in urinary oxalate were seen and all or almost all subjects got to urinary oxalate levels at or below 1.1mmol/24hrs/1.73m2, a level predictive of end-stage-renal-disease freedom.

More detailed data will be presented later this year where we will get a better sense in how the results stack up with those of Alnylam.  Earlier this summer, Alnylam reported 64% mean urinary oxalate reductions relative to baseline before following more than one dose.  Another area of concern is that it appears that 3 out of the 9 injections resulted in injection site reactions (ISR).  To see ISRs is not surprising per se, but the frequency appears to be on the high end based on early experience and could be a competitive disadvantage.  Similarly, no word was said about liver enzymes.

Given that Dicerna has been rushing the PHYOX trial without so much as testing multi-dose regimens, I expect the regulatory agencies to demand at least 2 dosing schemes in the upcoming pivotal trials.  A nightmare scenario would see Dicerna being sent back to phase II to test the safety of multi-dosing, a fate that Regulus Therapeutics had suffered before in Europe.

Disclosure: Over the last few months, I have been largely playing the volatility of DRNA- both on the long and short side.  Looking ahead to the end of the year, I would be hesitant of taking a substantial long position due to a market cap approaching $1B with the potential of negative surprises both on safety and efficacy when more detailed PHYOX data will be presented.  On the other hand, a deal (such as on the IND-ready mystery candidate) could provide a catalyst to the upside at least in the short-term.

Arrowhead sees best HBsAg knockdowns so far with new GalNAc candidate

When similar to Dicerna Arrowhead had to retool its lead programs with the GalNAc technology, one question was whether they could achieve knockdowns as potent as with DPC delivery which employed explicit cell penetrating chemistries.  It was therefore cause for celebration when the company reported -2log HBV surface antigen (HBsAg) knockdowns at the World Gastroenterologists Summit, better than with ARC520 and ARC521 before (slides here).  Also, the knockdown was observed regardless of e-antigen status, but that was to be expected with the new sequence design.

Intriguingly, following 3 monthly injections, the knockdown curves still kept coming down, making it almost look like HBV can be beaten into submission by the knockdown effect alone and without the help of an immune boosting effect.

Unfortunately, only HBsAg results from the 100mg and 200mg monthly dosing cohorts were disclosed even though the company had dosed 9 other dosing and patient cohorts.  Based on cohorts 8-11, it appears that best results may in fact have been obtained with the 300mg monthly regimen which will probably be disclosed in the run-up to this year’s AASLD meeting.

Similar to Alnylam in 2014, after showing impressive RNAi target knockdowns in the clinic, the wait is now on to show that the knockdowns will translate into therapeutic benefits.  Given the speed of the company’s execution in general, I would expect pertinent data to emerge from the HBV program in late 2019/early 2020.

Disclosure: similar to Dicerna, I have been recently playing the volatility of ARWR stock, getting long as it had been consolidating around the $14 level, then selling and going short into last week’s 50% spike to a $2B market cap.  With the puts I then sold ($21 and $20 September strikes), I have a ~10% cushion should the stock zoom past $21 by the September options expiration and my max gain is ~13%.  This is intended as a short-term trade


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By Dirk Haussecker. All rights reserved.

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