Another Second-Generation GalNAc-RNAi Rocked by Off-Target Concerns

With the approval of ONPATTRO and the current overall clinical picture, in particular the highly encouraging safety profile seen with PCSK9-targeting Inclisiran in well over a 1000 subjects (à The Medicines Company and Alnylam), the RNAi mechanism can be considered a clinically validated  new drug modality. 

Liver enzyme elevations, however, have been seen across a few clinical programs.  This includes ALN-AAT for alpha-1 antitrypsin-related liver disease, ALN-AT3 for hemophilia, and now also Givosiran (ALN-AS1).  The most likelyreason for these observations is that the minimization of off-targeting had been neglected for these ‘2^nd-generation GalNAc-RNAi triggers’, thereby raising the risk that the relatively high off-target noise (dozens of off-targets) can be detrimental to target cell health. 

To wit, the spectrum of off-target genes varies tremendously from RNAi trigger sequence to RNAi trigger sequence and affects biologically unrelated genes.  This makes it very hard to predict whether the off-target noise will have adverse effects or will be just irrelevant noise to the cell.  Not helping is the fact that lab animals due to their genome sequence differences cannot model the safety around off-targeting.  The hope is that perhaps organ explants or mice with humanized organs (e.g. humanized mouse livers) will be better predictors since the target cell is almost the same as in the clinical setting.

Marked liver enzyme elevation in Givosiran pivotal trial

This week, Alnylam provided an interim read-out from the ENVISION trial, the registrational study with GalNAc-siRNA Givosiran for acute hepatic porphyria (AHP).  AHP is a rare disease caused by defects in heme synthesis.  This results in the accumulation of toxic intermediates such as PBG and ALA which can cause a range of symptoms, including severe pain attacks.

The study envisioned an interim biomarker read-out in a first cohort of patients that had been treated for at least 3 months with study drug.  It had been agreed before with the FDA that if lowering of ALA could be found in this read-out, it might form the basis for an accelerated approval.

Unsurprisingly, urinary ALA levels were reported to be statistically significantly lower in patients treated with Givosiran compared to placebo- in-line with the phase I/II experience (p<0 .001="" span="" style="mso-spacerun: yes;"> 

Unfortunately, there were numerically more than twice as many Givosiran-treated sujects (5/23) that experienced a serious adverse event (SAE) than in the placebo group (2/20).  One of the Givosiran-treated subjects had to discontinue treatment due to liver enzyme levels above the pre-specified threshold (>8x upper limit of normal).  While no liver enzyme elevations had been reported in a similar number of patients in the earlier-stage studies, I wished the company could have talked more about the presence of other liver enzyme increases of less than 8x ULN to get a better sense of the magnitude of the problem and whether such incidence would be compatible with giving the drugs in a chronic fashion.

Having said that, with 5 SAEs in 23 subjects treated a little more than 3 months on average (on top of a case of drug-related anaphylaxis in the phase I/II open-label extension study), SAEs that might be drug-related, would already seem to invalidate Givosiran being used in those with the same genetic condition, but not necessarily with recurrent pain attacks.  This would have tremendously extended the market opportunity of Givosiran.   

In the same vein, with the present safety questions, an accelerated approval that would shave off a few months before the full dataset will be available in early 2019, can now be ruled out with high certainty.

To add insult to injury, Akcea reported earlier this week that a GalNAc-version of the competitive RNaseH antisense technology did not suffer from thrombocytopenia as unconjugated ASOs typically do, thus putting ASOs back in the race for liver targets.  Still, in the long-term and in particular with the more specific new GalNAc-RNAi trigger chemistries, RNAi should win for most liver targets, but for some targets where either RNAi has inherent difficulties achieving high potencies or in cases where off-targeting toxicity still strikes (albeit at a much lower rate), RNaseH ASOs may emerge victorious.

Disclosure: long ALNY, but have taken some off the table following these data and questions around cardiac issues with ONPATTRO; it is important now for Inclisiran to re-instill confidence in the safety of RNAi Therapeutics; short AKCA as I do not believe that their current TTR and triglyceride-lowering drugs TEGSEDI and WAYLIVRA, respectively, can be commercially successful drugs and its artificially bloated market cap is a result of the low float and short interest in this stock and not a reflection of the value that the market sees in Akcea.

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