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.

Givosiran on Track for Accelerated Approval, but Anaphylaxis Event Rattles Investors

Alnylam last weekend provided an update on its early clinical experience with Givosiran in patients with acute intermittent porphyria (AIP), a severe ultra-orphan disease characterized by debilitating abdominal pain.  The results further demonstrate that the ALA 1 Synthase (ALAS1)-targeting GalNAc-siRNA conjugate has a profound impact on disease symptoms, an impact that, excitingly, appears to improve over time based on the open-label extension data.

Given the severe nature of the disease, with intermittent acute pain by some referred to as being ‘incompatible with life’ and chronic pain in between attacks, the attack rate results and their remarkable correlation with ALA/PBG biomarker changes point towards smooth sailing towards accelerated approval of Givosiran in early 2019.  Accordingly, the ongoing registrational ENVISION phase III study has now recruited its 30^th patient, setting up for a biomarker read-out in the second half of this year which would form the basis of an IND submission.

Despite the solid efficacy results, biomarker and attack rate reductions down about 10x and 4x, respectively, the EASL update wasn’t all positive.  To begin, increasing the dose to 5mg/kg did not support the sustained ~70% ALAS1 mRNA and ~90% ALA/PBG lowering seen with 2.5mg/kg monthly dosing when given quarterly.  Such sustained reduction in neurotoxic ALA/PBG appear necessary for Givosiran disease-modifying efficacy.  Since there is no real competition for Givosiran on the horizon, this is a minor issue that will likely be addressed by next-generation AIP compounds by Alnylam.

More important, however, was the revelation of the first case of GalNAc RNAi-triggered anaphylaxis in the open-label extension (OLE) part of the study.  Within hours of a subcutaneous injection, a patient suffered anaphylaxis which, fortunately, was not fatal, but sufficient for the patient to drop out of the study.  Of note, there was no evidence of pre-existing anti-drug antibodies and this patient had a history of allergy.

The overall implications of this adverse events for Alnylam and the RNAi industry remain to be seen.  This was the first case of anaphylaxis among close to 3000 subjects dosed across various GalNAc-RNAi trigger studies by Alnylam, Arrowhead, and Dicerna.  This includes the hundreds of subjects exposed to PCSK9-lowering Inclisiran.  

At worst, anaphylaxis is a rare, unpredictable event to GalNAc-RNAi triggers in general which would have most impact of using this technology for less severe, large non-orphan indications.  More likely, however, anaphylaxis is a risk of specific compounds in this class and only seen in patients with a pre-disposition to allergy as in this instance.  

Both Alnylam and Arrowhead traded down 5% on the news, likely reflecting investor caution in light of the new data.   With Alnylam now trading over 35% below its recent all-time high and strong Patisiran and Givosiran approvals on the near-term horizon, Alnylam has now become my number one position.  Any such sustained weakness in share price makes it vulnerable to a hostile takeover attempt in this hot biotech M&A environment.

Going into 2018, OligoRx Has Become Mainstream Drug Modality

When I became interested in drug development almost 2 decades ago, I just didn’t get it: why was it that gene-centric biotech was seen as an esoteric, money-losing endeavor, and why did shot-in-the-dark small molecule drug development represent the pharmaceutical elite?  After all, biology has fully moved into molecular gear and how could medicine not follow that?

After a quarter of a lifetime I now understand that what makes sense often takes a decade or two to manifest.  So if you are dead sure about your view of the world, stick to your conviction and resist the urge to follow the herd.

The gene-centric drug development revolution has occurred, long live Oligonucleotide Therapeutics

In 2018 though, gene-centric drug development has taken the pharmaceutical world by storm.  This just 8 years after gene therapy, RNAi, and oligonucleotides were widely ridiculed for having been hyped and supposedly failed.

Yes, in 2017, antisense drugs Spinraza (for spinal muscular atrophy) and Exondys 51 (for Duchenne muscular dystrophy) made a big commercial splash, RNA knockdown for TTR amyloidosis proved positive in 2 large phase III trials, all the while the first gene therapy products (2 CAR-T cell/gene therapies and 1 ocular gene therapy) got approved.

This momentum will only pick up speed on 2018.  The year is already starting with an onslaught of drug development VC investments prominently featuring mRNA and gene-modulation startups (e.g. $270M investment in personalized/mRNA oncology Co bioNTech, and ~$100M for gene processing plays ExpansionTherapeutics and Stoke Therapeutics).

 

Further down the pipeline, we should see approvals and commercializations for at least 3 important oligonucleotide therapeutics drugs: Patisiran (RNAi/Alnylam) and Inotersen (RNaseH antisense/Ionis) for TTR amyloidosis in addition to Volanesorsen (RNaseH antisense/Ionis-Akcea) for lowering triglycerides.  At the same time, Sarepta will continue to walk the tightrope with their first-generation PMO splice skippers for DMD hoping for approvals of additional exons.

RNAi drug Givosiran should also be speeding towards approval in 2018.  After a sweet and brief phase I/IIa study sponsor Alnylam is pursuing a laser-like direct-into-pivotal study/biomarker-based approval strategy.  Expect this to become quite commonplace rather than the exception, especially under the new FDA.

Adding gravitas to all these activities will be the further commercialization successes of Spinraza and Exondys51 that will break down pretty much all commercialization barriers that may have been put up by payors.  After all, these are all delay tactics intended to save the system a few billion dollars (at the cost of childrens’ lives mind you), get a few bureaucratic underlings promoted, but really won’t stand a chance against the desire of patients and their families to get access to such foundational drugs.

It is my belief that with the commercial successes of Spinraza and Exondys51, all previous reservations with regard to oligonucleotide therapeutics being mere scientific tools rather than real-world drugs have disappeared among pharma and investors.

RNAi Therapeutics Stock Thoughts for 2018

Moving on towards the investment end of the business, Alnylam will be a show-me stock which will have its ups and downs as the market will challenge Patisiran sales numbers against its $12B market cap.  Alnylam knows this and is throwing everything behind the commercialization of Patisiran to the extent that it renegotiated its platform deal with Sanofi to retain full global responsibility for commercializing Patisiran and follow-on ALN-TTRsc02.

The easiest RNAi money in my opinion will be made with Arrowhead Pharmaceuticals (~400M market cap) which has impressed me recently with the vengeance with which it is getting back into the clinic (IND equivalents filed recently for its HBV and AAT drugs) and between it and Amgen it could have brought half a dozen drug candidates to the IND stage within the span of just one year (from having zero in the clinic!).  Just by executing on bringing these drugs to the clinic, Arrowhead’s market cap should exceed those of genome editing high-fliers like Sangamo and Editas (~$1.5B).

The topping on the cake, however, will come from potentially first proof-of-concept biomarker data from their GalNAc programs by the end of the year.  And who knows what will happen to the stock if they can declare HBsAg seroclearance based on the legacy HBV program (ARC-520/1)!  And this is not all as we have yet to learn more about Arrowhead’s lung delivery platform which could be a very big franchise onto its own without much competition.

In terms of striving towards first proof-of-concept and critical biomarker data for its GalNAc RNAi platform, Dicerna is similar to Arrowhead.  The difference is that Dicerna’s goals are not as grandiose as those of Arrowhead (Arrowhead is built to become a $50-100B biotech juggernaut) focusing its resources on a few (ultra-)orphan indications which they are addressing with much care and detail.  At a market cap of $450M after the recent conversion of their convertible debt, the downside could be enormous should the lead program for primary hyperoxaluria stumble.  The upside, however, is also significant as they have their eyes set on 2 orphan drug approvals by 2023.

Critically for Arrowhead, Dicerna, and other companies in the space, given the positive news from Spinraza and Exondys51 sales and TTR trial results, the resistance of more conservative investors to invest in second-tier companies so they can grow into substantial multi-billion companies themselves should also be alleviated.

Finally, investors in Ionis Pharmaceuticals face a critical year.  No, this time it’s not about hitting clinical endpoints and how well their drugs are selling.  Instead, Ionis will have to decide its corporate future.  Run away if it makes the mistake of continuing to try and dominate every area of oligonucleotide therapeutics development.  It is this ambition and resulting lack of focus that is responsible for the company giving away much of the commercial upside of its drugs to its partners.

As the basic oligonucleotide chemical building blocks and designs are coming off patent and more and more disease-focused, nimble companies come online, this train has left the station.  Boy, this company is in dire need of fresh management blood from the outside world. 

The macroeconomic environment also bodes well for a blockbuster oligonucleotides stock year: low inflation and interest rates, good economic growth at low unemployment, lowered corporate taxes in the US and an FDA that seeks to speed up and protect innovation in exchange for ensuring that off-patent drugs are highly affordable.  It is probably this blue sky, however, that scares me most and it is my New Year’s resolution to take it easy on my margin balance for a change.

The Wait is Finally Over

For some time now, I’ve been fascinated by how the RNAi Therapeutics sentiment cycle has been progressing in 3-year intervals.  Before I left off for my baby-break, I referred to 2014-17 as The Wait. The Wait was a reference to the ‘market’ having been convinced by early clinical data that RNAi can bring about deep and sustained gene knockdowns in WoMan, but that the ultimate clinical utility and subsequent commercial value remained to be proven.

We are now on the cusp of finding out with results from the registrational phase III study of the TTR-lowering Patisiran in familial amyloidotic polyneuropathy (FAP) imminent.

The wind is clearly in RNAi’s back with supporting developments in the related oligonucleotide therapeutics and, indeed, drug regulatory spaces.  In particular, the successful commercial launches of splice modulators EXONDYS51 (for Duchenne muscular dystrophy) and SPINRAZA (for spinal muscular atrophy) and promising phase III data from the triglyceride-lowering Volanesorsen (gene target: ApoCIII) should have removed the long-held doubt that oligonucleotides can be clinical practice-changing and profitable drugs.  And boy, are EXONDYS51 and SPINRAZA changing the clinical practice of two devastating, previously orphan diseases!

Equally important, drug regulation is strongly moving infavor of patient choice and access.  As a result, we are going to see many more drug candidates benefiting from accelerated approval pathways similar to EXONDYS51.  A number of RNAi Therapeutics programs such as Givosiran by Alnylam (àmetabolite ALA lowering as reasonably predictive endpoint) and DCR-PHXC by Dicerna (àoxalate lowering) are poised to benefit from this development.

But let’s not get ahead of ourselves and await the Patisiran APOLLO study outcome for which sponsor Alnylam has guided a ‘late September/summer’ read-out.  Drug development is full of surprises, so despite all the data* pointing towards a positive outcome, a number of variables (e.g. steroid use, lipid nanoparticle delivery) remain unknown in how they impact overall outcomes.  I for one will breathe a big sigh of relief should Patisiran be able to overcome this Make-or-Break event for RNAi Therapeutics.

 *

à positive open-label extension data from phase II Patisiran;

à positive phase III data from IONS-TTRRx targeting same gene and indication;

à the high roll-over rate into the open-label extension) indicating a positive outcome