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.

HBsAg Rules at International Liver Congress

Now that the HBV world has gathered extensive clinical experience with interferons and polymerase inhibitors (NUCs) and with the resolve to finally find a cure for a serious disease afflicting hundreds of millions worldwide, the hepatitis B surface antigen (HBsAg) has become recognized as the key determinant for treatment outcome.  This is being confirmed by trial after trial investigating combining the actions of both NUCs and interferons, either one after the other or together at once.

Some of these studies were presented at the International Liver Congress last week in Vienna (ILC2015).  Emerging from them are actionable HBsAg rules which can predict fairly well whether a patient will eventually seroconvert to (or at least lose) HBsAg.  No matter the excitement around CRISPR technologies, HBsAg seroconversion remains the gold standard outcome in HBV treatment in the foreseeable future.

These rules can be divided into pre- and post-IFN treatment onset.

In the pre-IFN setting, it is those patients that have below ~500 IU/ml serum HBsAg as a result of NUC treatment that will most likely respond to interferon treatment/immune stimulation with s-antigen seroconversion (see earlier blog entry).  Since NUCs alone hardly do anything to promote s-antigen seroconversion despite its dramatic lowering of viral HBV titers, it appears to be their slow impact on HBsAg levels ( 0.1 log per year HBsAg reduction) that has the synergistic effect with interferon: with HBsAg lowering you take off the foot on the immune brake, with interferon you step on the immmune gas pedal.

As such, HBsAg knockdown by RNA(i) Therapeutics would seem to do the same for interferons as NUCs do, only in a more rapid and potent manner.  Of course, both could be used concurrently as a run-in to IFN treatment.

However, once on IFNs (post-IFN onset), it is the relative HBsAg decline that has high positive predictive value in prognosticating who will seroconvert.  Of note, the HBsAg decline comes before any adaptive immunity can be detected.  This supports that HBsAg decline in itself contributes to seroconversion rather than it being a mere correlation.  In that setting, it is a 1 log decline in HBsAg the first few weeks after IFN treatment onset that separates the winners from the losers. 

It is uncertain to me, however, whether 1 log is a precondition to s-antigen seroconversion as the non-responders do not even come close to that (maybe 0.3log).  It is therefore possible that anything that pushes HBsAg below say -0.3-0.5log could have a dramatic effect on s-antigen seroconversion rates.

An RNAi Therapeutic for HBV used simultaneously with IFNs may therefore aim at helping IFNs to get to the  0.5-1log reduction threshold, and rapidly at that.

Ergo, there are now a number of obvious strategies that one can apply regarding the use of RNAi Therapeutics in HBV with various knockdown goals, both absolute and relative.  The exact strategy would depend on how the RNA agent is combined with polymerase inhibition/NUCs or immune stimulation. 

While a number of other HBV targets were reported at the conference such as core assembly and entry inhibitors, HBsAg (and HBV mRNA knockdown in general) lowering remains the most distinguished and the mechanism predicted to be most synergistic to existing treatment approaches.  As combination treatment is strongly predicted to be the future of HBV, HBsAg lowering should become a pillar of those treatment regimes.

Disclosure: long ARWR, looking for lower entry in TKMR.