Hereditary Angioedema: A High-Value RNA Therapeutics Target Confirmed by Antibody Trial

This week, Dyax released early, but arguably impressive data from a phase Ib trial of monoclonal antibody DX-2930 for the prophylaxis of Hereditary Angioedema (HAE), a rare disease (incidence of 1 in 10-50k births) with a rapidly evolving and growing market.  The results confirm that plasma kallikrein and, by extension, its precursor prekallikrein (PKK), are highly effective and safe targets for the treatment of HAE.

Due to the expression of kallikrein and other pathway components in the liver, HAE therefore shapes up as yet another high-value indication after PCSK9/cardiovascular disease and CC5/complement disorders PNH and aHUS (à Soliris) where RNA Therapeutics will be directly pitted against monoclonal antibodies to answer the following pharmasophical question: 

What would you prefer? Turn off the gene underlying a disease with a defined, synthetic molecule harnessing an endogenous biological mechanism, or mop up the disease-mediating gene product (protein) with a gemisch of cell-derived proteins?

You may know my preference already, and indeed, a phase I study of ISIS-PKKRx by Isis Pharmaceuticals targeting PKK has just been completed and showed a 80-90% gene knockdown at 300-400mg weekly subcutaneous injections.

Disease pathway: promoters and inhibitors

HAE is caused by the genetic absence or insufficient activity of C1 esterase inhibitor (C1-INH).  This predisposes to regular, often weekly to monthly episodes of tissue swelling which when abdominal can cause severe pain and when affecting the throat is life-threatening.

Although C1-INH is involved in a few intersecting pathways such as coagulation and complement, the results by Dyax confirm the growing evidence that in the end it is all about plasma kallikrein and subsequent vasoactive bradykinin generation.  The preclinical evidence includes an elegant study by Isis Pharmaceuticals (Bhattacharjee et al 2013) where the power of RNA Therapeutics was harnessed to knockdown a number of players in the coagulation and kinin-kallikrein pathways to show that only inhibition of members of the kinin-kallikrein pathway (e.g. PKK and factor 12) could reverse the symptoms caused by C1-INH deficiency.

Importantly, human genetics show that PKK deficiency is without apparent medical adverse consequence, thus making it a drug developer’s dream.

Therefore, although HAE is caused by a protein deficiency, a therapeutic knockdown approach is conceivable due to the presence of promoters and inhibitors in the pathway of disease. This is thus similar to antithrombin and hemophilia for which Alnylam is currently advancing a promising RNAi Therapeutics clinical candidate (ALN-AT3).

Poor pharmacokinetics of approved drugs leaves large unmet need

There are a handful of drugs approved for HAE.  Most of these are approved only for the mitigation of an acute HAE attack.  They have shown modest efficacy with kallikrein inhibitor Ecallantide/KALBITOR (a small protein by Dyax) and C1-INH protein replacement therapeutic CINRYZE (by Shire) approximately halving the severity of an attack or attack frequency, respectively. 

In addition to some potentially severe side effects like anaphylaxis (KALBITOR) and infusion reactions (CINRYZE), it is the poor pharmacokinetics necessitating frequent administration that render them impractical for prophylactic use.

For example, CINRYZE, the only agent approved for prophylactic use, has to be intravenously infused twice a week (and some investors/companies moan when Tekmira's RNAi LNP products have to be infused every 3-4 weeks), and still attack rates were reduced by only about a half.  This supports that despite frequent i.v. infusions, C1-INH levels cannot be kept above the needed threshold for long enough.

Given that once set in motion, the swelling cascade is probably difficult to stop cold, it is, however, chronic prophyxis that has the prospect of bringing most benefit to patients, in addition to filling the coffers of biotech companies and their investors (prophylactic CINRYZE: $300k per year).

DX2930 shaping up to be first satisfactory treatment

In light of the above, it is apparent that new drugs for HAE should have both increased potency and be sufficiently convenient for chronic prophylactic use.  In terms of dosing frequency, this means at a minimum once-a-quarter intravenous infusions, weekly subcutaneous injections, or daily oral pills.

As a subcutaneously administered antibody, DX-2930, of course, almost naturally satisfies the dosing frequency requirement.  Moreover, when 2 doses were given 14 days apart, the attack frequency for the 300 and 400mg cohorts dropped by ~10x from baseline during the time when plasma concentrations of the antibody were deemed above the threshold needed to keep the kinin-kallikrein pathway in check (~6 weeks after 2^nd dose).  13/15 patients (87%) were thus attack free from days 8-50 compared to only 3/11 (27%) in the placebo group.

Attack frequencies for the 30mg and 100mg cohorts were not reported.  This probably means that these were not successful and support the notion that whether an attack can occur or not is a rather sharp threshold effect.  Also consistent with this was the fact that the 300mg cohort numerically performed better than the 400mg cohort in this small sample size. 

[correction] Attack frequencies for the 30 and 100mg cohorts were also dramatically reduced from days 8-50 although these doses had been predicted by Dyax to yield suboptimal plasma antibody levels, possibly raising questions about the patient population chosen.

Nevertheless, DX-2930 appears overall very promising and has further validated kallikrein/PKK as targets, but larger patient numbers are required to determine the more precise efficacy benefit over existing drugs, the dose response relationshipo, and, of course, safety.

RNA Therapeutics closing in

In addition to 2^nd generation RNaseH antisense compound ISIS-PKKRx, I expect a number of additional RNA Therapeutics candidates to join the HAE fray due to the attractive economics of the market and the anticipated high rate of development success.  The latter is largely a function of the validated nature of the kinin-kallikrein pathway.

Although the DX-2930 study validates kallikrein, it should be cautioned that RNA Therapeutics cannot actually target kallikrein directly, but merely its precursor, PKK, as kallikrein is generated from PKK by enzymatic processing.  This means that the therapeutic threshold in terms of percent inhibition will be shifted either to the left or right depending on the enzymology of PKK processing.

In summary, HAE and the kinin-kallikrein pathway should be one to put on your RNA Therapeutics radar, also because it may offer new avenues towards important large markets such as diabetic macular edema and inflammatory bowel diseases.