NTLA-2002 More and More Looks Like a Cure for HAE

When Intellia Therapeutics set out to develop a CRISPR-based prekallikrein knockout for hereditary angioedema (HAE), it was as a compelling alternative to the newer prophylactic treatments. Cas9 nucleause-based NTLA-2002 (aka lonvo-z) was aimed at having similar efficacy and safety/tolerability, but with the added significant benefits of liberating patients from repeated injections, from having to worry about continued drug reimbursement, all while saving the healthcare system money and resources.

All this is changing as the company is presenting longer-term data strongly suggesting that NTLA-2002 could be a life-time functional cure for many, if not most people living with HAE.

Today, at the EAACI Annual Meeting, Intellia showed that there have been no more HAE attacks since the last update a year ago.  All 10 subjects in this now open-label extension trial have now been attack-free for at least 15 months with a median of almost 2 years.  These 10 patients would have conservatively had around 500 attacks based on their disease history.

500 versus zero, nothing short of a revolution in the management of HAE.  Importantly, with 9 of the 10 subjects having reached 20-30 months after dosing, no drug-related adverse event has been documented after day 28 following NTLA-2002 infusion.

As the data gets better over time, it looks like tonic PKK reduction below a certain threshold may normalize the bradykinin system und put a brake on a neurogenic attack feedback loop.  We know that attacks are frequently triggered by mental and hormonal stress.  In turn, attacks can increase anxiety.  It now looks similar to chronic itch that once the feedback loop is interrupted (HAE attack and scratching) there is a real chance of sustained outcomes.  That this is possible is also illustrated by the fact that people with C1 Inhibitor mutations (the causal mutation in HAE) often do not have any attacks before puberty.

Today’s development illustrates that CRISPR genome editing going after the same targets as competitive modalities can lead to superior outcomes and actually free people from disease instead of keeping them dependent on medicines.  Needless to say, patients are queuing up for the treatment and the pivotal phase 3 trial has been fully enrolled- well ahead of schedule.

Why I Am Taking My HAE Cure Idea to My Grave

Last year, as I was researching the hereditary angioedema (HAE) therapeutics landscape, I came across data in the C1 inhibitor gene regulation literature that gave me a proverbial heureka moment: if I could do ‘X’, then I would have a cure for HAE. Dazed by the excitement of being in possession of such an idea, I verified that the enabling technologies (genome editing and LNP delivery) were fit for purpose.

It basically seemed that all I had to do was to verify my approach in tissue culture and the rest would be ‘simple’ business development. In the vast majority of cases, HAE is caused by mutations in the C1 Inhibitor gene. It is a rare disease affecting close to 10000 patients in the US and EU. Nevertheless, it is a lucrative, currently ~5B market with therapeutics mostly replacing missing C1 inhibitor in the form of recombinant or purified C1 inhibitor or agents interfering with proteins involved in bradykinin generation or the bradykinin B2 receptor. 

It is getting a bit crowded, but there still is room for improvement to achieve the goal set by the HAE community: a life free from disease. Intellia’s NTLA-2002, a one-time CRISPR Cas9 therapeutic now in phase 3, achieves a 80-90% attack rate reduction by destroying prekallikrein gene activity. The efficacy is in line with competing therapeutics that need to be taken indefinitely and cost around half a million USD- annually. 

A good estimate for the price of NTLA-2002 would be $3M, meaning that after 6 years this convenient treatment would start saving the healthcare system serious money for a disease that gets diagnosed typically in the late teens or early 20s. Nevertheless, the financial market could not be less excited by NTLA-2002 as indicated by the lackluster response to its clinical data. In theory, NTLA-2002 could treat every HAE patient and rake in $30B in the process. Compare that to the annual $5B and growing market for the traditional forever treatment options which will cost the system $60B plus over the next 10 years alone…without even treating every patient and leaving treatment gaps due to insurance that like to drag their feet. 

We are talking here about cost alone, not even how a one-time treatment would benefit a HAE patient: less stress, both financial and emotional which in itself is a major risk factor for HAE attacks. Considering the lack of investor interest in NTLA-2002, I concluded that going from 80-90% attack rate reduction to 100% attack rate reduction following a one-time treatment, is not worth the time and financial risk. Disclosing the idea also does not make sense since it would destroy any IP value if the idea was picked by somebody else or conceived independently, further reducing chances it would ever get to patients. 

Just recently, Pfizer, a major player in hemophilia therapeutics, declined to bring a reasonably effective and safe hemophilia A one-time gene therapy discovered by Sangamo to market. Again, I ask myself, why would Pfizer ever want to destroy a lucrative market it participates in? I can only see how an outside company would want to disrupt such a rare disease market (hemophilia is bigger than HAE, so that situation could actually happen e.g. in the form of Regeneron). 

What about patients? I am slowly coming to accept that the best possible treatment for a disease will often not be the end-game in terms of therapeutic development. Sometimes it is pharma’s profit model, sometimes society that does not feel that a patient deserves better. Take for example a rich country like Singapore where patients do not have access to modern HAE medicines and where even women are still treated with the androgen sledgehammer. 

It seems we have arrived at a turning point where it has become hard to invest in best possible therapeutics in a resource-constrained environment where money gets diverted to the military and AI. Making matters worse for rare disease drug development, as international ties continue to deteriorate, the target population becomes even smaller.

Ionis Widens Its Modality Horizons

Over the weekend, blue chip antisense oligonucleotide company Ionis and genome editing competitor Intellia presented data on targeting prekallikrein (PKK) for treating hereditary hemeangioedema (Ionis donidalorsen here, Intellia NTLA-2002 here).

Using CRISPR Cas9 endonucleolytic disruption of the KLKB1 gene coding for PKK following LNP delivery, Intellia came out as the apparent winner in this showdown.  Not only did they demonstrate more pronounced PKK inhibition, but also more consistent elimination of debilitating attacks characteristic of the disease.  Moreover, by exploring less frequent antisense oligonucleotide administrations despite suboptimal low -60% knockdown, Ionis indicates that it is worried about the safety and tolerability profile of donidalorsen. 

Whether reversible approaches like antisense and RNAi or irreversible approaches like CRISPR gene disruption will ultimately prevail in the HAE race remains to be seen and will likely be decided by the safety of suppressing PKK expression over the long-term. If there is an overshoot of CRISPR-mediated gene disruption that would e.g. result in blood clotting abnormalities, even for a subset of patients, the field would be wide open for reversible methods.  

Ionis invests in genome editing

But whether that will be antisense remains to be seen.  Especially for targets in the liver, RNAi currently clearly rules the land for gene knockdown: highly potent, titratable and reversible knockdown with 5 years counting without a notable setback, especially related to off-target toxicity.  By contrast, Ionis is being held back by persistent safety issues as it has been beating a dead horse with its phosphorothioate-based backbone chemistry although it appears to be finally weaning itself off with chemistries such as the Mspa backbone.

So it is probably the hope of leap-frogging the RNAi competition by adopting genome editing as Ionis today announced that it was partnering with CRISPR genome editing company Metagenomi.  The HAE data comparison could not have come at a more opportune time.  

One declared aim of the investment in genome editing is life-cycle management of existing franchises.  In the liver, these franchises (TTR amyloidosis, ApoC3, PCSK9 etc) are currently and in the foreseeable future being dominated by RNAi despite Ionis’ heavy investments, so it clearly makes sense to amortize its investments in disease-specific market research, commercial infrastructure and clinical trial experience to accelerate the success of a more promising approach. 

TTR amyloidosis is a great example where even GalNAc-conjugated follow-on antisense compounds are unlikely to challenge Alnylam’s suite of RNAi triggers.  Also due to this dominance, it makes less sense for Ionis to develop an RNAi competitor drug despite its access and now actual adoption of this modality for targets in the muscle.  But as TTR shows, other genome editing companies are already competing for some of these targets so it won’t be all that simple trying to leap-frog RNAi and Alnylam like that.

 

The rise of the multi-modality oligonucleotide therapeutics companies

After straight-forward antisense for gene knockdown and then splice modulation, with the recent adoption of RNAi and genome editing, Ionis is rapidly expanding its oligonucleotide modality toolbox.

In fact, it is becoming a little bit like smaller competitor Wave Life Sciences which has been practicing all types of antisense (knockdown, splice modulation, more recently RNA editing) and RNAi using a bewildering mix of chemistries.  Not only are they burning through cash as if there was no recession and inflation problem, I never liked that because clinical failure after failure (esp. minute target engagements at best) suggest that the company is stretching itself too thin.

By comparison, Ionis, with $2 billion in cash and a more experienced and bigger operation is a different beast altogether and may be able to pull it off, at least on a technical level.  However, instead of spending $80M in upfront alone on a modality that is somewhat further removed from its traditional chemistries (longer mRNAs, LNP delivery for CRISPR), it could have much more synergistically leveraged its investments in chemistry and delivery by investing that same amount in the ripe-for-the-picking RNA editing.  Accordingly, $80M is more than the market cap of my currently favourite RNA editing investment, ProQR.

I’m sure the opportunity to expand druggable targets and indications by applying existing delivery technologies and chemistry know-how by adopting RNA editing is not lost on RNAi players such as Alnylam and especially Arrowhead Pharmaceuticals.  Arrowhead in particular, having scooped up the RNAi assets of Novartis and Roche for peanuts has demonstrated an ability to recognize and act on similar opportunities.

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.