Approving AMT-130 Now Will Incentivize Better Huntington's Drugs and Speed Access

To be clear: the FDA has just violated the trust of investors willing to risk significant capital throughout the ups and downs of the markets by reneging on an agreement it had with the sponsor of what it would take to bring the first Huntington's disease-modifying drug to a well educated community begging for treatment options. 

As the drug development and rare disease world is trying to digest the unprecedented turn of events around AMT-130, it has re-opened the wider debate around the term and value of 'flexibility' in the rare, orphan disease drug approval process.  So setting aside for a moment the fact that the FDA is mandated to make drug approval decisions independent of cost to the healthcare system, let us focus on what this debate is really all about: 

cost savings as perceived by supporters of socialized medicine versus speed of access to medicines and better drugs by incentivizing competition.

Cost savings

The argument for reducing healthcare expenditures by making sure that only drugs with crystal-clear, well-defined health benefits get approved for commercialization seems simple and obvious. Why spend a few hundred million or single-digit billions on drugs just deemed “plausible” based on biology and biomarkers and have not run the “gold-standard” double-blind placebo-controlled clinical trial gauntlet and then turn out to be worthless in the end? 

This is what Vinay Prasad, a smug academic Bernie Sanders supporter and proponent of socialized medicine has been all about.  Good riddance (again!).  It all sounds nice in theory, but even the beacon of communist drug development and public healthcare, Cuba, shows that such a mindset does not facilitate healthcare innovation and access to medicines, particularly to those suffering from rare and orphan diseases.

 

Better drugs by incentivizing competition

Yes, the failure to confirm benefit in stringent outcome trials following accelerated approvals can be frustrating, but I will make the case that this is a price worth paying. Even in instances where this has happened—Sarepta’s exon 51 skipper eteplirsen is a good example—the ability to generate financial returns earlier has spurred tremendous investments across dozens of biotechs funded by private, risk-taking capital to come up with improved versions of eteplirsen. The result: companies like Avidity and Dyne Therapeutics have invested hundreds of millions in new exon skippers backed by solid evidence of clinical efficacy.

I used to be a big critic of eteplirsen early on, suspecting shady science and Sarepta clearly dragging its feet on the confirmatory studies.  Yet in hindsight even I can now see the overall benefits that the accelerated approval of eteplirsen has brought to the DMD rare disease community, so that the argument of spending precious healthcare dollars while generating confirmatory evidence and spurring competition becomes quite compelling to me.

So as long as companies play by the rules and get busy on their confirmatory studies, the system is working very well.

Why approving AMT-130 for Huntington’s Disease does not entail much risk and cost

In this more libertarian view of drug approval, drugs that have been demonstrated in clinical trials to be “safe and well tolerated” should get approved when there is some evidence of efficacy. Importantly, safety can be demonstrated in studies that are not placebo-controlled.

The safety of AMT-130 has not been at the center of the recent controversy, so let’s accept that for a uniformly terminal disease like Huntington’s, AMT-130 meets that bar.

Given that the market for disease-modifying medicines for HD is significant, similar to Cystic Fibrosis which allowed Vertex Pharmaceuticals to build a franchise worth $100B around, accelerated approval for AMT-130 would energize uniQure’s competition to come up with drugs that have demonstrably better therapeutic profiles.

If everybody would just rely on the same type of natural history comparisons as AMT-130, competition would bring down prices rapidly as seen for HCV drugs which are a wildly successful story in effective and affordable healthcare following an initial public outrage around the '$1000 pills'.. Those that can demonstrate superior profiles will be rewarded with pricing power further incentivizing private risk capital to improve on AMT-130. Alnylam’s ALN-HTT02, an intrathecally repeat-administered synthetic RNAi trigger, could very well be that first molecule to achieve that. It also targets the critical exon 1a transcript and appears to have superior knockdown efficacy. There is also no reason why ALN-HTT02 cannot be given to an HD patient who had already received AMT-130.

After that, it will likely be systemically administered RNAi molecules targeting exon 1a transcript and with triplet repeat expansion inhibitors. The regulatory flexibility is a critical factor determining how much investment flows into HD drug development and how soon patients for whom every day is an opportunity missed can access promising drugs.

Finally, let’s be real: not every HD patient will get AMT-130 which I expect would to cost around $3M as a one-time treatment with a high cost of goods based on viral vector production.  In addition to surgical capacity constraints, a label that will likely expand not too much beyond the early symptomatic manifest study participants will throw up access barriers that insurance companies and government payors will seize on.  Still, the revenues would allow uniQure to stay at the forefront of HD drug development and help flesh out the actual value of AMT-130.

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.