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.

Plea to Sarepta and Arrowhead: Just Focus on Aberrant Exon 1 Transcript in Huntington’s Disease

Last week, uniQure achieved a breakthrough in developing disease-modifying therapies for Huntington’s Disease by showing that AMT-130 slowed disease progression by 75%.  AMT-130 is a DNA-directed RNAi construct targeting a sequence in the triplett-expanded exon 1 of the 67 exons-containing huntingtin gene.  Since other approaches aimed at lowering full-length huntingtin, but leaving exon 1 mRNA untouched, have fallen short (e.g. tominersen by Ionis and Roche) this is very strong support that targeting the aberrant exon 1 transcript is essential for success.

The aberrant exon 1 transcript, and likely the protein produced from that, is loaded with polyglutamine-encoding CAG tripletts, has been shown in animal studies to be exceptionally toxic and is also produced in patients (see previous blog entry 'Huntington's Disease Therapeutics Finally Breaking Through!'), the amount of which is correlated with triplett expansion size based on comments by uniQure CMO Walid Abi-Saab at a conference earlier this year.  Add to this the observation that a phase 3 trial with tominersen had to be stopped due to the oligo performing worse than control, maybe it is time for a heretical new idea:

accept that the old notion of Huntington’s Disease being an autosomal dominant disease caused by toxic full-length triplett-expanded huntingtin has been wrong, and full-length huntingtin indeed is an important protein to have. Instead, leave full-length huntingtin alone and exclusively target the aberrant exon 1 ‘fragment’.   Hey, have you ever considered the possibility that the polyQ htt protein aggregates are not cleavage products from full-length Htt?  Why always so complicated?  Why consider both exon 1 and full-length Htt contributing meaningfully to disease?  Shouldn't the properties of a short protein largely made up of polyglutamine be radically different from that of a much larger one containing the same polyglutamine stretch?

Sarepta and Arrowhead have shared plans to enter the clinic with a systemically administered RNAi conjugate for Huntington’s Disease.  A systemically administered option would be a very valuable one since, especially in light of the one-time administered AMT-130, repeat intrathecal administration is less attractive.   The Tfr1-targeted ARO-HTT being prepared for clinical trial application this year apparently does not affect exon 1 transcript.  The excuse given is that it is difficult to find an effective RNAi trigger in the merely 102 nucleotide exon 1 target space.

The good news: by focusing exlusively on aberrant exon 1 transcript, 7000+ nucleotides of additional target space (from 5’ end of intron 1) opens up.  

What good is it to have a trigger that is great at knocking down a transcript when it is aimed at the wrong target?  It is not too late and can be explained to the market.

RNAi Therapeutics A Bright Spot In Dark Biotech Winter

Over the last couple of weeks, we have seen business development activities in the RNAi space that made me realize that the modality has firmly established itself as the third drug development pillar next to antibodies and small molecules.  At the same time, surviving RNAi variations DNA-directed RNAi and microRNAs are catching a bid.

Biogen and Abbvie invest

Most Big Pharma companies have a history of making significant investments in the sector.  The early (2004-2009) significant moves by Roche, Novartis, Takeda, and Merck were not well rewarded.  This was partly because they lacked patience and the willingness to protect early platform development from the incongruent demands from their in-house therapeutic area groups.  Novo Nordisk got the timing right when acquiring Dicerna in late 2021.  Similar to Eli Lilly (through license to Dicerna IP and subsequent in-house work), they are now well placed to capitalize on the promise of RNAi for large cardiovascular and metabolic disease applications.

Amgen and Takeda stand to benefit from two opportunistic deals with Arrowhead Pharmaceuticals for candidates that are now in advanced phase 3 clinical development.  The RNAi agents for alpha1-antitrypsin-related liver disease (Takeda) and Lp(a) (Amgen) for cardiovascular disease will read out as early as next year.  Both companies speak highly of these products.  Amgen in particular highlights the Lp(a) program as its most exciting development candidate in corporate presentations and I expect the company to be back for more RNAi.

Two pharma/big biotech companies that stood out for having watched the developments from the sidelines are Biogen and Abbvie. 

Biogen has gone out of their way and tried it seems every oligonucleotide modality but RNAi.  This includes RNaseH antisense and splice modulation with Ionis and Stoke Therapeutics and microRNAs with Regulus.  It had done so after laughing off RNAi as a scientist’s sandbox idea when presented with it early on by Phil Sharp, scientific co-founder of both Biogen and Alnylam, and thus turned down the opportunity of a life-time to take a major stake in it.  

Instead, a certain former Biogen employee, John Maraganore would go on to build Alnylam into a major biotech player with Alnylam's market cap now exceeding Biogen's.  In a personal anecdote to illustrate the lack of appreciation of RNAi at Biogen at the time (2002), when I did an internship at Biogen and attended a job interview presentation there by a scientist on his RNAi work at Cold Spring Harbor, I was pretty much the only attendee not directly involved in the hiring process.   

It took a leadership generation and a realization that Biogen has become a dinosaur in the drug development industry that it recently finallyinvested $46M in a deal for a CNS target with you would not believe it: City Therapeutics, co-founded by John Maraganore. 

2 weeks before it, Abbvie did a broader collaboration and license option agreement with ADARx for $335M upfront.  Abbvie’s predecessor Abbott had dabbled a little bit in RNAi delivery around the early RNAi bubble, but with no serious intention behind it, really.

MicroRNA dinosaur Regulus taken out by Novartis

As with CRISPR now, the early RNAi bubble phase saw numerous start-ups not only around the core RNAi platforms, but also derivative technologies.  One of them was microRNA therapeutics, a technology targeting or mimicking the endogenous small RNAs of the RNAi apparatus. When the RNAi industry went through the 2010-12 financial bottleneck most of these companies either died or were well on their way. 

Regulus Therapeutics co-founded in 2007 by Alnylam and Ionis around microRNA-targeting oligonucleotides, had the good fortune of having deep-pocketed, influential backers that eventually enabled them to doggedly progress anti-miR17 antisense oligonucleotide farabursen for autosomal dominant polycystic kidney disease (ADPKD) to a stage where the FDA aligned with them on a speedy pivotal trial development plan earlier this year.

This triggered a bidding war between Novartis and an undisclosed bidder that on April 30 resulted in a ~10x premium over its 52-week low that will be paid by Novartis, including a $800M upfront and contingent value rights.

 

DNA-directed RNAi Therapeutics create tremendous value for uniQure

In the vibrant field of developing disease-modifying medicines for Huntington’s disease, uniQure stands out with its chance to gain FDA approval in less than a year should 3-year data replicate that seen after 2 years.  This is the big regulatory news of the day for genetically-targeted therapeutic development as uniQure aligned on a path towards accelerated approval, including a comparison with an external natural history cohort.  Turns out, new CBER chief Vinay Prasad is actually human and has compassion for those suffering from severe genetic diseases.

What few people are talking about is that AMT-130 is an RNAi Therapeutic.  It is a DNA-directed RNAi version where the RNAi trigger is expressed from a DNA template following AAV delivery.  The key to uniQure’s success is that delivery is done locally by intracranial access to where the gene suppression is thought to be required (Spronck et al 2021; cool video illustration here).  In the case of Huntington’s disease, it is the striatum; in the case of AMT-260 for mesial temporal lobe epilepsy where uniQure presented intriguing seizure reductions in the past week, the hippocampus. 

By precisely following how the target structure is filled up with the AAV solution, potential toxicities in off-target tissues can be avoided.  Obviously a big advantage at a time when the AAV field is struggling with toxicities due to systemic administration of large vector doses.

What is more, DNA-directed RNAi allows for durable, potentially permanent gene silencing without the need for an exogenous protein.  This comes as genome editing, be it via CRISPR or Sangamo’s zinc fingers, are hammering away at solutions for gene knockdown that require exogenous protein expression.  Sometimes the old ways are more elegant after all.  Being out of fashion has the advantage of allowing you to build value with less friction. uniQure is about to capitalize on that in a big way.

 

Pure-play RNAi stocks budding during biotech winter

All this is happening as RNAi bellwether Alnylam ($40B market cap) is hitting new all-time highs and is about to catch up with and likely overtake Regeneron ($53B market cap) to become the 3^rd most valuable biotech behind Amgen and Vertex Pharmaceuticals.  Besides the ATTR amyloidosis opportunity, this prices in the potential of Alnylam's pipeline to address huge markets such as Alzheimer’s and obesity with well tolerated, infrequently administered RNAi.

Silence Therapeutics has also risen slowly, but surely over 200% in the last 2 months.  As Lp(a) RNAi is increasingly seen as a must-have in the cardiovascular disease space, its phase 3-ready candidate SLN360 alone could be well worth a multiple of its current $275M market cap.  Add to this its 25 year experience as a pure-play RNAi developer and inhibinE for obesity being an easy target with their technology, Silence Therapeutics is ripe for an acquisition.

Arrowhead Pharmaceuticals is also up over 80% in the same period as revenues in the form of ApoCIII knockdown for high triglyceride-related disease and co-commercialization and royalty/milestone revenues come into closer focus.  Amgen would be an obvious candidate to make a play for Arrowhead, also because Arrowhead can now manufacture large amounts of RNAi triggers within the US.

There are a lot of lessons to be learned from the history of RNAi Therapeutics.  One is that financial bottlenecks can richly reward those that persevere, also because it creates scarcity value and reduces competition.  In general, the current biotech winter which forces companies to focus on their most promising and competitive product candidates will translate into greater profitabilities down the line.  In a twist of irony, as the CRISPR field is going through its own bottleneck, CRISPR Therapeutics now spending money on a non-core RNAi asset, thus keeping spend unnecessarily high and losing focus, is not what the doctor would order based on RNAi history. 

I believe that as long as Trump’s trade war does not result on a run on the US dollar pushing interest rates up, anticipation of Fed Chief Powell’s replacement in May 2026 will allow these assets to come to fruition in a much less capital-constrained environment for biotechs.

PTC Therapeutics Full-Length Huntingtin-Targeting Pill Comes Up Short, Setting Stage for Exon 1-targeting ddRNAi by UniQure

Today, PTC Therapeutics reported full results from a 52-week trial with PTC518 for Huntington’s Disease.  The data failed to support an intriguing early data cut last year that prompted Novartis to pay $1B for shared US profits and majority rights outside the US.  Unlike the previous n=32 data hinting at dose-dependent full-length huntingtin lowering (up to -43% in the CSF at the high dose) and corresponding improvements in functional outcome measures, the company had to dig deep to find hints of functional efficacy in today’s n=159 dataset.  In other words, an accelerated approval based on the PIVOT-HD trial is now highly unlikely.  Even huntingtin knockdown came down from -43% reported last year to the -20-25% range in the CSF and was not dose dependent.

That Novartis licensed the PCT molecule was surprising to me in the face of overwhelming evidence that protein derived from exon 1 huntingtin mRNA is the toxic molecule and increases in production as the CAG triplett somatically expands during the disease course (see this blog entry).  To me at least it seems that full-length huntingtin has fairly little to do with contributing to the disease.  Indeed, some had started to worry that targeting (full-length) huntingtin may even be harmful based on striatal atrophy caused by an antisense compound by Roche and Ionis (which I and others think can be attributed to the problematic phosphorothioate backbone chemistry of tominersen).  So at least in that sense, comfort can be taken from the PIVOT-HD results that there was no apparent worsening of disease caused by full-length huntingtin-lowering by the PTC518 splice modulator pill.

I can see that taking a once daily oral pill instead of drilling a hole in your skull may be preferable and an enticing prospect for a Big Pharma, but what good is that when the pill aims at the wrong target and will not work?  Of course, UniQure’s AAV-based DNA-directed RNAi therapy capable of targeting exon 1 mRNA will eventually be challenged and complemented by similar, but less invasive exon 1-targeting oligonucleotides or the nascent class of triplett expansion inhibitors, but a lot has to be said about the virtues of a drug that is not only targeted at the right transcript, but also where the exposure is limited to the main affected structure in the CNS.  

So while I understand that PIVOT-HD will cause some disappointment in the Huntington’s community, the data is making much more sense again from a mechanistic point of view following the confusion caused by the earlier data cut.  This should also give regulators further impetus to fast-track AMT-130 towards accelerated approval based on an upcoming 3-year comparison with propensity-matched natural history data.

The time for genome editing is now

Back from recent CRISPR conferences in Ireland and Denmark, I wanted to share my current thinking about the present and foreseeable future of clinical genome editing.

CRISPR is a clinically mature platform

First of all, genome editing, and in particular CRISPR Therapeutics have arrived big time.  Ignore for a moment the 90%+ declines in the share prices of Intellia, Verve, and Metagenomi, that all, with the exception of perhaps Beam Therapeutics, suggest that the industry will not survive.  Focus instead on the transformational results last week by Verve Therapeutics which will shape the management of chronic metabolic and cardiovascular disease for decades to come, Beam Therapeutics last month announcing that it  for the first time fixed a genetic disease (AATD) by reversing a point mutation, or the three ongoing phase 3 programs by Intellia Therapeutics which promise patients live unintruded by their disease.

So you say that this is only half the truth and many of them will develop cancer?  With hundreds of subjects having been given CRISPR therapeutics, we still have yet to hear about such cases, including for the hematopoietic stem cell applications, probably the most stringent test in that regard given the history of retroviral gene therapy.  This is supported by ample detailed genomic analyses demonstrating that many CRISPR modalities, in particular prime editing, often do not have any detectable off-targeting (!) and therefore are safer than going out in the sun or eating grilled meat.  And don’t get me started with analysts and investors pretending that small molecule drugs, 'dirty drugs' by design, are much safer in that regard when many of them like methotrexate and hydroxyurea are known to cause cancer which barely gets a mention or is routinely accepted as part of the risk-benefit of a drug.  Similarly, the currently more widely embraced antisense and RNAi technologies exhibit considerably more off-targeting, which in theory could result in cancer development with chronic use, than the average CRISPR therapeutic candidate today. 

Prime editing is the ultimate CRISPR manifestation

Prime editing is the foreseeable endgame for genome editing involving edits up to 50 nucleotides.  This is because in addition to being able to knock out genes like (Cas9) nuclease or base editing, it allows the developer to change nucleotides at will and with incredible specificity, and for gain-of-function.  It has therefore surprised me to see that prime editing is still such a niche part in these conferences and barely used in industry and even academia where IP is less of an issue.  This can likely be explained with it requiring a good deal of mental gymnastics when devising a prime editing strategy and subsequent tinkering to optimize efficacy.  Prime editing will likely also be part of strategies for achieving even larger edits, including whole gene replacements that are often desirable.

In some ways this is reminiscent of zinc fingers which make for poor screening and quick molecular biology tools and were quickly forgotten when CRISPR came along with the promise of simple sgRNA design.  However, a panel at the Copenhagen CRISPR meeting by genome editing veterans made it clear that when optimized, zinc fingers can be every bit as powerful as CRISPR and currently have a leg up where delivery is going to be viral for some time to come.  

This is particularly true for the CNS, the fourth major tissue/organ target for genome editing applications after the liver, hematopoietic stem cell, and immune cells.  Not only is it impossible to fit in prime and base editors in single AAV vectors, expressing a CRISPR effector nuclease of bacterial origin for years may be tricky (but not unsolvable) in terms of immunogenicity.  There is also some unease about having nucleases loiter around in cells for years after their job has been done.  Self-targeting/inactivation strategies may here be called for.  Zinc fingers by being small and mimicking human proteins by contrast are ready for clinical use, a fact, as the deal flow by Sangamo Therapeutics illustrates, is increasingly being recognized by the wider industry.

Genome editing versus non-permanent modalities

Another popular argument against CRISPR Therapeutics questions why one should take a ‘risk’ with permanently altering the genome when you have oligonucleotide therapeutics options that need to be administered as infrequently as every quarter, half annually, or even annually.  

While there is some application overlap between genome editing and oligonucleotide therapeutics, especially when it comes to knocking down genes, a closer look shows that the overlap is limited.  Where there is clear genetic evidence that a gene can be disabled for life without safety risks, then genome editing is the endgame, or at least capture a good portion of the market, and transient modalities may serve to de-risk the targets first.  

When it comes to bringing pathways back into finely tuned balance and/or the disease is not chronic and likely requires only temporary treatment (e.g. some cases of hypertension), transient options are preferable.  Still in other cases such as prion or Huntington’s disease where it is not clear whether it is the overall level or distribution of gene knockdown that is more important for efficacy, the preferred modality has yet to emerge from clinical studies. 

Part of the Wall Street fashion show

Wall Street is a fashion show when it comes to biotech platforms.  A little less than 10 years ago, it predicted that CRISPR would kill off the RNAi Therapeutics industry. Today, Alnylam sports a $30B market cap, about 4x that of the entire CRISPR industry combined (much of it in cash).  Of course, investing in technologies ahead of their time is fatal. The electric vehicle industry is just one example.  As I have laid out above, genome editing, however, is now and here to stay.  Having the potential to save the healthcare system money (e.g. $2M for a one-and-done HAE/ATTR treatment as opposed to $500k annually) or to lead to drastically improved outcomes (as can be predicted from chronic LDLc lowering) got to be embraced by patients, their caregivers, docs, regulators, and insurers alike.  

It's been a rough couple of years investing in development-stage, cutting-edge biotechs and current politics does not seem helpful, but if this is when it is darkest, then generational wealth awaits the survivors with the guts to hold on during a volatile comeback.  One of my two conviction bets that I look up to in this regard is therefore CRISPR therapeutic biotech Verve Therapeutics.  Uniqure, which works in the similarly unloved gene therapy arena and has a promising DNA-directed RNAi candidate for Huntington’s disease, is the other in case you were wondering.