An Explanation for the Disconnect between Z-AAT Editing Efficiency and Alpha-1 Antitrypsin Output

The commonly stated goal of alpha-1 antitrypsin editing approaches in addressing AATD is to achieve 50% editing of the mutant Z-allele.  This is based on human genetics showing that MZ heterozygotes have a much reduced risk of developing liver and lung disease.  

It therefore baffled me that Beam Therapeutics reported a year ago serum AAT levels of only ~12.4uM at day 28 despite having achieved 75-85% ZàM conversion with a 60mg dose of BEAM-302.  This compares to ~15-19uM concentrations seen in MZ heterozygotes, that is people who have just 50% of their AAT alleles in the M state.  

Back of the napkin math would have predicted ~22-30uM AAT levels with 75% M alleles if there was a corresponding relationship between the fraction of M alleles and AAT output.

Beam Therapeutics now reports improved serum AAT levels

This week, Beam Therapeutics reported that one additional year into the clinical trial, mean serum AAT levels in the 60mg cohort have increased to 16.1uM.  This includes an additional 3 patients over the 2025 data cut who had higher baseline AAT levels compared to the initial cohort of n=3.  Curiously, the company did not show how serum AAT changed over time, and now I think they did so on purpose because they did not want to steal the thunder from a future conference presentation.

Z-AAT relief effect following genetic correction takes time

ZZ homozygotes carry a high risk of developing liver fibrosis and ultimately liver failure in their lifetime because of the accumulation of Z-AAT aggregates in hepatocytes and resultant cell stress.  Consequently, less AAT gets out into circulation.  Arrowhead Pharmaceuticals and Takeda are addressing the liver disease aspect of AATD by Z-AAT RNAi knockdown with fazirsiran and are now running an unexpectedly long 4 year study after initial findings indicated slower than expected clearance of AAT aggregates and subsequent amelioration of fibrosis.

It therefore is plausible that the reason why serum AAT level undershoot following BEAM-302 treatment compared to genetic expectations is due to some lag in normalizing AAT output in subjects where Z-AAT had caused stress to the liver for decades of life already.  The increase from the mean 12.4uM reported last year to now 16.1uM could be a reflection of hepatocytes clearing the aggregates to relief endoplasmic reticulum stress and grease the AAT export machinery.  

Alternatively, you would have to explain why the inferred mean for the last 3 subjects comes out at 19.8uM versus the 12.4uM for the first 3 subjects.  Of course, you could try and explain some of it with the differences in baseline AAT output (which actually could also reflect Z-AAT-related liver stress), or time-dependent AAT increases as a result of a competitive growth advantage of corrected hepatocytes, or differences in the way serum AAT was measured last year and this year (turbidimetry vs LC-MS), but none of them explain both the serum concentration undershoot versus genotype expectation and the apparent increase over time.

Be prepared to be pleasantly surprised as more data from the BEAM-302 program emerges.  Also be wary of out-of-context data from investigator-initiated trials of obscure genome editing compounds like the YOLT-202 copycat.  

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.