AMT-130 - October 17, 1977 to today
Former commission report
COMMISSION FOR THE CONTROL OF HUNTINGTON’S DISEASE AND ITS CONSEQUENCES - HIGHLIGHTS
The President The White House Washington, D.C. 20500 Dear Mr. President: The Commission for the Control of Huntington’s Disease and Its Consequences is pleased to submit its report in compliance with Public Law 94-63. Volume I of the report describes the findings and recommendations which make up the Commission’s National Plan for the Control of Huntington’s Disease. Companion volumes provide more technical data and documentation.
The Fiscal year 1980 budget national plan budget allocated approximately $39M USD in funds for research on Huntington’s Disease and related disorders. It’s a report sent to the White House in 1977.
Take us to today and you have arguably the most important day for Huntington’s disease ever occur on September 24th, 2025. If not aware, they submitted a preliminary data release on 3 years of follow-up data post infusion of AMT-130. What exists in the trial today is a high and low dose cohort with a prior cross-over to the treatment arm of 4 of the original 10 individuals recruited into the placebo control arm. I believe 3 were put into the high-dose and 1 into the low-dose although this is from memory and can be wrong.
The source of the majority of contention I’ve seen in Uniqure’s HD clinical trial came from the use of external cohorts as a control followed by the UHDRS 12-month data compared to the former placebo arm, although maybe some people would reverse the order. I think the NFL spike at 12mo was a third “this isn’t good thing” to occur with AMT-130, and target engagement was also in question for some.
As for the data, a dosing response appears to exist between high and low dose cohorts. I believe a 7-year follow-up of the patients powers the trial to point where you no longer have to worry about having a placebo effect in the treatment arms. And I would guess that this also true by years 3 and 4 because of who was recruited into the trial. “Are the patients in the trial well matched to the control such that a comparison between UHDRS and who was in ENROLL-HD have a valid way to be compared” is the biggest question I can come up with in terms of advertising something as “slows progression”. I saw how they were matched and I couldn’t (read can’t) refute the matching. That there is a large data set to look at for the control improves the quality of the control arm (in my opinion) as compared to the prior 10 that served as a control arm. UHDRS has the most opportunity for inserting noise into data over shorter durations (my opinion), so I have less of a hard time getting over the 12mo outperformance of the placebo arm (n=10) versus the control arm in this endpoint.
Going into the readout, prior studies using contrast with GFP left me thinking they were going to achieve target coverage. From this perspective, this trial is an outlier in that it’s one of only a handful of trials that can ever say they definitely had a chance to expose the entire striatum to an investigational drug. The therapeutic is a microRNA intending to silence the production of what was thought to be a pathogenic element of the disease ever since 1993. While it’s invisible to what we see in the trial today if this experiment had been run 15-20 years ago, it probably would have failed because of the medtech surgeons had available at the time. Stereotaxis using convection enhanced delivery was running into issues with target coverage in prior gene therapy trials targeting the putamen in Parkinsons disease. Prior to introduction of a contrast agent to actively provide visual feedback to the surgeon during infusion, target coverage was being determined as inadequate to determine if prior failed therapeutics failed to produce a good outcome because of the drugs mechanism of action, i.e., delivery was the hurdle tripped over. For every procedure that’s happened in AMT-130’s trial, there’s a recording being held somewhere that shows where that infusion went. Target structures were being segmented with a preoperative MRI scan that determined appropriate infusate volumes before the surgery ever occurred and they had surgeons who had already practiced with CED. This put the trial into a good spot to not stumble over delivery of the drug and left it in the hands of whether or not neurologists were correct in their assessment of what is causing neurodegeneration in Huntington’s disease.
This is my opinion, and I reserve the right to be wrong, but I do believe there is enough evidence to constitute proof of AMT-130 having a therapeutic effect in the slowing of Huntington’s Disease progression. While the placebo arm made the 12-month data appear bad, repeat assessment with UHDRS can display an efficacy signal with time (this is how their trial can be powered off a small treatment arm). I’d also say the patient matching between controls improved substantially with the 940 individuals that are inside the external control arm.
What they’re going to be saying to people with this drug is your disease will kill you substantially slower should it be given to you (a remarkable claim), and I think to ever say that they absolutely needed the treatment arm to substantially outperform a large well matched control arm over many, many years. Uniqure recently increased the follow-up period to 7 years, and I take its extension as a good sign but also data that they will really want to have because their claims can improve with time.
In terms of the offering from the consumer side. The community has nothing- this elevates anything with a legitimate claim to slow progression as an obvious blockbuster. The patient is under general anesthesia, and there’s no scarring or hair loss required, so the ask with tolerating the procedure is rather low. There are risks associated with CED because anytime you make a pass with a cannula you can cause hemorrhage, but these risks will probably be tolerable to most. There are around 60 sites in the US that can do this today and around 100 globally. The infusions duration is several hours to about a dozen hours, although infusions have gone longer and they can be made faster with improvements to the vector. The surgical channel grew completely out of research centers so there’s opportunity for the channel size to be adaptive. I expect there will be something of a pareto distribution in terms of site level activity, especially in the event that anyone forms an independent practice around the patient population. I imagine a CED infusion clinic as probably the most relaxed neurosurgical practice that’s even possible to have so this may or may not reveal itself as a thing in time (remains to be determined).
Guess work is at play right now about what Uniqure’s label is going to look like. Neurologists are going to heavily argue for a label that’s inclusive of patients prior to them ever demonstrating any loss of motor function. But at the same time, it would be a surprise to see a label that included everyone with a confirmed HD diagnosis. The therapeutic is non-selective in the huntingtin protein that’s being silenced, i.e., AMT-130 may cause unintended side effects in development by reducing wild type huntingtin protein values. Further label limitations for the procedure are that CED runs into issues with advanced neurodegeneration. If I recall correctly, this last cohort recruited into trial is looking at more advanced cases of HD. Out of the 6 of the original 10 placebo control arm participants that failed to crossover in the trial, it is my guess that it would be the 12mo follow up scan that was looking at striatal volume which prevented them from joining into the trial out of concern of encountering any issues of delivery with CED. Though this is impossible to know without confirmation and I don’t believe Uniqure has ever shared why those 6 failed to crossover. People that were originally recruited into this trial had already exhibited the beginning signs of loss of their motor functions such that it would not be surprising to see any sort of overtly restrictive exclusion criteria of this nature pop up after 12 months.
In my opinion pills will not ever work for slowing the progression of HD, but that doesn’t mean much. Contending drugs in trial to follow most closely are anything that targets the exon1a transcript that either uses stereotaxis or intrathecal delivery. I do not think anything else will ever work, and intrathecal delivery may prove out to be inadequate as well.
This is the closest we’ve come to fully closing the loop on Huntington’s Disease with the commissioner’s report in 1977.
