Today, UniQure ( $QURE ) announced the 3 yr readout findings of their gene therapy trial for Huntington's disease (HD). At the bottom line, the company reports a statistically significant reduction of disease progression (~75%) compared to an external, propensity matched controls. Apparently, everyone is excited about the results, as can be seen from the >250% increase in $QURE stock price today. Understandably, a first positive trial news in a long time for a devastating disease with no cure has excited the scientific community and increased the hopes of patients. I am seeing headlines like "Huntington's disease successfully treated for the first time" and claims like scientists' have found a cure for HD. I am not sure if the findings are that groundbreaking to warrant such claims. It might be the case that treatment really is working, but I am not sure if the current findings are strong enough to be too confident on the treatment effect. There are many uncertainties around the results. Below are my some of my thoughts. HD is caused by a triplet repeat mutation HTT gene that somatically expand over time and cause neurodegeneration. The repeat mutation in HTT gene gets translated to polyglutamine repeats in the HTT protein, which is believed to be neurotoxic (though we don't know exactly what's killing the neurons). Past treatments have largely focussed on knocking down HTT gene using different approaches, none of which translated to clinical benefits. Most notable among them, is tominersen (developed by Roche and Ionis Pharmaceutials), an antisense oligonucleotides (ASO) drug that lowered the production of HTT protein in the brain (both the mutant and normal copies). Although, tominersen successfully reduced the HTT levels in the brain, it failed to treat HD. All past failed efforts on treating HD by reducing HTT production, led to many critical questions, such as - Is it safe to blindly knockdown HTT in the brain, as normal versions of the protein might play some important functions ? - How early one should intervene to make clinically meaningful impact on disease progression? Even though the clinical symptoms appear late in the disease course, the neuronal damage itself seem to start very early in the disease course. - At what level does the toxicity originates, protein or RNA or DNA? how much of the existing neuronal damage is reversible? There are many more unanswered questions. Recently, the therapeutic focus have shifted to reducing the somatic expansion of HTT mutation rather than reducing the HTT expression (refer to this article for more details on this, With this background, here we have a new gene therapy--AMT-130--developed by UniQure that is trying to treat HD by reducing HTT production using a viral vector based genetic drug surgically injected directly into the brain striatum (key brain region affected in HD). The idea is to permanently reprogram the neurons to produce microRNAs that reduce production of HTT proteins (both mutant and normal copies). It's challenging to have true controls for such trials, so scientists used external controls (in large numbers, n>100) that matched closely to the trial participants with regard to clinical characteristics. There were two groups. One (n=9) received the high dose injection and the other, low dose (n=12) The primary end point is a composite score called composite unified Huntington's disease rating scale (cUHDRS) calculated from multiple clinical scores measuring motor, cognitive and other functioning capacities of the patients. Additionally, neurofilament light chain, a CSF biomarker of neuronal death, is also measured. At 24 months follow up (July 2024), the press release reported a statistically significant reduction (~80%) in the cUHDRS decline in high dose group (n=12) vs external controls. But there was no significant effect in the low dose group (n=12). With regard to CSF Nfl, the report showed a slight decrease in trial participants (n=21) compared to baseline, both high and low dose pooled together the CSF. No data on this from individual groups. Now (Sep 2025), at 36 months follow up, the press release reports a statistically significant reduction (~75%) in the cUHDRS decline in high dose group (n=12) vs external controls. But there is no significant effect in the low dose group (n=12). With regard to CSF Nfl, the report shows average reduction in CSF Nfl in both low and high dose groups individually compared to baseline. No mention of P values. From the data, the reductions are likely not statistically significant from either baseline or between the high dose and low dose groups. Reviewing the data, I see two major concerns: small case sample size (paired with unusually large controls) and short follow up period for a noisy outcome measure such as cUHDRS. Firstly, there are only 12 individuals in each case arm (with 36 months data) and 568 individuals in control arm. The control sample is disproportionately larger than case sample size. It's difficult to confidently assess a different between these two groups. The variations in the control group would be smaller due to large N, but the variations in the case group would be bigger with mere chance pushing the average to extremely higher or lower levels. Currently, individual data points are not reported. It's possible that even one or two patients with extreme scores would have pushed the average of trial participants higher favoring a statistical significance. If the number of controls is reduced to, let's say, n<100, it's possible the P value becomes bigger, even to non-significant level (P>0.05). One might get excited about the large effect size, 80%, but effect estimates are meaningless for extremely small sample size. Secondly, the 3 year follow up is short for tracking HD's disease course. HD has a really long latent period and the disease progression happens slowly until very late stages when things escalate quickly. Also, the neuronal damage happens asynchronously. The disease course can differ wildly between patients with some staying stable for many years while other worsening quickly. Given this complexity, interpreting a 3 year readout based on n=12 individuals is challenging. My other major concern is the low dose group, in which there is no meaningful effects either at 24 months or at 36 months. Even worse, with regard to some measures they seem perform poorly compared to controls. This is worrying, as it suggests there is no dose dependent effect. But we don't know for sure. Much longer follow up is needed. Adding to the concern, the press release avoided mentioning anything about low dose group, and focussed only on high dose group. Of course, even a remote possibility that this gene therapy works and may give back years of quality life to HD patients should excite anyone in the field. I am excited too. But at the same time, one should be also cautious in interpreting the results and raising hopes for patients and families. For now, I'd say we should be cautiously optimistic about this readout and wait for longer follow up results. Of course, it's possible the drug clear regulatory approval and gets rolled out to many patients. But it's gonna take a long time before we really know if it's truly working.