Uniqure - 4-year data update

Uniqure dropped 37% yesterday following its 4-year data update on AMT-130 for Huntington.

My base case remains AMT-130 will be approved. Now turning back to what happened.

This is the punch line: " cUHDRS showed a 44% slowing of disease progression compared to the updated external control and did not reach statistical significance (p=0.144)." Did not reach statistical significance. Also note how its improvement slowed from 75% improvement in 3-year data to "only" 44%.

See Pic 1. It showed its patients deteriorated at a much faster pace between Yr3 and Yr 4. In comparison, the Enrol-HD population deteriorated at a much slower pace. Put simply, AMT-130 stopped working for its patients after 3 years ?

A few things going on:

1. In the Enrol-HD natural history population, missingness of data increased with duration of follow-up, reaching 53% in the updated ENROLL-HD matched controls at 48 months i.e. many patients stopped being followed as they advanced after disease onset for more than 4 years. Maybe they got sicker. Hard to move around etc etc... As a result, the Enrol-HD database only shows the "better off" patients relative to the general patient population. If true, it supports the slow down in the gradient of the decline between Yr3 to Yr 4. See Pic 1.

2. Remember Uniqure only has a sample of 12.... Thus, the signal noise is amplified. cUHDRS is a composite core (of TMS (motor score), SDMT (symbol digit modalities), total functional capacity (the quality of life, can still work), SWRT (stroop word reading test). In the final 4-year cut, outlier data in TMS of one patient apparently screwed up the composite score of the 4-year. Also some fluctuations in SDMT in a few of the patients.

3. Of the 4 sub-components, TFC is the important measure - it measures if the patient can carry on with their life. At 4-year mark, 61% slowing of disease progress for AMT-130 patients. See Pic 2.

So what is the take away ? My take is the Enrol-HD comparison pool probably got "healthier" as the sicker patients dropped out of the database. See Pic 3 for comment from Dr Sung (who is one of the investigator of the trial). His take is his patients typically deteriorates at similar pace (vs. the 4-year data showing slowing pace of decline).

The "better" TFC performance for AMT-130 patients is important as it is the "outcome" the confirmatory trial is going to track.

What does it mean for Uniqure ? Uniqure has submitted its drug for approval with the FDA and UK. Importantly, the regulators are asking for the 3-year data in the formal application. So the 4-year data is something for reference purpose. 3-year data still looks good (in the 4-year package, 2 more patients reached 3-year post treatment and the 3-year data got even better).

It is likely the FDA will hold an Adcom (where FDA will invite experts to hear and pro and con of AMT-130) as part of the approval process.

Given that there is no alternative for Huntington disease + my sense is the drug works (low dose vs. high dose + nfl data), my base case is it will still be approved despite the "less than stellar" front page news on the 4-year data. Also see Pic 4 for comment from Dr Sung i.e. his patients are still going about their live as before considering....

What we don't know ? How would insurance co/payor consider coverage for AMT-130 given that it will be quite expensive ? How about take up by patients ? The TFC score is especially important. The treatment will allow patients to live a normal life as long as possible. I still think take up will surprise (in a good way).

What to do with the stock ? After the fall, MV is $1.7bn. It has $800M in cash (runway to 2030). BLA was filed in Sept... So approval by Sept 27 remains possible (if not likely). I suspect peak sales will be better than $2-3bn expected in most models so upside to the stock from current level.

In addition, in 1H 27, we will get more data on its epilepsy program. Keep in mind the epilepsy TAM is much larger than Huntington (600K patients in USA alone vs. 40K symptomatic + 200K at risk for Huntington).

In summary, I still think the drug works. It will likely be approved. In the coming 1-2 years, stock should be higher than current level ($24.5).

PS... Do you own research. Not advice. I may own/trade the stock.