The pre-clinical data gives me slightly more strength in my positive conviction. The AEs related to selinexor and how they impact absTSS are the biggest ?, that’s the key risk.

Looking into the pre-clinical data a bit, they demonstrate a few key things - hemoglobin stabilization (anemia is a key consideration), active in JAKi-resistant cell lines, selective for MF cells, independent target ID via shRNA

Please note that this isn’t advice. Do your own work. Also, there is a lot of risk.

So what does all of this mean? Well, the risks are real. However, sel outperformed PELA (the drug from manifest-2) on most of the ph1/2 studies that I can find. I need to look more into the pre-clinical data, but I’m cautiously optimistic that $KPTI could hit both primary endpoints

I’m not a statistician (it get complex with multiple measurements), but my rule of thumb is that $KPTI will need to hit close to -18 to be statistically significant.

Third knock is the statistical challenge of hitting absTSS. Manifest-2 had 430 patients. There absTSS for the treatment arm was -16.24 vs -14.11 for the control. They missed statistical significance, barely. $KPTI is running a very similar but smaller study. $KPTI will need to outperform manifest-2

Another risk is that sel comes with safety risks. It is approved in other indications, but the knock has always been the safety. With that being said, one of the co-primary endpoints is absolute symptom score. Some of the symptoms are also some of the adverse effects of the drug (e.g., fatigue)

What are the risks/negatives? Well $KPTI essentially skipped from a single arm ph1 to a ph3 study. We don’t know the impact of patient enrichment on the ph1 study because it wasn’t placebo controlled

One more positive for $KPTI is that they demonstrated what is considered to be monotherapy-like activity in a ph2 (XPORT-MF-035). SVR35=4/12 for selinexor vs 1/8 for physicians choice.

Additional positives, are that the study demonstrated a dose correlation with the response. The 60mg selinexor group performed better than the 40mg group. Notably, there was limited safety issues (that is a common concern with selinexor)

What data does $KPTI have going for it? They have a small single arm ph1 study of Selinexor+ruxolitinib demonstrating strong results SVR35=78.6% in ITT and absTSS=-18.5. Historical comparison of resolution alone is 58% and 14.1, respectively in Manifest-2

The study is testing selinexor+ruxolitinib vs ruxolitinib alone. Co-primary readout of SVR35 and absTSS at week 24. Approximately 350 patients randomized 2:1 study vs control.

$KPTI has a ph3 readout in myelofibrosis in Q1. This readout, if positive would be a huge inflection point for the company. However, there is a bunch of risk. Let’s get into the data/study/science.

Well, data looked good, the stock didn’t follow through though