Transcript

Hello. My name is Abdulraheem Yacoub. I'm an associate professor at the University of Kansas Cancer Center. It's my pleasure to present this work on behalf of my co-investigators.

I'll be presenting the results of a phase 2 clinical trial with the addition of parsaclisib at PI3K-delta inhibitor in patients with myelofibrosis manifest suboptimal response to treatment with ruxolitinib as the first-line therapy.

PI3K pathway is JAK inhibition which allows patients with myelofibrosis to manifest less favorable outcomes with therapy with JAK inhibition. Parsaclisib is a potent and highly selective PI3K-delta inhibitor that allows once daily dosing and has synergistic activity with ruxolitinib.

We designed a Phase II study with the addition parsaclisib as an add-on therapy to patients with a stable dose of ruxolitinib, who meet definitions of suboptimal ruxolitinib response.

The definition of suboptimal response has evolved and the definition that was implemented in the study includes treatment with ruxolitinib for at least six months with a stable dose of at least eight weeks. In addition, patients would continue to have an enlarged spleen over 10 centimeters by population or enlarge spleen over five centimeters by population in addition to disease symptoms.

For inclusion criteria, the patients needed to meet criteria for suboptimal response, as well as meet an exclusion criteria count that is over 15,000.

The primary endpoint of the study was the change in the splenic volume at week 12 compared to baseline. Multiple secondary endpoints included changes [inaudible 2:10] length and implemented quality of life in symptom scores, as well as safety. The data presented today represents the cutoff of January 2020.

Study design included multiple patients, so 53 patients were enrolled on four parts of the study. The first part was a safety run-in cohort with addition of parsaclisib to ruxolitinib. Then, patients were enrolled in parts two, three, and four, in which patients received either a daily loading dose full by weekly maintenance. This will be called the daily-weekly protocol.

Then, the other treatment schedule was all daily loading followed by all daily maintenance. 20 patients were enrolled on the all-daily schedule and 33 patients were enrolled on the daily followed by weekly schedule.

The baseline characteristics of these patients were similar. I wanted to highlight that the median therapy with ruxolitinib in these patients was at least one and a half years to all patients and despite all of that, patients had median splenic volume of 2,000 cubic centimeters.

They continue to have a relatively high total score with a median of 55, which represents an unmet need for patients on parsaclisib with ruxolitinib and despite that they continue to manifest disease on a high-disease burden and high-disease symptoms.

Most patients who enrolled in the study are available for this analysis. Of the 20 patients enrolled in the all-day schedule, 12 continued to be on therapy and of the 33 patients who were enrolled on the daily-weekly schedule, six of which remain on therapy.

On the follow-up, the median drug exposure so far has been 28 weeks with the patients enrolled in the earlier part of their daily-weekly schedule and median exposure of 48 weeks. Patients who receive the all-day schedule will have a median exposure of 22 weeks. Patients who are older in the latter part, the old data schedule had less follow-up and less mature data.

That being said, almost 90% of all patients were treated, admitted to the primary endpoint analysis of 12 weeks. Five patients who enrolled in the study remain on therapy two years after enrollment...justifying to the safety of this combination.

The primary endpoint analysis would be the splenic volume change from baseline to week 12. As the graph shows -- I will share that with you on the subsequent slides -- is that the majority of patients who were randomized in the study had a favorable response with further splenic reduction after the addition of parsaclisib despite being on a maximum for a dose of ruxolitinib.

The effect was observed early at 12 weeks, and it was more profound and more visible at 24 weeks.

We also highlighted the results on patients receiving the all-day dosing, which we believe is the more favorable dosing schedule. The response in those cohorts of patients was even more deep and more prevalent.

On zeroing down on patients who received that five-milligram dosing schedule on an all-daily schedule, those patients seem to have had a consistent response that continues to improve with the best safety profile.

An important secondary endpoint for the study was improvement in symptom score and this was evaluated as planned secondary endpoint at 12 weeks. The majority of patients who have been on a maximum ruxolitinib dose for a median of a year and a half, had manifested a rapid and profound improvement in their symptom scores with the add-on therapy, parsaclisib.

In terms of non-hematologic side effects, there were few non-hematologic side effects, and the therapy was very well tolerated. The patients who receive the all-daily dosing, they were very few grade three or higher adverse events.

In regard to adverse events of special interest to PI3K-delta inhibitor, there were very few observed in the all-daily dosing and none were associated with colitis, pneumonitis, or opportunistic infections. We did not observe any anemia worsening with therapy. The hemoglobin values were stable through our therapy for most patients.

Obviously the admission of parsaclisib does not initiate anemia in this disease. However, thrombocytopenia was observed, and it was the dose limiting and most common reason for option of dose discontinuation.

In conclusion, for patients with myelofibrosis optimized and a stable dose ruxolitinib, the add-on therapy of parsaclisib resulted in an additional splenic volume reduction and further improvement in symptoms and disease symptoms.

This observation was noted early upon the introduction of the combination and was durable for duration of the study. The combination was well-tolerated with many patients on therapy for several years at this time. There were no dose-limiting, non-hematologic adverse events observed.

The all-daily dosing of parsaclisib seems to be more efficacious and more favorable in terms of side effects. We would like to explore that, hopefully in future larger clinical trials. Thank you very much.