ASH: Preliminary Clinical Data for TP-3654 in Myelofibrosis

On Saturday, December 10, at the 64th American Society of Hematology Annual (ASH) Meeting in New Orleans, Sumitomo Pharma Oncology, Inc. presented preliminary clinical data from an ongoing Phase 1/2 study of investigational agent TP-3654, a selective oral PIM1 kinase inhibitor, in patients with myelofibrosis (MF) previously treated with or ineligible for Janus Associated Kinase (JAK) inhibitor therapy. To view the full presentation, please visit here.

On Saturday, December 10, at the 64th ASH Annual Meeting, Sumitomo Pharma Oncology, Inc. presented preliminary clinical data from an ongoing Phase 1/2 study of investigational agent TP-3654, a selective oral PIM1 kinase inhibitor, in patients with MF previously treated with or ineligible for JAK inhibitor therapy.

Preliminary data in the dose-escalation portion of the study showed encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors. In this study, TP-3654 was generally well tolerated with limited myelosuppressive adverse events.¹

The TP-3654 study is a Phase 1/2, multicenter, dose-escalation, open-label trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of TP-3654 in patients with intermediate or high-risk primary or secondary MF. To learn more about the study and eligibility for enrollment, visit https://clinicaltrials.gov/ct2/show/NCT04176198.

About Myelofibrosis

MF is a rare and severe form of bone marrow cancer that disrupts an individual’s normal production of blood cells and causes scarring of the bone marrow.² There are approximately 1.5 reported cases of MF per 100,000 in the United States annually.³ MF is attributed to a dysregulation of the JAK/Signal Transducers and Activators of Transcription (JAK/STAT) signaling networks.⁴ A somatic JAK2-V617F mutation, which results in constitutive activation of the JAK2 tyrosine kinase, has been found in 40 to 60% of patients with MF.⁵

Current Treatment Options

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative intervention available for MF, but significant challenges include treatment-related toxicities, graft failures, graft-versus-host disease (GVHD), and high morbidity/mortality.⁶

With the discovery of the dysregulated JAK/STAT pathway and the JAK2-V617F mutation, small molecule inhibitors of the JAK pathways have emerged as standard of care for MF.⁵ However, the success of JAK treatment has been limited by thrombocytopenia and anemia side effects, as well as failure to modify disease. Most patients have either an inadequate response or eventual loss of response; patients who develop cytopenia or who progress have a poor prognosis, and those with anemia or thrombocytopenia (both common) are not candidates for JAK inhibitor dose optimization. Combination regimens are possible if overlapping toxicities (including cytopenia) can be avoided. The ideal combination partner would be disease modifying, have minimal cytopenia, reduce spleen volume, and improve symptoms.

“While there are several approved treatments for MF, there remains a need for improved MF therapies that bring novel or unique mechanisms of actions and can address some of the challenges experienced by patients on JAK inhibitors,” said Firas El Chaer, MD, assistant professor of hematology and oncology at University of Virginia (UVA) in Charlottesville, VA and principal investigator for the clinical trial at UVA. “Preliminary clinical data from the Phase 1/2 trial, including signals of spleen volume reduction, symptom improvement, and broad cytokine reduction, coupled with favorable safety data, reinforce the potential for PIM1 kinase inhibitors such as TP-3654 as a future treatment for myelofibrosis.”

Preliminary TP-3654 Clinical Data Presented at ASH

Data presented at ASH were based on 9 patients enrolled in the ongoing Phase 1/2 study (NCT04176198). Safety and tolerability were the primary endpoints, with secondary endpoints including spleen volume reduction, total symptom score reduction, overall survival, bone marrow fibrosis change, and pharmacokinetics.¹

Results from the Phase 1 monotherapy dose-escalation portion of the study (480 mg QD to 1440 mg BID) were as follows (data as of October 11, 2022):

• No dose-limiting toxicities or related serious adverse events (AEs) observed
• Most common AEs were transient Grade 1 diarrhea, nausea, and vomiting resolving within 1-2 weeks
• Transient Grade 3 anemia and thrombocytopenia observed in 1 patient
• No dose reductions or discontinuations needed due to AEs
• Lab values stable for platelet count, hemoglobin, and neutrophils during treatment

Among the 8 patients whose clinical activity was evaluable (treated for at least 12 weeks):

• 6 patients had spleen volume reduction (SVR)
• Median SVR was 11%
• 2 patients had at least 35% SVR
• 7 patients had total symptom reduction (TSS; MF-SAF v4.0)
• Median TSS reduction was 66%
• 5 patients had at least 50% TSS
• Cytokine reduction was observed as early at Week 4 and generally correlated with TSS reduction

Future Study Plans

TP-3654 dose escalation and enrollment as monotherapy are ongoing. The preliminary data support development of TP-3654 as potential combination therapy with JAK inhibitors, given the signals and lack of cytopenia observed to date.

Enrollment in the Phase 1/2 trial investigating TP-3654 is ongoing in the US and Japan. SMP Oncology plans to expand clinical trial sites for this study in the future. For more information about the study, study sites, and enrollment eligibility, visit https://clinicaltrials.gov/ct2/show/NCT04176198.

Jatin J. Shah, M.D., Chief Medical Officer of Sumitomo Pharma Oncology, Inc.

“We are encouraged by the preliminary results from the Phase 1/2 trial evaluating the potential of TP-3654 to advance treatment and potentially address unmet needs of patients with myelofibrosis,” said Jatin J. Shah, M.D., Chief Medical Officer of Sumitomo Pharma Oncology, Inc. “Our teams in the US and Japan are dedicated to the goal of purposefully advancing science, turning discoveries into meaningful treatments for patients with cancer.”

About Sumitomo Pharma Oncology, Inc.

Sumitomo Pharma Oncology, Inc., (SMP Oncology) is a wholly owned subsidiary of Sumitomo Pharma Co., Ltd. As a global oncology organization with teams in the US and Japan, SMP Oncology is committed to the goal of advancing purposeful science by transforming new discoveries into meaningful treatments for patients with cancer. SMP Oncology's robust and diverse pipeline of preclinical and clinical-stage assets spans multiple areas, including oncogenic pathways, survival mechanisms and novel protein interactions, which aim to address unmet clinical needs in oncology. For more information about our pipeline, please visit https://oncology.sumitomo-pharma.com/pipeline/.

References

1. Firas El Chaer, MD, James McCloskey, MD, et al. Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy. American Society of Hematology (ASH) 2022 Annual Meeting & Exhibition. 10 December 2022.

2. Myelofibrosis - symptoms and causes. Mayo Clinic. Accessed November 23, 2022. https://www.mayoclinic.org/diseases-conditions/myelofibrosis/symptoms-causes/syc-20355057

3. Myelofibrosis: symptoms, types, prognosis & treatment. Cleveland Clinic. Accessed November 23, 2022. https://my.clevelandclinic.org/health/diseases/15672-myelofibrosis

4. Krauth MT, Burgstaller S, Buxhofer-Ausch V, et al. Ruxolitinib therapy for myelofibrosis in Austria. Wien Klin Wochenschr. 2018;130(17):495-504. doi:10.1007/s00508-018-1365-5

5. Assi R, Verstovsek S, Daver N. “JAK-ing” up the treatment of primary myelofibrosis: building better combination strategies. Curr Opin Hematol. 2017;24(2):115-124. doi:10.1097/MOH.0000000000000320

6. Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood. 2012;120(7):1367-1379. doi:10.1182/blood-2012-05-399048