Hematology Drugs in the Pipeline

Jennifer R. Brown, MD, PhD

ABT-199

ABT-199 clears bone marrow very effectively, and appears to be more active than the other novel agents in the clinic in CLL. In the ABT-199 combination study with rituximab (Rituxan; Genentech, Biogen Idec) in patients with CLL who underwent a median of two prior regimens, the complete remission rate was 36%. Minimal residual disease negativity was observed in most patients who achieved complete response, as well as in some patients who achieved partial response.
These results have led to currently ongoing registration trials in CLL, although clinical development was slightly delayed by the need to understand and manage the tumor lysis syndrome that can be seen. The drug is now given via slow dose escalation over weeks, in the hospital for patients with high disease burden.
Moving forward, what is particularly unique about ABT-199 is that its mechanism of action is potentially complementary and synergistic with the BCR pathway inhibitors. Thus, combinations of ABT-199 and a BCR pathway inhibitor would be expected to be quite potent in inducing deep remissions, and might therefore allow fixed-duration therapy for some patients. ABT-199 also might work for consolidation or maintenance given its potency in clearing bone marrow. The future of CLL therapy is bright with the plethora of novel agents, and ABT-199 represents a unique class.

Jonathon B. Cohen, MD, MS

Nivolumab

The PD-1 antibody nivolumab (Opdivo, Bristol-Myers Squibb) currently is under investigation in relapsed non-Hodgkin’s lymphoma and Hodgkin’s lymphoma. The FDA granted breakthrough status to this agent for treatment of patients who have failed autologous stem cell transplant owing to promising preliminary results. PD-1 serves as an immune checkpoint, and this pathway may be harnessed by the tumor to evade the body’s immune system and allow for continued growth and progression. By blocking this pathway, nivolumab activates the immune system and allows for destruction of tumor cells. This agent is currently being studied in diffuse large B-cell lymphoma, follicular lymphoma and Hodgkin’s lymphoma in phase 2 studies as a follow-up to a phase 1 study in hematologic malignancies, and results are highly anticipated. The drug is well tolerated, although there have been cases of pneumonitis and other immune-mediated adverse events that merit further study. Overall, this is a very promising agent for patients with relapsed non-Hodgkin’s lymphoma after autologous transplant, where options remain sparse and often are limited to combination chemotherapy and/or allogeneic transplantation. In Hodgkin’s lymphoma, I expect this agent to be approved in the coming years if the current phase 2 study confirms promising activity, and I expect this agent will become a standard therapy for patients with relapsed disease.

Cristina Gasparetto, MD

Filanesib

A series of new agents have transformed therapy for multiple myeloma over the last decade. Although exciting progress has been made, cure remains elusive. Therefore, new therapies with unique mechanism of action and manageable toxicity are needed, particularly for heavily pretreated patients whose disease is refractory to immunomodulatory drugs (IMiDs) and protease inhibitors (PIs).
Filanesib (ARRY-520, Array BioPharma) promises further improvement in outcome as a first in class anti-proliferative agent that specifically targets kinesin spindle protein (KSP), leading to mitotic arrest and eventual apoptosis.  
Clinical studies have evaluated daily doses of 1 mg/m² to 2.25 mg/m² for 2 days of a 2-week cycle, with or without filgrastim support, with a maximum recommended dose in most current studies of 1.5 mg/m² daily. The primary single-agent toxicity has been varied cytopenias in half the patients. Common non-hematologic adverse events are fatigue, dizziness, arthralgias, nausea, constipation or diarrhea. Overall response rates range from 20% to 25%, with a median time to response of nearly 4 months and an encouraging duration of response in heavily pretreated patients. Improvements may come from identifying biomarkers predictive of response, such as alpha 1 acid glycoprotein (AAG). Levels of this protein are noted to be variable in patients with myeloma, and those with a higher level are noted in early studies to have a lower chance of response. Use of an AAG level to determine appropriateness of therapy with filanesib is under evaluation. In addition, as it targets cancer cells in a completely different way from currently available agents, there is significant interest in combination studies. In preclinical models, filanesib showed synergistic activity with bortezomib (Velcade, Millennium) and pomalidomide (Pomalyst, Celgene), providing the rationale of combining this agent with PIs and IMiDs. Preliminary results of studies of filanesib in combination with bortezomib or carfilzomib (Kyprolis, Onyx Pharmaceuticals) are very promising, with response rates of 30% to 40% in heavily pretreated patients. For example, in a phase 1 study, filanesib plus bortezomib and dexamethasone with prophylactic filgrastim appeared well tolerated, with partial responses observed in approximately 30% of patients who have failed multiple lines of therapy and with disease refractory to bortezomib (Chari A. Abstract #1938. Presented at: ASH Annual Meeting; Dec. 7-10, 2013; New Orleans). Studies to further assess the safety and efficacy of single-agent filanesib or filanesib in combination with other agents are ongoing.
 

Ruben A. Mesa, MD

Pacritinib, Momelotinib

As 2015 begins, there remains one FDA-approved therapy for myelofibrosis (primary myelofibrosis or post-polycythemia vera or post-essential thrombocythemia myelofibrosis), and this is ruxolitinib (Jakafi, Incyte). Ruxolitinib has been demonstrated to improve symptomatic burden to a significant degree in patients with myelofibrosis and improve splenomegaly, and long-term data suggest an impact on survival.
One area of unmet need in JAK inhibitor therapy centers around the ability to either (1) improve cytopenias, such as baseline anemia or thrombocytopenia; or (2) have less drug-induced cytopenias, as can be seen with ruxolitinib. On this basis, there are currently two JAK inhibitors in clinical development in phase 3 testing seeking FDA approval in this space.
Pacritinib (SB1518; CTI Biopharma, Baxter) is a selective JAK2 infiltrate inhibitor. Phase 1 and 2 clinical trials of pacritinib in the United States and Australia demonstrated activity in myelofibrosis, associated splenomegaly and symptom burden without any significant drug-associated thrombocytopenia or anemia. On this basis, two phase 3 clinical trials are both active.
The first, PERSIST-1 (NCT01773187), randomized patients with intermediate- and high-risk myelofibrosis without a baseline limitation on the presence of thrombocytopenia. Patients were randomly assigned 2:1 to pacritinib 400 mg daily or best alternative therapy excluding ruxolitinib. The goals of this trial are to show a >35% reduction in splenic volume, improvement in myeloproliferative neoplasm (MPN) symptoms by the MPN Symptom Assessment Form, and improvement in the peripheral blood counts, or at least stability in the peripheral blood counts. The PERSIST-1 study has completed accrual and continues to be monitored for appropriate results.
The parallel study, PERSIST-2 (NCT02055781), includes intermediate- and high-risk myelofibrosis in patients with baseline thrombocytopenia of <100 x 109 per liter. Patients with prior exposure to JAK inhibitors are eligible. In this study, patients are randomly assigned 1:1:1 to pacritinib at 400 mg once daily; pacritinib at 200 mg twice daily; and best alternative therapy. Again, outcome measures are >35% reduction in splenic volume, improvement in MPN Symptom Assessment Form, and issues around the blood counts.
This entire program will be analyzed and assessed for impact and might have the ability to not only highlight monotherapy in patients with baseline thrombocytopenia in particular, but perhaps make it amenable to pursue combination therapy with other agents in patients who have baseline cytopenias.
Momelotinib (Gilead) is a selective JAK1/JAK2 inhibitor. Phase 1 and phase 2 clinical trials demonstrated improvements in splenomegaly symptoms and anemia (either improvement from baseline or less drug-associated anemia), with an overall response rate of 59%.
There are two ongoing phase 3 clinical trials seeking demonstration of momelotinib’s activity. In the first (NCT01969838), patients with intermediate- and high-risk myelofibrosis with platelet counts >50 x 109/L are randomly assigned to momelotinib 200 mg twice daily vs. ruxolitinib (dosing chosen by the principal investigator). Outcome measures include response around >35% reduction in splenic volume, symptomatic improvement in the MPN Symptom Assessment Form, and improvements in anemia.
A parallel study (NCT02101268) includes patients with intermediate- and high-risk myelofibrosis based on anemia and/or thrombocytopenia, with no exclusion for prior JAK2 exposure. In this trial, patients are randomly assigned to momelotinib or best alternative therapy, including ruxolitinib. Endpoints include improvements in splenic volume, symptoms and anemia.

Srikanth Nagalla, MBBS, MS, FACP

Pacritinib

Pacritinib (SB1518; CTI BioPharma, Baxter), a novel JAK2/FLT3 inhibitor, is being studied for the treatment of myelofibrosis and acute myeloid leukemia. The currently approved JAK2 inhibitor, ruxolitinib (Jakafi, Incyte), has good efficacy in patients with splenomegaly and baseline symptoms but has treatment-emergent myelosuppression as one of the main side effects. Patients who have myelofibrosis with thrombocytopenia have a poor prognosis, and it is essential to have drug options to treat this group of patients. Pacritinib showed promising results in phase 2 studies in terms of spleen response rate, the duration of spleen response and control of baseline symptoms without the side effects of thrombocytopenia and anemia.
PERSIST-1 — a phase 3 study of pacritinib in patients with myelofibrosis irrespective of platelet counts but without prior JAK2 inhibitor therapy — has completed accrual, and we are awaiting results. PERSIST-2 is a phase 3 study currently underway in patients with a platelet count ≤100,000/microliter who underwent prior JAK2 therapy or are undergoing current JAK2 therapy. If the study results are positive, then pacritinib definitely would be a good option for the unmet need of myelofibrosis patients with cytopenia issues. The drug also is being studied in relapsed FLT3-mutated AML, and it has demonstrated some activity in relapsed Hodgkin’s and non-Hodgkin’s lymphomas.

Susan P. Perrine, MD

Vepoloxamer

Vepoloxamer (MST-188, Mast Therapeutics) — a rheological polymer that binds damaged endothelium and reduces blood viscosity and cell adhesion — is being studied for reduction in duration of sickle cell vaso-occlusive crises. Despite extensive basic science regarding polymerization of sickle hemoglobin with red cell adhesion to vascular endothelium, there are no therapeutics available that can halt an acute crisis and restore blood flow to an ischemic region. Every crisis is concerning due to potential for evolution to a life-threatening event and chronic organ damage. Only supportive symptomatic remedies are available, and patients routinely are discharged while still in significant pain.
Now a definitive therapy for sickle vaso-occlusive crisis is in sight. Vepoloxamer is being studied in the EPIC study, a phase 3 trial that includes 388 sickle-cell patients (NCT02093468). The well-defined primary endpoint is resolution of vaso-occlusive crisis. Secondary endpoints include rates of re-hospitalization and acute chest syndrome. Prior studies in more than 255 patients already demonstrated a significant change in proportion of subjects achieving crisis resolution, as well as improvement in mean duration of hospitalization for vaso-occlusive crisis (Orringer EP. JAMA. 2001;286:2099-2106). Vaso-occlusive crisis duration is a high bar, affected by many individual factors and regional practice, but if a portion of subjects who receive drug treatment demonstrate reduction in crisis duration, or in rates of a secondary outcome, vepoloxamer would provide a desperately needed therapy.