Navitoclax Shows Promise for Patients with Myelofibrosis

In an interview with Pharmacy Times at the American Society of Clinical Oncology 2022 Annual Meeting, Ahmed Kotb, MD, vice president of US medical affairs, oncology, at AbbVie, discussed new findings from the REFINE trial and what they could mean for patients with myelofibrosis.

What are current treatment approaches for myelofibrosis and why is there a need for new therapies?

Ahmed Kotb, MD: So, myelofibrosis is a rare hematological malignancy. It happens when a gene is mutated in stem cells of patients, and what happens is it leads to fibrosis of the bone marrow. And patients start suffering from decreased production of essential blood cells—so, anemia, fatigue, pain. Unfortunately, over the last decades, there's not been much innovation happening in therapies for these patients. So, patients are usually elderly when they're diagnosed. And they're classified either that they are eligible for a stem cell transplant, or they're not, depending on comorbidities and to the degree that bone marrow has fibrosis. The majority of patients are not eligible for transplant. And so, for those groups of patients, unfortunately, there's only 1 mechanism of action that today is currently available, which is the JAK inhibitors. Ruxolitinib, for example, has been around for nearly a decade. And so that's why there's definitely a need for more advanced mechanisms of actions so that they can enable physicians and patients to advance the standards of care and potentially improve the outcomes for these patients.

How does navitoclax work to fill these needs and how does it work with JAK inhibitors?

Ahmed Kotb, MD: So, navitoclax is a Bcl-xL inhibitor. Bcl-xL is one of the commonly expressed proteins in the cancer cells with myelofibrosis. And by doing that, navitoclax is able to induce cancer cell death. And so, by doing that, you reverse almost the process of inflammation and cytokine release that happens in the bone marrow, which we believe will eventually lead to a reversal or modification of the disease. So, it has a disease modifying activity. What we see in our clinical program so far is that, actually, the bone marrow fibrosis decreases over time and with therapy with navitoclax.

What are the methods and goals of the REFINE trial?

Ahmed Kotb, MD: So, the REFINE study is a phase 2 study. It has 4 cohorts: Cohort 1A, which was a dose finding cohort; cohort, 1B, which looked at adding navitoclax to ruxolitinib in patients who had failed a prior JAK inhibitor; cohort 2, which was navitoclax monotherapy; and cohort 3, which is adding navitoclax to ruxolitinib in patients who are JAK-naïve. The primary endpoint for this study was always looking at SVR, which is a standard endpoint in the setting and it looks at spleen volume reduction. And we usually measure it at a standard time point, which is 24 weeks after the start of therapy, and we look for at least a 35% reduction. The other endpoints were total symptom score, so reduction in the amount of symptoms that a patient reports, and we're looking at 50% of that reduction. And we also looked at the amount of bone marrow fibrosis and how navitoclax was able to reduce that.