Mesa Highlights JAK Inhibition for the Treatment of Myelofibrosis

Ruben Mesa, MD

JAK inhibitors have paved the way and improved clinical outcomes for patients with myeloproliferative neoplasms over the past decade. Not only have these agents shown significant improvements in efficacy outcomes, but they have demonstrated favorable safety profiles in this patient population.

Currently, 3 JAK inhibitors are approved for patients with myelofibrosis. The first was ruxolitinib (Jakafi), which was approved by the FDA in 2015 and continues to be the main therapy for patients with myelofibrosis. Patients treated with ruxolitinib have had improved splenomegaly and constitutional symptoms, as well as an observed survival benefit.

Following the approval of ruxolitinib came 2 more, including the JAK2 inhibitor fedratinib (Inrebic) which was approved in 2019, and pacritinib (Vonjo) in 2022. Studies of fedratinib have confirmed that the agent is a beneficial second-line treatment option for patients who are ruxolitinib-resistant. Pacritinib also continues to serve as a good treatment option for patients with myelofibrosis and severe thrombocytopenia.

Now, another JAK1/2 inhibitor is in clinical development, known as momelotinib, and is being evaluated in the phase 3 MOMENTUM trial (NCT04173494) for patients who are symptomatic and anemic with advanced myelofibrosis. Those enrolled in MOMENTUM must have previously been treated with a JAK inhibitor, and findings from the study already have revealed clinically significant improvements with momelotinib vs danazol in this patient population.

Data from the MOMENTUM study revealed that 25% of patients treated with momelotinib (n = 130) had a 50%, or more, reduction in patient’s Myelofibrosis Symptom Assessment Form Total Symptom Score (TSS) vs 9% of patients treated with danazol (n = 65), making a proportion difference of 16%. Researchers confirmed this difference to be statistically significant (95% CI, 6–26; P =.0095).

Now, the United States has assigned a Prescription Drug User Fee Act (PDUFA) action date of June 16, 2023.

“We are in an unprecedented period of excitement around new therapies for myeloproliferative neoplasms. Each response and benefit with JAK inhibitors showed a lot of great updated data, [including] momelotinib, which may be approved in 2023,” Ruben Mesa, MD, told Targeted Oncology^TM, in an interview.

In the interview, Mesa, director of the UT Health San Antonio MD Anderson Cancer Center, discussed the currently available JAK inhibitors for patients with myelofibrosis, and what is in store for the field.

Targeted Oncology: Can you discuss some of the approved JAK inhibitors in the myelofibrosis space?

Mesa: For myelofibrosis, we are excited to have 3 FDA-approved therapies, ruxolitinib, pacritinib, and fedratinib, that are all inhibitors of JAK2. Ruxolitinib is from 2011, fedratinib is from 2019, and pacritinib which [was approved in 2022]. Ruxolitinib and fedratinib are both approved in the frontline setting as well as fedratinib in the second-line setting. Now pacritinib is approved in the front and second-line settings for patients who have a platelet count of less than 50,000, and certainly, is a consideration for platelet counts under 100,000 or as a third-line in any patient. These have been a great help.

We have momelotinib coming up on the heels. That might become an approved therapy in 2023. We anticipate all these agents will hopefully improve spleen and symptoms. I think in responding patients, probably all will have a beneficial impact in terms of survival, and we're excited to have these to build from in this space.

Can you explain the purpose behind the MANIFEST trial and the SIMPLIFY-1 study?

What the MANIFEST study was looking at was pelabresib [CPI-0610] in combination with ruxolitinib, either in the frontline or second-line setting. That was the goal, and we've been excited by the data that shows a good depth of response as a single agent with JAK inhibition, as well as potentially extending further the types of benefits that might be seen. That's helped us to set up the MANIFEST-2 that is ongoing.

The MOMENTUM study, a different study, is [looking at] second-line therapy, symptomatic myelofibrosis with anemia, and showed that momelotinib is clearly superior compared with danazol. These data provide further study updates showing the durability of response screaming symptoms anemia. We are excited about this data.

What is the most new, exciting, and practice changing data in the myeloproliferative neoplasm space?

We are in an unprecedented period of excitement around new therapies for myeloproliferative neoplasms. Each response and benefit with JAK inhibitors showed a lot of great updated data, [including] momelotinib, which may be approved in 2023, as well as pacritinib and validating data with fedratinib. Combinations and phase 2 studies, whether with parsaclisib, venetoclax [Venclexta], pelabresib, or other combinations that may be coming, these combination therapies are truly the way of the future, so it is an exciting time.