Little evidence supports drug’s use for treating anemia in myelofibrosis
Analysis says therapy's 'superiority' over other meds not shown in trials
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A research team says more evidence is needed to demonstrate the benefits of Ojjaara for treating anemia in myelofibrosis. (Image from iStock)
The approved med Ojjaara (momelotinib) can help control spleen enlargement and disease symptoms in people with myelofibrosis, especially those with anemia, or a lack of healthy red blood cells. However, whether the drug’s potential benefits for anemia give it an advantage over other approved therapies of its type remains unclear, according to a new analysis.
Ojjaara, widely used to treat this blood cancer, is a JAK inhibitor — a mainstay of myelofibrosis treatment, which helps shrink the spleen and ease symptoms. While these medications can typically worsen anemia in patients, Ojjaara, which works in a different way, is believed to lessen this symptom.
In this analysis, the researchers sought to “critically [evaluate] the clinical benefit” of the oral therapy in people with myelofibrosis with anemia. To that end, the team examined two pivotal Phase 3 trials that supported Ojjaara’s approval.
The scientists found that, although the studies provided evidence of spleen and symptom control, they were not primarily designed to establish the treatment’s benefits for anemia — making it difficult to determine whether Ojjaara offers an additional clinical advantage.
“[Ojjaara] demonstrates a differentiated clinical profile with consistent spleen control and potential hematologic benefits, particularly in anemic patients,” the researchers wrote. “However, superiority over other improved JAK inhibitors has not been demonstrated in the pivotal phase 3 trials evaluated.”
The study, “Reassessing the clinical value of momelotinib in myelofibrosis: An ESMO-MCBS:H–based appraisal of SIMPLIFY-1 and MOMENTUM,” was published in Critical Reviews in Oncology/Hematology.
In myelofibrosis, scar tissue builds up in the bone marrow, the spongy centers of certain bones, interfering with the production of new blood cells. Common manifestations include an enlarged spleen and anemia, which can cause myelofibrosis symptoms such as fatigue and weakness, and are associated with poorer quality of life and shorter survival. As anemia worsens, some people may need regular blood transfusions.
JAK inhibitors, taken as tablets or capsules, are a standard treatment for myelofibrosis. However, established meds such as Jakafi (ruxolitinib) and Inrebic (fedratinib) can worsen anemia, potentially increasing the need for blood transfusions.
Ojjaara designed to potentially ease anemia
Ojjaara was designed to work differently. In addition to blocking JAK1 and JAK2, it inhibits ACVR1, which lowers hepcidin levels, a hormone that restricts the iron available for red blood cell production. This gives Ojjaara the potential to ease anemia while also controlling spleen enlargement and other symptoms, according to GSK, which markets the therapy, sold in Europe under the brand name Omjjara.
There is a catch, however: The pivotal late-stage trials that supported Ojjaara’s approval for adults with intermediate- or high-risk myelofibrosis and anemia were not primarily designed to assess the treatment’s benefits for anemia. Those trials, SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494), involved more than 600 people with this cancer, but tested the treatment against other meds.
That left the team with an important question: How meaningful are Ojjaara’s demonstrated benefits for people living with myelofibrosis?
To address this, researchers reassessed data from the two trials using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale for Hematological Malignancies (ESMO-MCBS:H), a standardized tool for evaluating how much meaningful benefit a cancer treatment provides.
Rather than looking only at whether a treatment met a certain trial endpoint, the scale considers outcomes that matter to patients, including survival, disease symptoms, quality of life, and treatment side effects. For treatments not intended to cure the disease, grades range from 1 — the lowest clinical benefit — to 5, for the highest. When the available evidence does not meet the requirements for formal scoring, the treatment’s clinical benefit is considered not evaluable.
Trials testing therapy did not assess anemia outcomes
In SIMPLIFY-1, adults who had never been given a JAK inhibitor were randomly assigned to receive Ojjaara or Jakafi. After 24 weeks, or nearly six months, slightly more than one-quarter of those given Ojjaara achieved at least a 35% reduction in spleen volume, compared with 29% on Jakafi. That met the study’s main goal of showing Ojjaara was not inferior to Jakafi at shrinking the spleen.
Under the ESMO scale, however, Ojjaara’s clinical benefit based on SIMPLIFY-1 was considered not evaluable. That was because the trial did not demonstrate an improvement in quality of life and/or treatment side effects, as required for a positive score in a noninferiority study.
In MOMENTUM, people with anemia and symptoms despite previous JAK inhibitor treatment received either Ojjaara or danazol, a steroid medication used to manage anemia.
After 24 weeks, 25% of those given Ojjaara had at least a 50% reduction in symptom scores, compared with 9% on danazol. Ojjaara therefore met the study’s main goal, demonstrating it was better than danazol at reducing myelofibrosis symptoms.
Under the ESMO scale, Ojjaara’s clinical benefit based on MOMENTUM was rated grade one, the lowest on the five-point scale. This was because the main outcome measured the proportion of participants who achieved a certain level of symptom lessening, which the scale treats as a response rate rather than as direct evidence of symptom improvement. Moreover, although Ojjaara improved several patient-reported aspects of quality of life, the study did not show an improvement in overall quality of life that would warrant a higher score.
MOMENTUM also assessed transfusion independence, but tested whether Ojjaara was not inferior to danazol rather than whether it was better, limiting the ability to establish a superior anemia-related benefit.
The magnitude of clinical benefit [for anemia with Ojjaara] remains moderate and somewhat uncertain, primarily due to limitations in trial design and endpoint selection.
“Collectively, these trials confirm [Ojjaara’s] capacity to control [spleen enlargement] and symptoms comparably to currently approved therapies,” the researchers wrote. However, they noted that “the magnitude of clinical benefit remains moderate and somewhat uncertain, primarily due to limitations in trial design and endpoint selection.”
Thus, although Ojjaara “shows promise particularly in the anemic and symptomatic setting,” the researchers said current evidence “does not fully establish its superiority over other JAK inhibitors,” particularly for blood-related outcomes.
“Future prospective, well-powered studies incorporating anemia-focused primary endpoints” are thus needed to more precisely define Ojjaara’s role in clinical practice, the researchers concluded.
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