Category Archives: Myelofibrosis

Karyopharm Receives FDA Fast Track Designation for Selinexor for the Treatment of Myelofibrosis

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– Regulatory Designation Includes Primary Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis and Post-Polycythemia Vera Myelofibrosis –

– Pivotal Phase 3 Study of Selinexor and Ruxolitinib in Treatment-Naïve Myelofibrosis Initiated in June 2023 –

NEWTON, Mass., July 17, 2023 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced that the United States Food and Drug Administration (FDA) has granted Fast Track Designation to the development program of selinexor for the treatment of patients with myelofibrosis, including primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis.

“Fast Track Designation for selinexor highlights its potential to address the unmet medical need in myelofibrosis, an important acknowledgement as we continue our pivotal Phase 3 study,” said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. “Selinexor’s unique mechanism of action, XPO1 inhibition, is a novel and potentially fundamental mechanism in myelofibrosis. We have been highly encouraged by the efficacy and safety data observed to date [in our Phase 1 study] with selinexor in combination with ruxolitinib in patients with treatment-naïve myelofibrosis and believe selinexor has the potential to shift the treatment paradigm. We look forward to continued interaction with the FDA as we advance the development of this promising treatment for patients in need.”

In June 2023, Karyopharm initiated a pivotal Phase 3 clinical trial (XPORT-MF-034) (NCT04562389) to assess the efficacy and safety of once-weekly selinexor 60 mg in combination with ruxolitinib in JAKi-naïve patients with myelofibrosis. Updated data from the Phase 1 study were presented at the American Association for Cancer Research Annual Meeting 2023, American Society of Clinical Oncology 2023 and European Hematology Association 2023, which showed rapid, deep and sustained spleen responses and robust symptom improvement in patients treated with selinexor 60 mg in combination with ruxolitinib as of the April 10, 2023 cut-off date.  Top-line data from the Phase 3 study is expected in 2025. The Company plans to expand its clinical development program in myelofibrosis by investigating selinexor in other JAKi-naïve settings, such as novel combinations, to benefit the greatest number of patients.

Fast Track Designation is intended to facilitate development and expedite review of drugs to treat serious and life-threatening conditions so that an approved product can reach the market expeditiously. Features of Fast Track Designation include frequent interactions with the FDA review team, and if relevant criteria are met, eligibility for Priority Review and Rolling Review.

Further information about the Phase 3 study can be found at www.clinicaltrials.gov.

About Karyopharm Therapeutics
Karyopharm Therapeutics Inc. (Nasdaq: KPTI) is a commercial-stage pharmaceutical company pioneering novel cancer therapies. Since its founding, Karyopharm has been an industry leader in oral Selective Inhibitor of Nuclear Export (SINE) compound technology, which was developed to address a fundamental mechanism of oncogenesis: nuclear export dysregulation. Karyopharm’s lead SINE compound and first-in-class, oral exportin 1 (XPO1) inhibitor, XPOVIO® (selinexor), is approved in the U.S. and marketed by the Company in three oncology indications and has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including Europe and the United Kingdom (as NEXPOVIO®) and China. Karyopharm has a focused pipeline targeting multiple high unmet need cancer indications, including in multiple myeloma, endometrial cancer, myelodysplastic neoplasms and myelofibrosis. For more information about our people, science and pipeline, please visit www.karyopharm.com, and follow us on Twitter at @Karyopharm and LinkedIn.

Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the ability of selinexor to treat patients with myelofibrosis; and expectations related to the clinical development of selinexor and potential regulatory submissions of selinexor. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm’s control, that may cause actual events or results to differ materially from Karyopharm’s current expectations. For example, there can be no guarantee that Karyopharm will successfully commercialize XPOVIO or that any of Karyopharm’s drug candidates, including selinexor and eltanexor, will successfully complete necessary clinical development phases or that development of any of Karyopharm’s drug candidates will continue. Further, there can be no guarantee that any positive developments in the development or commercialization of Karyopharm’s drug candidate portfolio will result in stock price appreciation. Management’s expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the adoption of XPOVIO in the commercial marketplace, the timing and costs involved in commercializing XPOVIO or any of Karyopharm’s drug candidates that receive regulatory approval; the ability to obtain and retain regulatory approval of XPOVIO or any of Karyopharm’s drug candidates that receive regulatory approval; Karyopharm’s results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including with respect to the need for additional clinical studies; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm’s ability to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development or regulatory approval of drug candidates by Karyopharm’s competitors for products or product candidates in which Karyopharm is currently commercializing or developing; the direct or indirect impact of the COVID-19 pandemic or any future pandemic on Karyopharm’s business, results of operations and financial condition; and Karyopharm’s ability to obtain, maintain and enforce patent and other intellectual property protection for any of its products or product candidates. These and other risks are described under the caption “Risk Factors” in Karyopharm’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2023, which was filed with the Securities and Exchange Commission (SEC) on May 4, 2023, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

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Anemia-Focused Treatment Approaches Represent Future Directions in Myelofibrosis

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July 12, 2023

Ashling Wahner

JAK inhibitor add-on agents may address an unmet need for patients with myelofibrosis with disease- or treatment-related myelofibrosis, according to Anna B. Halpern, MD, who noted that standard myelofibrosis treatments can cause adverse effects that interfere with patient quality of life (QOL).

“Myelofibrosis is generally a [relatively] rare disease,” Halpern said in an interview with OncLive®. “Having a second opinion at a center that treats a lot of myelofibrosis and has much clinical trial availability is a great option for any patient, particularly if they have higher-risk disease features.”

In the interview, Halpern discussed strides in the treatment of myelofibrosis with anemia, the shifting role of ruxolitinib (Jakafi) in this disease, and the importance of providing patients with access to clinical trials, as they may benefit from investigational treatment approaches.

Halpern also highlighted the potential benefits of moving JAK inhibitors to the upfront setting, as evidenced in cohort 3 of the phase 2 REFINE trial (NCT03222609), in which navitoclax plus ruxolitinib generated a spleen volume reduction of at least 35% (SVR35) at week 24 in subgroups of patients with JAK inhibitor–naïve myelofibrosis with historically poor prognoses, including patients at least 75 years of age (SVR35, 50%), those with a high Dynamic International Prognostic Scoring System score (SVR35, 33%), and those with HMR mutations (SVR35, 47%).1 Furthermore, she explained clinical outcomes with ruxolitinib plus pelabresib (CPI-0610) in the phase 1/2 MANIFEST trial (NCT02158858), which showed that the combination elicited an SVR35 at 24 weeks in 68% of patients with JAK inhibitor–naïve disease.2

Halpern is a physician and an assistant professor in the Clinical Research Division at Fred Hutchinson Cancer Center, as well as an assistant professor of hematology at the University of Washington School of Medicine, both in Seattle.

OncLive: How does the mechanism of action of JAK-STAT inhibitors like momelotinib contribute to their potential to ameliorate disease-related anemia?

Halpern: Disease-related anemia is partially mediated through the hepcidin pathway. JAK-STAT signaling drives overproduction of inflammatory cytokines, leading to elevated hepcidin dysregulated iron metabolism. Through the inhibition of JAK-STAT signaling, JAK inhibitors have the potential to intervene in this pathway and improve anemia.

How does the clinical benefit seen with momelotinib compare with that seen with standard agents like ruxolitinib and danazol in the anemic myelofibrosis setting?

In a study that compared momelotinib with ruxolitinib in the upfront or JAK inhibitor–naïve setting, momelotinib was better than ruxolitinib at improving anemia-related outcomes, [such as] improving or decreasing transfusion dependence, increasing transfusion independence at week 24, and decreasing the need for red blood cells. Ruxolitinib was probably better for controlling symptoms, and [the agents] were generally similarly [effective] at controlling spleen [size].

Regarding the comparison [of momelotinib] with danazol, the phase 3 MOMENTUM trial [NCT04173494] was a randomized trial of momelotinib vs danazol. This was for patients who had previously been treated with a JAK inhibitor. [In this trial], momelotinib was superior to danazol in multiple outcomes, including symptom response score, at 25% vs 9% respectively, spleen response, at 23% vs 3% respectively, and transfusion independence, at 40% vs 13%, respectively. Overall, momelotinib probably has several advantages compared with danazol.

What unmet needs exist for patients with myelofibrosis, and what should be done to address these?

One of the biggest unmet needs I see often in clinic is anemia. [Anemia occurs] both because of disease and because it’s a treatment-emergent effect with some JAK inhibitors. Ruxolitinib primarily interferes with erythropoietin signaling in the JAK-STAT pathway, which is essential for erythropoiesis. We see anemia, both because of disease and ruxolitinib, that is challenging to treat. This is a big unmet need, particularly as anemia is correlated with QOL. It’s not the only aspect correlated with QOL in patients with myelofibrosis. Their inflammatory and cytokine profile, which JAK inhibitors can control, is also important. [Anemia is] just 1 component.

Another big unmet need is treating high-risk disease and preventing progression of disease and leukemic progression. That’s a big issue because we’re not yet sure whether our therapies are disease modifying.

What efforts are being made to move ruxolitinib and navitoclax to the frontline setting?

At the 2022 ASH Annual Meeting and Exposition, many exciting therapies in myelofibrosis, both standalone and JAK inhibitor add-ons, were presented. The data we saw at ASH with navitoclax were encouraging. An arm in the REFINE trial [investigated] ruxolitinib and navitoclax in a JAK inhibitor–naïve cohort. This study was interesting because we saw changes in bone marrow fibrosis as well as reduction in the variant allele frequency [VAF] of the driver gene mutation in many patients. Those outcomes are particularly of interest because they have the potential to be biomarkers for disease modification or the disease-modifying ability of this drug combination.

It’s hard to study whether the longer-term outcomes are correlates for leukemia, progression, and survival, so we need [outcomes] in the shorter term to study. The 2 candidates of bone marrow fibrosis and VAF are strong. We’ll look forward to larger trials with these [agents] in the upfront setting.

What did the MANIFEST trial reveal about the efficacy and clinical significance of pelabresib plus ruxolitinib?

The MANIFEST trial [investigated] the BET inhibitor pelabresib plus ruxolitinib. There were multiple arms, [including a] JAK inhibitor–naïve cohort, an upfront treatment arm. We saw a good reduction in spleen volume, as well as symptom score. Considering the outcomes that may correlate with disease modification, improvement in bone marrow fibrosis and reduction in VAF, we saw that 28% of patients had 1 or greater grade 1 improvement in fibrosis, and 29.5% had an over 25% reduction in the JAK2 V617F VAF. This is promising for this combination. Now, the randomized, double-blind, phase 3 MANIFEST-2 trial [NCT04603495] is evaluating this combination in the upfront setting in a larger cohort.

What new JAK inhibitor add-ons coming down the pike in myelofibrosis are you excited to see?

It’s hard to know. We have a lot of data in phase 2 trials investigating different cohorts of different patients. In oncology, sometimes we can have many promising data in phase 1 and 2 trials, but those do not always bear fruit or come out as clearly in randomized phase 3 trials. It’s hard to compare the results of these trials, even though they have similar eligibility criteria and outcomes. I will need to wait for the phase 3 trials to know how these drugs will go.

What is your main message for colleagues regarding emerging therapies in myelofibrosis?

We have had several new drugs approved for myelofibrosis in the past few years, which is wonderful. We always like to have many treatment options for patients. However, we have much room to go. If possible, referring patients early on to our center or other centers that have many clinical trials for myelofibrosis is wonderful. That way, they have access both to standards of care and treatments coming down the pipeline. We can help study whether these treatments will improve unmet needs and help modify the natural history of this disease, which is our goal. Referral to us, even just for a second opinion, [is important], so we can help guide treatment and think about [whether patients are] eligible for any of these clinical trials.

What ongoing myelofibrosis clinical trials at Fred Hutchinson Cancer Center are you excited about?

DISC-0974 is in an early-phase trial [NCT05320198]. We don’t have any data yet. However, this trial is open at our center, and it’s interesting. DISC-0974 is a first-in-class anti-HJV monoclonal antibody that is a key regulator of hepcidin production in humans. This is a monthly subcutaneous injection for only 6 injections, and it prevents signaling in the HJV pathway, which results in suppressed hepcidin and improved erythropoiesis. This is [a particular focus in the] issue of anemia in myelofibrosis. This is an add-on agent to a patient’s ruxolitinib, JAK inhibitor, or hydroxyurea. They stay on their baseline treatment, and we add this on for anemia.

These drugs that are [being investigated] and targeting the hepcidin pathway, both in this disease as well as in other myeloid neoplasms, like myelodysplastic syndrome, are exciting. I’m hopeful that this different mechanism of action with non-overlapping toxicities with traditional JAK inhibitors could be an interesting treatment approach for anemia. This trial is currently open, so we are happy to see any patients with anemia on their current therapies.

References

  1. Passamonti F, Foran JM, Tandra A, et al. The combination of navitoclax and ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis mediates responses suggestive of disease modification. Blood. 2022;140(suppl 1):583-585. doi:10.1182/blood-2022-157949
  2. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: pelabresib in combination with ruxolitinib for janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol. Published online March 7, 2023. doi:10.1200/JCO.22.01972

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Pelabresib Combo Improves Spleen/Symptom Burden in JAKi-Naïve Myelofibrosis

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July 9, 2023

Russ Conroy

Combination treatment with pelabresib (CPI-0610) and ruxolitinib (Jakafi) was well tolerated and demonstrated enduring improvements in spleen and symptom burden among patients with JAK inhibitor treatment–naïve patients with myelofibrosis, according to findings from arm 3 of the phase 2 MANIFEST study (NCT02158858).

At week 24, 68% (95% CI, 57%-78%) of patients who received the combination achieved a spleen volume reduction of at least 35% (SVR35), which included a median SVR of –50% (range, –84% to 28%). Additionally, SVR35 responses at 24 weeks were observed in 70% and 67% of patients with intermediate-1– and intermediate-2– or high-risk disease based on Dynamic International Prognostic Scoring System (DIPSS) criteria, respectively, and 82% and 66% of patients based on International Prognostic Scoring System (IPSS) criteria. Kaplan-Meier estimates indicated that 93.5% (95% CI, 87.4%-99.7%) of those with a SVR35 response maintained their response at 36 weeks after onset.

A total symptom score reduction of at least 50% (TSS50) was reported in 56% (95% CI, 45%-67%) of patients at week 24, with a best TSS50 response at any time of 83% and a median change in TSS of –59% (range, –100% to 225%). Additionally, 43% of patients had a TSS50 response at 48 weeks, which included a median change in TSS of –54.8% (range, –100% to 307.1%).

At 24 weeks, study treatment yielded an absolute change in hemoglobin levels from baseline between –1 and at least 1.5 g/dL in 55% of patients; hemoglobin levels improved in 36% of patients, including a mean change of 1.3 g/dL and a median of 0.8 g/dL. Moreover, 24% of patients had a mean hemoglobin increase of at least 1.5 g/dL from baseline over any 12-week period while forgoing red blood cell transfusions.

“To our knowledge, the MANIFEST trial in JAK inhibitor treatment-naïve patients is the first study with a rational combination of BET [inhibitor] pelabresib and ruxolitinib that showed clinically meaningful durable improvements in splenomegaly and symptoms, was associated with biomarker findings indicating potential disease modification, and demonstrated a generally favorable safety profile,” the study authors stated. “This combination has the potential to improve the standard of care for treatment-naïve patients with myelofibrosis and warrants further investigation.”

Investigators of the global, open-label, nonrandomized phase 2 MANIFEST study evaluated pelabresib in combination with ruxolitinib in a cohort of JAK inhibitor treatment-naïve patients with myelofibrosis. Patients received an initial dose of 125 mg of pelabresib once daily for 14 days followed by a 7-day pause in combination with continuous ruxolitinib twice a day. Patients could receive a maximum pelabresib dose of 175 mg once daily.

The study’s primary end point was SVR35 from baseline to 24 weeks measured by imaging. The secondary end point was TSS50, and exploratory end points included bone marrow fibrosis improvement based on blinded central hematopathologist review following European consensus guideline criteria for reticulin fibrosis grading and improvement in anemia and transfusion requirements.

Patients who had not been exposed to treatment with JAK inhibitors and BET inhibitors and had confirmed diagnoses of primary myelofibrosis, or post–essential thrombocythemia or post–polycythemia vera myelofibrosis were eligible for enrollment on the trial. Additional eligibility criteria included having a spleen volume of at least 450 cm3, intermediate-2– or high-risk disease based on DIPSS criteria, and at least 2 measurable symptoms using the Myelofibrosis Symptom Assessment Form v4.0.

Overall, 84 patients received at least 1 dose of the study treatment, 53 of whom remained on treatment at the time of data cutoff. The median patient age was 68 years (range, 37-85), and 70% were male. Additionally, 24% had intermediate-1, 61% had intermediate-2, and 16% had high-risk disease by DIPSS criteria. In terms of mutations, investigators most frequently observed JAK2V617F (74%), ASXL1 (46%), CALR (21%), and MPL (8%).

Blinded central pathology review of bone marrow samples indicated at least 1 grade improvement in reticulin fibrosis at week 24 in 28% of evaluable patients, including 7% who had improvements of 2 grades. Among 24 patients with grade 1 or 2 reticulin fibrosis at baseline, 4 had worsening conditions, including 2 patients each with grade 1 and 2 fibrosis. Investigators observed no significant relationship between reticulin fibrosis improvement and clinical end points in the study,

Overall, 96% of patients experienced at least 1 treatment-emergent adverse effect (TEAE), and 63% had grade 3 or higher TEAEs. The most frequent hematologic TEAEs included thrombocytopenia (52%) and anemia (42%), and the most common nonhematologic TEAEs included diarrhea (35%), fatigue (33%), musculoskeletal pain (30%), respiratory tract infection (29%), and constipation (25%).

Pelabresib dose reductions were necessary among 37% of patients, and 36% had ruxolitinib dose reductions due to TEAEs. There were 5 deaths during study treatment or within 30 days following the final pelabresib dose, including 4 determined to be unrelated to pelabresib treatment. One patient died to multiorgan failure due to sepsis secondary to pneumonia, which investigators deemed to be related to pelabresib.

Reference

Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol. Published online March 7, 2023. doi:10.1200/JCO.22.01972

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Examining Pelabresib for Patients With Myelofibrosis

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July 9, 2023

Joseph Scandura, MD, PhD

Joseph M. Scandura, MD, PhD, Weill Cornell Medicine, discusses next steps for research of pelabresib (CPI-0610) for use in patients with myeloproliferative neoplasms.

Pelabresib is an oral, small molecule inhibitor of BET, which has the potential to downregulate the expression of genes that reside within the pathogenic pathways that underlie MPN progression.

One study evaluating pelabresib is the phase 3 MANIFEST-2 trial (NCT04603495). In this multicenter, double-blind, placebo-controlled trial, investigators are examining the safety and efficacy of pelabresib plus ruxolitinib (Jakafi) vs ruxolitinib alone in patients with JAK inhibitor-naïve myelofibrosis.

Patients aged 18 years and older with primary, post-polycythemia vera, or post-essential thrombocytopenia myelofibrosis, who had advanced disease requiring therapy, splenomegaly by computed tomography or magnetic resonance imaging, and were symptomatic were eligible for enrollment. Patients must also have had a prognostic risk-factor score of intermediate-1 or higher per the Dynamic International Prognostic Scoring System.

In the study, patients were randomly assigned in a 1:1 ratio to receive ruxolitinib in addition to oral pelabresib or matched placebo daily for 14 days, which was followed by 7 days off treatment. The starting dose of pelabresib was 125 mg daily. Then, ruxolitinib was given to patients twice a day in doses of 10 mg or 15 mg. Dose increases for both were allowed per protocol criteria.

Transcription:

0:10 | The first one is that we need to wait for the data to mature. My personal bias is, all of these biomarkers are invaluable until we know outcomes such as survival or time to treatment failure or event-free survival. Until we know that, we are just kind of stuck in this circular loop of what should be, what we hope will be, what our intuitive beliefs are, but we do not really know what any of these things mean until we have those outcomes. That just takes time.

0:46 | The nice thing is there are a number of phase 3 studies, randomized trials, collaborative studies. MANIFEST-2 is a randomized phase 3 study, and that will allow us to address and follow up on some of these findings, and hopefully get to those answers about whether or not these changes that we’re observing in the short-term are predicting these long-term beneficial outcomes. It just takes time for that data to mature

REFERENCE
Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated April 6, 2023. Accessed July 6, 2023. https://clinicaltrials.gov/ct2/show/NCT04603495

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Navtemadlin With Ruxolitinib Leads to SVR Benefit in TP53 Wild-Type Myelofibrosis

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July 7, 2023

Kyle Doherty

The addition of the MDM2 inhibitor navtemadlin (formerly KRT-232) to ruxolitinib (Jakafi) led to clinically meaningful improvements in spleen volume reduction (SVR) among patients with primary or secondary TP53 wild-type myelofibrosis who had a suboptimal response to ruxolitinib, according to findings from the phase 1/2 KRT-232-109 study (NCT04485260) presented during the 2023 European Hematology Association (EHA) Congress.

Results from the trial showed that at 24 weeks among efficacy-evaluable patients (n = 19) adding navtemadlin to ruxolitinib conferred a minimum SVR of 25% in 42% of patients and an SVR of at least 35% in 32%. Additionally, a minimum total symptom score (TSS) improvement of at least 50% was observed in 32% of patients.

“This therapeutic approach is clearly active,” John O. Mascarenhas, MD, said. “The combination of navtemadlin and ruxolitinib achieves two things: synergy in terms of cell kill directed at the CD34 myeloblasts population, which is really what we’re trying to accomplish, and an improved toxicity profile [compared with] monotherapy. This is a combination that could potentially even be used upfront in the JAL inhibitor-naïve patient population. MDM2 inhibition is here and likely is going to be a component in the future. Navtemadlin is poised to be at the forefront as a first-in-class agent to deliver that kind of clinical activity.”

In an interview with OncLive®, Mascarenhas, professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of Tisch Cancer Institute in New York, New York, discussed the design and rationale of KRT-232-109, more key findings from the trial, and potential future directions of the study.

OncLive: What is the mechanism of action of navtemadlin and what was the rationale for evaluating it in KRT-232-109?

Mascarenhas: Myelofibrosis is predominantly a TP53 wild-type disease. MDM2 negatively regulates TP53. [The] p53 pathway is important for regulating cell fate and balancing prosurvival and prodeath signals.

In myelofibrosis, MDM2 is overexpressed in CD34 cells, and this negatively regulates TP53 activity. It’s an alternative mechanism for cancer cells to increase the threshold for induction of apoptosis. Navtemadlin interrupts that interaction between MDM2 and wild-type TP53, thereby activating TP53 and inducing apoptosis.

What’s exciting about the phase 1b/2 study adding navtemadlin to patients receiving ruxolitinib with a suboptimal response is [the fact that] ruxolitinib works synergistically with navtemadlin in reducing p21. [This] essentially lowers the threshold to induce apoptosis in the setting of navtemadlin, so the two work well together to induce apoptosis in myelofibrosis CD34 cells—there’s great preclinical data that justify this concept.

What were the goals of the KRT-232-109 study?

The goal of the phase 1 was to determine the recommended phase 2 dose of navtemadlin in combination with ruxolitinib in these suboptimal ruxolitinib-[responding] myelofibrosis patients.

We evaluated 3 different dose levels and different dose schedules, and the recommended phase 2 dose based [not only] on the clinical results, but also on some of the pharmacokinetic results that were that were conducted is 240 mg of navtemadlin 7 days in a row of a 28-day cycle. [It’s a] 1-week-on-3-week-off [schedule of] 1-month cycles with the stable dose of ruxolitinib that the patient is on. So, you don’t adjust the dose of ruxolitinib, you simply add navtemadlin.

The ongoing purpose of the phase 2 [study] is to document the efficacy as measured by SVR and symptom improvement at 24 weeks.

What were some of the key inclusion criteria?

Patients had to have a platelet count greater than 100,000 because we often use platelet counts in these trials to determine eligibility. Patients had to have TP53 wild-type disease. Importantly, this approach is probably not effective in patients who have mutant disease because MBM2 doesn’t regulate mutant TP53. [Patients also needed to be] on ruxolitinib for at least 18 weeks, which is the minimal amount of time needed to determine whether someone has an optimal [response], suboptimal [response], or progressive disease, and at a stable dose of ruxolitinib for 8 weeks.

What were the key efficacy findings from KRT-232-109 presented during the 2023 EHA Congress?

We looked [what] we would normally look at in myelofibrosis, [such as] spleen response. The SVR [of] at least 35% at 24 weeks in evaluable patients was 32%. If you look at SVR [of at least] 25%, which is also considered by regulatory agencies a meaningful spleen response at 24 weeks, it was 42%. There was clear spleen reduction, and most patients [experienced] some degree of spleen response.

Symptom improvement was also seen; 32% of patients at week 24 had a 50% or greater TSS score and some of these patients had very significant spleen symptom burden at baseline. The drug was effective in addressing those 2 clinical end points.

What was really interesting was that patients, in some cases, had ruxolitinib doses of 5 mg twice daily going into the study, meaning they were coming in at low doses. And despite low doses of ruxolitinib, there was synergistic activity with navtemadlin[and] we were seeing very deep spleen and symptom responses. This speaks to the fact that biologically there is a priming almost of the diseased cells for TP53 induction of apoptosis with ruxolitinib. The preclinical data supported and translated very nicely into the clinical findings.

Are there any safety concerns clinicians should be aware of when using navtemadlin plus ruxolitinib?

[This was a] well-tolerated drug. We know that, as a class of agents, there is a degree of gastrointestinal [GI] toxicity with MDM2 inhibitors, [including] nausea, vomiting and diarrhea. [These events were] rarely grade 3/4 [in severity]; 70% of were grade 1. [Approximately] 60% of patients experienced some GI toxicity, usually in the first 2 cycles. Preemptively, we give antiemetic and an antidiarrheal. That is a very effective way of managing those nausea and diarrhea type toxicities.

The [inclusion] of ruxolitinib it seems to offset some of that toxicity. There may be some biologic reasons why there’s synergy with ruxolitinib, not just an efficacy, but also in improving the safety profile with navtemadlin. The deep responses that we see are also complemented by a well-tolerated combination.

What are the next steps for this research?

We want to finish the follow-up of patients enrolled in phase 2. We still have ongoing correlatives to look at. We presented correlatives that were very encouraging [showing] that we were having on-target stem cell–directed therapeutic effects, [such as] reduction of CD34 cell burden, reduction in bone marrow fibrosis, and reduction in driver RAF level in these patients that were treated.

We were clearly having disease-modifying effect, biologic response modification. We want to see that in a greater number of patients [and] I’d love to see some of the cytokine results. There’s still more to be done from a correlative science aspect and patient follow-up to be conducted.

Ultimately, where this will go is to a phase 3 study, which will be entitled BOREAS-2, where we’ll be [enrolling patients with] suboptimal ruxolitinib response and adding navtemadlin [and evaluating this treatment] vs placebo to improve responses.

Reference

Mascarenhas J, Jain T, Otoukesh S, et al. An open-label, global, phase (Ph) 1b/2 study adding navtemadlin (NVTM) to ruxolitinib (RUX) in patients (Pts) with primary or secondary myelofibrosis (MF) who have a suboptimal response to RUX. HemaSphere. 2023;7(suppl 3):S210.

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Phase 3 Trial of Selinexor and Ruxolitinib Starts in JAKi-Naive Myelofibrosis

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June 30, 2023

Jordyn Sava

A phase 3 clinical trial (NCT04562389) has been initiated to assess the efficacy and safety of selinexor (Xpovio) given once a week at 60 mg in combination with ruxolitinib (Jakafi) in JAK inhibitor (JAKi)-naïve patients with myelofibrosis, according to Karyopharm Therapeutics, Inc.1

The start of this phase 3 study is supported by phase 1 study results that showed rapid, deep, and sustained spleen responses and robust symptom improvement among patients at week 24 who were treated at the 60 mg dose level.

Findings revealed a 78.6% spleen volume response rate of ≥ 35% (SVR35) and 58.3% symptom improvement of ≥ 50% (TSS50) in the intent to treat patients, and SVR35 responses were observed in all 12 of the evaluable patients at any time. Additionally, rates were consistent regardless of subgroups, including patients treated with low dose ruxolitinib.

An improvement in major spleen and cytokine-related symptoms were observed and treatment with selinexor was generally well tolerated with a manageable adverse event (AE) profile. Most patients were able to remain on therapy for up to 74 weeks, and the most common treatment emergent AEs experienced with the 60 mg selinexor dose with ruxolitinib included nausea (78.6%), anemia (64.3%), thrombocytopenia (64.3%) and fatigue (57.1%).

The most common treatment-emergent grade ≥3 AEs with the combination with ruxolitinib were anemia (42.9%), thrombocytopenia (28.6%), and back pain (14.3%). Moreover, 75% of nausea events were grade 1 and did not lead to treatment-related discontinuations.

“The substantial degree of spleen volume reduction observed across all subgroups with selinexor 60 mg in combination with ruxolitinib is very encouraging. There is a significant unmet need in the treatment of patients with myelofibrosis, and these data demonstrate that the addition of XPO1 inhibition with selinexor with standard-of-care ruxolitinib has the potential to significantly improve outcomes for first-line myelofibrosis patients,” said John Mascarenhas, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Center of Excellence for Blood Cancers and Myeloid Disorders, in a press release. “As the principal investigator for the phase 3 study, I look forward to defining a potential new standard of care for JAK-naïve patients [with myelofibrosis].”

In the randomized, double-blind, placebo-controlled phase 3 study, approximately 306 JAKi-naive patients with intermediate or high-risk myelofibrosis will be enrolled and randomized in a 2:1 fashion to receive ruxolitinib plus selinexor 60 mg or ruxolitinib plus placebo in 28-day cycles.2

Enrollment in the study is open to patients aged 18 years and older with a diagnosis of primary myelofibrosis, post-essential thrombocythemia, or post polycythemia vera myelofibrosis who have a measurable splenomegaly during the screening period, an international prognostic scoring system risk category of intermediate-1, or intermediate-2, or high-risk, an ECOG performance status of less than or equal to 2, and a life expectancy of greater than 6 months. Additionally, patients must have active symptoms of myelofibrosis, and provide bone marrow biopsy samples at screening and during the study.

The coprimary end points of the study include SVR35 and TSS50 at week 24. The key secondary end point of the study is anemia response at week 24 with other secondary end points for the phase 3 portion including overall survival, overall response rate, pharmacokinetics, and number of patients with AEs.

The study is currently recruiting patients in Virginia and is active at sites in California, Tennessee, and Utah. The estimated study completion date is December 2027.

Top-line data are expected to read out from this phase 3 study in 2025, and the company plans to further investigate selinexor in other frontline opportunities, including in combinations for the treatment of myelofibrosis.1

“Selinexor and ruxolitinib appear to work synergistically, resulting in meaningful improvements in spleen response and total symptom score for patients with myelofibrosis,” said Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, in a press release. “We believe that an opportunity exists to expand upon the initial response, depth, and duration of JAK inhibitors to ultimately improve patient outcomes. This combination has the potential to become a cornerstone treatment in frontline myelofibrosis and we are excited to start this pivotal trial to deliver on our goal of bringing forward an innovative new approach for the treatment of myelofibrosis that can benefit [patients with myelofibrosis].”

REFERENCES:
  1. Karyopharm initiates pivotal phase 3 study of XPO1 inhibitor selinexor and ruxolitinib in JAK inhibitor (JAKi) naïve myelofibrosis. News release. Karyopharm Therapeutics, Inc. June 28, 2023. Accessed June 30, 2023. https://tinyurl.com/4phpud2y
  2. Study of selinexor in combination with ruxolitinib in myelofibrosis. ClinicalTrials.gov. Updated June 29, 2023. Accessed June 30, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04562389

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Jaktinib shows promise in treatment of myelofibrosis

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June 23, 2023

David Statman

In this video, Idoroenyi Amanam, MD, discussed a study presented at ASCO Annual Meeting, examining the treatment of anemia in myelofibrosis patients.

Amanam, an assistant professor in the Division of Leukemia at City of Hope Cancer Center, highlighted a study that examined the effects of jaktinib (Suzhou Zelgen Biopharmaceuticals Co, Ltd) versus hydroxyurea in patients with intermediate to high-risk myelofibrosis, with a primary endpoint of spleen volume reduction.

“From a response and efficacy perspective, jaktinib appears to be promising,” Amanam said. “What they have right now is exciting, and it’s another option in a space where we don’t have too many options.”

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FDA Extends Review Period for Momelotinib NDA in Myelofibrosis

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June 16, 2023

Kristi Rosa

The FDA has extended the review period for the new drug application (NDA) seeking the approval of momelotinib as a potential therapeutic option in patients with myelofibrosis.1 The regulatory agency pushed the decision date back by 3 months, to September 16, 2023, to allow for more time to review recently submitted findings.

The application was based on data from the phase 3 MOMENTUM trial (NCT04173494), in which momelotinib significantly improved symptoms, spleen size, and anemia vs danazol in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor.2

Specifically, more patients who received momelotinib (n = 130) experienced a reduction in tumor symptom score (TSS) of 50% or higher at week 24 vs those who were given danazol (n = 65), at 25% and 9%, respectively (proportion difference, 16%; 95% CI, 6%-26%; P = .0095), which met the primary end point of superiority with momelotinib. Moreover, more patients on the investigative arm achieved transfusion independence (TI) at week 24 than those on the control arm, at 30% (95% CI, 22%-39%) and 20% (95% CI, 11%-32%), respectively (noninferiority difference, 14%; 95% CI, 2%-25%; 1-sided P = .0016); TI rates from baseline to week 24 increased by 17% with momelotinib compared with 5% with danazol.

Momelotinib also demonstrated superiority over danazol with regard to splenic response rates at week 24. Thirty-nine percent of patients who received momelotinib experienced a reduction of 25% or more in spleen volume from baseline to week 24 vs 6% in those given danazol (P < .0001); moreover, 22% and 3% of patients, respectively, experienced a reduction of 35% or more (P = .0011).

In a recent news release, GlaxoSmithKline, the drug developer, stated that they were “confident in the momelotinib NDA” and that they “look forward to working with the FDA as they finalize their review.”1

The international, double-blind, randomized, controlled MOMENTUM trial enrolled patients with a confirmed diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post–essential thrombocytopenia myelofibrosis who were at least 18 years of age and who received a prior approved JAK inhibitor for at least 90 days.2

Patients were symptomatic, defined as a TSS of at least 10 at screening; were anemic, defined as a hemoglobin of less than 10 g/dL; a platelet count of more than 25 x 109 cells/L; and had splenomegaly at baseline. Moreover, patients had an ECOG performance status of 0 to 2, and could have had high-risk, intermediate2-risk, or intermediate-1 risk disease by Dynamic International Prognostic Scoring System criteria.

Study participants were randomly assigned 2:1 to momelotinib at 200 mg once daily or danazol at 300 mg twice daily.

The primary end point of the trial was week-24 TSS response rate, which was defined as the proportion of participants achieving a reduction in mean TSS of at least 50% over the 28 days prior to the end of week 24 vs baseline. Important secondary end points comprised week-24 TI rate, 25% splenic response rate at week 24, change in TSS from baseline to week 24, 35% splenic response rate at week 24, and rate of zero transfusions at week 24. Other end points focused on anemia, transfusions, survival, and safety.

A total of 195 patients were enrolled in the trial and were treated. Of those in the momelotinib and danazol arms, 72% and 58% of patients, respectively, completed treatment. The most common reason for early discontinuation in these arms was toxicity (12% vs 17%), followed by patient decision (5% vs 8%).

Data from the study were published in The Lancet and have a data cutoff date of December 3, 2021.

In all patients, the median baseline age was 71 years (interquartile range, 66-76), and most were male (63%) and White (81%). Moreover, the majority of patients had primary myelofibrosis (64%), intermediate-2 risk disease (57%), and harbored a JAK2 mutation (76%). Fourteen of the patients were TI and 50% were dependent. The mean duration of prior JAK inhibition in these patients was 2.6 years, and all patients previously receives ruxolitinib (Jakafi). Five percent of patients had prior fedratinib (Inrebic). The mean TSS at baseline was 27.2, mean hemoglobin was 8.0 g/dL, and the mean platelet count was 144.7 x 109 cells/L.

Additional findings indicated that in the group of patients who were transfusion dependent at baseline (n = 168), 26% and 15% of those in the momelotinib and danazol arms, respectively, achieved TI by the end of week 24.

Momelotinib also proved to be superior to danazol with regard to mean TSS change from baseline to end of week 24, at –11.5 vs –3.9, respectively (least squares mean difference, –6.2; 95% CI, –10.0 to –2.4; P = .0014). This was also true for the rate of zero transfusions to week 24, at 35% (95% CI, 27%-44%) and 17% (95% CI, 9%-28%), respectively (P = .0012). There was also a higher rate of zero transfusions at week 24 in those with hemoglobin at least 8 g/dL vs those with less than 8 g/dL (49% vs 21%) with momelotinib and with danazol (24% vs 9%).

Currently, momelotinib is not approved in any market.1

References

  1. GSK announces extension of FDA review period of momelotinib. News release. GlaxoSmithKline. June 16, 2023. Accessed June 16, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-extension-of-fda-review-period-for-momelotinib/
  2. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0

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Pacritinib Provides Spleen, Symptom Reduction Regardless of Blood Counts, Association Between SVR and OS in Myelofibrosis

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June 16, 2023

Caroline Seymour

Spleen volume reduction (SVR) was associated with overall survival (OS) with pacritinib (Vonjo) in patients with myelofibrosis. Treatment with the JAK2 inhibitor also demonstrated comparable improvements in spleen and symptom response regardless of baseline platelet counts and hemoglobin levels, according to findings from the pivotal phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781) trials that were presented at the 2023 ASCO Annual Meeting.1,2

Symptoms of myelofibrosis include marrow fibrosis, splenomegaly, and progressive cytopenia and prior approved agents include ruxolitinib (Jakafi) and fedratinib (Inrebic).

“The previous 2 JAK inhibitors ruxolitinib and fedratinib were for patients at a certain platelet cutoff, so that’s 50 [x 109/L] and above, and pacritinib ended up becoming approved for patients with myelofibrosis with platelets less than 50 [x 109/L], filling that urgent unmet medical need,” Naveen Pemmaraju, MD, associate professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncLive®.

Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 associated with improved SVR vs best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis with platelets below 100 x 109/L in the PERSIST-2 trial. However, the relationship between SVR and OS in patients with thrombocytopenia is not well known. As such, investigators evaluated whether SVR with pacritinib or BAT is associated with improved survival in those with thrombocytopenia.

The analysis included patients from PERSIST-2 who were alive and on study who had received 200 mg of pacritinib twice daily or BAT at week 10 (week-12 SVR window).

In the pivotal PERSIST-2 trial, baseline characteristics in the pacritinib arm for responders (n = 65) and nonresponders (n = 24), respectively, were presented for age (median in years: 66 vs 67), Dynamic International Prognostic Scoring System (DIPSS) high risk (18.5% vs 46%), platelet count (median, 58 x 109/L vs 67 x 109/L), hemoglobin (median, 9.7 g/dL vs 9.3 g/dL), red blood cell transfusion requirement (38% vs 58%), prior JAK2 exposure (45% vs 50%), spleen volume (median, 2573 cm3 vs 2094.5 cm3), and palpable spleen length (median, 15.00 cm vs 12.75 cm).

Responders (n = 28) and nonresponders (n = 56) in the BAT arm had median ages of 66 years and 69 years, respectively. Moreover, 21% and 25% of patients, respectively, had DIPSS high-risk disease, median platelet counts of 68 x 109/L and 47 x 109/L, median hemoglobin of 10.0 g/dL and 9.6 g/dL, red blood cell transfusion requirement in 32% and 54%, prior JAK2 exposure in 64% and 45%, median spleen volume of 2907 cm3 and 2393 cm3, and median palpable spleen length of 12.00 cm and 14.50 cm.

Results showed that at least 10% SVR with pacritinib was prognostic for survival between responders and nonresponders (P <.0001). At least 20% and 35% or more SVRs were also prognostic for survival but to a lesser extent, with P values of .0199 and .3516, respectively. Authors also noted that any degree of SVR was associated with improved survival with pacritinib (HR, 0.08; 95% CI, 0.01-0.51; P = .0007).

Adjusting for baseline spleen volume and red blood cell transfusion requirement in univariate analysis did not affect the survival benefit with pacritinib at the 10% or greater SVR threshold.

Notably, SVR was not associated with survival with BAT at any threshold (SVR ≥10%, P =.4888; SVR ≥20%, P =.9821; SVR ≥35%, P =.8881).

“What is very encouraging is that we’re starting to see disease modification with these JAK inhibitors, not only showing spleen and symptom improvement, but also trying to show OS improvement and that the two can correlate,” Pemmaraju said. “Once we start to see spleen symptom improvement, as well as OS improvement, we can start to try to aim for and achieve disease modification, [which is] what matters to the patient. We’re starting to see that now, as we did with ruxolitinib and perhaps now with the newer JAK inhibitors.”

Additional findings from the analysis indicated that median dose intensity through week 12 was maintained with pacritinib at 200 mg twice daily in all patients who achieved SVR of at least 10%. Of the 28 patients who achieved SVR of at least 10% on BAT, the majority (n = 23) received ruxolitinib prior to the week-12 SVR evaluation. Of these patients, 78% were receiving no more than 10 mg of ruxolitinib twice daily and 43% were receiving no more than 5 mg of ruxolitinib twice daily. Other BATs included hydroxyurea (Hydrea) and prednisone.

Additionally, OS was associated with achieving at least 20% reduction in spleen length with pacritinib (HR, 0.14; 95% CI, 0.02-1.26; P =.0406; OS by spleen length reduction ≥35% and ≥50%, P =.0990 and P =.3008). However, separation of the curves was not as great for prognostication as SVR among responders and nonresponders.

“As pacritinib can be given at full dose regardless of platelet count, it is possible that pacritinib may offer a unique survival advantage for patients with myelofibrosis with moderate or severe thrombocytopenia who achieve ≥10% spleen reduction,” the authors wrote in the poster.

Although pacritinib is approved for use in patients with low platelet counts, clinical studies with the agent have included patients regardless of baseline anemia and thrombocytopenia. As such, another analysis was conducted, pooling the results of the PERSIST-1 and PERSIST-2 trials, to determine dosing patterns and efficacy outcomes by degree of baseline cytopenia.

Results showed that patients maintained median dose intensity of 100% regardless of whether they had baseline platelet counts below or above 100 x 109/L or baseline hemoglobin levels below 8 g/dL, between 8 g/dL and 10 g/dL, or 10 g/dL or above.

Additionally, between 21% and 28% of all patients, regardless of platelet and hemoglobin levels, achieved SVR of at least 35%; between 39% and 44% of patients achieved SVR of at least 25%; between 75.5% and 82% achieved SVR of at least 10%; and between 84% and 93% of patients achieved any spleen volume reduction. Moreover, the depth of the 24-week spleen reduction was similar across all platelet and hemoglobin strata.

Similarly, all patients achieved spleen reduction by week 12, and SVR remained consistent over time across all subgroups. Median hemoglobin also remained stable through week 24 across all hemoglobin thresholds, though some improvement was reported in patients with baseline levels below 8 g/dL.

Any improvement in total symptom score (TSS) was documented in between 80% and 87.5% of patients across all cytopenic groupings, although most patients with baseline hemoglobin below 8 g/dL (62.5%) derived the greatest magnitude in symptom improvement (TSS ≥50). Notably, 12-week TSS improvement occurred with deepening improvement through week 36, particularly in patients with baseline hemoglobin below 8 g/dL.

Regarding Patient Global Impression of Change response across all baseline blood count strata, approximately 80% of patients reported clinical improvement in disease symptoms and approximately 50% of patients classified their symptoms as “much” or “very much” improved at week 24.

“[This study] takes a look at the totality of the pacritinib data across doses across levels of cytopenias among patients and shows that while this drug is best known for its efficacy in cytopenic patients, it shows that the efficacy is about the same in those with higher blood counts as well, or at least it is certainly preserved in those patients as well,” Prithviraj Bose, MD, associate professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, told OncLive®.

References

  1. Ajufo H, Bewersdorf JP, Harrison C, et al. Spleen volume reduction (SVR) predicts overall survival (OS) in myelofibrosis (MF) patients on pacritinib (PAC) but not best available therapy (BAT): PERSIST-2 landmark OS analysis. J Clin Oncol. 2023;41(suppl 16):7018. doi:10.1200/JCO.2023.41.16_suppl.7018
  2. Bose P, Gagelmann N, Gupta V, et al. Consistency of pacritinib for spleen and symptom reduction in patients with myelofibrosis regardless of cytopenias. J Clin Oncol. 2023;41(suppl 16):7068. doi:10.1200/JCO.2023.41.16_suppl.7068

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Jaktinib Bests Hydroxyurea in in Intermediate-2/High-Risk Myelofibrosis

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Kyle Doherty
In a phase 3 study (ZGJAK016; NCT04617028), the novel JAK/ACVR1 inhibitor jaktinib led to a statistically significant improvement in the proportion of patients with a spleen-volume reduction of at least 35% from baseline (SVR35) at week 24 vs hydroxyurea in patients with intermediate-2 or high-risk myelofibrosis.1

The results were presented at the 2023 EHA Congress and met the primary end point of the trial.

At the April 28, 2022, data cutoff, findings from the interim analysis of the study showed that the 24-week independent review committee (IRC)-assessed SVR35 rate was 72.3% (95% CI, 57.4%-84.4%) in the jaktinib arm (n = 47) compared with 17.4% (95% CI, 5.0%-38.8%) in the hydroxyurea arm (n = 23; P ≤ .0001). Additionally, the best spleen response rates were 80.9% vs 26.1%, respectively (P ≤ .0001). The median maximum percentage change in spleen volume from baseline per IRC assessment were –46.6% vs –18.5%, respectively.

“Three small molecule JAK inhibitors have been approved for myelofibrosis by the FDA, including ruxolitinib [Jakafi], fedratinib [Inrebic], and pacrritinib [Vonjo],” Jie Jin, MD, PhD, a professor of medicine in the Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, in Hangzhou, China, said during the presentation. “Currently in China, ruxolitinib is the only one that is available. Therefore, the treatment [options for] myelofibrosis in China is limited.”

ZGJAK016 was a double-blind, active-controlled, multicenter trial that enrolled adult patients with DIPSS intermediate-2 or high-risk myelofibrosis with an ECOG performance status of 1 or 0. Eligible patients also needed to have a palpable spleen of at least 5 cm below the left costal margin, a platelet count of at least 100 ´ 109/L, and no prior or a maximum of 10 days of treatment with a JAK inhibitor.

Following a 28-day screening period, enrolled patients were randomly assigned 2:1 to receive either jaktinib 100 mg twice daily plus a hydroxyurea placebo or hydroxyurea 0.5 g twice daily plus a jaktinib placebo for four 6-week cycles. At week 24, the extension period began, and patients who achieved SPV35 remained on their initially assigned treatment and those who did not received jaktinib 100 mg twice daily until criteria for termination. Patients were stratified by DIPSS risk status (intermediate-2 vs high-risk).

The primary end point of the study was SVR35 at week 24, measured by MRI or CT imaging and assessed by IRC. Key secondary end points included investigator-assessed SVR35 at week 24, best spleen response rate (defined as achieving SVR35 at any time), proportion of patients with reduction in MPN-SAF Total Symptom Score (TSS) of at least 50%, improvement in terms of anemia, and safety.

The baseline characteristics were well-balanced between the 2 arms; the median age was 63 years (range, 46-76) in the jaktinib arm compared with 62 years (range, 42-74) in the hydroxyurea arm. Most patients in both arms were women (61.7% vs 60.9%), had intermediate-2 DIPSS risk status (89.4% vs 87.0%), did not previously receive a JAK inhibitor (97.9% vs 91.3%), were JAK2 V617F positive (59.6% vs 69.6%), and had primary myelofibrosis (70.2% vs 73.9%). The median spleen volumes upon central review were 1389.7 cm3 (range, 433.6-5070.5) and 1249.1 cm3 (range, 579.6-3011.4), respectively. Additionally, the median platelet count and hemoglobin levels were similar between the 2 arms.

Most patients in the jaktinib arm completed 24 weeks of treatment (89.4%) and entered the extension period (83.0%). In the control arm, these rates were 69.6% and 69.6%, respectively. One patient in the hydroxyurea arm also received open-label jaktinib without unblinding. Four patients died on the jaktinib arm compared with 1 on the hydroxyurea arm; no death was determined to be treatment related.

Additional findings from the study showed that the SVR35 benefit was observed with jaktinib over hydroxyurea across all prespecified subgroups. The greatest differences in SVR35 rate in favor of jaktinib were observed among patients with a baseline MPN-SAF TSS greater than the median (72.0% [95% CI, 35.5%-85.9]), those with a DIPSS risk status of intermediate-2 (66.2% [95% CI, 42.2%-80.4%]), and those whose disease harbored a JAK2 V617F mutation (63.4% [95% CI, 35.0%-81.2%]).

More patients in the jaktinib arm experienced a reduction in MPN-SAF TSS from baseline compared with the hydroxyurea group at every time point examined in the interim analysis. This included week 6 (55.3% vs 34.8%), week 12 (59.6% vs 43.5%), week 18 (66.0% vs 39.1%), and week 24 (63.8% vs 43.5%).

Hemoglobin levels were increased from baseline in the jaktinib arm and decreased in the hydroxyurea arm. Among patients who received jaktinib who required a red blood cell transfusion (n = 7), 5 achieved a decreased in red blood cell transfusion unit of at least 50% by week 24 compared with 2 who received hydroxyurea and required a transfusion (n = 5).

Safety findings demonstrated that nearly all patients in the jaktinib and hydroxyurea arms experienced an any-grade treatment-emergent adverse effect (TEAE), at 97.9% and 100%, respectively. Most patients in both arms experienced a TEAE of grade 3 or higher severity (51.1% vs 60.9%).

Serious TEAEs were present in 27.7% of patients in the jaktinib arm compared with 47.8% in the hydroxyurea arm. TEAEs leading to dose reduction or interruption (23.4% vs 34.8%), as well as those leading to treatment discontinuation (8.5% vs 17.4%), were reported in both arms.

In the jaktinib arm, the most common any-grade TEAEs included thrombocytopenia (40.4%), anemia (38.3%), respiratory tract infections (21.3%), leukopenia (14.9%), fever (12.8%), and reduced blood bilirubin (12.8%). Common grade 3 or higher TEAEs consisted of anemia (25.5%), thrombocytopenia (17.0%), leukopenia (2.1%), neutropenia (2.1%), and decreased lymphocyte count (2.1%).

Comparatively in the hydroxyurea arm, the most common any-grade TEAEs included thrombocytopenia (52.2%), anemia (52.2%), leukopenia (30.4%), neutropenia (26.1%), decreased lymphocyte count (26.1%), and decreased blood bilirubin (26.1%). Grade 3 or higher TEAEs included anemia (43.5%), thrombocytopenia (39.1%), leukopenia (21.7%), neutropenia (21.7%), and decreased lymphocyte count (13.0%).

“At the time of this prespecified interim analysis, jaktinib has demonstrated an improved trend in symptom response vs hydroxyurea,” Jin said. “[Additionally], there were [fewer] cytopenias in the jaktinib group than the hydroxyurea [arm]. Our interim results demonstrate that jaktinib could be a new treatment option for patients with myelofibrosis [who are] DIPSS intermediate-2 or high-risk.”

Reference

Zhang Yi, Zhhuan J, He A, et al. A randomized double-blind phase 3 study of jaktinib versus hydroxyurea in patients with intermediate-2 or high risk myelofibrosis. Hemasphere. 2023;7(suppl 3):S212.

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