Category Archives: Clinical Trial

BMS-986158–Based Combos May Provide Another Viable Treatment Approach in Myelofibrosis

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August 4, 2023

Courtney Flaherty

Haifa Kathrin Al-Ali, MD, provides background on the phase 1/2 study of BMS-986158, presents initial efficacy and safety data from the study, and discusses her hope that novel combination regimens like these could achieve the challenging goal of disease modification in myelofibrosis in the future.

The investigational, oral BET inhibitor BMS-986158 administered with either first-line ruxolitinib (Rituxan) or second-line fedratinib (Inrebic) showcased early efficacy and tolerability in patients with intermediate- or high-risk myelofibrosis. These data suggest that strategies combining BET and JAK inhibition can not only address myelofibrosis-related symptoms but may show potential for disease modification, according to Haifa Kathrin Al-Ali, MD.

Findings from the dose-escalation portion of the phase 1/2 CA011-023 trial (NCT04817007) were reported at the 2023 EHA Congress, and showed that both regimens had manageable toxicity profiles. In part 1A of the study, 82% of patients given BMS-986158 plus ruxolitinib experienced an any-grade treatment-related adverse effect (TRAE); this percentage was 75% in part 1B, which evaluated BMS-986158 plus fedratinib. Dose-limiting toxicities (DLTs) occurred in 2 patients in part 1A and 3 patients in part 1B.

Early efficacy data demonstrated that first-line BMS-986158 plus ruxolitinib led to spleen volume reduction (SVR) that became particularly robust by week 24. By week 48, 80% of patients (95% CI, 28%-100%) given the first-line ruxolitinib combination (n = 5) and 50% of those given the second-line fedratinib regimen experienced an SVR of at least 35%. In the ruxolitinib arm, the mean spleen volume change was –46.7% at week 12, –59.9% at week 24, and –56.3% at week 48; in the fedratinib arm, these percentages were –29.1%, -30.8%, and -33.0%, respectively.

“There is still a way to go, but these preliminary data are quite encouraging,” said Al-Ali, a professor of Translational Oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

In an interview with OncLive®, Al-Ali provided background on the phase 1/2 study of BMS-986158, presented initial efficacy and safety data from the study, and discussed her hope that novel combination regimens like these could achieve the challenging goal of disease modification in myelofibrosis in the future.

OncLive: What was the rationale for investigating the use of BET inhibitors as monotherapy or in combination with JAK inhibitors in myelofibrosis?

Al-Ali: We know that in patients [with myelofibrosis] there is a NF-κB–mediated pro-inflammatory cytokine profile. [This] leads to a dysregulated bone marrow microenvironment and osteoblastic differentiation, which contributes to the bone marrow fibrosis. It’s rational to use BET inhibitors because they have been shown to reduce or inhibit the expression of BET-targeted oncogenes like c-MYC and MYC.

Please describe the design of this study. Which patients were included this analysis, and what were the key objectives of the research?

This is an open-label, phase 1b/2 study. It mainly included patients with myelofibrosis who had splenomegaly and [had] either intermediate-1 [disease] plus symptoms, intermediate-2 [disease], or high-risk [disease, according to the Dynamic International Prognostic Scoring System]. The trial consisted of a dose-escalation phase followed by a dose-expansion phase. In the dose-escalation phase, there were also 2 parts. Part 1A [involved] first-line treatment with the BET inhibitor plus ruxolitinib in patients who had no previous exposure to ruxolitinib. [Part 1B consisted of] the second-line combination, [where] the BET inhibitor was combined with 400 mg of fedratinib and [was administered] once daily [to] patients with either intolerance or resistance to ruxolitinib.

This was a phase 1 study. [At the 2023 EHA Congress,] we presented the data from the dose-escalation phase, so the primary objective is always safety. The secondary objective was efficacy in terms of SVR. There were some exploratory analyses on JAK2 allele burden as well as bone marrow fibrosis.

According to data presented at the congress, what should be known about the safety of BMS-986158?

Regarding safety, [we] found that both the first-line combination with ruxolitinib or the second-line combination with fedratinib were feasible, tolerable, and the safety profiles were manageable. The main AE was thrombocytopenia, which is a class effect; it’s manageable and transient with dose modification or dose holding. The second major AEs were gastrointestinal [toxicities, including] diarrhea and nausea. Generally, these [effects] were mild, never led to the discontinuation of patients from the trial and were quite manageable.

What were the efficacy findings reported with these combinations?

Regarding efficacy, there are very promising results [showing] SVR of at least 35% from baseline by MRI. In the first-line cohort, there was a rapid and relevant reduction from baseline spleen volume [of at least 35%] in [73%] of patients [at week 12]. This seemed to be sustainable. Looking at SVR at week 24, 100% of patients [experienced] SVR. This is a phase 1 [study], and we should be careful, but these are encouraging results.

[Similar results were seen] with the second-line treatment, although the [duration of] follow-up was shorter. At week 12, at least [38%] of the patients [experienced] more than a 35% reduction in spleen volume. These are also encouraging results.

Finally, evidence for disease modification might be seen regarding JAK2 allele burden reduction. [This was] seen quite early, starting by cycle 6 in all the patients [with] JAK2-mutated [disease]. Additionally, in patients with follow-up bone marrow biopsies that could be evaluated, there seems to be a significant reduction in at least 1 grade of fibrosis by week 12 or week 24. [The study includes a] small number of patients, and these are preliminary, encouraging data. This bone marrow fibrosis regression seems to be associated with a hematological, [specifically] anemic, response.

You mentioned that potential evidence for disease modification may have been observed with this in the form of JAK2 allele burden reduction. In myelofibrosis, what efforts are currently underway to develop disease-modifying therapies that go beyond standard approaches focused on symptom management?

One of the major challenges [in myelofibrosis] is to see [clear evidence of successful] disease modification. All the biomarkers you can measure, like bone marrow fibrosis or a reduction in allele mutational burden, should have a clinical outcome correlation. This is a big challenge.

In the future, it is crucial to move away from only SVR and symptom improvement. We have great drugs that could do that. We have to wait for data from phase 3 randomized trials, and we need time to learn and [understand] the benefit of these combination treatments. My wish is to [achieve] sustainable, durable, clinical responses for patients with these combinations, but this is still an area with a lot of unanswered questions.

Are any next steps planned for the investigation of BMS-986158 in this disease?

The next step [for this research] is going further with the trial. The expansion phase has started for the first-line combination treatment in patients who are ruxolitinib naïve. The same will hopefully be happening for the second-line treatment. If these all [show] positive signals, we will move to a phase 3 clinical trial.

What is your main takeaway message for colleagues regarding this presentation?

The takeaway message is that it is feasible to have these combinations. We have learned how to dose [them] and how to manage AEs, which is the first step [for] every treatment. We have [also] shown encouraging preliminary clinical data regarding SVR, [as well as] some encouraging translational aspects like reduction in JAK allele burden or improvement in bone marrow fibrosis.

Overall, what was most exciting about this year’s EHA Congress?

[This year’s EHA Congress has] been particularly exciting. It is almost [solely] a myeloproliferative neoplasm congress because [there are] so many new, exciting datasets [being presented]—not only for a myelofibrosis, but also for polycythemia vera and essential thrombocythemia. At the end of the day, the most important winners will be the patients.

Reference

Ayala R, Lopez N, Abulafia AS, et al. BMS-986158, a potent BET inhibitor, as monotherapy and in combination with ruxolitinib or fedratinib in intermediate- or high-risk myelofibrosis (MF): results from a phase 1/2 study. Presented at the 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S213.

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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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EXCEED-ET Investigates an Alternative Option for Disease Modification in Essential Thrombocytopenia

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July 16, 2023

Nichole Tucker

An overperforming JAK-STAT pathway, including the presence of JAK2, CALR, and MPL gene mutations leads to high platelet count in patients with essential thrombocytopenia (ET).1 Safe and potent therapies are needed for these populations, especially for those requiring cytoreduction, regardless of their prior exposure to hydroxyurea and/or anagrelide, according to Lucia Masarova, MD, et al.

There is also an unmet need for treatments that can reduce the risk of thrombohemorrhagic events, ultimately stopping or preventing the development of post-ET myelofibrosis.1

Ropeginterferon alfa-2b-njf (Besremi) is a next-generation interferon alfa agent. It is FDA-approved to treat another myeloproliferative neoplasm (MPN), polycythemia vera (PV). In ET, ropeginterferon alfa-2b-njf is being investigated for the treatment of adult patients in a single-arm, multicenter trial (EXCEED-ET; NCT05482971).

At the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, Masarova, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, presented the EXCEED-ET study design, noting its potential to fill an unmet need for new therapies to treat adults with ET.

“Eventually, we can hopefully add it to something and maybe keep on some agents that have been around to help control the counts. At the same time, maybe we can do a low-dose interferon for a longer time as a disease modification agent, and hopefully you will wake up in an era where there’s going to be no ET or PV,” Masarova told Targeted OncologyTM, in an interview.

In the interview, Masarova, discussed EXCEED-ET in detail and provided insights into the treatment options for ET and PV.

Targeted Oncology: In terms of disease modification, what is the current state of treatment in MPNs?

Masarova: We hope there will be a goal of therapy in the coming decades. Currently, the therapy goals are kind of focused more in controlling the accounts displaying the symptoms and getting deeper responses. Right now, with some therapies that showed us that we could decrease the allele burden, or we could alter the bone marrow fibrosis, or the bone marrow morphology is going to be the disease modification. As of now, there is no agent that would do it, except for the interferon, which showed quite promisingly that we can bring it into the landscape of the disease.

What does the treatment landscape currently look like for ET?

ET is considered a benign disease. People live with it for a very long time. Currently, treatment is for only those we call high-risk disease patients. Patients that had thrombosis in the past, and then patients that are over the age of 60 years and have a dAkt mutation, and that’s according to the revised International Prognostic Score of Thrombosis for Essential Thrombocytopenia score. Those patients are treated to decrease the risk of thrombosis, but not to do anything else. This is modified just to simply increase the thrombosis risk. That is hydroxyurea, it’s a standard frontline agent, which is an easy to take oral drug. However, it could lead to some resistance or about 30% patients can become.

Because ET also affects younger people, plenty of younger females, they don’t really want to take chemotherapy forever, which I don’t blame them for. They are interested in taking something else. The standard interferon, recombinant or pegylated, which is called the peginterferon alfa-2a [Pegasys]. We’ve recently used this for the couple years has been around for MPNs, particularly for ET and the PV. That is about 40 years almost. This treatment has a lot of data, and a lot of implications. This may be a disease modifying agent, which is an agent that could decrease the allele burden, eradicate the malignant clone, and ultimately change the disease behavior. We were excited. We had novel interferon called ropeginterferon-alpha-2b-njft approved in patients with progressive disease back in 2021. That has been preceded by approval in European Union in 2019. That’s an excellent option in terms of interferons. The normal alternative with the ropeginterferon, which is the novel mono-pegylated form, is kind of more convenient because it’s used every other week. Once we reached complete hematologic control, it’s used once a month. That’s a significant improvement in inconvenience for patients and in tolerability as well as compliance issues. We were excited to get it in PV, and we have it in some studies in PV to expand the access and maybe try a different schedule, and you move it to ET patients. That’s something that we’re going to be looking at.

Then, for patients with PV refractory to hydroxyurea, we have approved sunitinib [Sutent] which is the JAK inhibitor that has solid data in the field after hydroxyurea based on results from the RESPONSE [NCT01243944] and RESPONSE-2 [NCT02038036] trials. It will be 10 years since we had refractory patients treated with ruxolitinib [Jakafi]. It’s an excellent drug for controlling the symptoms and spleen count.

Last year, we had a very excited study called MAGIC-PV [ISRCTN61925716], which was reported by our European colleagues that showed the advantage of ruxolitinib for decreasing the rate of thrombosis hemorrhage. It also actual improved event-free survival, death, and adverse events in terms of progression to myelofibrosis. So, it was exciting. If we consider disease modification is what’s going to be preventing the disease to go into myelofibrosis, I think that will be exciting to see how far we can get in that field.

Can you discuss the rationale of the EXCEED-ET study [NCT05482971]?

The EXCEED-ET study is getting the ropeginterferon, which is the novel interferon into the space of ET. It is phase 1/2 study that gets the ropeginterferon in patients in North America. The patients are hydroxyurea-refractory or hydroxyurea-naive. Patients that have ET platelets over 450,000 need the therapy with some symptoms, and do not have a contraindication for interferons, which also had to be mentioned that the drugs could not be used in patients that have previous autoimmune disease, psychiatric diseases, or neurological because it could aggravate their symptoms. But those patients, if they would be eligible, they could be getting the full access to the drug. Also, with patients with ET, the escalation is going to be a lot faster to 250 micrograms, every other week, 350, and then 500 is the maximum dose that has been explored. However, I have to say the approval of ropeginterferon for PV had even higher dose, and the maximum-tolerated dose was not reached. This is a perfectly safe dose that we have patients on. We’re going to see how it’s going to do in ET patients. There is a core treatment period, which continues after the 4 weeks of escalation of up to 56 weeks. The patients will be dosed every other week with a tolerable dose. We will be monitoring the primary end points of durability of control, hematologic control, platelets less than 450, white cells less than 10. That will basically sustain 80% of 36 consecutive weeks. Then, the key secondary end points are going to include all important end points in ET patients, such as complete hematologic response, composite hematologic response, that includes control of spleen, control of symptoms, absence of disease progression, and absence of thromboembolic events. Then, it’s going to also have this excited end point, which is basically a decline or allele burden. We’ll be checking the allo burden, what we call the molecular response, and then bone marrow morphology response.

Also, there are a couple other exploratory or pharmacokinetic studies that we’re going to be conducting. It’s a study that does not allow patients that were exposed to interferon. For example, patients and [peginterferon alfa-2a] would not be eligible. However, with a plan amendment, there is going to be measurement of neutralizing antibodies against ropeginterferon. If patients are not detected to carry those, they will be still eligible.

If positive, how do you see this study impacting the field?

I’m excited about it. I’ve used interferons in the off-label setting ever since I came to MD Anderson, and it’s been proven to be an effective therapy for young people. I have a lot of patients come in from everywhere and they don’t want to do chemotherapy, they seek the agent. So far, we’ve been only able to give them the [peginterferon alfa-2a], where we have to deal with insurance companies, because it was off-label setting.

Last year, we published 15 years follow-up on our phase 2 study. But this is going to open the use of the agent, I’m excited about the less frequent interactions, which my patients are excited about as well. I’m going to be really comparing and lucky for me, I’ve seen the tolerance of the [peginterferon alfa-2a] in these patients. I will really be comparing them to the ropeginterferon, seeing what this agent could offer, and seeing the results in PV. I’m quite excited about it. I don’t think we will have any data about what we call the disease modification or how we call it in the next 10 years, maybe because it’s a very low progressing disease, but I’m looking forward to seeing whether we’re going to see elimination or absence of disease progression to myelofibrosis. I also wonder if we will see minimization of the thromboembolic events. That will be the ultimate disease modification change.

Afterwards, hopefully we can add it to something and maybe keep patients on some agents that have been around and help control the counts. At the same time, maybe we can do a low dose interferon for a longer time as a disease modification agent, and hopefully you will wake up in an era where there’s going to be no ET or PV.

REFERENCE:

Masarova L, Mascarenhas J, Qin A, et al. EXCEED-ET: A single-arm multicenter study to assess the efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft (P1101) in North American adults with essential thrombocythemia. J Clin Oncol. 2023;41(suppl 16): TPS7088- TPS7088. doi:10.1200/JCO.2023.41.16_suppl.TPS7088

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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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Dr Kremyanskaya on the Efficacy of Rusfertide in Phlebotomy-Dependent Polycythemia Vera

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June 16, 2023

Marina Kremyanskaya, MD, PhD

Marina Kremyanskaya, MD, PhD, assistant professor of medicine, hematology, and medical oncology, Icahn School of Medicine, Mount Sinai, medical director, Inpatient Oncology Unit, The Mount Sinai Hospital, discusses key efficacy data for rusfertide (PTG-300) in the phase 2 REVIVE trial (NCT04057040) of phlebotomy-dependent polycythemia vera.

Polycythemia vera is a specific type of erythrocytosis that also features systemic symptoms and a high risk of thromboembolic and/or cardiovascular (CV) complications. High levels of the iron-regulator hepcidin have been implicated in uncontrolled red blood cell formation.

The REVIVE trial compared the ability of the first-in-class hepcidin mimetic rusfertide vs placebo to control erythrocytosis in patients with polycythemia vera who had previously received 3 or more phlebotomies in 28 weeks with or without concurrent cytoreductive therapy. The trial was composed of a dose-finding stage (part 1), blinded randomized withdrawal (part 2), and an open-label extension portion (part 3).

Patients in part 1 received a weekly subcutaneous dose of rusfertide that was individually adjusted to achieve a hematocrit level below 45% (range, 10 mg-120 mg). In part 2, patients were randomized to continue rusfertide or to receive placebo. The study’s primary end point was efficacy as characterized by the proportion of responders in part 2, Kremyanskaya says. Responses were achieved if patients had a hematocrit level below 45% without phlebotomy eligibility, did not receive therapeutic phlebotomy, and had completed 12 weeks of treatment, she explains.

Results from the randomized withdrawal phase were presented at the 2023 EHA Congress and demonstrated that rusfertide produced a significantly higher percentage of responders vs placebo, Kremyanskaya reports. These percentages were 69.2% (n = 18/26) with rusfertide vs 18.5% (n = 5/27) with placebo. Additionally, most patients on the study had low ferretin levels at baseline, indicating iron deficiency, Kremyanskaya states. After treatment with rusfertide, ferretin levels were normalized and maintained for many of these patients, she says.

Analysis of symptom improvement was based on data from part 1, as the majority of patients in the placebo arm of part 2 discontinued treatment prior to the 12-week mark, Kremyanskaya continues. Rusfertide treatment significantly improved the rate and severity of problems with concentration, itching, fatigue, and inactivity, which tend to be moderate or severe at baseline. Regarding safety, the agent was generally well tolerated, Kremyanskaya concludes.

Disclosures: Dr Kremyanskaya reported receiving honoraria and being on the advisory board for Protagonist Therapeutics, Inc.

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