MANIFEST-2 Study of Pelabresib Plus Ruxolitinib Completes Enrollment in Myelofibrosis

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Kristi Rosa

Enrollment to the phase 3 MANIFEST-2 trial, which is examining the safety and efficacy of pelabresib plus ruxolitinib vs ruxolitinib alone in patients with JAK inhibitor–naïve myelofibrosis, has completed and topline findings are anticipated by the end of 2023.

Enrollment to the phase 3 MANIFEST-2 trial (NCT04603495), which is examining the safety and efficacy of pelabresib plus ruxolitinib (Jakafi) vs ruxolitinib alone in patients with JAK inhibitor–naïve myelofibrosis, has completed and topline findings are anticipated by the end of 2023.1

The multicenter, double-blind, placebo-controlled, trial enrolled patients with primary, post–polycythemia vera, or post–essential thrombocytopenia myelofibrosis who were at least 18 years of age, had advanced disease requiring therapy, splenomegaly by computed tomography or magnetic resonance imaging, were symptomatic, and had a prognostic risk-factor score of intermediate-1 or higher per the Dynamic International Prognostic Scoring System (DIPSS).2,3

After a screening period that lasted for up to 28 days, participants were randomly assigned 1:1 to receive ruxolitinib plus oral pelabresib or matched placebo daily for 14 consecutive days, followed by 7 days off treatment.1 Pelabresib had a starting dose of 125 mg daily, with additional dose increases allowed in accordance with trial protocol. Ruxolitinib was given in twice-daily doses of 10 mg or 15 mg based on baseline platelet counts for all 21 days of each cycle; again, dose increases were allowed per protocol criteria.

Treatment was continued until progressive disease and withdrawal of treatment. Notably, those in the control arm who experience disease progression following 24 weeks of treatment are allowed to crossover to receive the pelabresib doublet.

Patients were stratified based on DIPSS risk category (intermediate-1 vs intermediate-2 vs high), platelet count (>200 x 109/L vs 100 to 200 x 109/L), and spleen volume (≥1800 cm3 vs <1800 cm3).3

The primary end point of the trial is the proportion of patients who achieve a reduction in spleen volume of at least 35% (SVR35) at week 24 vs baseline, and a key secondary end point is the proportion of patients achieving a total symptom score improvement of at least 50% (TSS50) at week 24 vs baseline.

Other secondary end points include percentage change in TSS at week 24 vs baseline, improvement in bone marrow fibrosis by at least 1 grade at week 24 compared with baseline, SVR35 and TSS50 response at week 48 vs baseline, red blood cell (RBC) transfusion rate over the first 24 weeks of treatment, and conversion from RBC transfusion dependence to independence. Other end points include category change of Patient Global Impression of Change at week 24 vs baseline, progression-free survival, overall survival, percentage of patients with transformation to acute myeloid leukemia, toxicities, and pharmacokinetics.

“Now that MANIFEST-2 has completed enrollment earlier than anticipated, we look forward to the coming insights into the therapeutic potential of pelabresib in combination with ruxolitinib for JAK inhibitor–naïve patients with myelofibrosis,” Tim Demuth, MD, PhD, chief research and development officer at MorphoSys AG, stated in a press release. “MANIFEST-2 is the latest milestone in our efforts to improve outcomes for [patients with] blood cancer and is a testament to our continued commitment to the myelofibrosis community.”

The launch of the trial was supposed by findings from the phase 2 MANIFEST trial (NCT02158858).4 Data from the latest analysis of the trial, which had a data cutoff date of July 29, 2022, showed that 68% of JAK inhibitor–naïve patients with myelofibrosis who received pelabresib plus ruxolitinib (n = 84) achieved SVR35 at 24 weeks; at week 48, this rate was 61%, and at week 60, this rate was 54%.

Moreover, of 82 evaluable patients, 56% achieved TSS50 at week 24, indicative of a reduction in symptom burden with the combination. At week 48, 44% achieved TSS50; this rate was 43% at week 60.

Findings from an exploratory analysis of the trial showed that 27% of 63 evaluable patients experienced an improvement of at least 1 grade by week 24. This improvement was maintained at week 48 for 59% of these patients.

In terms of safety, 55% of patients experienced thrombocytopenia and 43% had anemia; these effects were grade 3 or higher in 18% and 34% of patients, respectively. Other common any-grade treatment-emergent toxicities included diarrhea (43%), respiratory tract infection (41%), asthenic conditions (38%), musculoskeletal pain (32%), constipation (30%), nausea (29%), dizziness (27%), and abdominal pain (26%).

“I think the data are exciting because they continue to demonstrate over a number of patients, over a number of centers, the benefit of combining these 2 therapies,” John Mascarenhas, MD, director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai in New York, New York, said in a past interview with OncLive®. “We’ve done analysis that showed whether you separate patients by their prognostic score, by their molecular profile, etc, the benefit seems to be across these patients’ subgroups. It really provides additional confidence in moving this therapy into the phase 3 setting.”

References

  1. MorphoSys completes enrollment of phase 3 MANIFEST-2 study of pelabresib in myelofibrosis with topline results expected by end of 2023. News release. MorphoSys AG. April 4, 2023. Accessed May 8, 2023. https://www.morphosys.com/en/news/morphosys-completes-enrollment-phase-3-manifest-2-study-pelabresib-myelofibrosis-topline
  2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated April 6, 2023. Accessed May 8, 2023. https://clinicaltrials.gov/ct2/show/NCT04603495
  3. Harrison CN, Gupta VK, Gerds AT, et al. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naïve myelofibrosis. Future Oncol. 2022;18(27):2987-2997. doi:10.2217/fon-2022-0484
  4. MorphoSys presents new longer-term phase 2 results on pelabresib in myelofibrosis, including potential disease-modifying activity, at ASH 2022. News release. MorphoSys AG. November 12, 2022. Accessed May 8, 2023. https://www.morphosys.com/en/news/morphosys-presents-new-longer-term-phase-2-results-pelabresib-myelofibrosis-including

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‘Knowledge Is Exponential’ in the Rare Blood Cancer Space

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Brielle Benyon

The treatment landscape for myeloproliferative neoplasms (MPNs) is ever-changing. “It’s hard to keep up, but it’s exciting,” said Dr. Steven Applebaum, a hematologist oncologist at UCLA Health in Pasadena, California.

In an interview with CURE®, Applebaum, who was recognized at 10th Annual MPN Heroes® event in December, explained that discoveries in other diseases could pave the way for a better understanding of MPNs, a rare group of blood cancers including polycythemia vera, essential thrombocythemia and myelofibrosis.

“Knowledge is somewhat exponential,” he said. “You make one discovery, which seems big, and then that kind of leads to not one more, but five more.”

Of note, Applebaum said that researchers and clinicians continue to learn more about genetic mutations and targeted therapies that will help personalize MPN therapies and make them more effective — helping patients with the disease to live longer and with a better quality of life.

Transcription

Looking at a lot of other diseases, I mean, knowledge is somewhat exponential. You make one discovery, which seems big, and then that kind of leads to not one more, but five more. The guys doing research in the lab, I expect us to learn a lot more different mutations, you know, targeted therapy. So I think we’re all really excited just looking at a lot of other diseases as a model, that there’s going to be increasing numbers of treatments that again, are going to help people live longer, but also improve their quality of life.

So the thing about being an oncologist is that (when) you’ve finished your training, you realize you don’t know anything; everything’s in evolution. So, the things I knew back then are really so cursory relative what we know now, so it’s part of what motivates us to keep going as you know that the changes in the discoveries and new treatments are going to be coming almost daily. I mean, it’s hard to keep up but it’s exciting.

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Blood cancer trial finds ruxolitinib better than current treatments

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Results from a new trial sponsored by the Cancer Research UK Clinical Trials Unit at University of Birmingham have found that ruxolitinib is better for treating patients with polycythaemia vera (PV) than the existing treatments.

PV is an incurable blood cancer and part of some conditions that affect the blood called myeloproliferative neoplasms (MPNs).

During the Phase II MAJIC-PV randomised trial, researchers studied ruxolitinib in patients who do not respond well to first line treatment.

Altogether, 180 PV patients were included in the trial, which saw the participation of various hospitals under the co-ordination of the Cancer Research UK Clinical Trials Unit.

The researchers compared the ruxolitinib drug and existing therapies.

Ruxolitinib has been designed to target JAK2 and already approved for use in PV. However, the drug is not available in the UK.

Data from the trial showed that ruxolitinib led to better disease control with normal blood counts and a minimised spleen size.

It was also found that both controlling the blood count and minimising mutated JAK2 by 50% led to fewer disease related events.

Furthermore, patients with reduced JAK2 mutation survived longer and had lower disease progression risk.

University of Birmingham Cancer Research UK Clinical Trials Unit director Pamela Kearns said: “Working on new treatments for incurable cancers is just the kind of thing that the Birmingham Cancer Research UK Clinical Trials Unit is about.

“I am really pleased that this important clinical trial has found that ruxolitinib has long-term clinical benefit for the ongoing treatment of patients with PV, and that further trials will be able to identify whether the drug can be used as an effective first line treatment.”

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Learn About Rare Cancer Because ‘Uncertainty Creates Anxiety,’ Expert Says

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Brielle Benyon

After a patient is diagnosed with a rare disease such as a myeloproliferative neoplasm, learning about their condition and seeking expert clinicians can help put their mind at ease.

When it comes to rare diseases such as myeloproliferative neoplasms (MPNs), gaining an understanding of the disease and seeking a specialist for treatment can help patients feel more at ease with their diagnosis, explained Dr. Raajit Rampal, an associate attending physician at Memorial Sloan Kettering Cancer Center in New York City.

MPNs are a group of rare blood cancers that many people have not heard of at the time of their diagnosis, according to Rampal, who was recognized at CURE®’s 10th Annual MPN Heroes® program in December. However, learning more about the disease and its treatment can help ease patients’ minds, as “uncertainty creates anxiety,” according to Rampal.

When it comes to developing new treatments and sparking new scientific discoveries in the MPN space, specialized doctors and researchers are essential, Rampal said.

“Sometimes (a patient will say), ‘You know, this disease is a one-in-a-million diagnosis.’ And I’ll say, ‘Yes, but you are the 10th or 11th person who I’m going to see today with it.’ That helps to further this type of research,” Rampal said in an interview with CURE.

Transcription

Well, (there are) a couple of things, a couple of challenges.

No. 1 is education. You know, when patients get diagnosed … this is a rare disease, as I often say to the patients, “This is not something your neighbor has, you’re not going to have a chat with them about that in all likelihood.” And oftentimes, what is lacking when we meet somebody who’s newly diagnosed is them having an education about this disease, they, in most cases, have never heard of this. And the doctors who see them or their primary care doctors, they’ve read about it, they don’t have seen many of these cases.

So part of our job is to educate them thoroughly. This is what you have, this is what it’s about, these are the things we can do about it. That’s partly just for the sake of education of patients, but partly because, to some extent, it relieves anxiety, right? Uncertainty creates anxiety. I’m a firm believer in that. And so, giving any type of education that will alleviate that or give somebody a better understanding will help with anxiety.

Now, on the other side of things, it’s a rare disease, and how do you bring ideas forward? You’re dealing with small numbers of patients, right? I think if you have good ideas, they are translatable. But it doesn’t stop there. Because you’re right, you can have a fantastic scientific idea. How are you going to get patients on to the study? Part of it is building a cohort and having a specialization. Doctors and researchers who are specialized in these diseases, this is most of what they see. Sometimes … (a patient will) say, “Well, you know, this disease is a one in a million diagnosis.” And I’ll say “Yes, but you are the 10th or 11th person who I’m going to see today with it.”

That helps to further this type of research. It’s not everyone (who is) going to qualify for every trial. But if you don’t have the numbers, you can’t do the research. And so making sure that, you know, us, we, as specialists, have a focus in these diseases makes a difference and that allows us to bring concepts forward for clinical trials because then we have the patients who are going to be eligible.

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PharmaEssentia Initiates Phase 3b Trial of Ropeginterferon alfa-2b-njft Investigatng New Dosing Regimen for Patients With Polycythemia Vera (PV)

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Published: May 03, 2023

Single-arm trial will evaluate an accelerated dosing schedule

BURLINGTON, Mass.–(BUSINESS WIRE)– PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced that the first patients are now being dosed in ECLIPSE PV, a Phase 3b clinical study evaluating an accelerated dosing schedule for ropeginterferon alfa-2b-njft using a prefilled syringe for the treatment of adults with polycythemia vera (PV).

Ropeginterferon alfa-2b-njft (marketed as BESREMi®) was approved by the U.S. Food and Drug Administration in November 2021 as a treatment for adults with PV.1 PV is a rare, chronic and life-threatening blood cancer caused by a mutation in hematopoietic stem cells in the bone marrow, resulting in the overproduction of red blood cells, white blood cells and platelets. Individuals with PV are at risk for serious health problems, including blood clots, stroke and heart attack.2,3 Without proper management, this debilitating cancer can progress into myelofibrosis and other malignancies, including acute myeloid leukemia.4

“This therapy represents an important addition to the treatment arsenal for PV in the U.S., and clinical data supports its use across a broad range of patients regardless of their treatment history,” said John Mascarenhas, M.D., professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York. “This new study is addressing an important therapeutic and clinical question regarding whether treatment utilizing accelerated dosing leads to a more rapid hematologic and molecular response, indicating potential disease modifying activity and long-term disease control.”

The study will evaluate an accelerated dosing schedule for ropeginterferon alfa-2b-njft compared to the current labeled dosing. The primary endpoint is the proportion of patients achieving a CHR, defined as hematocrit <45% for at least 3 months since last phlebotomy, platelets ≤ 400 x 109/L, leukocytes ≤10 x 109/L, at 24 weeks of treatment. Approximately 100 adults with PV in the U.S. and Canada will be randomized to receive either the accelerated dosing (i.e., starting dose of 250 mcg, then 350 mcg at week 2, with a target optimal dose of 500 mcg at week 4, and then dosing will remain fixed at the highest tolerated dose for the remainder of the treatment period) or patients will receive the current labeled dosing (50 or 100 mcg starting dose with 50 mcg titration every 2 weeks). There is a 48-week study period followed by a 28-day safety follow-up. Those who respond to treatment will be eligible to participate in a long-term extension phase of the study.

“Our goal with this study is to deliver evidence on the potentially enhanced benefits of treating patients with BESREMi through this accelerated dosing schedule and to bring additional confidence to clinicians and patients in the utility of the treatment to manage this chronic cancer,” said Raymond Urbanski, M.D., Ph.D., U.S. Head of Clinical Development and Medical Affairs. “We believe this study will deliver further insight into the potential of BESREMi to meet the needs of PV patients.”

More information on the study including eligibility criteria can be found by visiting www.eclipsepv.com or www.clinicaltrials.gov and searching for the trial identifier NCT05481151. Topline data from the trial are expected by 2024.

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Determinants of Covid19 disease and of survival after Covid19 in MPN patients treated with ruxolitinib

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Authors: Francesca Palandri, Elena M. Elli, Giuseppe Auteri, Massimiliano Bonifacio, Giulia Benevolo, et al.

Blood Cancer Journal  volume 13, Article number: 65 (2023) 

Introduction

The coronavirus disease 2019 (Covid19) pandemic caused by the spreading of the coronavirus SARS-CoV-2 has led to substantial mortality in patients with hematological diseases [1]. During the first wave of pandemic, patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) were reported at higher risk of acquiring SARS-CoV-2 and of having a poor outcome after infection, with a mortality rate of about 30%, increasing to 48% in MF patients [2].

Ruxolitinib is a JAK1/2 inhibitor that is widely used both in MF and PV [3]. It may affect immunological response by decreasing the production of pro-inflammatory cytokines and by altering the function of several immune cells, including macrophages and B/T-lymphocytes [4]. Its use and discontinuation have been identified as risk factors for SARS-CoV-2 infection and Covid19-related death [5] Additionally, ruxolitinib-treated patients show lower serological response to anti-SARS-CoV-2 vaccination [6, 7].

Previous studies on Covid19 in MPN patients have included patients regardless of treatment type, with few patients treated with ruxolitinib at the time of the pandemic. Here, we explored features associated with Covid19 disease and survival after Covid19 in a large cohort of ruxolitinib-treated PV and MF patients.

This analysis could provide useful information for identifying those ruxolitinib-treated patients that are at higher risk of SARS-CoV-2 infection and assessing prognostic factors for survival in a homogeneously treated cohort. The final objective is to provide decision-support tools for viral therapy and/or hospitalization.

Methods

Study setting

The observational retrospective cohort studies “RUX-MF and “PV-ARC” were promoted by the IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy. The PV-ARC study involves 934 PV patients, while the “RUX-MF” study collects 886 MF patients in chronic phase who received ruxolitinib outside clinical trials. Details of protocol design, list of participating Centres and operational procedures have already been reported [8, 9]. For the purposes of this analysis, data concerning MF/PV and characteristics related to first Covid19 infections during ruxolitinib therapy were recorded. The data cut-off date was January 2022.

Waves of the Covid19 pandemic were divided into three periods, according to the type of predominant circulating variants in Europe: first (wild-type variant, February–June 2020); second (alpha/beta/gamma variants, July 2020–June 2021) and third (delta variant, July 2021–January 2022).

Covid19 severity was categorized according to the NIH Guidelines [10].

Statistical analysis

Statistical analysis was carried out at the biostatistics laboratory of the MPN Unit at the Institute of Hematology “L. and A. Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria, Bologna.

Continuous variables have been summarized by their median and range, and categorical variables by count and relative frequency (%) of each category. Comparisons of quantitative variables between groups were carried out by Wilcoxon–Mann–Whitney rank-sum test; association between categorical variables was tested by the χ2 test. By Receiver Operating Characteristic (ROC) curve, the optimal cut-off for neutrophil to lymphocyte ratio (NLR) was found at 5.5 (AUC: 0.66) for hospitalization and at 6.8 (AUC: 0.71) for death.

Using Cox proportional hazard model, association with COVID-19 hospitalization and Covid19-related survival was evaluated for the following variables: age ≥ 70 years, sex, presence of at least one comorbidity, MPN type, NLR ≥ 5.5 (hospitalization), NLR ≥ 6.8, vaccination, wave, previous thrombosis, and platelet count/hemoglobin at infection. The same factors were evaluated using a logistic regression model for PV and MF patients (adding DIPSS and spleen response at Covid19 infection in the latter). The association between thromboses that occurred during the pandemic and Covid19 infection, MPN type and NLR was also investigated.

For all analyses, the starting time was February 2020, corresponding to the pandemic start.

Overall survival was calculated by Kaplan–Meier analysis, starting from the date of Covid19 infection and considering only Covid19-related deaths.

Pearson’s test was used to measure the collinearity of covariates.

Akaike’s Information Criterion (AIC) and Schwarz’s Bayesian Information Criterion (BIC) were used to choose the model that best fits the data.

For all tested hypotheses, two-tailed p-values < 0.05 were considered significant. Statistical analyses were performed using STATA Software, 15.1 (StataCorp LP, College Station TX, USA).

Results

Study cohort

Overall, 886 MF and 172 PV patients treated with ruxolitinib outside clinical trials have been registered in the RUX-MF and in the PV-ARC databases, respectively. At pandemic start, 560 patients (413 MF and 147 PV) were receiving ruxolitinib and were included in this analysis. Ruxolitinib dose was evaluable in 135 and 409 PV and MF patients, respectively. Median dose at pandemic start was 5–10 mg BID in all PV and 189 (46.2%) MF patients, 15 mg BID and 20 mg BID in 114 (27.9%) and 106 (25.9%) MF patients.

From February 2020 to January 2022, 83 (14.2%) patients acquired the Covid19 disease (PV n = 16, 10.8%; MF n = 67, 16.2%; p = 0.12), with an overall incidence rate of 10.5 per 100 patient-years. Overall, 15, 41, and 27 infections were observed during the first, second, and third pandemic wave, with incidence rates of 6.5, 7.8, and 7.3 per 100 patient-years in the three waves, respectively (p = 0.75).

Infection was asymptomatic/mild in 21 patients (25.3%), moderate in 17 (20.5%), severe in 18 (21.7%), critical in 6 (7.2%) and fatal in 21 (25.3%) patients (Supplementary Fig. 1).

Characteristics associated with Covid19 infection and hospitalization

Differences between non-Covid19 and Covid19 ruxolitinib-treated patients are summarized in Table 1. Overall, 371/467 evaluable patients (79.4%) received ≥ 1 dose of anti-SARS-CoV2 vaccine. All but one patient received an mRNA vaccine (BioNTech/Pfizer n = 327 [88.1%], Moderna n = 43 [11.6%]).

Compared to Covid19 patients, those who did not acquire the infection had more frequently received ≥ 1 dose of anti-SARS-Cov2 vaccine (p < 0.001). The protective effect of vaccination was confirmed also in the MF and in the PV population separately (39.5% and 56.3% of vaccinated patients vs. 82.5% and 86.8% of unvaccinated patients with Covid19 infection in MF and PV, p < 0.001 and p = 0.003, respectively).

All the 45 (54.2%) patients with severe, critical, fatal infections were hospitalized. The frequency of hospitalization in the first and second waves (66 and 68%) was higher compared to the third one (26%), (p = 0.002). Compared to outpatients, those admitted to hospital were more likely to be ≥ 70 years (p = 0.05), had a significantly lower median platelet counts (150 vs. 226 × 109/L, p = 0.02) and higher neutrophil counts (7.2 vs. 4.2 × 109/L, p = 0.04), with a significant increase of neutrophil to lymphocyte ratio (NLR) (5.6 vs. 3.5, p = 0.04). At Covid19 diagnosis, ruxolitinib was reduced in 11 (13.3%) patients. Ruxolitinib discontinuation occurred in 9 patients (10.8%) in the 1st, 2nd and 3 wave in 4, 4 and 1 patients, respectively, and comparably in MF and PV. The cause of discontinuation was severe Covid19 infection in all cases, together with severe thrombocytopenia (platelet < 50 × 109/l) in 2 cases.

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Incyte Reports 2023 First Quarter Financial Results and Provides Updates on Key Clinical Programs

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Published May 2, 2023

– Total net product revenues of $693 million in Q1’23 (+14% Y/Y)

– Jakafi® (ruxolitinib) net product revenues of $580 million (+7% Y/Y) in Q1’23; raising the bottom end of full year guidance to new range of $2.55 – $2.63 billion for FY 2023

– Opzelura® (ruxolitinib) cream approved as the first and only treatment for repigmentation of nonsegmental vitiligo in Europe; continued strong U.S. launch in atopic dermatitis and vitiligo

– Multiple positive data readouts from dermatology portfolio at AAD and EHSF 2023

WILMINGTON, Del.–(BUSINESS WIRE)– Incyte Corporation (Nasdaq:INCY) today reports 2023 first quarter financial results, and provides a status update on the Company’s clinical development portfolio.

“Our first quarter results demonstrate continued year-over-year double-digit revenue growth driven by Jakafi, which grew across all indications, and Opzelura, which is on track to become one of the most successful dermatology launches in recent years. In addition, we further expanded our commercial portfolio with several regulatory approvals including Opzelura for vitiligo in Europe.” said Hervé Hoppenot, Chief Executive Officer, Incyte. “Furthermore, in Q1 we made a decision to focus our development efforts on eight programs that have high potential value for us and discontinued six other programs. This allows us to optimize our allocation of resources on programs that can have a high impact for patients and for Incyte.”

Key Product Sales Performance

Jakafi:

Net product revenues of $580 million:

  • Net product revenues grew 7% compared with the first quarter of 2022, driven by strong underlying patient demand growth (+7% Y/Y) including an 8% growth in new patients. Total patients grew across myelofibrosis (MF), polycythemia vera (PV) and graft-versus-host disease (GVHD).
  • Net product revenues were unfavorably impacted by:
    • Higher gross-to-net deductions, compared to fourth quarter of 2022, as a result of the Medicare coverage gap and higher commercial patient deductibles at the beginning of the plan year, as well as an increase in 340B orders.
    • Lower than normal levels of channel inventory at the end of Q1, representing an $11 million impact.

Opzelura:

Net product revenues of $57 million:

  • Net product revenues grew 343% compared with the first quarter of 2022, driven by growth in patient demand and expansion in payer coverage as the launch in atopic dermatitis (AD) and vitiligo continues.
  • Compared to the fourth quarter of 2022, net product revenues were unfavorably impacted by:
    • Increase in co-pay assistance due to higher commercial patient deductibles at the beginning of the plan year, consistent with first quarter dynamics and higher Medicaid utilization volume.
    • Acceleration of refills in December 2022 driven by patient demand in advance of annual deductible reset or health plan changes that negatively impacted refills during the months of January and February this year.

Pipeline Updates

MPNs and GVHD – key highlights

LIMBER (Leadership In MPNs and GVHD BEyond Ruxolitinib): Our LIMBER development program encompasses multiple monotherapy and combination strategies, with the goal of improving upon the standard of care in MF, PV, GVHD and now, essential thrombocythemia (ET).

  • Combination trials of ruxolitinib BID with zilurgisertib (ALK2) and INCB57643 (BET) are ongoing and progressing well.
  • In early development, INCA33989 (mCALR) is on track for initiating first-in-human study in MF and ET in 2023. Additionally, a Phase 1 study evaluating ruxolitinib BID in combination with Cellenkos’ CK0804 in MF is continuing to recruit patients.
  • AGAVE-201, a global pivotal Phase 2 trial of axatilimab in patients with cGVHD is ongoing and results are on track for mid-2023. A Phase 1/2 combination trial of axatilimab in combination with ruxolitinib is being planned.
  • The Phase 3 LIMBER-304 trial, evaluating parsaclisib in combination with ruxolitinib BID in suboptimal responders in MF and the Phase 3 LIMBER-313 trial, evaluating parsaclisib in combination with ruxolitinib BID in first-line MF, were discontinued following results of interim analyses that indicated that the studies were unlikely to meet their primary endpoints in the intent-to-treat patient population. The studies were not stopped due to safety.
  • The U.S. Food and Drug Administration (FDA) issued a complete response letter for ruxolitinib extended-release (XR) tablets for once-daily (QD) use in the treatment of certain types of MF, PV and GVHD. Incyte will work with the FDA to determine appropriate next steps.

Indication and status

Ruxolitinib XR (QD)

(JAK1/JAK2)

Myelofibrosis, polycythemia vera and GVHD

Ruxolitinib + zilurgisertib

(JAK1/JAK2 + ALK2)

Myelofibrosis: Phase 2

Ruxolitinib + INCB57643

(JAK1/JAK2 + BET)

Myelofibrosis: Phase 2

Ruxolitinib + CK08041

(JAK1/JAK2 + CB-Tregs)

Myelofibrosis: Phase 1 (LIMBER-TREG108)

Axatilimab (anti-CSF-1R)2

Chronic GVHD: Pivotal Phase 2 (third-line plus therapy) (AGAVE-201)

Ruxolitinib + axatilimab2

(JAK1/JAK2 + anti-CSF-1R)

Chronic GVHD: Phase 1/2 in preparation

INCA33989

(mCALR)

Myelofibrosis, essential thrombocythemia: Entering clinic in 2023

1 Development collaboration with Cellenkos, Inc.

2 Clinical development of axatilimab in GVHD conducted in collaboration with Syndax Pharmaceuticals.

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FDA Grants Priority Review to Luspatercept for First-line Treatment of Anemia in Lower-risk MDS

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May 1, 2023

Chris Ryan

The FDA has granted a priority review to the supplemental biologics license application seeking to expand the current indication of luspatercep to include treatment of anemia in patients with very low- to intermediate-risk myelodysplastic syndrome who have not previously received erythropoiesis-stimulating agents and who may require red blood cell transfusions.

The FDA has granted a priority review to the supplemental biologics license application (sBLA) seeking to expand the current indication of luspatercept-aamt (Reblozyl) to include treatment of anemia in patients with very low- to intermediate-risk myelodysplastic syndrome (MDS) who have not previously received erythropoiesis-stimulating agents (ESAs) and who may require red blood cell (RBC) transfusions.1

Additionally, the European Medicines Agency (EMA) has validated the type II variation application for luspatercept in the same indication.

The applications were supported by data from the phase 3 COMMANDS trial (NCT03682536), which showed that luspatercept demonstrated a statistically significant and clinically meaningful improvement vs epoetin alfa in RBC transfusion independence of 12 weeks or more with a concurrent hemoglobin increase of at least 1.5 g/dL in patients with very low-, low- or intermediate-risk MDS requiring RBC transfusions.

Detailed findings from COMMANDS will be presented at an upcoming medical meeting.

The FDA has assigned a target action date of August 28, 2023, under the Prescription Drug User Fee Act. The EMA will also begin its centralized review process after validating the application.

“Initial treatment options for [patients with] very low- to intermediate-risk MDS, including ESAs, can alleviate anemia in some patients but others will either not respond or become resistant to therapy, and additional therapy options have remained urgently needed,” Noah Berkowitz, MD, PhD, senior vice president, Hematology Development, Bristol Myers Squibb, stated in a news release. “Results from the COMMANDS study showed [luspatercept] significantly improved transfusion independence and elevated hemoglobin compared [with the] ESA therapy, epoetin alfa. [Luspatercept] is an important option available for the treatment of anemia in patients with transfusion-dependent, lower-risk MDS who have experienced ESA failure, and we look forward to working with the FDA and EMA to expand its potential use as a first-line therapy in eligible patients.”

In November 2019, the FDA approved luspatercept for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions.2 Additionally, in April 2020, the FDA approved the agent for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.3

The open-label, randomized COMMANDS study enrolled patients with a documented diagnosis of MDS per World Health Organization 2016 classification meeting revised international prognostic scoring system (IPSS-R) classification of very-low, low-, or intermediate-risk disease.4 Other key inclusion criteria included bone marrow blasts of less than 5%, an endogenous serum erythropoietin level of less than 500 u/L, and an ECOG performance status of 0 to 2. Patients must have required RBC transfusions, which was defined by an average transfusion requirement of 2 to 6 units every 8 weeks of packed RBCs confirmed for a minimum of 8 weeks immediately preceding randomization.

Patients were excluded if they had clinically significant anemia due to iron, vitamin B12, or folate deficiencies; autoimmune or hereditary hemolytic anemia; hypothyroidism; or any type of known clinically significant bleeding or sequestration or drug-induced anemia. Other key exclusion criteria included a known history of acute myeloid leukemia or uncontrolled hypertension.

The study enrolled 363 patients who were randomly assigned to receive luspatercept or epoetin alfa.

RBC transfusion independence for 12 weeks with a mean hemoglobin increase at least 1.5 g/dL served as the trial’s primary end point. Key secondary end points included RBC transfusion independence for 24 weeks, and RBC transfusion independence for at least 12 weeks and erythroid response of at least 8 weeks during weeks 1 to 24.

Regarding safety, findings from COMMANDS were reported to be consistent with the toxicity profile of luspatercept observed in previous clinical trials and in the post-marketing setting.

References

  1. US FDA accepts for priority review supplemental biologics license application and EMA validates application for Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb. May 1, 2023. Accessed May 1, 2023. https://news.bms.com/news/details/2023/
  2. FDA approves luspatercept-aamt for anemia in patients with beta thalassemia. FDA. November 8, 2019. Accessed May 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-patients-beta-thalassemia
  3. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 3, 2020. Accessed May 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds
  4. A study to compare the efficacy and safety of luspatercept (ACE-536) versus epoetin alfa for the treatment of anemia due to IPSS-R very low, low, or intermediate risk myelodysplastic syndromes (MDS) participants who require red blood cell transfusions and are ESA naïve (COMMANDS). ClinicalTrials.gov. Updated April 18, 2023. Accessed May 1, 2023. https://clinicaltrials.gov/ct2/show/NCT03682536

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CTI BioPharma Announces Two Abstracts Accepted for Presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting

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Mon, May 1, 2023 at 7:03 AM EDT

– Data presentation on spleen volume reduction in patients with myelofibrosis also accepted for poster discussion –

SEATTLE, May 1, 2023 /PRNewswire/ — CTI BioPharma Corp. (Nasdaq: CTIC), a commercial biopharmaceutical company focused on the development and commercialization of novel targeted therapies for blood-related cancers, today announced that two abstracts have been accepted for presentation at the upcoming 2023 American Society of Clinical Oncology (ASCO) Annual Meeting taking place June 2-6, 2023 in Chicago, IL.

Presentation details are as follows:

Title: 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
Abstract #: 7018
Presenter: Helen Ajufo, M.D., Memorial Sloan Kettering Cancer Center
Session Title: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Session Date and Time: Monday, June 5, 2023, 8:00 – 11:00 a.m. CT
Location: Hall A, Poster #148
Poster discussion: In addition to the poster presentation, Dr. Ajufo will host a poster discussion session on Monday, June 5, 2023 from 11:30 a.m. – 1:00 p.m. CT in Room E450.

Title: Consistency of pacritinib for spleen and symptom reduction in patients with myelofibrosis regardless of cytopenias
Abstract #: 7068
Presenter: Dr. Prithviraj Bose, M.D., The University of Texas MD Anderson Cancer Center
Session Title: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Session Date and Time: Monday, June 5, 2023, 8:00 – 11:00 a.m. CT
Location: Hall A, Poster #198

About CTI BioPharma Corp.

CTI BioPharma is a commercial biopharmaceutical company focused on the development and commercialization of novel targeted therapies for blood-related cancers that offer a unique benefit to patients and their healthcare providers. CTI has one FDA-approved product, VONJO® (pacritinib), a JAK2, ACVR1,­­ and IRAK1 inhibitor, that spares JAK1. VONJO is approved for the treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. This indication is approved under FDA accelerated approval based on spleen volume reduction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). CTI is conducting the Phase 3 PACIFICA study of VONJO in patients with myelofibrosis and severe thrombocytopenia as a post-marketing requirement. For more information, please visit www.ctibiopharma.com.

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Looking Ahead in Treating Myeloproliferative Neoplasms

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Aaron Gerds, MD
Pankit Vachhani, MD
Naveen Pemmaraju, MD

Naveen Pemmaraju, MD: In this booming time of research for our patients with MPNs [myeloproliferative neoplasms], particularly myelofibrosis [MF], I’m energized by the worldwide community that has not only persisted during the time of the pandemic but has really augmented. I recently returned from presenting at the ESH [European Society of Hypertension] meeting in Berlin, Germany, for MPN and CML [chronic myelogenous leukemia]. And I was energized to talk to my fellow colleagues from around the world. I think we identified 3 major areas to focus on in terms of emerging trends and special considerations over the coming year. One, I believe, is the further investigation of these novel combinations. So far, we have focused on JAK inhibitors plus novel agents, but the discussions will be over the coming years together. What about different JAK inhibitors as the backbone beyond ruxolitinib? What about newer targets, and novel agents? And then, of course, novel, novel agents, as we call them, which is the combination of 2 beyond JAK inhibitor agents in a non-JAK inhibitor-containing regimen. So, I think those clinical trials would be of the highest importance to the field based hopefully on rational design and preclinical signals.

The number 2 concern I think is that of toxicity. I think as we introduce these novel agents and novel combinations, we, our patients, and scientists need to be thinking about what the new toxicities. What are the emerging toxicities? What are the unexpected ones that either result in longer-term follow-up or unexpected toxicities and side effects from combinations? What is the benefit to the patients in terms of adding a second and potentially even a third drug at some point vis-a-vis the toxicity, financial toxicity, the cost of these drugs, access to them, monitoring of them, and then the medical adverse effects.

Then I think the third area for us is the optimization of stem cell transplants. We know that transplant remains the only curative approach thus far in the myelofibrosis space, but with improvements in immune modulation, GVHD [graft-vs-host disease] monitoring, new medicines, pre-, and poststem cell transplant, can we optimize the transplant by offering it to more patients in a safe way, improving transplant access across the world, and reducing the short and long-term risks and mortality that are associated with transplant in some cases?

I think on that note of immune modulation, another exciting area to keep in mind is the development of immune therapies beyond interferon and stem cell transplants, which admittedly are the original immune therapies in our field. And so, entities such as CAR [chimeric antigen receptor] T-cell therapies, and monoclonal antibodies, we heard about the new mutant CalR-specific antibody, perhaps other immune approaches, combined vaccines against CalR with immune therapy drugs that are starting in clinical trials. So, an exciting area, we’ll call that immune modulation. So, optimization of the existing forms, the interferons, the stem cell transplant, and then keeping an eye towards the new ones. I think those are some of the emerging areas to keep our eyes on for 2023 and beyond.

Aaron Gerds, MD: The treatment of MPNs is a field that is rapidly evolving, and it has rapidly evolved over the last 5 years. And it’s exciting to see that we’re moving past simply giving JAK inhibitors to patients and looking to combination therapies to better the outcomes of these patients. And certainly, that’s the big next wave of therapy where we’re not just giving JAK inhibitors, but we’re giving combinatorial therapies to try to illicit a deeper effect on the disease. I think we need to continue to work to find better biomarkers of this disease modification, and we often look at changes in allele burden and changes in the scar tissue in the bone marrow, but this is often a biomarker of a biomarker or a reflection of a reflection. I think it doesn’t really get to the true modification of the pathobiology of the disease.

Many are looking at additional markers, like Dr Joseph Michael Scandura, MD, PhD, whom I mentioned earlier, who’s looking at megakaryocyte density and spacing within the marrow it has a perhaps better predictor of disease modification, so better biomarkers are needed, better therapies are needed. And again, it’s super exciting to see these combinatorial therapies as the next wave in drug development in therapy development in myelofibrosis. But we can look even further onto the horizon into some of the exciting things that might be coming in the future. The plenary session at this year’s ASH [American Society of Hematology] Annual Meeting was a monoclonal antibody targeting calreticulin disease protein. And so, that’s really exciting.

And this is a monoclonal antibody. You think about how much rituximab revolutionized the care of b-cell malignancies, and you can see that calreticulin may do the same for myelofibrosis. Not only could we use just the negative antibody, but you think about all this you can build bispecific antibodies or even modified cellular therapies like CAR T-cells or end-modified NK [natural killer] cells to really dramatically change the way we treat these patients. So, you can see that being the wave after the next wave, which is absolutely mind-blowing and exciting to think about.

Pankit Vachhani, MD: There are several areas that we are looking to improve upon and bring new options for our patients and also trying to sort out with all this new knowledge that is coming along in the field. Patients with cytopenic fibrosis, despite the numerous therapies that have come and are coming, continue to do worse than other patients. We need to improve their outcomes. It is tremendous that we have pacritinib [CPI-0610] now, whereby patients with thrombocytopenia have a good treatment option available for them to benefit from, but I think more agents like that and momelotinib [C23H22N6O2] for sure, is looking promising to deliver outcomes for thrombocytopenic and anemic patients, but I think we need some additional disease-modifying agents in this space, especially for cytopenic myelofibrosis patients. That is something that I’m definitely looking forward to coming about in the field over the next few years.

Along that same vein, we need to improve the survival outcomes of patients, more so than what we have already done with ruxolitinib. Many of these combination therapies which are ongoing are great, but I’m looking forward to seeing genuine, good survival outcomes happening from that. That would be the ultimate marker of a disease-modifying agent. While we are on the topic of combination therapies, should 1 or more of these combination therapies come out and there is a very high likelihood that that’s going to happen, I think the very next question that will come about in the field, is sorting out what biomarkers can we identify either at baseline, or let’s say, at 3 months, 6 months, or a year, to identify patients who are going to benefit or not going to benefit from one combination therapy vs the other, who may benefit on the initial half vs through continuous maintenance of a combination therapy. The field of biomarkers is going to evolve in line with the new therapies that are going to come out. After all, biomarkers have to be looked upon in the context of treatment as well.

While these are the 3 points that I think need to be answered and need to be looked into, there are some additional things that I do want to mention. JAK2 Keller vaccines are being developed and these hold tremendous promise. We are hoping that they work out. They may really help us down the line in thwarting the progression of a disease in its very early course and may serve as a brand-new way of treating our patients with myelofibrosis, PV [polycythemia vera], or ET [essential thrombocythaemia]. For polycythemia vera patients, there are many drugs that are currently being developed, which work on the iron homeostasis pathway. Should 1 or more of these drugs come out to the market, they may offer yet another option for our patients, and in doing so, they may help eliminate phlebotomies. While not directly a supportive care method, it may very well help in supporting patients on their other therapies as well. Not to mention, they may help in maintaining a target hematocrit of 45% or more on a long-term basis and in a consistent manner and therefore, also decrease the need for phlebotomies and prevent thrombotic episodes.

Last but not least, interferon-based therapies have always been talked about, but they’re probably being talked about now more than ever before and these truly may slow the progression of myeloproliferative neoplasms speed that ET, PV, or maybe even profibrotic MF and in selected cases, even possibly overt myelofibrosis. But more studies need to be done and I think there is more and more emerging evidence suggesting the use of interferon as early as possible in patients with MPNs.

Transcript edited for clarity.

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