Category Archives: Clinical Trial

$72 Million Funds Neoantigen-based Cancer Vaccine Candidates

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November 14, 2023

(Precision Vaccinations News)

Nouscom recently announced the completion of its Series C equity financing, raising $72 million that will be used to continue advancing and expanding Nouscom’s wholly-owned clinical pipeline to achieve multiple clinical value catalysts.

As of November 13, 2023, the funding proceeds will support the following initiatives:

Readout from Nouscom’s ongoing randomized Phase 2 clinical trial for NOUS-209, an off-the-shelf vaccine targeting 209 shared neoantigens, in combination with pembrolizumab for the treatment of Mismatch Repair/Microsatellite Instable Metastatic Colorectal Cancer.

Final readout from the ongoing Phase 1b study and advancement of NOUS-209 monotherapy in Lynch Syndrome carriers investigating the potential to intercept, prevent, or delay cancer before it occurs. LS carriers have a genetic predisposition to and, consequently, a higher risk of developing certain cancers. Promising initial results from this study were reported on October 31, 2023.

Completion of a Phase 1b study evaluating NOUS-PEV, a personalized cancer immunotherapy, in combination with a checkpoint inhibitor in patients with advanced melanoma and entry into randomized Phase 2 trials in indications with high unmet medical needs.

Nouscom has also exclusively out-licensed VAC-85135, an off-the-shelf immunotherapy developed under a multi-project agreement, which is currently under evaluation in a Phase 1 clinical trial for the treatment of Myeloproliferative Neoplasms sponsored by Janssen Research & Development and Bristol Myers Squibb.

Dr. Marina Udier, Chief Executive Officer of Nouscom, commented in a press release, “…. This financing will allow us to further accelerate development across our wholly-owned clinical portfolio reporting multiple clinical trial readouts, including from our ongoing randomized Phase 2 clinical trial with NOUS-209.”

“These Phase 2 data, if positive, have the potential to position Nouscom’s neoantigen-based cancer vaccines amongst the most thrilling developments in the field.”

According to a Review Article published by the journal Frontiers in Immunology in February 2023, Neoantigen vaccines are based on epitopes of antigenic parts of mutant proteins expressed in cancer cells. These highly immunogenic antigens may trigger the immune system to combat cancer cells.

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Azacitidine, Venetoclax, Ruxolitinib Shows Encouraging Responses in MPNs

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October 19, 2023

Sabrina Serani

The combination of azacitidine, venetoclax (Venclexta), andruxolitinib(Jakafi) for the treatment of myeloproliferative neoplasms in blastic phase (MPN-BP) did not demonstrate any treatment-related toxicity in patients, and patients’ quality-of-life improved, according to a study published in the British Journal of Haematology.1

Azacitidine and venetoclax were used to control BP transformation, and ruxolitinib was added to control constitutional symptoms. The overall response rate was 80%, and the complete remission (CR) rate was 40%. The median overall survival was 13.4 months (95% CI, 4.2-13.4), with a median follow-up of 10.0 months (range, 4.2-13.4).

“[Patients with] MPN-BP have a poor prognosis with the current treatment options, and standards of care unless they are offered [allogeneic stem cell transplant, (allo-SCT)]. Unfortunately, there is a lack of treatment guidelines for the management of allo-SCT-ineligible MPN-BP patients,” study authors wrote. “We observed encouraging hematological responses, which were prolonged for some patients. In addition, the combination appeared manageable, without unexpected adverse events.”

Five patients with myelofibrosis (MF) were enrolled in the study. One had primary MF, and 4 had secondary MF. The median patient age was 76 (range, 72-84) years. Three patients were treated exclusively outpatient. There were 2 CRs and 2 partial response remissions. Investigators noted that all patients could complete their activities of daily living, and clinical spleen reduction ≥50% was observed.

At best response, the median platelet count was 150 × 109/L (range, 60–380) with a median improvement of 125 × 109/L (range, 5–200), and median hemoglobin level was 10.6 g/dL (range, 9.0–13.8) with a median gain of 2.7 g/dL (range, 1.5–7.6).

Three patients died due to disease progression; however, there were no deaths due to treatment reported. Observed adverse events (AEs) included neutropenia (n = 4, 80%), anemia (n = 2, 40%), and thrombocytopenia (n = 1, 20%). Febrile neutropenia was reported in 2 patients during the initial cycle. Grade 4 neutropenia was the primary reason reported for postponing a cycle.

Patients were administered ruxolitinib and a dose ≥10 mg twice daily. Venetoclax was administered orally at a dose of 200-400 mg on days 1-14. Azacitidine was administered subcutaneously at a dose of 50 or 75 mg/m2 on days 1-7. The median cycle duration was 29 days (range, 27-38). A median of 11 cycles (range, 5-14) was administered to patients, and the median time to best response was 4 cycles (range, 3-9).

“Further studies are needed to confirm these promising results,” study authors wrote.1

The combination of venetoclax and azacitidine are also being studied in a phase 3 trial of patients with treatment-naïve acute myeloid leukemia, as well as a phase 1 trial of pediatric and young adult patients with hematologic malignancies.2,3

REFERENCES:
1. Systchenko T, Chomel JC, Gallego-Hernanz P, et al. Combination of azacitidine, venetoclax and ruxolitinib in blast phase myeloproliferative neoplasms. Br J Haematol. 2023;202(2):284-288. doi:10.1111/bjh.18853
2. A study of venetoclax in combination with azacytidine versus azacytidine in treatment naïve participants with acute myeloid leukemia who are ineligible for standard induction therapy. News release.National Cancer Institute. Accessed October 13, 2023. https://tinyurl.com/my5yh7nm
3. Venetoclax and azacytidine for the treatment of hematologic malignancies in pediatric and young adult patients. News release. National Cancer Institute. Accessed October 13, 2023. https://tinyurl.com/my5yh7nm

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Bomedemstat as an investigative treatment for myeloproliferative neoplasms

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By Hugh Young Rienhoff Jr. & Harinder Gill

Abstract

Introduction

Myeloproliferative neoplasm (MPN) is a heterogeneous group of hematopoietic stem cell disorders characterized by clonal proliferation of one of more of the hematopoietic stem cell lineages. Clinical manifestations result from uncontrolled myeloproliferation, extramedullary hematopoiesis with splenomegaly and excessive inflammatory cytokine production. Currently available therapy improves hematologic parameters and symptoms but does not adequately address the underlying neoplastic biology. Bomedemstat has thus far demonstrated clinical efficacy and tolerability in the treatment of MPNs with recent evidence of impacting the malignant stem cell population.

Areas covered

This review summarizes the mechanisms of action, pharmacokinetics and pharmacodynamics, safety and efficacy of bomedemstat in MPN with specific emphasis on essential thrombocythemia (ET) and myelofibrosis (MF).

Expert opinion

In patients with MPNs, bomedemstat appears effective and well tolerated. The signs and symptoms of these diseases are managed as a reduction in the frequency of mutant cells was demonstrated in patients with ET and MF. Ongoing and planned studies of bomedemstat in MPN will establish the position of bomedemstat in MPNs and may help to redefine treatment endpoints of MPNs in the future.

KEYWORDS:

  • Bomedemstat
  • lysine-specific demethylase-1
  • LSD1
  • myeloproliferative neoplasm
  • polycythemia vera
  • essential thrombocythemia
  • myelofibrosis

Article highlights

  • Myeloproliferative neoplasm (MPN) are clonal hematopoietic stem cell disorders characterized by uncontrolled cellular proliferation, cytokine mediated symptoms and clonal instabilty leading to leukemic progression.

  • Conventional therapeutic approaches in MPN are not adequate in altering the underlying disease biology.

  • Lysine specific demethylase 1 (LSD1) is overexpressed in the malignant hematopoietic stem cell population in MPN.

  • Bomedemstat, an inihibitor of MPN, effectively controls cellular proliferation and reverses disease biology in mouse models of MPN.

  • Phase 2 studies in essential thrombocythemia and myelofibrosis has demonstrated that Bomedemstat is highly efficacious and safe.

Declarations of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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MWTX-003 Wins FDA Fast Track Designation for Polycythemia Vera

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Kristi Rosa

The FDA has granted fast track designation to the investigational, anti-TMPRSS6 monoclonal antibody, MWTX-003 (DISC-3405), for use in the treatment of patients with polycythemia vera, according to an announcement from Disc Medicine, Inc.1

Patients with hematologic diseases such as polycythemia vera, myelodysplastic syndrome (MDS), and beta-thalassemia are known to develop high levels of iron, which leads to survival and quality-of-life complications.2 MWTX-003 was designed to boost the production of hepcidin, which suppresses serum iron. Preclinical data in animal models of beta-thalassemia and polycythemia vera have confirmed this ability.

“We are delighted to have received fast track designation for MWTX-003, which highlights the unmet need for [patients with] polycythemia vera and the potential of MWTX-003 in a disease where there are few treatment options,” John Quisel, JD, PhD, president and chief executive officer of Disc Medicine, Inc., stated in a press release.1 “We believe MWTX-003 is uniquely positioned to address the needs of [patients with] polycythemia vera and are excited to initiate a phase 1 trial in the coming months.”

Preclinical studies have demonstrated strong pharmacodynamic effects that are reflective of TMPRSS6 inhibition.3 Specifically, a single administration of MWTX-003 led to an approximate 70% suppression of serum iron that lasted for 3 weeks. Moreover, in non-clinical GLP safety studies, the agent showcased a strong toxicity profile.

In a model of beta-thalassemia, treatment with MWTX-003 resulted in significant effects on disease hallmarks such as iron overload, ineffective erythropoiesis, and splenomegaly. The production of hepcidin was boosted up to 4-fold, serum and liver iron was reduced by approximately 60% to 65%, red blood cell production increased, and spleen weight decreased.

MWTX-003 was in-licensed from Mabwell Therapeutics, and in November 2022, the FDA accepted an investigational new drug application for the agent.1 In January 2023, the clinical-stage biopharmaceutical company shared development plans for MWTX-003 which consisted of establishing phase 1 proof-of-mechanism; this was planned for initiation in the second half of 2023, and would examine hepcidin, iron, and other hematologic parameters.3

They also shared plans to advance the agent into point-of-care studies focused on polycythemia vera. In a phase 1b/2a proof-of-concept study, they hope to evaluate the safety and pharmacokinetic profile of MWTX-003 in patients with polycythemia vera. These data could provide clarity on the regulatory development path for the agent, according to Disc Medicine.

There is interest in examining the agent in additional POC studies spanning a range of indications, including hereditary hemochromatosis, beta-thalassemia, and MDS.

References

  1. Disc Medicine receives FDA fast track designation for MWTX-003 for the treatment of polycythemia vera. News release. Disc Medicine, Inc. September 20, 2023. Accessed September 21, 2023. https://ir.discmedicine.com/news-releases/news-release-details/disc-medicine-receives-fda-fast-track-designation-mwtx-003
  2. MWTX-003. Disc Medicine, Inc. website. Accessed September 21, 2023. https://www.discmedicine.com/our-pipeline/mat-2-inhibitor/
  3. Novel anti-TMPRSS6 monoclonal antibody portfolio: exclusive in-licensing agreement with Mabwell Therapeutics. Disc Medicine, Inc. January 20, 2023. Accessed September 21, 2023. https://ir.discmedicine.com/static-files/549caf12-e7be-45ff-8667-86908e4e6bdd

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Ezobresib by Bristol-Myers Squibb for Myelofibrosis: Likelihood of Approval

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September 14, 2023

Ezobresib is under clinical development by Bristol-Myers Squibb and currently in Phase II for Myelofibrosis. According to GlobalData, Phase II drugs for Myelofibrosis have a 40% phase transition success rate (PTSR) indication benchmark for progressing into Phase III. GlobalData’s report assesses how Ezobresib’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

Ezobresib overview

Ezobresib (BMS-986158) is under development for the treatment of solid tumors including triple-negative breast cancer, small-cell lung cancer, epithelial ovarian cancer, peritoneal cancer, renal cell carcinoma, fallopian tube cancer, Burkitt’s lymphoma/leukemia, Uveal melanoma, Uterine carcinosarcoma, NUT-midline carcinoma, Non-small cell lung cancer, metastatic hormone refractory (castration resistant, androgen-Independent) prostate cancer, blood cancer (hematologic malignancies), primary myelofibrosis (PMF), post-essential thrombocythemia (ET) or post-polycythemia vera (PV) myelofibrosis. It is administered orally as a capsule. The drug candidate acts by targeting bromodomain and extra-terminal (BET) proteins. It was under development for Ewing sarcoma.

Bristol-Myers Squibb overview

Bristol-Myers Squibb (BMS) is a specialty biopharmaceutical company that is engaged in discovery, development, licensing and manufacturing, marketing, distribution and sale of medicines and related medical products to patients with serious diseases. Its primary focus is on cancer, cardiovascular, immunology and fibrotic therapeutic projects. The company offers its products across the world to wholesalers, retail pharmacies, medical professionals, hospitals and government entities. BMS provides its products in the US, Europe, and Japan. The company conducts research to focus on the discovery and development of novel medicines that address serious diseases in areas of significant unmet medical need. BMS is headquartered in New York City, New York, the US.

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An Update on Current and Emergent Therapies for Essential Thrombocytosis

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Daniel H. Foley, MD
Kristen Pettit, MD

Our understanding of pathophysiology driving Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) has evolved considerably over the past decade. As a result, the therapeutic landscape is shifting toward a goal of meaningful disease modification. For patients with essential thrombocytosis (ET), the immediate goals remain thrombosis risk reduction and symptom control, but newer therapies on the horizon are likely to change our treatment paradigms considerably for this disease.

How do you approach a new patient with ET?
When it comes to the treatment of patients with ET, the main goal of current approved therapy is to mitigate the risk of thrombotic events, as the treatments have minimal impact on disease progression. The choice of treatment is determined by an individual’s specific risk factors for these events. The International Prognostic Score for Thrombosis in ET revised score is used to stratify patients into 4 risk groups: very low risk, low risk, intermediate risk, and high risk. For the majority of low-risk patients, low-dose aspirin is recommended, as it aids in preventing clotting, but patients classified as intermediate or high risk are generally advised to undergo cytoreductive therapy.

What are the standard options for cytoreductive therapy?

The selection of the most suitable cytoreductive agent depends on factors such as the patient’s comorbidities, tolerability of the treatment, future family planning, and individual preferences. Hydroxyurea (HU) and pegylated interferon alfa (peg-IFN) are the primary options for frontline cytoreductive treatment. In the phase 3 study MPD-RC 112 [NCT01259856], which included patients with both ET and polycythemia vera (PV), HU and peg-IFN demonstrated comparable rates of complete response and thrombotic events after 12 months.1 However, over time peg-IFN has shown improved molecular responses in both ET and PV.1-4 Although the clinical implications of these molecular responses aren’t yet entirely clear, these findings are quite exciting to see in this disease that has been so difficult to target. A longer-acting interferon (ropeginterferon alfa-2b-njft; Besremi) is currently in evaluation for patients with ET and has been approved in the United States for patients with PV. In cases where initial treatment approaches do not yield satisfactory results, anagrelide is another option, though its use is often limited by toxicities (eg, headaches, dizziness, palpitations, and fluid retention).

What is on the horizon for treatment of ET?

As we delve deeper into understanding the biologic drivers of ET, promising new therapeutic directions are emerging, including JAK inhibitors, epigenetic agents, and mutation-specific biologic/immunologic therapies.Ruxolitinib (Jakafi), a JAK1/2 inhibitor already widely used for other MPNs, continues to be evaluated in ET. In a randomized study, MAJIC [NCT05057494], ruxolitinib was compared with best available therapy (BAT) for patients with ET who had resistance or intolerance to HU. Both treatments showed similar rates of hematologic response, thrombosis, and hemorrhage. However, ruxolitinib outperformed BAT in improving disease-related symptoms.5 Another ongoing trial called Ruxo-BEAT [NCT02577926] is further exploring the use of ruxolitinib in ET.

When it comes to epigenetic regulators, BET inhibitors and LSD1 inhibitors are emerging as potential therapeutic targets. Both BET inhibitors and LSD1 inhibitors have shown the ability to reduce cytokine production via different mechanisms and impair self-renewal of malignant hematopoietic stem cells, so they may have more significant disease-modifying activity compared with other agents.6,7 The BET inhibitor pelabresib (CPI-0610) is currently being evaluated for ET as well as myelofibrosis. The LSD1 inhibitor bomedemstat is also being studied for both ET and MF, and preliminary reports from the ET study show encouraging ability to control platelets and improve symptoms for many patients.8

Biologic and immunologic approaches are emerging as promising strategies as well. Recently, at the American Society of Hematology annual meeting in 2022, preclinical data were presented on a monoclonal antibody that targets mutant CALR, a key diver for approximately 25% of patients with ET.9 This antibody showed impressive potency in selectively targeting mutant CALR-driven oncogenic mechanisms. There are also other antibody-based therapies showing significant efficacy in preclinical studies, and these strategies are now moving toward the development phases.10 Furthermore, the discovery of T-cell responses against mutant CALR has sparked the development of vaccine-based treatment strategies.11,12 

What are your final thoughts regarding the future of ET?

The development of more targeted agents with the potential to meaningfully disrupt the mechanisms driving MPNs provides a lot of optimism for the future in these diseases. As these therapies move toward “prime time,” we will need to reassess our treatment goals for our patients. Hopefully we will be able to raise the bar for response from simply hematologic control and thrombosis prevention toward the more lofty aims of lengthening survival, improving quality of life, and lowering risk of disease progression.

REFERENCES:

1. Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized phase 3 trial of interferon-alpha vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022;139(19):2931-2941. doi:10.1182/blood.2021012743

2. Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165-e175. doi:10.1016/S2352-3026(17)30030-3

3.Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013;122(6):893-901. doi:10.1182/blood-2012-07-442012

4.Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072. doi:10.1182/blood-2008-03-143537

5.Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889-1897. doi:10.1182/blood-2017-05-785790

6.Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29-43.e27. doi:10.1016/j.ccell.2017.11.009

7.Jutzi JS, Kleppe M, Dias J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3):e54. doi:10.1097/HS9.0000000000000054

8.Gill H, Palandri F, Ross DM, et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of essential thrombocythemia (ET). Blood. 2022;140(suppl 1):1784-1787. doi:10.1182/blood-2021-148210

9.Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms (MPNs). Blood. 2022;140(suppl 1):14-15. doi:10.1182/blood-2022-159435

10.Tvorogov D, Thompson-Peach CAL, Foßelteder J, et al. Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody. EMBO Rep. 2022;23(4):e52904. doi:10.15252/embr.202152904

11.Holmström MO, Martinenaite E, Ahmad SM, et al. The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. Leukemia. 2018;32(2):429-437. doi:10.1038/leu.2017.214

12.Holmström MO, Riley CH, Svane IM, Hasselbalch HC, Andersen MH. The CALR exon 9 mutations are shared neoantigens in patients with CALR mutant chronic myeloproliferative neoplasms. Leukemia. 2016;30(12):2413-2416. doi:10.1038/leu.2016.233

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Momelotinib Could Represent Pivotal New Treatment Option in Myelofibrosis

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Ryan Scott
Aaron T. Gerds, MD, PhD, expands on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, details the data from MOMENTUM, and explains what FDA approval of momelotinib could mean for the treatment of this patient population.

The benefits in symptom burden, spleen size, and transfusion dependence demonstrated by treatment momelotinib in patients with myelofibrosis represent a potential key advance for this treatment paradigm, according to Aaron T. Gerds, MD, PhD.

A new drug application (NDA) seeking the approval of momelotinib as a potential therapeutic option in patients with myelofibrosis is currently under review by the FDA, and the review period was extended to a target action date of September 16, 2023.1

The NDA is supported by data from the phase 3 MOMENTUM trial (NCT04173494), which evaluated the agent in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor. Data showed that 25% of patients treated with momelotinib (n = 130) experienced a reduction in tumor symptom score of at least 50% at week 24 compared with 9% of patients treated with danazol (n = 65; proportion difference, 16%; 95% CI, 6%-26%; P = .0095).2

Additionally, 39% of patients in the momelotinib arm achieved a spleen volume reduction of at least 25% from baseline to week 24 vs 6% in the danazol arm (P < .0001); moreover, 22% and 3% of patients, respectively, experienced a reduction of 35% or more (P = .0011). At week 24, the rates of transfusion independence were 30% (95% CI, 22%-39%) for momelotinib and 20% (95% CI, 11%-32%) for danazol (noninferiority difference, 14%; 95% CI, 2%-25%; 1-sided P = .0016).

“The potential approval of momelotinib is incredibly important for patients. Having additional agents to treat myelofibrosis would be welcomed. As little as a couple of years ago, we only had 1 approved therapy to treat myelofibrosis,” Gerds said in an interview with OncLive®. Gerds is an assistant professor in the Department of Medicine, a member of the Developmental Therapeutics Program, and medical director of the Case Comprehensive Cancer Center in Cleveland, Ohio.

In the interview, Gerds expanded on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, detailed the data from MOMENTUM, and explained what FDA approval of momelotinib could mean for the treatment of this patient population. Gerds also serves as an associate professor of Medicine in the Department of Hematology and Medical Oncology at the Cleveland Clinic Taussig Cancer Institute.

OncLive: How could the potential approval of momelotinib affect current and future practice patterns for patients with myelofibrosis?

Gerds: The [potential] approval of momelotinib could be another pivotal moment in the care of patients with myelofibrosis. I would argue that the first pivotal moment was the discovery of recurrent JAK2 mutations, followed several years later by the approval of ruxolitinib [Jakafi], the first JAK inhibitor.

Momelotinib provides an extra opportunity for patients, specifically patients who have anemia along with enlarged spleens and significant symptom burden. This drug promises to try to hit all 3 of those key elements of care in patients with myelofibrosis with a single pill.

What unmet needs exist for patients with myelofibrosis and anemia?

Anemia itself in these patients is a key unmet need. Roughly 40% of patients will be anemic at the time of diagnosis. It is common diagnostic and prognostic criteria that is used to predict who may have aggressive disease. Anemia will also develop in patients within the first year after diagnosis, and at some point, every patient will develop anemia as the [bone] marrow begins to fail. Therefore, anemia is something that is incredibly common and difficult to treat.

We can give red blood cell transfusions to combat anemia, but that comes with adverse effects, such as iron overload, transfusion reactions, and the development of alloantibodies. Moreover, blood is a valuable and somewhat scarce resource. The Red Cross is constantly trying to get us to donate more blood because it is a scarce commodity, and it is also expensive to do red blood cell transfusions. In general, it’s one of the biggest costs in delivering health care for patients with hematologic malignancies. For all these reasons, treating anemia is incredibly important.

Treatments for anemia are somewhat limited. I mentioned transfusions already, and there are also erythropoiesis stimulating agents [ESAs] that can be given. Another drug, luspatercept-aamt [Reblozyl], is already approved to treat anemia in patients with myelodysplastic syndrome and beta thalassemia. It is used off-label to treat anemia in patients with myelofibrosis. danazol is also commonly used.

We already have these 3 agents; however, none of them are perfect or work 100% of the time, and there are still many patients who suffer from anemia who have [myelofibrosis]. Any new agent that is coming along that can potentially treat anemia in a different mechanism of action is always welcome.

What is the mechanism of action of momelotinib, and what prompted this agent’s examination in patients with myelofibrosis?

Momelotinib, in terms of treating anemia, works very differently than ESAs, luspatercept, and danazol. It works by inhibiting ACVR1, also known as ALK2, which is a regulator of hepcidin. Hepcidin is a key piece in what we think about in hematology in iron regulation and red blood cell production. It is a hot topic in myeloproliferative neoplasms right now, and it has been in the world of hematology for some time.

Hepcidin is a master iron regulator that helps regulate the shuttling of iron out of the iron stores, making it available for the body to use, for example, to make red blood cells. In patients with myelofibrosis, they have anemia or an inflammatory block, meaning that hepcidin levels are very high and can shut a lot of those iron stores. By lowering the levels of hepcidin by blocking ACVR1, we can restore effective erythropoiesis by dropping that anemia or inflammatory block. That component of a patient’s anemia can be reversed, potentially by this medication.

What were some of the key efficacy data from MOMENTUM?

The MOMENTUM study pitted momelotinib vs danazol, looking at a couple of key end points. The first was symptom burden reduction, and we also looked at spleen volume reduction—traditional end points for measuring response with JAK inhibitors in patients with myelofibrosis. Another key end point was transfusion independence, and that was the proportion of patients who were transfusion independent at weeks 24 and 48.

We saw that momelotinib outperformed danazol in terms of spleen volume reduction, as well as symptom burden reduction. Momelotinib was also statistically not inferior—this was a non-inferiority analysis—for transfusion independence at week 24 compared with danazol.

What does the safety profile look like for momelotinib in this population?

With respect to safety, one of the early concerns during the development of momelotinib was an increased risk of peripheral neuropathy. This was seen in some earlier studies. However, in subsequent investigations, such as the SIMPLIFY trials [NCT01969838; NCT02101268] and the MOMENTUM study, we did not see excess neuropathy in patients treated on momelotinib compared with best available therapy or danazol, respectively. The rates of peripheral neuropathy were similar in the 2 groups. That was a key take-home point in terms of safety data from the MOMENTUM study.

Certainly, some patients did develop cytopenias while on momelotinib, as well as danazol. There weren’t excess gastrointestinal toxicities, as we see with some of the other JAK inhibitors. There was no signal toward increased risk of non-melanoma skin cancers or bile reactivations. However, we certainly watch for those things whenever we’re treating a patient with a JAK inhibitor.

If it is approved, where do you see momelotinib fitting into the current treatment paradigm for this population?

With the potential approval of momelotinib, we will see what the uptake looks like in everyday practice. That will be a big part of what happens with this medication: how organically it is picked up by different oncologists and hematologists out there in the community. Clearly, it has efficacy in patients with anemia, so it would be right at home in the treatment of a patient who has myelofibrosis who needs spleen volume reduction and symptom control, and has anemia.

If we look closely at the MOMENTUM inclusion criteria, those patients did have prior exposure to a JAK inhibitor for at least one month, and they all had hemoglobin [levels] less than 10g/dL; that is where this drug tends to shine. However, the amount of JAK inhibition given to those patients prior to going on MOMENTUM was limited. We also do have up-front data in patients previously untreated [with a JAK inhibitor] from the SIMPLIFY trials. You could say that if a patient with myelofibrosis and is borderline anemic, they could also benefit from momelotinib, not just in the second line, but potentially in the frontline setting as well.

References

  1. 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
  2. GSK announces extension of FDA review period of momelotinib. News release. GlaxoSmithKline. June 16, 2023. Accessed August 31, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-extension-of-fda-review-period-for-momelotinib/

CWP-291 by JW Pharmaceutical for Thrombocythemia Myelofibrosis: Likelihood of Approval

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August 30, 2023

CWP-291 is under clinical development by JW Pharmaceutical and currently in Phase I for Thrombocythemia Myelofibrosis. According to GlobalData, Phase I drugs for Thrombocythemia Myelofibrosis have a 90% phase transition success rate (PTSR) indication benchmark for progressing into Phase II. GlobalData’s report assesses how CWP-291’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks.

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

CWP-291 overview

CWP-291 (CWP-232291) is under development for the treatment of hematological tumors including relapsed or refractory acute myeloid leukemia (AML), chronic myelomonocytic leukemia-2, relapsed and refractory multiple myeloma, gastric cancer, myelofibrosis (PMF), post-polycythemia vera (PPMF), castration-resistant prostate cancer (CRPC) and post-essential thrombocythemia (PTMF). The drug candidate is administered intravenously. It acts as Sam68 inhibitor. It was also under development for the treatment solid tumors such as breast cancer, liver, lung cancer and myelodysplastic syndrome.

JW Pharmaceutical overview

JW Pharmaceutical, a subsidiary of JW Holdings Corp, is a provider of generic drugs. The company develops and markets analgesics, antipyretics and cold remedies, antidote agents, antimicrobials, anticancer agents, and others. It offers multivitamins and antianemia agents, contact lens care and ophthalmic agents, antifungal agents, cardiovascular agents, and gastrointestinal agents. JW Pharmaceutical also offers topicals, amino acid solutions, flexible IV containers, IV solutions, respiratory agents, nephrology agents, CNS, urology agents and diabetic agents. The company offers products for cardiovascular, gastrointestinal, nephrology and antianemia, anticancer and neuropsychiatry. It operates through its production and manufacturing facilities in South Korea. JW Pharmaceutical is headquartered in Seoul, South Korea.

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Dr Halpern on the Investigation of Upfront Ruxolitinib and Navitoclax in Myelofibrosis

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Anna B. Halpern, MD

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch; assistant professor, hematology, University of Washington School of Medicine, discusses investigational efforts being developed to expand on the use of ruxolitinib and navitoclax in earlier treatment lines for patients with myelofibrosis.

In cohort 3 of the phase 2 REFINE trial (NCT03222609), the combination of ruxolitinib and navitoclax was evaluated in the upfront setting for patients (n=32) who had not been previously exposed to a JAK inhibitor. The study’s primary end point was spleen volume reduction of 35% or greater from baseline at week 24.

An exploratory analysis of this cohort was presented at the 2022 ASH Annual Meeting and Exposition, Halpern begins. Findings showed that navitoclax plus ruxolitinib produced a spleen volume reduction of at least 35% at week 24 across specific patient subsets, she details. These subsets consisted of patients 75 years of age or older, those with a high Dynamic International Prognostic Scoring System score, and those with HMR mutations. The percentage of patients who experienced optimal spleen volume reduction in these subgroups are 50%, 33%, and 47%, respectively.

Notably, changes in bone marrow fibrosis and reductions in the variant allele frequency (VAF) of the driver gene mutation were seen with the combination regimen in many patients, Halpern continues. Half of patients achieved a greater than 20% reduction in VAF from baseline at week 12 or 24, while a greater than 50% VAF reduction from baseline occurred in 18% of patients. When comparing those with or without HMR mutations, no differences in greater than 20% VAF reduction from baseline to week 12 or 24 were observed between populations.

These results indicate the potential disease-modifying ability of ruxolitinib and navitoclax, suggesting that reductions in bone marrow fibrosis and VAF may serve as biomarkers for disease modification, Halpern states. Notably, long-term outcomes cannot be definitively assessed as correlates for leukemia, progression, and survival, she adds. The viability of these 2 biomarker candidates should be assessed more short term, and in larger study populations, Halpern concludes.

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Dr Halpern on the MANIFEST Trial of Pelabresib and Ruxolitinib in Myelofibrosis

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Anna B. Halpern, MD

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch, assistant professor, hematology, University of Washington School of Medicine, discusses key efficacy data from the phase 1/2 MANIFEST trial (NCT02158858) investigating the BET inhibitor pelabresib (CPI-0610) plus ruxolitinib (Jakafi), and highlights the agents clinical significance in patients with myelofibrosis.

The global, open-label, nonrandomized, multicohort study evaluated the efficacy of the JAK inhibitor combination therapy vs pelabresib alone for treatment-naive or pretreated patient populations, Halpern begins. The trial involved 4 separate cohorts. These cohorts included the use of pelabresib in patients with JAK inhibitorpretreated myelofibrosis, pelabresib plus ruxolitinib in patients with ruxolitinib-pretreated myelofibrosis, pelabresib plus ruxolitinib in patients with JAK inhibitor–naïve myelofibrosis, and pelabresib alone in patients with essential thrombocythemia.

Halpern reports that results from the JAK inhibitor–naïve cohort showed that pelebresib plus ruxolitinib reduced spleen volume by at least 35% in 68% of patients, emphasizeing that total symptom score decreased by at least 50% in 56% of patients at 24 weeks. The data cutoff date for these findings was July 29, 2022.

Moreover, exploratory analysis revealed that 28% of patients had a grade 1 or greater improvement in fibrosis, while 29.5% experienced a greater than 25% reduction in JAK2 V617F VAF by week 24, Halpern details. These outcomes are of particular interest because they may indicate the disease-modifying ability of this combination, Halpern explains.

Based on these findings, the ongoing randomized, double-blind, phase 3 MANIFEST-2 trial (NCT04603495) is evaluating upfront pelabresib plus ruxolitinib vs ruxolitinib alone in a larger cohort of patients with JAK inhibitor–naïve myelofibrosis, Halpern concludes. Enrollment to this study was completed in May 2023, and topline findings are anticipated to report out in late 2023.

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