Disc wins orphan drug tag for rare blood cancer

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February 12, 2024

By Jeanne Philpott

The US Food and Drug Administration (FDA) has granted an orphan drug designation (ODD) to US-based biotech Disc Medicine’s DISC-3405 to treat rare blood cancer polycythemia vera (PV).

Disc gained exclusive rights to develop and market the anti-TMPRSS6 (Transmembrane Serine Protease 6) humanized antibody in the US and other territories when it teamed up with Mabwell Therapeutics in a $412.5m licensing agreement in January 2023.

In October 2023, DISC initiated an ongoing Phase I clinical trial (NCT06050915) for DISC-3405, previously named MWTX-003 with data from the study now expected in H1 2024. The orphan drug designation comes after the drug had previously received fast-track designation from the FDA.

The 64-patient Phase I study is divided into groups receiving either a single or multiple doses of DISC-3405, or a placebo. In the single ascending dose (SAD) phase, two subjects serve as sentinels: one receives DISC-3405, and the other placebo. Additional subjects in the cohort are dosed at least 24 hours after the last sentinel dosing, following approval from the principal investigator. Subsequent multiple ascending dose (MAD) cohorts are enrolled only after a sufficient safety observation period for the SAD cohort, removing the need for sentinels in MAD cohorts.

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Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms

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Taylor B. Collins, Angelo B.A. Laranjeira, Tim Kong, Mary C. Fulbright, Daniel A.C. Fisher, Christopher M. Sturgeon, Luis F.Z. Batista, and Stephen T. Oh

Abstract

Myeloproliferative neoplasms (MPN) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induce a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1. Furthermore, genetic perturbation of PRMT6 exacerbated MPN disease burden including leukemic engraftment and splenomegaly in patient-derived xenograft models, highlighting a novel tumor-suppressive function of PRMT6. However, augmented erythroid potential and bone marrow human CD71+ cells following PRMT6 knockdown were reserved only to primary MPN samples harboring ASXL1 mutations. Lastly, treatment of CD34+ hematopoietic/stem progenitor cells with PRMT6 inhibitor, EPZ020411 induced expression of genes involved in heme metabolism, hemoglobin, and erythropoiesis. These findings highlight interactions between JAK2 and ASXL1 mutations and a unique erythroid regulatory network in the context of mutant ASXL1.

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CD123 As a Therapeutic Target in Accelerated and Blast Phase Myeloproliferative Neoplasms (MPNs)

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Melissa A. Babcook MD, PhD, Gerard Lozanski, MD, Sarah A. Wall MD, MPH

Background

CD123 expression in MPNs has been reported in case series and targeted in one phase I study of patients with chronic phase MPN. We describe the clinical phenotype of patients with accelerated (AP) or blast phase (BP) MPNs paired with CD123 co-expression on CD45(dim) myeloid blasts.

Methods

Subjects were identified by diagnosis in the Ohio State University Comprehensive Cancer Center Leukemia Tissue Bank (OSUCCC-LTB). Clinical data were collected by retrospective chart review with IRB approval. CD123 expression was measured by immunophenotyping of cryopreserved peripheral blood (PB) or marrow (BM) samples. Blasts were identified by CD45(dim) gating and co-expression of CD7/13/33/34/117/123 was measured. CD123 expression was stratified by quartile and correlation with clinical characteristics measured by Chi-square test.

Results

41 PB or BM samples from 24 subjects were identified from the OSUCCC-LTB. Nine subjects had paired PB and BM specimens, 6 had samples obtained at multiple timepoints. Median age at sample collection was 65.8 years (range 35.2-79.7) and median time from diagnosis was 13.1 months (range 0-96.5). Constitutional symptoms were present at collection for 24 samples (58.5%) and splenomegaly present for 20 samples (51.3%). At sample collection, 19.5% had never received treatment, 19.5% had been previously treated, and 61% were currently on treatment, most (n=16, 64%) with JAK inhibitor. 19 samples were obtained in chronic phase (46.3%), 9 in AP (22.0%), and 13 in BP (31.7%). 16 samples (39.0%) were from transfusion-dependent patients, most (68.8%) for both red blood cell and platelets. Median PB blasts were 3.2% (range:0-76) and BM blasts were 3% (range 0-82) by morphology. Molecular sequencing and karyotype were available for 18 (43.9%) and 27 (65.9%), respectively. The most common mutations identified were JAK2 (50%), ASXL1 (27.8%), SRSF2 (22.2%), CALR (16.7%), and TP53 (16.7%). Normal karyotype was found in 37%, 33.3% had complex karyotype, 11.1% had del 5q or 7q/-7, and 18.5% had del 13q or 20q. CD123 expression on the CD45-gated blasts ranged from 0.3-95.6% with a median value of 11.02%. CD123 expression is shown in figure 1. Figure 2a shows correlation between CD123 expression and disease phase (p < 0.01). Figure 2b shows CD123 expression correlation with ASXL1 mutation status (p =0.023). There were no statistically significant associations between CD123 expression and any other tested variables.

Conclusions

These data support a clinical trial targeting CD123 in high risk MPNs, defined by blasts >10% or the presence of ASXL1 mutation, an important subpopulation of patients in need of more effective and less toxic therapy than current standards of care that typically include cytotoxic chemotherapy.

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Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study

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James T. England, Natasha Szuber, Shireen Sirhan, Tom Dunne, Sonia Cerquozzi, Madeleine Hill, Pierre J. A. Villeneuve, Jenny M. Ho, et al.

Abstract

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that lead to morbidity and early mortality due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs and are used commonly to guide therapeutic decisions, including allogenic stem cell transplant, in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively examined in this population. We conducted a retrospective review of patients evaluated at eight Canadian centers for MPN patients diagnosed at ≤45 years of age. In total, 609 patients were included in the study, with median overall survival of 36.8 years. Diagnosis of prefibrotic or overt PMF is associated with the lowest OS and highest risk of AP/BP transformation. Thrombotic complications (24%), including splanchnic circulation thrombosis (9%), were frequent in the cohort. Mutations in addition to those in JAK2/MPL/CALR are uncommon in the initial disease phase in our AYA population (12%); but our data indicate they may be predictive of transformation to post-ET/PV myelofibrosis.

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NIH Analysis Reveals Rising Use of Complementary Health Approaches

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February 6, 2024

An analysis conducted by the National Institutes of Health’s National Center for Complementary and Integrative Health (NCCIH) reveals a substantial increase in the overall use of complementary health approaches by American adults from 2002 to 2022.

The study, published in the Journal of the American Medical Association, highlights a surge in the adoption of complementary health approaches for pain management over the same period.

Researchers utilized data from the 2002, 2012, and 2022 National Health Interview Survey (NHIS) to evaluate changes in the use of seven complementary health approaches, including yoga, meditation, massage therapy, chiropractic care, acupuncture, naturopathy, and guided imagery/progressive muscle relaxation.

The key findings include:

  • The percentage of individuals who reported using at least one of the seven approaches increased from 19.2% in 2002 to 36.7% in 2022.
  • The use of yoga, meditation, and massage therapy experienced the most significant growth from 2002 to 2022.
  • Use of yoga increased from 5% in 2002 to 15.8% in 2022.
  • Meditation became the most used approach in 2022, with an increase from 7.5% in 2002 to 17.3% in 2022.
  • Acupuncture, increasingly covered by insurance, saw an increase from 1% in 2002 to 2.2% in 2022.
  • Additionally, the analysis showed a notable rise in the proportion of U.S. adults using complementary health approaches specifically for pain management. Among participants using any of the complementary health approaches, the percentage reporting use for pain management increased from 42.3% in 2002 to 49.2% in 2022.

Despite the findings, the authors acknowledge study limitations, including decreasing NHIS response rates over time, possible recall bias, cross-sectional data, and differences in survey wording.

The study also highlights the role of factors such as higher quality research supporting the efficacy of complementary health approaches, the inclusion of these approaches in clinical practice guidelines for pain, and the expanded insurance coverage for approaches such as acupuncture, which has contributed to increased patient access.

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Myeloid Neoplasms: Better Understanding of their Molecular Pathogenesis with Improvised Genomic Testing: A Ray of Hope for Better Clinical Outcomes

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With the increase in incidence and prevalence of myeloid neoplasms in India, it has become a necessity to understand its molecular mechanisms, acquisition of genomic alterations, and understand its primary and secondary resistance pathways which ultimately impact the decision of therapeutics. The objective of this review is to investigate the molecular aspects of this disease type and identify the biomarkers that help with diagnosis, risk assessment, prognosis, and selecting the best line of treatment for a speci icmyeloid neoplasm. Advancements and innovations in molecular technologies from simplest Real-Time PCR to high throughput next-generation sequencing have played a vital role in screening the most common mutations and fusions to the novel and rare. Molecular technologies have helped to enumerate the genomic landscape of myeloid malignancies. The understanding of both- the mechanisms and the technology is a strong combination as it has helped revolutionize precision oncology and helped in giving better therapeutic choices with better clinical outcomes. The importance of cellular morphology, clinical symptoms, and molecular pathology in assessing the risk of myeloid malignancies is emphasized and summarized in the review. The review concludes that understanding molecular pathogenesis can be improved by using clinical-pathological-molecular strategies for diagnosis and therapy decision-making.

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Caregivers Are In Good Company

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“There are only four kinds of people in the world: Those who have been caregivers. Those who

are currently caregivers. Those who will be caregivers, and those who will need a caregiver.”

– Rosalyn Carter

 

After caring for her father who passed from terminal leukemia when she was just 12 years old, Rosalyn Carter found herself caring for her widowed elderly grandfather. These early life experiences prompted former First Lady Rosalyn Carter to start the Rosalyn Carter Institute for Caregivers (RCIFG).

According to the RCIFG, there are currently 53 million caregivers in America. While each caregiver experience has its own unique set of circumstances, there are some experiences that were shared across cultures and disease-type. Issues such as finding time for self-care, building a caregiver support community, juggling complex schedules, increased financial burden, missing work, having to leave the workforce prematurely, or having to return to the workforce, possible feelings of exhaustion, guilt, resentment, and alienation from friends and family are some commonly reported experiences. Interestingly, in spite of the large number of caregivers in the US, the feeling most often communicated is that of isolation.

Here at MPNA&EI we want you to know that caregivers are in good company. We will have our first monthly online caregiver support group meeting on Thursday, February 15th from 12:00-1:00 pm EST. We would like this first meeting to be a time to connect, share information and set up for our subsequent meetings. Over the course of the year, we will discuss a range of topics from building relationships with professional caregivers to increase cooperation, understanding, and support, learning ways to cope with the stressors of being a caregiver, accessing resources, discovering ways to work together with others to reduce frustrations and barriers in the caregiver role, sharing common concerns, and most importantly recognizing that caregivers are not alone.

In the meantime, here are 10 tips for caregivers from the Caregiver Action Network:

  1. Connect with other caregivers (which you can do at our caregiver support group meeting on February 15th)
  2. Don’t forget to take care of your own health.
  3. Accept offers to help and suggest things people can do to help.
  4. Learn how to communicate effectively with doctors.
  5. Be open to new technologies that could help.
  6. Watch for signs of depression.
  7. Take breaks.
  8. Organize medical information so it’s up-to-date and easy to find.
  9. Make sure legal documents are in order
  10. Give yourself credit for doing the best you can at one of the toughest jobs!

Understanding Philadelphia Chromosome-Negative Myeloproliferative Neoplasms in Young Patients: A Comprehensive Study

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By Mason Walker
Published Feb 6, 2024

Insights into Philadelphia Chromosome-Negative Myeloproliferative Neoplasms in Young Patients

Myeloproliferative neoplasms (MPNs) are a group of diseases in which the bone marrow makes too many red blood cells, white blood cells, or platelets. A recent study involving 609 patients diagnosed with Philadelphia chromosome-negative MPNs at the age of 45 or younger has brought new insights into the understanding of these diseases in younger patients.

Demographics, Clinical Variables, and Management Strategies

The study reported a variety of demographic, clinical, and laboratory variables, as well as the management strategies used for these patients. The majority of patients were diagnosed with essential thrombocythemia (ET) and polycythemia vera (PV). The median follow-up for the cohort was 9.1 years, and germline testing for hereditary MPN was not available.

The Association of Driver Mutation Variant Allele Frequency and Next-Generation Sequencing

The study also investigated the association of driver mutation variant allele frequency (VAF) and next-generation sequencing (NGS) with disease outcomes. This is important as these factors can play a significant role in the progression and management of MPNs.

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Study Reveals Real-World Characteristics of Patients With Secondary Myelofibrosis

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February 6, 2024

Jonathan Goodman, MPhil

A study published in the Annals of Hematology has highlighted the characteristics of patients with post-essential thrombocythemia or post-polycythemia vera myelofibrosis (PET-MF and PPV-MF, respectively) treated during the ruxolitinib era.

Although the characteristics of patients with primary MF are well-established, less research has evaluated real-world data from patients with PET-MF or PPV-MF. Given that primary and secondary forms of the disease may have different prognoses, a greater understanding of the clinical and patient characteristics in the latter group is important. For this prospective study, researchers in Japan aimed to determine the real-world characteristics and prognoses among patients with PET-MF or PPV-MF.

Overall, data from 314 patients were evaluated, among whom 197 had PET-MF while 117 had PPV-MF. At the time of diagnosis, in the PET-MF and PPV-MF groups, the median ages were 70 and 70 years, respectively, 49.7% and 53.8% of patients were male, and the periods from ET or PV diagnosis to MF progression were 9.64 and 10.38 years. The majority of patients in both groups received ruxolitinib treatment (74.6% in the PET-MF group and 83.8% in the PPV-MF group).

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MorphoSys Enters into Business Combination Agreement to be Acquired by Novartis for € 2.7 Billion Equity Value

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PLANEGG/MUNICH, Germany – February 5, 2024 – MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announced the company entered into a Business Combination Agreement with Novartis data42 AG and Novartis AG (hereinafter collectively referred to as “Novartis”) based on Novartis’ intention to submit a voluntary public takeover offer for all outstanding MorphoSys no-par value bearer shares at an offer price of € 68.00 per share in cash. As part of the Business Combination Agreement with Novartis, Novartis seeks to obtain exclusive, worldwide rights to develop and commercialize pelabresib, an investigational BET inhibitor, and tulmimetostat, an investigational next-generation dual inhibitor of EZH2 and EZH1, across all indications. Separately, MorphoSys entered into a Purchase Agreement to sell and transfer all rights worldwide related to tafasitamab to Incyte Corporation (“Incyte”). Currently, MorphoSys partners with Incyte on the development and commercialization of tafasitamab. MorphoSys’ Management Board and Supervisory Board unanimously approved both agreements.

“Novartis shares our steadfast commitment to develop and deliver transformative medicines that address the dire needs of cancer patients. Pelabresib – the investigational therapy at the forefront of our promising oncology pipeline – has the potential to shift the treatment paradigm in myelofibrosis and further expand into other indications. Novartis will provide ample resources currently unavailable to MorphoSys as a standalone biotech company to help accelerate the development opportunities and maximize the commercialization potential of pelabresib at a greater speed and scale,” said Jean-Paul Kress, M.D., Chief Executive Officer of MorphoSys. “We are also pleased that Incyte will assume full responsibility of tafasitamab. Given the proposed acquisition by Novartis and our long-standing partnership with Incyte, we know Incyte is best positioned to drive tafasitamab’s future growth opportunities forward successfully and more efficiently on its own at this time. We believe these agreements are in the best interest of MorphoSys, our shareholders and cancer patients.”

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