Expanding the Use of JAK Inhibitors and Relevant Clinical Trials

Novel Approaches Show Promise in Targeting JAK Pathway

Following the identification of the JAK kinase family in the late 1980s, the novel enzyme group was colloquially known as “just another kinase.”1,2 Since then, these tyrosine kinases have defied that reputation amid abundant evidence showing that they transmit a variety of signals into the cell with many biological consequences.

Dysregulation of the JAK pathway plays a role in the development of numerous tumor types; it is particularly central to the pathophysiology of myelofibrosis (MF) and has long been recognized as a potentially valuable therapeutic target in that malignancy. Ruxolitinib (Jakafi), the first JAK inhibitor to gain FDA approval, has become a centerpiece in the treatment of patients with MF. JAK inhibition has not proved effective in other tumor types, and thus far, no other JAK-targeting therapies have become available.

That picture, however, may be changing. A better understanding of the complexities of JAK signaling in normal and cancerous cells and the design of rational drug combinations, are poised to expand the use of JAK inhibitors in anticancer therapy for hematologic, and possibly solid, tumors. Ruxolitinib continues to be explored in multiple malignancies, and several promising novel agents are being evaluated in clinical trials (TABLE).

JAK Pathway

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Imago BioSciences Receives FDA Approval of IND Application for the Treatment of Myeloid Malignancies

SAN CARLOS, Calif., Feb. 1, 2018 /PRNewswire/ — Imago BioSciences, a clinical-stage pharmaceutical company developing novel therapies for hematological and inflammatory diseases, announced that the U.S. Food and Drug Administration (FDA) has accepted their Investigational New Drug (IND) application providing clearance to proceed with the clinical development of IMG-7289 in the U.S. The IND supports the company’s ongoing Phase 1/2 clinical trial of IMG-7289 for myelofibrosis (MF).

“There is a pressing need for novel approaches to the treatment of myeloproliferative disorders including myelofibrosis,” said Hugh Young Rienhoff, Jr. M.D., Imago’s Chief Executive Officer.  “We are pleased to have received FDA acceptance of our clinical trial protocol and look forward to the imminent expansion of this study into the United States.”

This Phase 1/2 open-label clinical trial is designed to assess the pharmacodynamics of IMG-7289, an oral inhibitor of the epigenetic enzyme lysine-specific demethylase 1 (LSD1) in high-risk myelofibrosis patients aged 18 or older (www.clinicaltrials.gov Identifier NCT03136185).  Assessments include measuring changes in spleen volume, patient reported total symptom scores, mutant allele burden, inflammatory cytokines and bone marrow fibrosis over the course of the treatment period.  The trial commenced in Australia in 2017 and will add multiple sites in the United States in 2018.

This is the second clinical trial of IMG-7289 sponsored by Imago BioSciences, Inc.  The first, evaluating IMG-7289 for the treatment of high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), was initiated in 2016 (www.clinicaltrials.gov Identifier NCT02842827) and continues to enroll patients.

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Novel Agent Active in Refractory Polycythemia Vera

Dr. John Mascarenhas, MD is associate professor of medicine at Icahn School of Medicine at Mount Sinai

Idasanutlin demonstrated clinical activity among patients with refractory polycythemia vera, according to study results presented at ASH Annual Meeting and Exposition.

The agent also appeared well tolerated. Polycythemia vera and essential thrombocythemia are associated with considerable symptom burden. These chronic myeloproliferative neoplasms also are associated with a heightened risk for thrombosis and progression to myelofibrosis.

JAK2 inhibitors, hydroxyurea and interferon are commonly used to treat these conditions; however, hematopoietic stem cell-depleting therapies may offer an alternative option to improve outcomes.

MDM2, a negative regulator of P53, often is overexpressed in CD34-positive, p53 wild-type myeloproliferative neoplasm cells.

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Qiagen JAK2 Test Gets FDA Clearance for Additional Blood Cancer Types

NEW YORK (GenomeWeb) – Qiagen said after the close of the market on Tuesday that it received US Food and Drug Administration clearance for its Ipsogen JAK2 RGQ PCR Kit for additional use in the diagnosis of all myeloproliferative neoplasms (MPNs).

In March 2017 the FDA cleared the assay as a qualitative in vitro diagnostics test for the detection of the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood to aid in the diagnosis of the blood cancer polycythemia vera.

The new FDA clearance now covers two additional types of MPNs: essential thrombocythemia and primary myelofibrosis.

The assay runs on Qiagen’s Rotor-Gene Q MDx instrument, a component of the modular QiaSymphony family of laboratory automation products.

Qiagen said that it is the exclusive worldwide licensee of intellectual property covering the detection of the JAK2 V617F mutation for diagnostic purposes, and that it recently reached a settlement with an unspecified molecular diagnostics industry supplier in Europe, which agreed to stop selling its own JAK2 V617F test kit.

“We are eager to expand the use of our Ipsogen JAK2 assay, which is already available in Europe and other markets, for use in a wider range of patients in the US,” Thierry Bernard, senior vice president and head of Qiagen’s molecular diagnostics business area, said in a statement. The assay “makes it easier for hematologists and oncologists to follow recommended diagnostic testing algorithms and international guidelines for their patients suspected of having MPNs.”

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New Data Proves Role of Thrombosis in Patients with MPNs

New research published in Annals of Internal Medicine shows that the rate of arterial and venous thrombosis was significant in patients with myeloproliferative neoplasms (MPNs).

MPNs include a variety of blood disorders, like myelofibrosis, polycythemia vera, and essential thrombocytosis, and patients with them have been reported to be at increased risk for thrombotic events. Pharmacologic treatment can stabilize the blood counts, but they generally provide only partial symptom improvement. Until recently, no population-based study has estimated the excess risk with matched control participants.

Malin Hultcrantz, M.D., PhD and colleagues, in an effort to address the gap in knowledge, evaluated data from 9,429 patients – 46% of whom were male – diagnosed with MPNs who reported to the Swedish Cancer Register between 1987 and 2009, and matched them to 35,820 control participants and compared their rates of arterial and venous thrombosis. Median age of study participants was 72 years, and a mong them, 3,001 had polycythemia vera, 3,462 had essential thrombocythemia, 1,488 had PMF, and 1,478 had MPN unclassifiable.

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Incyte and Syros to collaborate in cancer R&D

  • Gene expression-focused biotech Syros Pharmaceuticals, Inc. has snagged a collaboration deal with biopharma Incyte Corp. to develop potential therapeutics to treat rare bone marrow disorders known as myeloproliferative neoplasms (MPNs).
  • In return for $20 million upfront in cash and R&D funding, and $10 million in stock, Syros will use its platform technology to find targets in MPNs. Incyte gets options to exclusive rights for therapies modulating up to seven validated targets discovered under the collaboration.
  • If Incyte exercises these options, Syros could see up to $54 million in option fees, and up to $115 million for products against each of the targets, as well as low-single digit royalties.

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Remembering Robert “Bob” Rosen

By Ann Brazeau, CEO, MPN Advocacy and Education International

In 2005, I met with the MPN Research Foundation for a potential job opportunity. Chairman Bob Rosen, Barbara Van Husen, President, and another Board member conducted the invigorating interview. The JAK2 Gene mutation had just been discovered and the energy and enthusiasm in the room was palpable. I was intrigued to say the least. A few months later I began my career there as Associate Director.

As Bob and I learned each other’s work habits and styles, we eventually hit a stride that took the Foundation to new and rewarding places. On any given day, conversations centered on MPN science, fundraising strategies, children, and of course, how we cooked our chicken the night before.

I remember the early days at the office on the river. The logo on the front door said Bridge Development, and I always thought my job was a bridge to another calling. I loved the absolute freedom to be creative, launch a project, or find new ways to increase visibility. Bob never refused to hear me out, look at the facts and inevitably say, “Go for it.” Our travels over the years to meet with donors and other potential partners always ended with a story to add to a growing list for a laugh or two later. I still laugh when I think about meetings he would request with me and Barbara, and we’d sit baffled that no one could quite remember why we were meeting.

We always used the expression, “The earth was moving under our feet.” That has certainly continued to be the case at the Foundation and in the greater MPN Community. Every day offered new hopes and new challenges and none were too mighty for a small group of dedicated people eager to get the job done.

Bob’s legacy will forever live on in the MPN Community. From the innovative, cutting edge, funded science he blessed, to the individual lives he touched, like mine. I would not be where I am without the years of experience at the Foundation. Bob could be fatherly when you needed it, and a big brother. Mostly, he was courageous, hard working, and unwavering in his pursuit for answers to MPN mysteries. Despite his own health issues, Bob always maintained his sense of humor. He will be greatly missed.

Click here to make a donation in his name

MPN Research Foundation Announces the Passing of its Chairman and Founder Robert Rosen

MPN Research Foundation announced today with great sadness the passing of its Chairman and Founder, Robert Rosen, age 74. Diagnosed with polycythemia vera in 1997, Rosen was shocked to discover that little research was being conducted on his condition and that there were no advocacy groups working to assist people with these rare blood cancers. Polycythemia vera (PV) is one of a cluster of blood cancers known as myeloproliferative neoplasms (MPNs), which includes PV, essential thrombocythemia (ET) and myelofibrosis (MF).

In 1999 Rosen, an established and highly successful Chicago businessman, formed the MPN Research Foundation to catalyze research and advance treatments for MPN patients. To date, Rosen’s MPN Research Foundation has awarded in excess of $12 million in MPN funding that has led to over 60 MPN-focused research projects, the advancement and development of new drug therapies, the publication of cutting edge research in numerous peer-reviewed scientific journals and the development of much needed patient advocacy initiatives, including effective outreach to the U.S. Food and Drug Administration, and highly beneficial education tools for the MPN community.

Andrew I Schafer, M.D., Director of the Richard T. Silver Center for Myeloproliferative Neoplasms (MPNs) at Weill Cornell Medical College, stated, “Because of Bob Rosen’s relentless tenacity, intense work ethic and limitless optimism, the MPNRF has been involved in every major scientific and medical advancement in the field of MPN research. Bob and the MPNRF have made immeasurable differences in the lives of people living with MPNs, the physicians who care for these patients, and the researchers who continue to search diligently for a cure.”

“There are no words to describe our sense of loss over Bob’s passing,” added Barbara Van Husen, MPNRF’s President and long-time friend of Rosen. “Our best and most significant tribute to Bob will be our continued efforts to accelerate and fund innovative research, create greater connectivity and resources for improving the lives of patients, and ultimately discover a cure for families living with an MPN. This was Bob’s mission and I’m confident that the MPNRF is in a strong position both professionally and financially to succeed with his goal.”

Bob’s daughter Molly Rosen Guy, also a director on the MPN Research Foundation board, said “Dad sought the only available curative treatment – a stem cell transplant – which is fraught with complications and often unsuccessful. His death is further evidence of the unmet need to find better ways to improve and extend the lives of patients with polycythemia vera and other blood cancers. Our work will continue.” A video produced by Molly about Bob’s diagnosis and her entry to the board can be seen here.

About the MPN Research Foundation
Founded by patients for patients, the MPN Research Foundation is a catalyst for research funding in pursuit of new treatments – and eventually a cure – for myeloproliferative neoplasms (MPNs). To date, the MPNRF has funded more than $12 million in MPN research.

Research funding is only part of what we do. The MPNRF is also dedicated to helping people living with MPNs change their prognosis by serving as a valuable source of education and resources in the MPN community.

Click here to make a donation in Bob Rosen’s name

Celgene to Acquire Impact Biomedicines, Adding Fedratinib to Its Pipeline of Novel Therapies for Hematologic Malignancies

  • Fedratinib is a highly selective JAK2 kinase inhibitor that is being evaluated for myelofibrosis and polycythemia vera
  • Fedratinib demonstrated clinical improvement in a phase III trial with treatment-naïve myelofibrosis patients and in a phase II trial with myelofibrosis patients resistant or intolerant to ruxolitinib
  • A New Drug Application (NDA) submission for fedratinib in myelofibrosis is planned for mid-2018

SUMMIT, N.J. & SAN DIEGO–(BUSINESS WIRE)–Celgene Corporation (NASDAQ:CELG) and Impact Biomedicines today announced the signing of a definitive agreement in which Celgene will acquire Impact Biomedicines, which is developing fedratinib for myelofibrosis and polycythemia vera. Under the terms of the agreement, Celgene will pay approximately $1.1 billion upfront and up to $1.25 billion in contingent payments based on regulatory approval milestones for myelofibrosis. Additional future payments for regulatory approvals in additional indications and sales-based milestones are also possible.

“Myelofibrosis is a disease with high unmet medical need as the number of patients who are ineligible for or become resistant to existing therapy continues to increase”

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Fedratinib, a highly selective JAK2 kinase inhibitor, was evaluated in 877 patients across 18 clinical trials. In a randomized, placebo-controlled, phase III pivotal trial (JAKARTA-1) for patients with treatment-naïve myelofibrosis, fedratinib demonstrated statistically significant improvements in the primary and secondary endpoints of splenic response and total symptom score, respectively. In an exploratory subgroup analysis, these improvements were observed regardless of a patient’s baseline platelet count.

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ASH: Stemline Presents on Recent Clinical Trial Results

Stemline Therapeutics Presents Detailed SL-401 Pivotal Data in BPDCN at ASH and Kicks Off its BPDCN Awareness Campaign; Updated Results From Ongoing Trials in Additional Malignancies Also Presented

NEW YORK, Dec. 13, 2017 (GLOBE NEWSWIRE) — Stemline Therapeutics, Inc. (Nasdaq:STML), a clinical-stage biopharmaceutical company developing novel therapeutics for difficult to treat cancers, presented detailed data from its SL-401 pivotal trial in BPDCN, as well as results from other ongoing trials in additional indications, at the 2017 American Society of Hematology (ASH) Annual Meeting and Exposition, held in Atlanta, GA. Presentations are available on the Stemline website, www.stemline.com, under the Scientific Presentations tab…

SL-401: Phase 1/2 Trial in myeloproliferative neoplasms (MPN): chronic myelomonocytic leukemia (CMML) and myelofibrosis (MF)

  • Key outcomes (ASH ’17 data)
    – SL-401 Phase 1/2 trial consists of a Stage 1 (lead-in, dose escalation) and Stage 2 (expansion); has enrolled 24 patients
    – No dose limiting toxicities (DLT) were identified and a maximum tolerated dose (MTD) was not reached. Most common TRAEs include hypoalbuminemia (33%), thrombocytopenia (33%), and fatigue (29%). Most common TRAEs (grade 3 or higher), include thrombocytopenia (24%) and anemia (19%)
    – Durable CR (14+ months) in CMML patient
    – 65% (11/17 evaluable) of CMML and MF patients had spleen reductions >25% (range 29% to 100%)
    – Durable SD in 4 patients (2 CMML, 2 MF) for 5+ to 8+ months. Three ongoing SD patients enrolled with baseline platelet counts <100,000, including 1 patient platelet count <50,000 are on treatment
  • Next Steps in MPN
    – Continue enrollment and patient follow-up
    – Favorable tolerability and preliminary signs of activity support both single agent and combination development strategies, including JAK-inhibitors and hypomethylating agents

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