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Medical Network

Fall, 2021

Research at the NIH Points To Promising New Drugs To Treat Juvenile Myositis

Travis B. Kinder, PhD summarizes the research in a recent presentation to Cure JM's Research Committee.

Cure JM-funded research at the NIH’s National Center for Advancing Translational Sciences (NCATS) analyzed thousands of drugs to identify which of those drugs could effectively treat JM.

The research was conducted by Travis B. Kinder, PhD, Patricia K. Dranchak, PhD, and James Inglese, PhD.

The team genetically modified samples of human muscle cells to create conditions of chronic inflammation. Using a sophisticated robot, they ran thousands of drugs against the muscle cells in order to identify which drugs decreased inflammation.

Of the thousands tested, several broad classes of drugs were identified including inhibitors to JAKs, HDACs, CDKs, HIF1, and DNA topoisomerase II. Here’s a shortlist of the most promising drugs, which are JAK and HDAC inhibitors that are approved or in clinical trials:

  • Deucravacitinib
  • Upadacitinib
  • Ruxolitinib
  • Baricitinib
  • Peficitinib
  • Tofacitinib
  • Givinostat
  • Panobinostat

Assays of all available JAK inhibitors showed that generally, the unapproved JAK inhibitors were not more effective, or less toxic than the approved ones, with the exception of Deucravacitinib, which is in phase III clinical trials for psoriasis. JAK inhibitors block signals that produce inflammation. They are widely prescribed to patients with rheumatoid conditions. Deucravacitinib is being tested by Bristol Myers Squibb for use in other inflammatory conditions.

The NCATS team will continue to explore all active compounds with a focus on JAK inhibitors (particularly the most potent Deucravacitinib), screen more drugs, and also explore potential environmental triggers for JM.

Stephen M. Rose, PhD, Joins Cure JM’s Research Committee

Dr. Rose

Steven Rose, PhD

Cure JM is honored to welcome Stephen M. Rose, PhD, to its Research Committee. The committee drives the research priorities of the organization.

Dr. Rose is the former Chief Scientific Officer for The Foundation Fighting Blindness where he was responsible for the leadership and direction of the Foundation’s research efforts. Prior to joining the Foundation, Dr. Rose served as Director, Division of Clinical Recombinant DNA Research, Office of Biotechnology Activities (OBA), NIH Office of Science Policy. In this position, he served as the Executive Secretary for the Recombinant DNA Advisory Committee and provided oversight and coordination for the recombinant DNA program. He also provided scientific input to the Health and Human Service Secretary’s Advisory Committee on Xenotransplantation.

Before joining OBA, Dr. Rose was Director of the Office of Clinical Applications in the Division of Allergy, Immunology and Transplantation at the National Institute of Allergy and Infectious Diseases, NIH. Before accepting that position, Dr. Rose was the Chief of the Transplantation Immunobiology Branch in the same NIAID Division and established the adult and children’s kidney transplant clinical trial program where new drugs to prevent kidney transplant rejection were tested. From this program two new modalities were introduced into standard of care of kidney transplantation- ProGraft (FK506) as a primary immunosuppressive and Cellcept (Mycophenolate mofetil) for induction therapy.

Dr. Rose received his B.S. in Biology with Honors from American University and his Ph.D. from the University of Virginia. Upon completion of his doctorate, he was a NIH postdoctoral fellow at Washington University in St. Louis. He also held academic positions at the University of Texas Southwestern Medical School and the University of New Mexico Cancer Research Center.

“Dr. Rose is an extraordinary scientist and his experience in transitioning basic research into clinical trials for new drugs will provide invaluable guidance to the Cure JM Research Committee," said Jim Minow, Cure JM’s Executive Director. "Steve’s background in immunology, having worked with the scientific leadership at NIH and major research institutions around the world will help bring Cure JM’s research outcomes to even higher levels of achievement.”

Autoantibodies in Juvenile-onset myositis

In this educational podcast for researchers, Raquel Marques, MD, MSc, Sarah Tansley, MD, and Liza McCann, MD, discuss the diagnostic process to test for Myositis in children with Juvenile Dermatomyositis.


Abstract of Cure JM Supported Study
Anti-MDA5 autoantibodies associated with juvenile dermatomyositis constitute a distinct phenotype in North America

Gulnara Mamyrova, Takayuki Kishi, Min Shi, Ira N Targoff, Adam M Huber, Rodolfo V. Curiel, Frederick W. Miller, Lisa G. Rider

Myositis-specific autoantibodies have defined distinct phenotypes of patients with juvenile myositis (JIIM). We assessed the frequency and clinical significance of anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-associated JIIM in a North American registry.

Read the full paper here.

Abstract of Cure JM Supported Study
JAK inhibitors: a potential treatment for JDM in the context of the role of interferon-driven pathology

Meredyth G. Ll Wilkinson, Claire T. Deakin, Charalampia Papadopoulou, Despina Eleftheriou, Lucy R. Wedderburn

Juvenile Idiopathic Inflammatory Myopathies (IIM) are a group of rare diseases that are heterogeneous in terms of pathology that can include proximal muscle weakness, associated skin changes and systemic involvement. Despite options for treatment, many patients continue to suffer resistant disease and lasting side-effects. Advances in the understanding of the immunopathology and genetics underlying IIM may specify new therapeutic targets, particularly where conventional treatment has not achieved a clinical response. An upregulated type I interferon signature is strongly associated with disease and could be a prime target for developing more specific therapeutics. There are multiple components of the IFN pathway that could be targeted for blockade therapy.

Downstream of the cytokine receptor complexes are the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, which consists of JAK1–3, TYK2, and STAT1–6. Therapeutic inhibitors have been developed to target components of this pathway. Promising results have been observed in case studies reporting the use of the JAK inhibitors, Baricitinib, Tofacitinib and Ruxolitinib in the treatment of refractory Juvenile Dermatomyositis (JDM). There is still the question of safety and efficacy for the use of JAK inhibitors in JDM that need to be addressed by clinical trials. Here we review the future for the use of JAK inhibitors as a treatment for JDM.

Read the full paper here.

Promising Results with Innovative Therapy (baricitinib) in JDM

By Hanna Kim, MS, MD

Dr. Kim

Hanna Kim, MS, MD

Standard treatments for juvenile dermatomyositis are generally broadly immunosuppressive with multiple side effects. Also, some patients have refractory disease despite multiple therapies. Thus, there remains a need for more targeted therapy that may have less side effects and more efficacy. Interferon (IFN) signaling has consistently been identified as a dysregulated pathway in JDM. The mechanism of action of Janus kinase (JAK) inhibitors such as baricitinib includes blockade of IFN signaling so we hypothesized this may be a promising medication in JDM.

We (NIAMS Intramural Research Program) studied safety and efficacy of baricitinib in JDM through a compassionate use program with some support from Eli Lilly and Company. Four JDM patients, between 5.8 and 20.7 years old, who remained active despite reasonable trials of 3-6 other immunomodulatory medications were enrolled. Biologics other than IVIG had to be washed out before starting baricitinib. Significant improvement was noted by week 4 in the validated disease activity measures including physician assessment of global disease activity (PGA), patient/parent assessment of global disease activity (PtGA) , and skin disease by Cutaneous Dermatomyositis Disease Area and Severity Index Activity Score, also seen in photographs. The two patients who had weakness when enrolled showed clinically relevant improvement in strength by Manual Muscle Testing-8 by week 8, confirmed by blinded MRI scoring. Daily corticosteroids and other immunosuppressive medications were able to be decreased or discontinued. There were no serious adverse events and none of the patients had to stop or hold baricitinib due to an adverse event. Cell count changes and infections were observed and should be monitored. Inconsistent elevation in muscle enzymes were observed, which did not correlate with decreased strength or MRI changes so other assessment of strength/myositis should be included.

Proof-of-concept also validated including elevated IFN markers before started baricitinib that decreased after starting baricitinib and a dose-dependent decrease in IFN-signaling (STAT phosphorylation) most prominent in T cells. The clinical improvement of disease activity, including both skin and muscle involvement, paired with decreased IFN-signaling without any major safety concerns point to this as a promising therapy in refractory JDM. We are planning a controlled study with baricitinib to better assess efficacy and safety in a larger group of JDM patients.

Read the full paper here.

This issue is brought to you with the support of:

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CSI Pharmacy Clinical Specialty Infusions, LLC
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