NEWTON, Mass.—Karyopharm Therapeutics Inc., a clinical-stage pharmaceutical company, today reported that its SINE nuclear transport compounds are being evaluated for the treatment of Amyotrophic Lateral Sclerosis (ALS) and that preclinical data abstracts will be presented at two upcoming neuroscience meetings. A recent publication appearing in the journal Nature confirmed that nuclear transport is disrupted in a common mutation found in ALS. Given the tremendous unmet need for new treatments for ALS, Karyopharm is advancing its oral SINE compound KPT-350 for this indication.
While Karyopharm's primary clinical focus is in advancing its lead SINE compound oral selinexor for cancer, other SINE compounds have already shown beneficial pharmacological effects in several neurodegenerative and anti-inflammatory preclinical models, including multiple sclerosis, systemic lupus and traumatic brain injury.
The Nature publication entitled "The C9orf72 repeat expansion disrupts nucleocytoplasmic transport" reported that C9orf72, the most common cause of familial and sporadic ALS and frontotemporal degeneration, results in problems with nuclear protein trafficking that affect neural function and survival. The mutation causes the affected cells to create long strands of repeating RNA, thus blocking critical pathways for nuclear transport of proteins. A first set of experiments using a fruit-fly model of human ALS to screen for candidates that block brain cell death in a living organism identified a protein RanGAP, a key regulator of nucleocytoplasmic transport, that acts as a potent suppressor of neurodegeneration. Consistent with the interaction of RanGAP with XPO1 (exportin 1), the studies further showed that suppressing nuclear export of proteins also suppresses neurodegeneration. The results were validated in human stem cell-derived motor neurons and autopsied brains.
In a second set of experiments, using fly and human stem cells, the addition of antisense oligonucleotides targeting C9orf72 or small molecule inhibitors of XPO1 including one of Karyopharm's SINE compounds, restored proper protein nuclear localization. Importantly, this effect was sufficient to suppress neurodegeneration. This study supports the premise that nucleocytoplasmic transport defects may be a fundamental pathway for ALS that is amenable to pharmacotherapeutic intervention. The results from this publication will also be presented at the Society for Neuroscience (SfN) meeting in Chicago on October 19, 2015 by Thomas E. Lloyd, M.D., Ph.D., of Johns Hopkins University.
"This valuable research reinforces that modulation of nucleocytoplasmic transport presents a potential therapeutic strategy for neurodegenerative diseases such as ALS," said Sharon Shacham, Ph.D., president and chief scientific officer of Karyopharm. "More broadly, this work extends earlier findings in multiple sclerosis, traumatic brain injury, and auto-inflammatory disorders, further validating the vast therapeutic applicability of Karyopharm's SINE compounds across a broad spectrum of diseases."
In addition to the above presentation, Karyopharm's other collaborators will be presenting abstracts on the neuroprotective effects of SINE compounds at two upcoming neuroscience meetings this fall. Sami Barmada, M.D., Ph.D., from the University of Michigan will be presenting an abstract entitled "Selective inhibition of nuclear export in amyotrophic lateral sclerosis and frontotemporal dementia" at the upcoming American Neurological Association (ANA) Meeting in Chicago on September 26, 2015. Hilary Archbold, also from the University of Michigan, will be presenting an abstract entitled "The role of nuclear export in TDP-43-mediated neurodegeneration" at the Society for Neuroscience (SfN) meeting in Chicago from October 18, 2015.
Karyopharm's SINE compound research efforts in ALS are being supported entirely by collaborator grant funding. The ALS Therapy Alliance is funding the in-vitro research of Karyopharm's collaborator Sami Barmada, M.D., Ph.D., of the University of Michigan until 2016. The goal of that grant is to investigate the mechanism of neuroprotection by SINE compounds and determine if they are protective in human stem cell-derived neurons from patients with ALS and FTD. Another collaborator, Ronald Klein, Ph.D., of Louisiana State University Health Sciences Center, Shreveport, has been funded by the ALS Association beginning in July 2015 for two years to evaluate the therapeutic efficacy of KPT-350 in an adult onset ALS model. This in-vivo research is expected to confirm whether Karyopharm's compound can ameliorate the ALS-like disease state in rats induced by gene transfer of cytoplasmic TDP-43, a major disease protein in ALS.
ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. The degeneration of nerve cells eventually causes people with ALS to lose the ability to initiate and control muscle movement. There is no cure for the disease and few treatment options exist. Approximately 6,400 new cases of ALS are diagnosed each year in the United States. ALS usually strikes between the ages of 40 and 70 with death occurring within three-to-five years from diagnosis. Death is usually due to respiratory failure because of diminished strength in the skeletal muscles responsible for breathing. ALS affects approximately 400,000 people worldwide, with approximately 30,000 in the United States.
KPT-350 is Karyopharm's orally active, brain penetrant, anti-inflammatory SINE XPO1 antagonist. It is an analog of SINE compound selinexor (KPT-330), which is being developed for the treatment of cancer. KPT-350 has been evaluated in preclinical studies in traumatic brain injury (TBI). In animal studies, the gross size of lesions resulting from TBI were dramatically reduced in rats treated with KPT-350. Furthermore, the KPT-350-induced protection at the site of the injury resulted in healthy adjacent tissue with viable neurons, which appears to indicate that KPT-350 exerted a neuroprotective effect to prevent permanent neuronal loss due to the blunt force injury. Karyopharm is evaluating SINE compounds, including KPT-350, in additional inflammatory, neuroprotection and autoimmune models including multiple sclerosis, TBI and systemic lupus erythematosus.
Karyopharm Therapeutics Inc. is a clinical-stage pharmaceutical company focused on the discovery and development of novel first-in-class drugs directed against nuclear transport targets for the treatment of cancer and other major diseases. Karyopharm's SINE compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). In addition to single-agent activity against a variety of different human cancers, SINE compounds have also shown biological activity in models of cancer, inflammation, autoimmune disease, certain viruses, and wound-healing.