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Mitobridge

targeting mitochondria. advancing human health.

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Mitobridge’s Novel Treatment Approach for Duchenne Muscular Dystrophy Advances into Clinical Development

Mitobridge’s Novel Treatment Approach for Duchenne Muscular Dystrophy Advances into Clinical Development

First-in-Class PPARδ Modulator with Potential to Improve Mitochondrial Health

CAMBRIDGE, MA, August 8, 2017 -- Mitobridge, Inc., a pioneer in the discovery and development of products that improve mitochondrial function, today announces a key milestone with the initiation of the first-in-human Phase I trial of its PPAR-delta (PPARδ) modulator, MA-0211 (also known as MTB-1). The study will assess the safety, tolerability, pharmacokinetics and pharmacodynamics of MA-0211 in healthy volunteers, which will provide the basis for a trial program in Duchenne Muscular Dystrophy (DMD) patients. MA-0211 is the first clinical compound to emerge from Mitobridge’s mitochondrial enhancement platform. The PPARδ modulator aims to reverse the mitochondrial deficits in DMD, which play a key role in disease progression.

DMD is a rare genetic disease caused by loss-of-function mutations in the dystrophin gene. This debilitating fatal disorder affects males and leads to progressive cardiac, skeletal and smooth muscle weakness and eventual loss of muscle mass. Mitobridge’s research has confirmed and expanded upon previous studies showing that mitochondrial defects contribute to abnormalities in the dystrophic muscle and play a central role in the etiology of DMD.

“PPARδ modulation represents a promising therapeutic approach to improving mitochondrial function and muscle health in DMD patients,” stated Mike Patane, CSO of Mitobridge. “This milestone with our lead program further validates our mitochondrial enhancement platform and ability to generate promising drug candidates that modulate mitochondrial function. Our research teams are actively evaluating MA-0211 in other diseases associated with mitochondrial dysfunction and developing other novel approaches to restoring healthy mitochondria.”

Mitobridge scientists have assembled extensive nonclinical data in patient samples and genetic animal models demonstrating that MA-0211 may be therapeutically beneficial to DMD patients. Treatment of DMD patient muscle cells with MA-0211 upregulated genes related to fatty acid oxidation, which increased mitochondrial function and mitochondrial biogenesis. MA-0211 was evaluated in the widely used DMD mouse model, the mdx mouse, which has a point mutation in the dystrophin gene and recapitulates many of the deficiencies seen in DMD patients. Once-daily oral dosing of MA-0211 for five weeks in mdx mice produced several therapeutic benefits including increased running endurance on a treadmill, decreased muscle necrosis and inflammation and decreased diaphragm fibrosis. In a similar study, six months of dosing in older mdx mice resulted in decreased serum creatine kinase and improved cardiac and respiratory function compared to untreated mdx mice. The strong pre-clinical data are the basis for advancing the compound into clinical development and highlight MA-0211’s potential to reverse key defects and slow disease progression. MA-0211 is being developed with the Company’s corporate partner, Astellas Pharma, Inc.

Recently, George Mulligan, Mitobridge’s SVP of Translation Medicine, presented an update of the MA-0211 program at the Parent Project Muscular Dystrophy Annual Connect Conference on June 30, 2017. The presentation is available here: https://youtu.be/leQnKrVm4YI

About MA-0211

MA-0211 (MTB-1), an orally bioavailable PPARδ modulator, is the first clinical compound to emerge from Mitobridge’s mitochondrial enhancement platform. In studies with patient muscle cells and animals, MA-0211 improves mitochondrial function, overall energy metabolism, muscle performance and regeneration. As DMD is characterized by mitochondrial defects, inadequate energy supply and muscle fibrosis, intervening with MA-0211 may be therapeutically beneficial for all DMD patients, regardless of their underlying dystrophin mutation. Additional clinical studies in other diseases characterized by mitochondrial deficiencies are currently being planned.

About Mitobridge

Mitobridge is dedicated to delivering therapeutics that improve mitochondrial function. Our team of experienced drug discovery and development scientists are leveraging their exceptional knowledge of mitochondria biology to develop a pipeline of innovative programs for the treatment of kidney and muscle diseases with high unmet medical need. Headquartered in Cambridge, MA, Mitobridge was launched in October 2013 with funding from Astellas Pharma, Inc., MPM Capital and Longwood Ventures. For more information about the Company, please visit www.mitobridge.com.

Contact information:
Lisa Paborsky, PhD
Senior Vice President, Corporate Development and Strategic Relations
Mitobridge, Inc
1030 Massachusetts Avenue, Suite 200
Cambridge, MA 02138
Email:
Phone: 617.401.9108

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Mitobridge Announces Sponsored Research Agreement to Evaluate PPARδ Compounds in Cells from Patients with Mitochondrial Disease

Mitobridge Announces Sponsored Research Agreement to Evaluate PPARδ Compounds in Cells from Patients with Mitochondrial Disease

CAMBRIDGE, MA-- Mitobridge, Inc., a biopharmaceutical company pioneering the discovery and development of products that improve mitochondrial function, announces the signing of a sponsored research agreement to assess Mitobridge’s selective Peroxisome Proliferator-Activated Receptor Delta (PPARδ) modulators in mitochondrial disease patient cell lines. Mitobridge will support research in the laboratory of Dr. Marni J. Falk, Assistant Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, and Director of The Children’s Hospital of Philadelphia Mitochondrial-Genetic Disease Clinic. The aim of the collaboration is to evaluate the therapeutic effects of PPARδ modulators on mitochondrial function in fibroblasts derived from patients with genetically-defined mitochondrial disorders.

“We have a shared commitment to progressing innovative treatments for mitochondrial diseases, a group of disorders with tremendous unmet medical need,” commented Effie Tozzo, PhD, Vice President of Translational Biology at Mitobridge. “We are delighted to be collaborating with a leading mitochondrial disease clinician-scientist who has demonstrated expertise in translating her experience with patients into important scientific advancements.”

The research plan is designed to evaluate the ability of Mitobridge’s proprietary compounds to improve mitochondrial function in patient cells. The cells harbor specific disease-causing mutations in mitochondrial DNA and in nuclear genes that are essential for mitochondrial energy production. Positive results could support the clinical development of the PPARδ modulators for certain mitochondrial diseases such as MELAS and Leigh’s Syndrome. Earlier this year, Mitobridge convened a panel of key opinion leaders in the field including, Patrick Chinnery, MD, PhD, Richard Haas, MD, Gregory Enns, MD, Michio Hirano, MD, and Tanja Taivassalo, PhD, and they recommended that Mitobridge study the activity of PPARδ modulators on mitochondrial function in patient-derived cell lines.

Mitobridge believes that testing therapeutic candidates in Dr. Falk’s collection of fibroblast cell lines, which are derived directly from mitochondrial disease patients’ skin biopsies, should lead to a better understanding of the defects in these cells and the potential benefit for patients.

Members of Mitobridge Mitochondrial Myopathy Advisory Panel

Patrick Chinnery, MD, PhD, Professor of Neurology and Head of the Department of Clinical Neurosciences at the University of Cambridge, Richard Haas, MD, Professor of Neuroscience at UC San Diego (UCSD) School of Medicine and Director of the UCSD Mitochondrial Disease Laboratory, Gregory Enns, MD, Professor of Pediatrics (Medical Genetics) at Stanford University, Michio Hirano, MD, Professor of Neurology at Columbia University and Co-director of the North American Mitochondrial Disease Consortium (NAMDC) and Tanja Taivassalo, PhD, Associate Professor, Department of Kinesiology at McGill University.

About Mitobridge

Mitobridge is a leader in the emerging field of mitochondria-related drug discovery and development. The Company is utilizing its innovative screening platform to identify and develop novel therapeutics that improve mitochondria function and provide treatments for mitochondrial genetic diseases, musculoskeletal, kidney and neurodegenerative disorders as well as diseases and conditions of aging. Mitobridge’s scientific founders and advisors include world-renowned leaders in biology and mitochondrial function. For more information about Mitobridge, please visit the company's website at www.mitobridge.com

Contact information:

Lisa Paborsky, PhD

Senior Vice President, Corporate Development and Alliance Management

Mitobridge, Inc

1030 Massachusetts Avenue, Suite 200

Cambridge, MA 02138

617.401.9108

Mitobridge Secures Key Intellectual Property from the Salk Institute

– Agreement includes comprehensive intellectual property estate for multiple programs

–CAMBRIDGE, Mass., February 23, 2015 — Mitobridge, Inc., previously known as Mitokyne, Inc., a biopharmaceutical company pioneering the discovery and development of products that improve mitochondrial function, today announced that the Company has entered into an agreement with the Salk Institute for Biological Sciences to access intellectual property and technology related to Peroxisome Proliferator-Activated Receptor Delta (PPARδ). The exclusive worldwide license grants key patents and reagents developed in the laboratory of Mitobridge co-founder Professor Ronald Evans for the diagnosis, prevention and treatment of diseases in both humans and animals. Dr. Evans, who was bestowed the Lasker Award for his work in nuclear hormone receptors, is the March of Dimes Chair in Developmental and Molecular Biology and Professor and Director of the Gene Expression Laboratory at the Salk Institute. He is also a Howard Hughes Medical Institute investigator.


Mitobridge is advancing a selective PPAR modulator (SPPARM) program based on recent developments in the understanding of the pharmacology of this drug target and the potential to utilize a PPARδ modulator as an exercise mimetic. The Company’s latest results indicate that a PPARδ modulator may be working through mitochondria and have potential to treat mitochondrial myopathies as well as other musculoskeletal disorders.

“We are excited about the opportunity to capitalize on the innovative PPARδ technology that has been developed over the past several years in the Evans lab. The results from pre-clinical studies suggest that our molecules might be safer yet similarly effective to earlier generation PPARδ compounds”, commented Mike Patane, PhD, Senior Vice President of Drug Discovery at Mitobridge. “We hope to translate the original discoveries from the Evans lab into meaningful therapeutics for disorders that will benefit from improving mitochondrial function.”

The Company was launched in October 2013 under the name Mitokyne to capitalize on the emerging biological understanding of how mitochondria function impacts health via bioenergetics, signaling, dynamics and biosynthesis. The Company recently changed its name to Mitobridge and filed a trademark application for that name. In addition, Mitobridge has closed a second tranche of financing led by MPM Capital, Longwood Fund and Astellas Pharma Inc.

“I am pleased with the progress the Company has made in our first year and the commitment demonstrated by our investors and our therapeutics partner, Astellas Pharma,” said Kazumi Shiosaki, PhD, President and CEO of Mitobridge. “Considerable insight linking mitochondrial dysfunction and disease pathologies has been gained over the last few years, and Mitobridge is poised for a leadership position in discovering innovative therapies.”

About Mitobridge

Mitobridge is a leader in the emerging field of mitochondria-related drug discovery and development. The Company is utilizing its innovative screening platform to identify and develop novel therapeutics that improve mitochondria function and provide treatments for mitochondrial genetic diseases, musculoskeletal and neurodegenerative disorders as well as diseases and conditions of aging. Mitobridge’s scientific founders and advisors include world-renowned leaders in biology and mitochondrial function. For more information about Mitobridge, please visit the company's website at www.mitobridge.com

About the Salk Institute for Biological Studies

The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probes fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, MD, the Institute is an independent nonprofit organization and architectural landmark.

Contact information:

Lisa Paborsky, PhD
Senior Vice President, Corporate Development and Alliance Management
Mitobridge, Inc.
1030 Massachusetts Avenue, Suite 200
Cambridge, MA 02138

617.401.9108

Astellas and Mitokyne to Pursue Mitochondria-Related Disease Therapies

– Collaboration Will Focus on Expanding the New Frontier of Mitochondria-Related Disease –

Tokyo and Boston, October 7, 2013 --- Astellas Pharma Inc. (Tokyo Stock Exchange: 4503, President and CEO: Yoshihiko Hatanaka, hereinafter called “Astellas”) and Mitokyne, Inc. (President and CEO: Kazumi Shiosaki, hereinafter called “Mitokyne”) announced today that the two companies have entered into an exclusive R&D collaboration focused on discovering and developing novel drugs that improve mitochondrial functions. These drug candidates have the potential to treat genetic, metabolic or neurodegenerative disorders as well as conditions of aging. The emerging biological understanding of mitochondria, along with new tools and assays available to better elucidate mitochondrial function and processes, will enable the identification of breakthrough treatments for patients suffering from mitochondria-related diseases and improve their quality of life.

Concurrently, Mitokyne closed a $45M series A equity financing from Astellas, MPM Capital, and Longwood Founders Fund. In connection with the financing, Ansbert Gadicke, MD, MPM Capital, Rich Aldrich, Longwood Founders Fund, and a designee from Astellas joined the Mitokyne Board of Directors.

Under the collaboration agreement, Astellas and Mitokyne will collaborate to discover and develop compounds that target mitochondrial function. Mitokyne will lead all the research and drug discovery activities and be responsible for delivering IND candidates, whereupon Astellas will assume all clinical development activities as well as commercialization. In addition to generating a pipeline of novel drug candidates, Mitokyne is developing a novel mitochondrial screening platform to enhance ongoing R&D programs and identify new drug targets. Astellas has the exclusive right to acquire Mitokyne during certain periods during the term of the five– year agreement. Including upfront, R&D funding, acquisition and milestone payments, the total value of the partnership agreement could reach up to $730M. Taking into account Astellas’ participation in Mitokyne’s equity financing, Astellas’ actual payment for the acquisition based on equity in Mitokyne could be over $500M in accordance with conditions of the agreement.

“This R&D partnership is an excellent opportunity for Astellas to utilize more external capabilities and resources, and to undertake initiatives related to new therapeutic areas, as we announced “Reshaping Research Framework” in May,” said Yoshihiko Hatanaka, President & CEO of Astellas. “Through this partnership, we expect to pursue advanced drug discovery and establish a winning model with which it can solidify its position as the leader in the field of mitochondria-related diseases, and eventually develop advanced medical solutions for patients around the world, adding to our portfolio of innovative new drugs.”

Mitokyne’s scientific founders include world-renowned leaders in biology and mitochondrial function. Johan Auwerx is the Nestle Chair in Energy Metabolism and Professor at the cole Polytechnique Fdrale de Lausanne. Andrew Dillin is the Siebel Distinguished Chair of Stem Cell Biology, HHMI Investigator and Professor of Genetic, Genomics and Development at UC Berkeley. Ronald Evans is the March of Dimes Chair in Developmental and Molecular Biology and Professor and Director in the Gene Expression Laboratory at Salk Institute for Biological Studies and was awarded the Lasker Award for his work in nuclear hormone receptors. H. Robert Horvitz is Professor in the Department of Biology and a member of the McGovern Institute for Brain Research and of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology. Professor Horvitz received the Nobel Prize in 2002 for his contributions to mechanisms of cell death. The scientific founders will join Mitokyne’s Scientific Advisory Board, which also includes founding member Jodi Nunnari, a Professor of Molecular & Cellular Biology at University of California, Davis.

“I am delighted that we were able to bring together a committed corporate partner in Astellas along with great investors and scientific advisors to help shape and build this company in such an exciting area,” said Kazumi Shiosaki, CEO and co-founder of Mitokyne. “Clearly Astellas and Mitokyne share a singular vision to become leaders in discovering and developing novel compounds that beneficially modulate mitochondrial function. Both companies will be able to contribute their complementary strengths to forge a robust partnership.”

The impact of this collaboration has been accounted in Astellas’ forecasts for fiscal year ending March 2014.

About Astellas
Astellas Pharma Inc., located in Tokyo, Japan, is a pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceuticals. Astellas has approximately 17,000 employees worldwide. The organization is committed to becoming a global category leader in Urology, Immunology (including Transplantation) and Infectious diseases, Oncology, Neuroscience and Diabetes Mellitus (DM) Complications and Kidney diseases. For more information on Astellas Pharma Inc., please visit the company website at www.astellas.com/en.

About Mitokyne
Mitokyne is a biotech company focused on mitochondria-related drug discovery and development. The company is utilizing its innovative screening platform to identify and develop novel drugs that improve mitochondria function and provide treatments for genetic, metabolic and neurodegenerative disorders as well as diseases and conditions of aging. Mitokyne’s scientific founders and advisors include world-renowned leaders in biology and mitochondrial function.

About MPM Capital
MPM Capital is one of the world's largest life science-dedicated venture investors. With committed capital under management in excess of $2.6 billion, MPM Capital is uniquely structured to invest globally in healthcare innovation.

About Longwood Founders Fund
Longwood Founders Fund is a healthcare venture capital firm that founds, manages, and builds biotechnology companies. Longwood’s mission is to identify technologies and to found companies that will advance new therapeutics that can not only make a difference in the lives of patients worldwide, but also create significant value for investors. This is achieved by leveraging the management team’s history of successful biotechnology company formation and operational leadership.

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About Mitochondria
Mitochondria are present in almost every cell of the human body. The main function of mitochondria is generation of ATP as the energy for humans to function. In addition, mitochondria are involved in numerous other functions including fatty acid metabolism, reactive oxygen species (ROS) production/elimination, cell death regulation, and so on.

About Mitochondrial Diseases and Mitochondria-Related Diseases
Mitochondrial diseases are caused by various mutations, acquired or inherited, in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Dysfunction of mitochondria can affect only certain tissues due to factors not yet fully understood. Affected patients suffer from muscular dysfunction, neurological dysfunction, cardiac dysfunction, ocular/otic dysfunction, metabolic dysfunction and so on. Typical onset in most cases is during early childhood, impairing a patient’s quality of life.

Three disorders account for 60~70% of mitochondrial diseases:
1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS);
2) chronic progressive external ophthalmoplegia/ Kearns-Sayre syndrome (CPEO/KSS); and
3) myoclonus epilepsy associated with ragged-red fivers (MERRF).

Other mitochondria-related diseases include Leigh’s syndrome, mitochondrial neurogastrointestinal encephalopathy (MNGIE), Alpers’ disease, Leber's hereditary optic neuropathy (LHON), neuropathy, ataxia, and retinitis pigmentosa (NARP) and fatty acid oxidation disorders (FAOD).

Mitochondrial dysfunctions are suspected of playing roles in seemingly unrelated disorders, such as muscular, metabolic, neurodegenerative, ophthalmic, aural and other disorders that include cancer, heart failure and kidney damage. Specific disorders considered to be linked to mitochondria-related diseases include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), stroke, mood disorders, diabetes, fatty liver disease, osteoporosis, cancer, peripheral arterial disease (PAD), agerelated hearing loss (AHL) and others.

Today, the diagnosis of mitochondria-related diseases remains a complicated process due to the wide range of symptoms.

Presentations

PPMD: 2017 Connect Conference; Chicago, IL

Presentation: MA-0211 Activates mitochondria and improves multiple abnormalities in DMD patient muscle cells and mdx mice

PPMD: 2017 Connect Conference; Chicago, IL

UMDF:  2017 Scientific Program Mitochondrial Medicine;  Washington, DC

Euromit 2017: International Meeting on Mitochondrial Pathology; Cologne, Germany

FASEB SRC - Mitochondrial Biogenesis and Dynamics in Health, Disease and Aging; West Palm Beach, FL

2017 Keystone Symposia Conference: Mitochondria Communication; Taos, New Mexico

PPMD 2016 Annual Connect Conference; Chicago, IL

NHLBI/NIDDK Mitochondrial Biology Symposium: Novel Roles of Mitochondria in Health and Disease; National Institutes of Health in Bethesda, Maryland

Publications

A Novel Mitophagy Assay for Skeletal Myotubes

Webb M, Malhotra J, Tham C, Goddeeris M, McMillin DW, Tozzo E
Open Access J Neurol Neurosurg. 2017; 4(5): 555649. DIO: 10.19080/OAJNN.2017.04.555649

PPARδ Promotes Running Endurance by Preserving Glucose.

Fan W, Waizenegger W, Lin CS, Sorrentino V, He MX, Wall CE, Li H, Liddle C, Yu RT, Atkins AR, Auwerx J, Downes M, Evans RM
Cell Metab. 2017 May 2;25(5):1186-1193.e4. doi: 10.1016/j.cmet.2017.04.006.

NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.

Ryu D, Zhang H, Ropelle ER, Sorrentino V, Mázala DA, Mouchiroud L, Marshall PL, Campbell MD, Ali AS, Knowels GM, Bellemin S, Iyer SR, Wang X, Gariani K, Sauve AA, Cantó C, Conley KE, Walter L, Lovering RM, Chin ER, Jasmin BJ, Marcinek DJ, Menzies KJ, Auwerx J.
Sci Transl Med. 2016 Oct 19;8(361):361ra139.

Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis.

Berendzen KM, Durieux J, Shao LW, Tian Y, Kim HE, Wolff S, Liu Y, Dillin A.
Cell. 2016 Sep 8;166(6):1553-1563.e10. doi: 10.1016/j.cell.2016.08.042.

The Emerging Network of Mitochondria-Organelle Contacts.

Murley A, Nunnari J
Mol Cell. 2016 Mar 3;61(5):648-53. doi: 10.1016/j.molcel.2016.01.031.

Nature Biotechnology

Specialty firm Edison Pharmaceuticals of Mountain View, California, has entered a strategic alliance worth up to $4.3 billon with Dainippon Sumitomo Pharma (DSP) of Osaka, Japan, to develop drugs for inherited respiratory chain diseases of the mitochondria. Under terms of the deal, the companies will jointly expand Edison's pipeline, bringing…
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