Quartet Medicine Announces Neuron Publication Validating Role Of The BH4 Pathway In Chronic Neuropathic And Inflammatory Pain

-- Cutting-edge genetic techniques combined with small molecule pharmacology confirm drug discovery approach for developing novel pain therapies --

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Quartet Medicine, a biotechnology company focused on the discovery and development of novel treatments for chronic pain and inflammation, today announced that new study findings, for the first time, demonstrate the critical role that tetrahydrobiopterin (BH4) plays in regulating disease at the intersection of the peripheral nervous system and the immune system. Using tissue-specific genetic models combined with small molecule tool compounds, the article provides preclinical validation for the therapeutic modulation of BH4 to treat pain hypersensitivity. Additionally, the article describes a novel, translational biomarker for specifically assessing target engagement in preclinical and clinical testing.

“The article also underscores sepiapterin reductase as an attractive drug target for the development of a potentially safe and efficacious treatment for chronic pain and inflammation.”

The research was conducted by Quartet’s scientific co-founder, Clifford Woolf, M.D., Ph.D., Professor of Neurology and Neurobiology at Harvard Medical School and Director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, and his colleagues. The article was published today in Neuron (Volume 86, Issue 6, June 17, 2015 pp.1393-1406). Key findings of the article include:

• Overexpression of GTP cyclohydrolase 1 (GCH1, the rate limiting enzyme in de novo BH4 synthesis) in peripheral neurons increases BH4 levels leading to increased pain hypersensitivity in mice,
• Peripheral nerve-specific inducible knockout of GCH1 reduces BH4 and reverses painful hypersensitivity,
• Systemic inhibition of sepiapterin reductase (SPR, the final enzyme in the BH4 de novo synthesis pathway) using a small molecule tool compound in multiple preclinical efficacy models reduces elevated BH4 levels in injured neurons and macrophages resulting in an improvement in pain-related behavior, and
• Sepiapterin is a specific, sensitive and quantifiable biomarker of SPR inhibition.

These preclinical findings further support the development of BH4 modulators as promising alternatives to existing pain therapies that largely target the central nervous system, and offer a potentially better side effect profile without the risk of addiction.

“These studies from the Woolf Lab and their collaborators expand Quartet’s understanding of BH4’s role in mediating pain and inflammation, and further support the association between the human genetics linking reduced BH4 levels to improved outcomes in chronic pain,” said Kevin Pojasek, Ph.D., Quartet’s President and acting Chief Executive Officer. “The article also underscores sepiapterin reductase as an attractive drug target for the development of a potentially safe and efficacious treatment for chronic pain and inflammation.”

About Tetrahydrobiopterin and its Link to Chronic Pain and Inflammation

The de novo tetrahydrobiopterin (BH4) synthesis pathway has been implicated in a range of chronic human pain and inflammatory conditions. Up-regulation of BH4 synthesis in response to injury or inflammation increases cellular levels of BH4, an important cofactor for several classes of enzymes, resulting in neuronal hypersensitivity and chronic immune cell activation. Multiple human genetic studies have linked a haplotype in the gene encoding GTP cyclohydrolase I, a BH4 synthetic enzyme, to lower BH4 levels and a reduced risk of developing chronic pain after nerve injury or chronic disease. Pharmacological modulation of either GTP cyclohydrolase I or sepiapterin reductase, another enzyme in the BH4 synthesis pathway, safely restores BH4 to normal levels leading to an improvement of pain symptoms in preclinical models.

Quartet is using human genetic and BH4-based biomarker tools, along with preclinical disease models, to select the ideal early clinical proof-of-concept indications for a modulator of the BH4 synthesis pathway. In addition, the company is enabling a translational biomarker strategy for clearly establishing human target engagement early in phase 1 clinical trials. This dual indication discovery and translational biomarker-based approach will help de-risk Quartet’s lead program as it advances through early clinical development.

About Quartet Medicine

Quartet Medicine is a private, biotechnology company focused on discovering and developing novel treatments for chronic pain and inflammation. Human genetics and preclinical target validation data point to increased tetrahydrobiopterin (BH4) as a critical mediator of peripheral nerve dysfunction and immune cell regulation. Quartet is capitalizing on these insights by safely restoring BH4 homeostasis in neuronal and inflammatory cells.

Quartet was founded by scientists at Boston Children’s Hospital and École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland in conjunction with Atlas Venture. Quartet’s Series A investors included Atlas Venture, Novartis Venture Fund, Pfizer Venture Investments and Partners Innovation Fund. The company is based in Cambridge, Massachusetts and has research efforts underway with collaborators in the U.S., Europe and Asia. For more information, visit www.quartetmedicine.com.