Technology

• Introduction: Building Better Medicines
• DCE Platform^® - Less Time, Less Expense, Higher Probability of Success
• A Novel Drug Discovery Paradigm
• Pipeline / Disease Targets
• Intellectual Property Summary

Introduction: Building Better Medicines

Since its founding in 2006, Concert Pharmaceuticals has been dedicated to creating new medicines through its proprietary DCE Platform^® (deuterated chemical entity platform) that utilizes the safe and naturally occurring element deuterium.  In select cases, deuterium modification can improve upon the metabolic properties of a drug with little or no change in its intrinsic pharmacology.  Concert has executed on this approach to become a clinical stage biotechnology company with its lead program in Phase 2 clinical testing: CTP-499 for diabetic kidney disease.  In addition, Concert is developing a robust pipeline of preclinical candidates in several therapeutic areas. 

Concert’s DCE Platform provides the potential for improved drug efficacy, safety, and tolerability.  

It is a promising and novel approach to address what are often intractable limitations for many drugs: poor oral bioavailability, pharmacokinetics, or metabolite profile.  Concert focuses its efforts in areas where there is a significant opportunity to improve the ADME (absorption, distribution, metabolism, and excretion) profile of pharmacologically well-characterized compounds, and where such an improvement has the potential to provide a clinical benefit.  Concert has investigated the effects of selective deuterium modification on dozens of such compounds including many validated drugs and currently has 37 issued US patents. [ back to top ]

DCE Platform^® - Less Time, Less Expense, Higher Probability of Success

Unlike traditional methods of drug discovery which involve a great deal of trial and error, Concert’s approach generally begins with compounds that have been previously characterized including, in many cases, extensive clinical experience. Usually these compounds have excellent pharmacological properties, but suffer from less than ideal ADME profiles.  Selective deuterium modification has the unique potential, in certain cases, to improve ADME without altering desirable pharmacological properties.  This approach facilitates drug development by reducing R&D risk, time and expense. [ back to top ]

A Novel Drug Discovery Paradigm

Deuterium is a safe and stable relative of hydrogen that has been widely used in human clinical studies for a number of purposes, including examination of pharmacokinetics and metabolism.  It is a naturally-occurring element derived from water and due to its natural abundance, the average human adult body contains approximately 2 grams of deuterium.

In addition to its safety, another important feature of deuterium is that its size and shape are essentially identical to hydrogen. Thus, deuterium substitution of hydrogen does not materially alter the way a drug “looks” to the body. Deuterium-substituted drugs generally retain full biochemical potency and selectivity. 

An overlay of the crystal structures of CTP-347 hydrochloride hemihydrate (purple) and
paroxetine hydrochloride hemihydrate derived from the Cambridge database (pale green)
reveal that they are indistinguishable.

While deuterium is nearly the same as hydrogen in many ways, there is one compelling characteristic of deuterium that is highly useful for drug development purposes.   It forms a strong chemical bond with carbon relative to the carbon-hydrogen bond (the C-D bond is typically about six to nine times more stable than the C-H bond). Since drug metabolism often involves the breaking of a C-H bond, in certain cases a stronger C-D bond at or near a metabolically active site has the potential to alter drug metabolism.  In select cases, therefore, deuterium substitution at specific molecular positions can improve metabolic stability, reduce formation of toxic metabolites, or increase the formation of desired active metabolites.   It is important to note, however, that even when deuterium is incorporated at a known site of oxidative metabolism, the resulting deuterium effect on ADME is unpredictable.  For example, complex enzymatic mechanisms often have other rate-limiting steps.  Also, the presence of a stabilized C-D bond may cause metabolism to shift or “shunt” to another site or sites on the molecule.  Concert investigated this phenomenon of metabolic shunting with its first clinical candidate CTP-347, a deuterated version of paroxetine.  CTP-347 was the first example in a clinical setting of the use of deuterium to inhibit formation of an unwanted metabolite that causes potent and irreversible inactivation of a key liver enzyme.

¹Median DM/DX ratio in urine used to determine activity of CYP2D6

Deuterated drugs have a long history of use in clinical settings as probes for pharmacokinetic and metabolism studies of the corresponding non-deuterated drugs, until recently deuterium modification has received very little attention as an approach to creating important new therapeutic agents.  In fact, the two uses of deuterium - for metabolic fate studies of non-deuterated drugs and to create new therapeutic agents with improved properties - are quite different.  Metabolic fate studies generally rely on deuterated probes where the ADME properties of the drug being studied are unchanged.  In such studies, the presence of a deuterium effect on ADME will compromise the effectiveness of the probe compounds.  In contrast, Concert seeks to develop drugs where substantial deuterium effects provide an important clinical benefit.  Concert believes that its DCE Platform has the potential to create a wide range of new chemical entities in multiple therapeutic areas that result in first-in-class and best-in-class products.   [ back to top ]

Disease Targets

Concert’s technology has broad potential applicability to many chemical entities for use in a wide spectrum of therapeutic areas.  Target compounds for Concert’s DCE Platform include many drugs listed in the United States Pharmacopeia and in development pipelines worldwide, as well as compounds that possess important pharmacological benefits but that cannot be developed as drugs due to intrinsic ADME liabilities.  Concert seeks to create new chemical entities that provide unique clinical benefits, can be rapidly developed, and enjoy long patent protection after approval. 

One of Concert’s lead product candidates is a treatment for diabetic kidney disease, which is currently in Phase 2 clinical testing. Concert is also developing treatments for a broad range of diseases including those focused hematologic and CNS disorders. (click here to view Concert’s product pipeline)

Select program highlights: CTP-499 ¦ CTP-354

CTP-499 - First-in-Class Treatment Candidate for Diabetic Kidney Disease

CTP-499, a novel, potentially first-in-class treatment for diabetic kidney disease, possesses multiple pharmacological properties in inhibiting inflammation, oxidation and fibrosis. Its unique qualities may enable it to intervene in the pathophysiology of diabetic kidney disease as well as other forms of kidney disease and certain fibrotic indications.

CTP-499 was developed using Concert’s DCE Platform® in which deuterium was incorporated at select positions of 1-((S)-5-hydroxyhexyl)-3,7-dimethylxanthine (HDX). This deuterium-stabilized analog of HDX is a new chemical entity with a unique pharmacokinetic profile. Deuterium incorporation enhances the metabolism profile of HDX, resulting in high and consistent plasma levels of both CTP-499 and active metabolites. Concert’s own research, as well as literature reports suggesting that HDX may play a major role in providing these beneficial effects, led Concert to develop CTP-499.

CTP-499 is intended to be additive to the current standard-of-care, angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy, to slow progression of kidney damage in diabetic kidney disease and other types of chronic kidney disease. Despite the effectiveness of these agents, many patients continue to have progressive kidney disease leading to increased cardiovascular risk or end-stage kidney disease, demonstrating the need for new, innovative therapies such as CTP-499.

CTP-499 is currently in Phase 2 testing.

Diabetic Kidney Disease

Diabetes is a fast growing epidemic.  There are approximately 21 million diagnosed diabetics in the US and more than 220 million worldwide.  Diabetic kidney disease is a chronic progressive disease associated with increased morbidity and mortality, and is the leading cause of end-stage renal disease, or kidney failure.  As of 2008, over 200,000 people in the US were receiving chronic dialysis, or were living with a kidney transplant, as a result of diabetic kidney disease.  Diabetic kidney disease accounts for 30 to 40% of patients who are on renal replacement therapy in industrial nations.  The overall incidence of end stage renal disease due to diabetic kidney disease increased 2.5 times from 1990 to 2006.  This rapid increase is unfortunately projected to continue.  According to the US Center for Disease Control and Prevention (CDC), the prevalence of diabetics, currently about 10% of the US adult population, is projected to increase to between about 20-33% of US adults by 2050.  In addition to causing damage to the kidneys themselves, kidney function declines prior to end-stage disease dramatically increase the risk of cardiovascular events, such as heart attack and stroke, resulting in considerable morbidity and mortality.

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CTP-354 (previously C-21191) is a non-sedating subtype-selective GABA(A) modulator that represents a new therapeutic modality for the potential treatment of spasticity, neuropathic pain and anxiety.  Subtype selective GABA(A) modulators have the potential to retain the known beneficial actions of the benzodiazepines including spasmolytic and anxiolytic actions.  Benzodiazepines, which include well-known drugs such as Valium® and Xanax®, exert their effect non-selectively across the GABA(A) receptors. However, their use is often limited by undesirable effects such as sedation and ataxia. CTP-354 lacks agonist activity at the specific GABA(A) receptor subtype associated with those side effects.  In preclinical models CTP-354 preserves the desirable pharmacology of benzodiazepines with no apparent sedation at therapeutic doses.  Additionally, CTP-354 has demonstrated strong efficacy in preclinical models neuropathic pain.

CTP-354 has been selected as a lead development candidate and Concert is conducting preclinical studies to support the potential advancement of CTP-354 into clinical testing. In March 2012, Concert formed a collaboration with Fast Forward, a subsidiary of the National Multiple Sclerosis Society, to fund the preclinical advancement of CTP-354.

Spasticity

Spasticity is a debilitating aspect of multiple neurological disorders, including multiple sclerosis, spinal cord injury, stroke and cerebral palsy.  Spasticity is an abnormal increase in involuntary muscle tone caused by damage to the CNS and is characterized by painful muscle spasms as well as muscle stiffness and rigidity.  Spasticity affects motor performance, quality of life, activities of daily living and functional independence, e.g. mobility, feeding and hygiene. Severe spasticity can leave patients bed-ridden and unable to move without assistance.  According to We Move, less than 50% of patients with spasticity are adequately managed with current treatments.

Neuropathic Pain

Neuropathic pain, a specific type of chronic pain, results from dysfunction of the peripheral or central nervous system.  It is associated with a variety of etiologies, including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies.   An estimated 1.4 million people in the US per year are diagnosed with diabetic neuropathy, trigeminal neuralgia or post-herpetic neuralgia. Other causes include multiple sclerosis, post-stroke pain, HIV-associated pain, spinal cord injuries, herpes virus infection, and cancer.

Despite their side effects and risk of addiction, opioids often play a role throughout the acute and chronic phases of pain management.  Other agents that may be used during the chronic phase include anti-inflammatories, anti-depressants (tricyclic antidepressants and SNRI’s), muscle relaxants, and anti-convulsants, including clonazepam (a benzodiazepine).  Unfortunately, these options are frequently ineffective and/or are associated with limiting adverse effects (e.g., sedation, dependence, tolerance, etc).  As with spasticity, many patients do not achieve adequate relief with currently available agents.  With its unique profile, CTP-354 could provide an important new therapeutic approach to managing neuropathic pain.

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Intellectual Property Summary

Concert has >90 patent application families for new drug candidates addressing a broad range of therapeutic areas. All of these are wholly owned by Concert. The DCE Platform has resulted in 37 issued U.S. Patents and additional notices of allowances. Additionally, our patent portfolio includes numerous issued foreign patents. View list of U.S. Issued Patents.

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