SBIR-STTR Award

More than 25 million people in the United States suffer from neuropathic pain. Currently available drugs include opioids, anti-epileptics, topicals such as lidocaine, NMDA antagonists, and tricyclic antidepressants, none of which achieve clinical significance greater than 50%. To address this problem of significant clinical need and poor clinical significance, new mechanisms of action must be identified for pain therapeutics. Genome-scale technologies such as gene expression microarray data have contributed an exponential amount of diverse biological information available to the public. The goal of this project is to analyze this data to generate new understanding of underlying biological mechanisms which can lead directly to a marketable pain therapeutic. Recently, many researchers have extracted biological pathway information from gene expression microarray experiments performed in-house. In order to take advantage of the much more diverse information contained in public microarray data, this proposal tests the feasibility of new methods to combine unstructured information from multiple public datasets to derive new insight on biological pathways underlying neuropathic pain. Newly associated pathway information is used to identify therapeutics which affect the identified pathway and which have been tested in man, but whose mechanism of action has not been previously associated with pain. The identified drugs will be validated in animal models. Since the identified therapeutic by definition is an IND, successful demonstration of efficacy in animals will lead directly to clinical phase 2 proof of concept in man during the SBIR Phase II renewal. Thus this project proposes a method to significantly reduce drug discovery and early development risk by triaging public gene expression data to progress directly to product identification and late stage clinical studies for pain therapeutics with new mechanisms of action. Neuropathic pain patients tend to become globally disabled and are heavy users of healthcare resources. Current therapies have limited efficacy and issues with side effects. The present project proposes a method to significantly reduce drug discovery and early development risk by triaging public gene expression data to progress directly to product identification and late stage clinical studies for pain therapeutics with new mechanisms of action

Neuropathic pain is a common complication of cancer, diabetes mellitus, viral infections, and other causes. Although physicians currently employ a variety of treatments to manage moderate to severe neuropathic pain, including non-steroidal anti-inflammatory drugs, opioids, tricyclic antidepressants, anti- seizure medications, serotonin-norepinephrine reuptake inhibitors, and others, many patients are still inadequately treated. The poor success with the currently approved agents has been attributed to both inadequate efficacy and dose limiting toxicity. This unmet clinical need has generated numerous efforts to identify novel therapeutic agents for the treatment of neuropathic pain, but most of these efforts have focused on identifying additional members of drug classes that have previously shown to have some efficacy in this area. Not surprisingly, many of these agents offer little improvement over what is already in use. By means of our proprietary technology, Aestus Therapeutics has identified new classes of substances that may prove effective in treating neuropathic pain by means of novel mechanisms. This approach is particularly promising for targeting the high percentage of patients who are refractory to established therapies. While there are many causes of neuropathic pain, postherpetic neuralgia (PHN) is a particularly useful model for investigating novel analgesic agents. PHN is commonly defined as persistence of the pain associated with herpes zoster for more than three months after resolution of the herpes zoster rash. In the United States more than one million new cases of herpes zoster are reported each year. The pain associated with PHN is typically moderately severe and poorly responsive to established therapies. The focus of our proposal is to conduct a clinical phase 2a proof of principle study to determine whether one of the identified products is likely to be effective at improving PHN pain when administered over a seven day period. A positive outcome of the study will enable us to commercialize the product by partnering with a large pharmaceutical company for late stage clinical studies, filing New Drug Application at FDA and market the product to the benefit of patients and society.

Public Health Relevance:
Neuropathic pain patients tend to become globally disabled and are heavy users of healthcare resources. Current therapies have limited efficacy and issues with side effects. By means of our proprietary technology a new class of compounds has been identified that may prove effective in treating neuropathic pain by means of novel mechanisms. This approach is particularly promising for targeting the high percentage of patients who are refractory to established therapies. The focus of the present project is to establish proof of concept in the clinic, focusing on patients suffering postherpetic neuralgia.

Thesaurus Terms:
1,2-Benzenediol, 4-(2-Amino-1-Hydroxyethyl)-, (R)-; 2-(Diethylamino)-N-(2,6-Dimethylphenyl)Acetamide; 2-2etn-2mephacn; 2-Diethylamino-2',6'-Acetoxylidide; 3-(2-Aminoethyl)-1h-Indol-5-Ol; 5-Ht; 5-Hydroxytryptamine; 5ht; Absence Of Pain Sensation; Absence Of Sensibility To Pain; Acute; Address; Adverse Experience; Adverse Effects; Adverse Event; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Analgesics; Animals; Anodynes; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-Epileptic; Anti-Inflammatory; Antidepressant Drugs, Tricyclic; Antidepressants, Tricyclic; Antidepressive Agents, Tricyclic; Antiepileptic Agents; Antiepileptic Drugs; Antiepileptics; Antiinflammatories; Antiinflammatory Agents; Antinociceptive Agents; Antinociceptive Drugs; Area; Blood Plasma; Blood Sample; Blood Serum; Blood Specimen; Burning Pain; Businesses; Cancers; Capital; Care, Health; Chronic Low Back Pain; Clinic; Clinical; Clinical Research; Clinical Study; Clinical Trials, Phase Ii; Development; Diabetes Mellitus; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type Ii; Diabetic Neuropathies; Diagnosis; Disabled Persons; Disabled Population; Dose; Dose-Limiting; Drug Kinetics; Drug Therapy; Drugs; Enteramine; Epileptiform Neuralgia; Esthesia; Evaluation; Exanthem; Exanthema; Feels No Pain; Fothergill Disease; Fothergill's Neuralgia; Future; Goals; Grant; Handicapped; Healthcare; Herpes Zoster; Herpes Zoster Disease; Hippophaine; Hour; Hyperalgesia; Hyperalgesic Sensations; Individual; Japan; Laboratories; Lead; Levarterenol; Levonorepinephrine; Licensing; Lidocaine; Lignocaine; Mody; Malignant Neoplasms; Malignant Tumor; Marketing; Maturity-Onset Diabetes Mellitus; Measures; Mechanics; Medical Inspection; Medication; Methods; Modeling; Monitor; N Methyl D Aspartic Acid; N Methyl D Aspartate; N-Methyl-D-Aspartate; N-Methylaspartate; Niddm; Nmda; Neuropathy; No Sensitivity To Pain; Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; Noradrenaline; Norepinephrine; Omega-Diethylamino-2,6-Dimethylacetanilide; Opioid; Outcome Study; Pbo; Pain; Painful; Pathway Interactions; Patients; Pb Element; People With Disabilities; Persons With Disabilities; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacodynamics; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Pharmacotherapy; Phase; Phase 2 Clinical Trials; Phase Ii Clinical Trials; Physical Examination; Physicians; Placebos; Plasma; Postherpetic Neuralgia; Process; Protocols, Treatment; Rgm; Rash; Refractory; Regimen; Reporting; Research Design; Research Resources; Resistance; Resolution; Resources; Reticuloendothelial System, Serum, Plasma; Risk; Running; Sbir; Sbirs (R43/44); Sched; Safety; Schedule; Seizures; Sensation; Serotonin; Serum; Serum, Plasma; Severities; Sham Treatment; Shingles; Skin; Skin Rash; Small Business Innovation Research; Small Business Innovation Research Grant; Societies; Staging; Stimulus; Study Type; Surface; Symptoms; T2d; T2dm; Tactile; Tactile Hyperalgesias; Technology; Testing; Therapeutic; Therapeutic Agents; Tic Douloureux; Time; Touch; Touch Sensation; Toxic Effect; Toxicities; Treatment Period; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treatment Side Effects; Tricyclic Antidepressive Agents; Trifacial Neuralgia; Trigeminal Neuralgia; Trigeminal Pain; Type 2 Diabetes; Type Ii Diabetes; United States; Viral Diseases; Virus Diseases; Work; Zona; Zoster; Adult Onset Diabetes; Allodynia; Analgesia; Base; Cancer Complication; Channel Blockers; Clinical Significance; Clinically Significant; Design; Designing; Diabetes; Diabetes-Associated Neuropathy; Disabled; Disabled People; Drug Discovery; Drug Market; Drug/Agent; Effective Therapy; Efficacy Trial; Heavy Metal Pb; Heavy Metal Lead; Herpes Zona; Hyperalgia; Improved; Inhibitor; Inhibitor/Antagonist; Instrument; Ketosis Resistant Diabetes; Malignancy; Maturity Onset Diabetes; Mechanical Allodynia; Member; Neoplasm/Cancer; Neuropathic; Neuropathic Pain; New Approaches; New Therapeutics; Next Generation Therapeutics; Novel; Novel Approaches; Novel Strategies; Novel Strategy; Novel Therapeutics; Painful Neuropathy; Pathway; Phase 2 Study; Phase 2 Trial; Phase Ii Trial; Post Herpetic Neuralgia; Protocol, Phase Ii; Public Health Relevance; Resistant; Response; Reuptake; Sham Therapy; Side Effect; Study Design; Study, Phase Ii; Success; Therapeutic Target; Therapy Adverse Effect; Treatment Adverse Effect; Treatment Days; Treatment Duration; Trifocal Neuralgia; Viral Infection; Virus Infection