SBIR-STTR Award

Direct to Phase II

Psoriasis is a chronic, genetically influenced, remitting and relapsing scaly and inflammatory skin disorder that affects 1-3% of the world's population, resulting in total annual costs of $5.2 billion in the United States in 2012. Approximately 20% of patients with moderate-to-severe chronic plaque psoriasis require phototherapy and/or a variety of systemic treatments, where methotrexate (MTX) is the mostly widely used oral systemic agent. Despite the relative effectiveness of MTX, as a monotherapy, it does not achieve greater than a 75% reduction in the baseline psoriasis area-and-severity index (PASI 75) in 40% of patients, and fails to achieve remission (i.e. > PASI 90) in 60% of patients. Furthermore, up to 30% of patients with moderate-to-severe plaque psoriasis discontinue oral MTX primarily because of intolerance to the drug. While much effort has been directed to identifying the mechanism behind poor and/or toxic responses to MTX based on genetic factor and quantitation of its active metabolites, the majority of MTX failures remain unexplained. Given the efficacy and safety limitations of MTX and the cost of biologics compared to MTX (~$20,000 vs. $300 per year), there is a clear market opportunity for an improved antifolate with better efficacy and/or safety than MTX, but that is priced between MTX and biologics. LD-Aminopterin (LD-AMT) is a patented composition developed by Syntrix Biosystems that studies indicate has greater cellular uptake (i.e. polyglutamylation to the active metabolites) than MTX, and less liver and CNS toxicity, properties that may translate into better efficacy and/or safety. In addition to identifying LD-AMT as a potential improvement on MTX, gaining a mechanistic understanding of antifolate resistance in general has important clinical implications for treating inflammation with LD-AMT or MTX, by possibly identifying clinical biomarkers to predict optimal response or risk of toxicity in advance of initiating treatment. This U44 Fast-Track proposal aims to advance LD-AMT to the clinic by testing LD-AMT for efficacy in a placebo-controlled phase 2 trial and advancing a novel hypothesis-driven mechanistic explanation for antifolate resistance.

Public Health Relevance Statement:


Public Health Relevance:
Psoriasis is a chronic scaly and inflammatory skin disorder that affects 1-3% of the world's population. Current treatments often involve the use of methotrexate (MTX), which is not effective in many patients or causes side effects, or exceedingly expensive biologic therapies that can cost $20,000 to $30,000 per year. This proposal aim to develop a drug, LD-aminopterin that is better than MTX and less expensive than biologics. Also, we aim to carry out studies that we hope will tell us how drugs like MTX and LD-aminopterin fail in patients.

Project Terms:
Affect; L-Glutamic acid, N-(4-(((2,4-diamino-6-pteridinyl)methyl)amino)benzoyl)-; Aminopteroylglutamic Acid; APGA; 4-Aminopteroylglutamic acid; 4-Aminofolic acid; Aminopterin; Biologic Assays; Bioassay; Assay; Biological Assay; biotherapy; biotherapeutics; Biological Therapy; Biologic Therapy; Biological Response Modifier Therapy; Clinical Study; Clinical Research; Deoxyribonucleic Acid; DNA; domestic dog; canine; Dogs Mammals; Dogs; Canine Species; Canis familiaris; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Lack of Energy; Fatigue; folate antagonist; Folic Acid Inhibitors; Folic Acid Analog; Folate Inhibitors; Folate Analog; Antifolates; Folic Acid Antagonists; guanosine 3'5' monophosphate; cGMP; Guanosine, cyclic 3',5'-(hydrogen phosphate); Guanosine Cyclic Monophosphate; Guanosine Cyclic 3',5'-Monophosphate; Cyclic GMP; head ache; Head Pain; Cranial Pain; Cephalodynia; Cephalgia; Cephalalgia; Headache; Modern Man; Man (Taxonomy); Human; In Vitro; indexing; Inflammation; bowel; Intestinal; Intestines; Isozymes; Isoenzymes; hepatic organ system; hepatic body system; Liver; Marketing; Methods; Metotrexato; Methotrexatum; Methotrexate Methylaminopterin; L-Glutamic acid, N-(4-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-; 4-Amino-4-deoxy-10-methylpteroyl-L-glutamic Acid; 4-Amino-10-methylfolic Acid; Methotrexate; mitochondrial; Mitochondria; Murine; Mice Mammals; Mice; Mus; Patents; Legal patent; Patients; Photoradiation Therapy; Light Therapy; Actinotherapy; Phototherapy; sham therapy; Sham Treatment; Placebos; Hydrogen Ions; H+ element; Protons; psoriatiform; psoriatic; psoriasiform; Psoriasis; Relapse; Rest; Risk; Safety; Skin Diseases and Manifestations; Skin Diseases; Dermatoses; Cutaneous Disorder; skin disorder; Testing; dTMP Synthase; Thymidylate Synthetase; TMP synthetase; EC 2.1.1.45; Thymidylate Synthase; Time; Translating; United States; 4-hydroxy-2-(1H)-pyrimidione; 2-hydroxy-4-(3H)-pyrimidione; 2,4-pyrimidinediol; 2,4-dioxopyrimidine; 2,4(1H,3H)-pyrimidinedione; Uracil; pricing; Price; Relative; Relative (related person); Restlessness; Psychomotor Restlessness; Psychomotor Hyperactivity; Psychomotor Excitement; Psychomotor Agitation; Agitation; Caring; base; Folate; improved; Area; Chronic; Clinical; Pharmacoeconomics; Pharmaceutical Economics; failure; FLR; Failure (biologic function); Disorientation; Memory Deficit; Memory impairment; hepatoxicity; Toxic effect on liver cells; Liver Toxicity; Hepatotoxic effect; Hepatotoxicity; uptake; phase II trial; phase II protocol; phase 2 trial; Phase 2 Clinical Trials; Phase II Clinical Trials; Genetic; Inflammatory; Psoriasis vulgaris; Plaque psoriasis; Nummular psoriasis; Discoid psoriasis; Chronic small plaque psoriasis; Severities; Oral; Clinic; Reaction; Nuclear; Remission; Disease remission; meetings; experience; enantiomer; placebo controlled trial; placebo controlled study; Toxicities; Toxic effect; novel; Reporting; LOINC Axis 2 Property; Property; response; treatment adverse effect; therapy adverse effect; side effect; Treatment Side Effects; Adverse effects; Effectiveness; DHFR; DHFR gene; Dose; in vivo; resistant mechanism; resistance mechanism; feelings; Feeling; Placebo Control; preclinical trial; pre-clinical trial; pre-clinical study; preclinical study; cost; Population; Coupled; resistant; Resistance; public health relevance; biomarker; biologic marker; Biological Markers; cellular development