Aminotrexate? (AMT) is an antifolate in the same class as MIX that we have established is nearly 100%orally bioavailable in humans with a lower interpatient coefficient of variation than MTX, and is much more rapidly taken up by cells and tissues. With regard to non-CNS toxicities and response to the antidote leucovorin, AMT is indistinguishable from MTX. Accordingly, we hypothesize (clinical hypothesis 1) that oral AMT will be efficacious in a greater maximum fraction of patients with moderate-to-severe psoriasis than oral MTX, and/or reach a particularlevel of symptom improvement quicker than after oral MTX. We have also discovered that at equipotent doses of AMT and MTX, human CSF and animal brain parenchyma accumulatesignificantly less AMT than MTX. As such, we also hypothesize (clinical hypothesis 2) that oral AMT will result in fewer patients with postdosing neurotoxicity,and/or patients experiencing less severe postdosing neurotoxicity. As a result, AMT may potentiallybe better tolerated, resulting in better long-term adherence to AMT compared to MTX. If a greater fraction of patients with respond to AMT than to MTX, and/or can be treated longer withoutbecoming intolerant to the side-effects, AMT could have a major impact on the standard of care in psoriasis and would have critical pharmacoeconomic consequences by obviating cost-intensive biologic treatments. This SBIR Fast-Track proposal aims to test the above hypotheses by conducting a series of two sequential Phase 2/3 clinical trials. In the first Phase 2 dose-findingclinical trial to be conducted in SBIR Phase I (36 subjects, 12 weeks per subject, 6-12 month enrollmentperiod), the Specific Aims will be to: (1):assess the safety of oral AMT in the treatment of moderate-to-severe plaque psoriasis; (2) establish the dose- response relationship of oral AMT in moderate-to-severe plaque psoriasis; and (3) determine if splitting the weekly dose over two tablets, given every 12 hours, is preferred over giving the fully weekly dose once, using PASI scoring and safety assessments. From the Phase 2 study results we will select the dose of oral AMT that results inmaximum efficacy and best time-to-response while not resulting in treatment-emergenttoxicities or intolerance. We will then carry this oral AMT dose forward into the Phase 3 double-blind, randomizedclinical trial to be conducted in SBIR Phase II (390 subjects, 26 weeks per subject, 30-36 month enrollmentperiod) to test AMT vs. MTX head-to-head via the followingSpecific Aims: (1) Compare the efficacy of oral AMT and oral MTX in the treatment of subjectswith moderate-to-severe plaque psoriasis who have not previouslyreceived MTX; and (2) Compare the safety and tolerance of AMT with MTX by comparing adverse events and laboratory parameters, expanded with a specific assessment of neurocognitive and CNS related-side effects of both drugs. The primaryefficacy end-point is improvementin area under the PASI-N curve at Week 26, where PASI-N is the mean percent reduction in the PsoriasisArea-and-Seve'rity Index (PASI). Secondary efficacy and neurocognitiveend-points include: proportion of subjects achievingPASI 50 and PASI 75 at Week 10 and Week 26; time to PASI 75 (Kaplan Meier); physicianGlobal Assessment (PGA); Dermatology Life Quality (DLQI), Psoriasis Symptom Assessment (PSA); and neurocognitive scores from MMSE, FAClT-Fatigue, and FACT/GOG-Ntx. At the conclusionof the Phase 2 and 3 clinical trials proposed herein, we aim to have the necessary efficacy and safety data requiredfor a Product License Application (NDA,) to the FDA for the use of AMT in psoriasis.
| Menter, Alan; Thrash, Breck; Cherian, Christina et al. (2012) Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter. J Pharmacol Exp Ther 342:696-708 |
| Cole, Peter D; Drachtman, Richard A; Masterson, Margaret et al. (2008) Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia. Cancer Chemother Pharmacol 62:65-75 |
| Vijayanathan, Veena; Smith, Angela K; Zebala, John A et al. (2007) High-performance liquid chromatography separation of aminopterin-polyglutamates within red blood cells of children treated for acute lymphoblastic leukemia. Transl Res 150:367-73 |
| Olivry, T; Paps, J S; Bizikova, P et al. (2007) A pilot open trial evaluating the efficacy of low-dose aminopterin in the canine homologue of human atopic dermatitis. Br J Dermatol 157:1040-2 |
