Many currently available therapies for autoimmune disease are marked by low remission rates and limited duration of efficacy, leading to inadequate control of disease for many patients. Treatments may also result in significant side effects and safety issues, including global immune suppression, making them poor options for long-term treatment, early stage intervention, or use in combination therapy. Over time, persistent autoimmune disease can cause patients to develop serious and life-threatening complications such as fibrosis, for which very few therapies are available.

Lycera’s novel immune suppressor portfolio positions the company to have a significant impact in treating autoimmune disease. The Company’s programs originate from several important areas of research, including immune metabolism, cell signaling, and immune cell differentiation, and are anticipated to dampen or suppress auto-immune reactions. These agents have been shown to be beneficial in several widely-accepted models for autoimmune disease, as well as in human translational systems, acting through pathways directly involved in immune regulation.

Lycera’s lead immune suppression program originates from our deep expertise in immune metabolism, a field of biology focused on how energy is made and utilized. Unlike normal cells, disease-causing immune cells have metabolic abnormalities that sensitize them to modulation of the mitochondrial enzyme F1F0-ATPase. Lycera has developed proprietary compounds targeting this enzyme in order to selectively induce cell death (apoptosis) of chronically activated disease-causing immune cells, while sparing normal immune cells that fight infection. ATPase modulators are unique, first-in-class drugs with the potential to treat a broad spectrum of conditions. Such drugs are designed to have significant advantages over existing products, including broad efficacy, fewer side effects, and an absence of global suppression.

LYC-30937-EC for Inflammatory Bowel Disease (IBD)

Lycera’s clinical candidate in this area is LYC-30937-EC, an orally administered ATPase modulator designed as a gut-directed therapy for the treatment of (IBD). Local delivery to the site of disease in IBD has the potential to achieve improved efficacy versus systemic agents. By combining localized activity with selective action against disease-causing immune cells, LYC-30937-EC is expected to exhibit fewer serious side effects than drugs currently administered systemically to treat IBD.

In preclinical models of acute and chronic IBD, Lycera’s ATPase modulators have displayed consistent and reproducible activity. In human translational research, ATPase modulators have effectively targeted and depleted pathogenic immune cells resident in tissue samples from patients with IBD and improved histology at the site of disease. In December 2015, Lycera completed a randomized, double-blind, placebo-controlled, single and multiple ascending dose Phase 1 study in healthy volunteers to evaluate safety, tolerability, pharmacokinetics, and food effect of LYC-30937-EC.

In August of 2016, Lycera announced the initiation of a Phase 2 clinical trial for LYC-30937-EC, in patients with ulcerative colitis (UC). The UPSTART study (Ulcerative Colitis Phase 2 Study TAssess Remission by Treatment with LYC-30937-EC) is expected to enroll up to 120 patients and is designed to assess the efficacy and safety of LYC-30937-EC given orally once daily in subjects with active ulcerative colitis. Patients will be randomized on a 1:1 basis to receive either treatment with LYC-30937-EC or placebo. Subjects will be treated for 8 weeks, with an additional 2-week safety follow-up. The primary efficacy endpoint will be the proportion of subjects who achieve clinical remission at Week 8 using a modified Mayo score (MMS), while safety will be measured over 10 weeks.  Continuation of treatment will be offered to participants in a separate open label extension study.

LYC-30937-EC for Psoriasis and other autoimmune diseases

The migration of lymphocytes from immune cell-rich tissues to target organs in autoimmune disease has been referred to as the ‘hub and spoke’ model of autoimmunity1. Approximately, 70% of the human immune cells traffic through the gut which could include chronically activated lymphocytes in patients with autoimmune diseases. Lycera will investigate whether the gut-directed therapy LYC-30937-EC can deplete these trafficking inflammatory cells.

LYC-30937-EC achieves high local drug concentrations in GI tissue with very low systemic exposures. Migration of lymphocytes through the gut has been demonstrated at both steady state and in animals with experimental models of inflammation2. Studies with ATPase modulators with low systemic exposures following oral administration have demonstrated efficacy in an animal model of psoriasis and other systemic autoimmune diseases. Thus, it is hypothesized that inducing apoptosis of chronically activated, pathogenic lymphocytes trafficking to the gut would eliminate these cells before they can migrate to the distal tissue (ie, the skin in psoriasis) and cause disease.

Lycera’s Phase 2 study UPRISE (gUt-directed LYC-30937-EC study in Psoriasis as oRal treatment for auto-Immune diseaSE), is a randomized, double-blind, placebo-controlled parallel group trial designed to assess the efficacy and safety of LYC-30937-EC given orally once daily in subjects with moderate psoriasis. The study is expected to enroll up to 30 patients, randomized on a 2:1 basis to receive either treatment with LYC-30937-EC or placebo. Subjects will be treated for 12 weeks, with an additional 2-week safety follow-up. The primary efficacy endpoint will be the change in mean PASI Score and Investigator global assessment; safety will be measured over 14 weeks. If successful, the potential therapeutic value of LYC-30937-EC in rheumatoid arthritis, multiple sclerosis and other autoimmune diseases could be explored.

1 Steinman, et al. Nat Med (2013) V.19 N.2 P.139

2 Lycera Corp. Data on file

 

Publications for ATPase Modulators

2016 European Crohn’s and Colitis Organization (Oral): Targeting Immune Cell Metabolism: LYC-30937. A Novel Therapeutic Approach for Inflammatory Bowel Disease. L. Carter, R. Morgan, C. Lesch, M. Spahr, L. Franchi, I. Monteleone, G. Monteleone, G. Glick, H.J. Wilkins, P. D. R. Higgins


Digestive Disease Week 2014 (Presentation). Modulation of the F1F0-ATPase Induces Apoptosis of Mouse and Human Lamina Propria T-cells and Is Efficacious in Models of IBD. Luigi Franchi, Ivan Monteleone, Rodney Morgan, Anthony W. Opipari, Laura Carter, Gary Glick, Giovanni Monteleone


Digestive Disease Week 2014 (Poster). F1F0-ATPase Modulation Is Efficacious in Models in IBD and Induces Apoptosis of Human CCR9+ Gut-Tropic T-cells. Luigi Franchi, Kelan A. Hlavaty, Ivan Monteleone, Rodney Morgan, Kelli Porzondek, Brian Sanchez, Charles Lesch, Mark A. Spahr, Corrin Hepburn, Anthony W. Opipari, Giovanni Monteleone, Gary Glick, Laura Carter, Peter D. Higgins


E. Gatza, D.R. Wahl, A.W. Opipari, T.B. Sundberg, P. Reddy, C. Liu, G.D. Glick, J. L.M. Ferrara. “Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft versus host disease,” Science Translational Medicine, 2011; 3: 67ra8.


D.R. Wahl, B.Petersen, R. Warner, B.C. Richardson, G.D. Glick, A.W. Opipari. “Characterization of the metabolic phenotype of chronically activated lymphocytes,” Lupus, 2010; 19: 1492.