The Need

HF afflicts ~6.5 million adults in US with 50% mortality in first 5 years. It has an estimated market size of $4.2B USD in US alone with a forecasted CAGR of 23% from 2018-2028. Current HF treatments are mostly aimed at alleviating symptoms rather than treatment, resulting in progressive cardiac dysfunction and LV remodeling. It is clear that inflammation and immune cell activation play a critical pathophysiological role in the development of HF. However, clinical trials aimed at neutralizing pro-inflammatory cytokines failed in HF patients and, paradoxically, showed increased mortality and morbidity, probably mainly due to two reasons: 1) cytokines exert highly non-specific and wide ranging effects on different cell types, some of which are necessary for healing, and 2) appropriate timing of immunomodulatory therapies may be critical to ensure appropriate healing. This analysis suggests that temporal modulation of selective pathological immune cells would be a better approach to manage HF. However, no such therapies exist in the clinics.

The Technology

Researchers at the Ohio State University, led by Dr. Shyam S. Bansal, have identified that CD4+ T cells undergo a pathological change during chronic HF, and studies in male mice showed that estrogen receptor (ER) α signaling plays an important role in promoting this pathological effect. In collaboration with the OSU’s Drug Development Institute, researchers identified a highly selective, non-steroidal small molecule ERβ agonist (OSU-ERb-012) that can functionally block the undesired effects of ERα. This novel molecule was designed and developed at the Ohio State University and is orally active, with no known side-effects at up to 200 mg/kg (oral dosing) in rodents. Activating ERβ signaling at a specific time-point during HF (which can be identified by systemic changes in T-cells) completely blunts left-ventricular remodeling and stops progressive cardiac dysfunction in male mice. Ex vivo and in vivo studies further confirmed that this drug selectively inhibited activated pro-inflammatory CD4+ T cells without affecting other immune cells such as macrophages, neutrophils, B-cells or CD8+ T cells. Ex vivo studies also showed similar effects on T cells isolated from female mice. Analogs of OSU-ERb-012 are in development.

Commercial Applications

• Pharmaceutical
• Medicine
• Small molecule
• Estrogen receptor signaling
• Heart failure

Benefits/Advantages

• Short synthetic route and novel
• High selectivity for Estrogen Receptor β (as non-steroidal agonist)
• High potency
• Orally active at easily translatable (10 mg/kg) doses
• Reversible effects and amenable to combination therapy

Patent Filing(s)

PCT/US2021/021909 and PCT/US2021/021903