Scientific Overview

Vitamin D Receptor:

Calcitriol (1,25(OH)2D3), the active metabolite of vitamin D and 25D3, is a secosteroid hormone that, by activating vitamin D receptor (VDR), modulates multiple signaling pathways in a cell and tissue-specific manner.

A large body of data show that VDR agonist (VDRA) therapy can reduce proteinuria and slow kidney disease progression in chronic kidney disease (CKD) patients receiving the current standard of care (e.g. ACE inhibitors or ARBs) and, more importantly, provide cardiovascular and survival benefits for CKD patients.

VDRAs such as calcitriol and its pro-drug, 1α-hydroxyvitamin D3 (alfacalcidol), have been used as therapeutic agents for osteoporosis since 1983 in many ex-US countries. It is well documented that these drugs increase bone mineral density (BMD) and reduce the incidence of bone fracture in patients with osteoporosis. More recently (in 2011), eldecalcitol, a new VDRA, was approved for the treatment of osteoporosis in Japan.

Despite encouraging data on VDRA’s benefits for various indications, currently VDRA therapy is mainly indicated for managing secondary hyperparathyroidism (SHPT) in CKD, and to a lesser degree is used to treat osteoporosis and psoriasis. The reason for this is partially due to the narrow therapeutic window of current VDRAs in the 1-4-fold range as determined by comparing doses required for efficacy vs. hypercalcemic toxicity. Hypercalcemia is a serious side effect. Consequently, on-the-market VDRAs require frequent serum calcium monitoring and dose adjustment to minimize hypercalcemia.

This is a $>5B market in need of a novel VDRA that is highly efficacious with minimal side effects to achieve desirable efficacy for multiple indications.

Phosphate Imbalance

Phosphate imbalance in CKD can lead to various pathologies of clinical importance such as further deterioration of kidney function, cardiovascular complications, renal osteodystropy, and increased mortality. There is a robust association between serum phosphorous levels and all-cause mortality in dialysis CKD.

A majority of currently available oral phosphate binders work by binding phosphate in the gastrointestinal tract, leading to less phosphate to be absorbed into the body. Current therapy has the following shortcomings: (1) suboptimal and inefficient phosphate binding, (2) high pill burden (large number of pills per day), unpalatable and hence low compliance, (3) side effects and safety concerns.

This is a >$1.5B market in need of an efficacious novel binder with minimal side effects to achieve desirable efficacy for managing phosphate imbalance associated with CKD.