Research and Development Initiatives

Dual Acting Receptor Agonist (DARA)

In February 2009, Ligand announced positive preliminary results from the Phase IIb study for PS433540, the first-in-class Dual Acting Receptor Agonist (DARA) that targets the angiotensin and endothelin receptors. In May 2009, Ligand presented DARA Phase IIb results at the American Society of Hypertension Annual Meeting. Both the 400 mg and 800 mg doses of DARA produced statistically significant better blood pressure control than irbesartan, a current standard of care.

The 261-patient, randomized, double-blind, placebo- and active-controlled study evaluated safety and efficacy at three different doses in subjects with Stage 1 and Stage 2 hypertension over 12 weeks of treatment. PS433540 was found to be safe and well tolerated and demonstrated statistically significant greater reductions in blood pressure than placebo. The high dose of PS433540 produced a statistically significantly greater reduction in blood pressure than the active comparator, irbesartan which was tested at its highest approved dose.

Selective Androgen Receptor Modulators (SARM) Program

Tissue-selective SARMs is a novel class of non-steroidal, orally active molecules that selectively modulate the activity of the androgen receptor in different tissues, providing a wide range of opportunities for the treatment of many diseases and disorders in both men and women. Tissue-selective androgen receptor agonists may provide utility in the treatment of patients with frailty, cachexia, osteoporosis, sexual dysfunction and hypogonadism. PS178990, previously a Pharmacopeia program, is highly potent in animal models suggesting that low doses may be adequate to treat patients, thereby providing flexibility for drug delivery. LGD-4033 is a novel SARM mechanism demonstrating full agonist activity on muscle and bone versus partial agonist activity on prostate and sebaceous glands. In January, the FDA notified Ligand that it had completed the review of Ligand’s Investigational New Drug (IND) application and that the company could proceed with clinical testing for LGD-4033, a selective androgen receptor modulator (SARM). Ligand initiated a Phase I trial for LGD-4033 in June 2009.

Erythropoiein (EPO) Research Program

We are developing small molecule agonists for the EPO receptor. EPO stimulates the differentiation of blood marrow stem cells to form red blood cells. Various recombinant human EPO derivatives are marketed for the treatment of anemia due to renal failure or cancer chemotherapy (e.g., Aranesp, Epogen, Eprex, and Procrit). We believe that a small molecule agonist for the EPO receptor would provide additional benefit in the treatment of anemia and the convenience of oral administration compared to recombinant human protein therapeutics. EPO and TPO act on the same bone marrow hematopoietic stem cell to guide the development of blood cells. We expect that our prior experience in developing small molecule TPO mimetic drugs will lead to increased efficiency in discovering small molecule EPO mimetic drugs.

Chemokine Receptor (CCR1)

Ligand is conducting preclinical development from the internal chemokine receptor CCR1 program. PS031291, previously a Pharmacopeia program, is a potent and highly selective antagonist at the chemokine receptor CCR1, which has been implicated in playing a significant role in multiple inflammatory and autoimmune disease processes. Ligand believes that PS031291 has potential in the treatment of various inflammatory diseases, including rheumatoid arthritis.

Wyeth - JAK-3

Ligand is in collaboration with Wyeth to conduct research, and to develop and commercialize JAK-3 kinase inhibitors for the treatment of immunological conditions. The inhibition of JAK3 kinase has been shown to modulate disease outcomes in both preclinical animal models and clinical studies. Potential indications for an inhibitor of JAK3 include rheumatoid arthritis, transplantation and psoriasis.