Pre-clinical & Discovery Programs

In addition to zilucoplan and the Ra Pharma® collaboration with Merck, the Company has discovery and pre-clinical programs targeting selective inhibition of other complement factors, including Factor D administered by intravitreal injection for Dry Age-Related Macular Degeneration (AMD), Factor D administered SC for C3 Glomerulonephritis (C3GN) and Dense Deposit Disease (DDD), an oral, small molecule C5 inhibitor and C1s inhibitors for certain autoimmune and CNS diseases.

Factor D Inhibitor

C3 Glomerulonephritis/Dense Deposit Disease

C3 Glomerulonephritis (C3GN) and Dense Deposit Disease (DDD) are closely-related but distinct alternative pathway complement-mediated diseases characterized by C3 deposition in the kidney, with absent or minimal immunoglobulin deposition. The combined prevalence of C3GN and DDD is 1-3 per million individuals, with an estimate of approximately 1,000 patients in the United States. The clinical features of C3GN and DDD include compromised renal function and high blood pressure.

There are no approved therapies for C3GN or DDD. Patients are usually treated with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to modulate proteinuria, and with nonspecific immunosuppressants, including corticosteroids, when kidney inflammation is present.

Ra Pharma is developing specific inhibitors of Factor D as targeted drug candidates for C3GN. By blocking the alternative pathway upstream of C3, the Company believes this mechanism may prevent C3 deposition and subsequent renal injury.

Oral C5 Inhibitor

Ra Pharma® is actively pursuing the identification of orally-available inhibitors of C5 that bind to and inhibit targets in similar ways as the Company’s peptides, providing an additional option for the treatment of gMG. For example, Ra Pharma’s lead C5 inhibitor binds to a previously unrecognized site for inhibiting cleavage and activation of C5. With a long-term aim of developing a traditional small molecule inhibitor of C5 that can be delivered in pill form, Ra Pharma has developed an assay for high throughput screening of small molecule libraries for compounds that bind to the site defined by zilucoplan and related peptides.

This screening campaign has led to the identification of small molecules that bind to C5 at this site, inhibit cleavage, and inhibit red blood cell lysis in an in vitro assay. Small molecules and peptides that bind to other sites on C5 have yielded information on new mechanisms for C5 inhibition that are expected to contribute to a pipeline of highly differentiated, orally-available products.

C1s Inhibitor

Inappropriate C1s and classical complement convertase activity is linked to a variety of immune complex-mediated indications, including cold agglutinin disease, warm autoimmune hemolytic anemia, systemic lupus erythematosus, antibody-mediated rejection (such as with kidney transplant), Guillain-Barre Syndrome, neuromyelitis optica, gMG, multiple sclerosis, bullous pemphigoid (a rare and debilitating skin disease), and other diseases. Furthermore, inappropriate activity of the C1q-C1r-C1s complex and C4 levels has been implicated in a variety of neurologic conditions, including Alzheimer’s disease, Huntington’s disease, spinal muscular atrophy, frontal temporal dementia, glaucoma, and schizophrenia.

Ra Pharma® is using this platform technology to generate cyclic peptides that bind C1s and inhibit the protease activity of C1s, C4b production, and red blood cell lysis in an in vitro assay. The Company expects C1s inhibitors to have broad utility in a number of disease areas.