Has the future of complement therapeutics arrived?
Silence Therapeutics, a pioneer in the development of novel small interfering RNA (siRNA) therapeutics, and Mallinckrodt plc, a global biopharmaceutical company, announced the submission of a clinical trial application (CTA) for SLN501, a siRNA therapy targeting the complement C3 protein, on March 23, 2022. Silence will receive a $3 million milestone payment from Mallinckrodt as a result of the clinical trial application.
RNA interference (RNAi) involves the use of siRNAs to silence messenger RNAs (mRNAs), molecules that carry genetic instructions for producing specific proteins with specific functions in the body. When mRNA is produced from a mutated gene or when the body produces too much of a certain mRNA, it affects the production of its corresponding protein, which can cause adverse effects and/or disease.
Complement was discovered in 1890 by the Belgian immunologist Bordet, and it aided and complemented specific antibodies to kill microorganisms, hence the name Complement. Since the discovery, research on the complement system and its drug development has never stopped. However, it was not until 2007, when the first C5 complement inhibitor, Sorilis®, developed by Alexion, was approved for marketing, that complement drugs became available. To date, there are still only a handful of complement drugs on the market.
Complement is a group of enzymatically active globulins found in human and animal blood, tissue fluid, and cell membrane surfaces that "replenish" antibodies to kill microorganisms. These glycoproteins are normally present in the plasma in an inactive state, and only when triggered by activating substances do they exhibit various biological functions and participate in immunopathological reactions.
However, abnormal complement activation can lead to excessive complement depletion, attack on own normal cells, and release of a large number of inflammatory response mediators, which induces an immune inflammatory response, thus causing damage to the organism.
The complement system is involved in the progression of many diseases, and complement activation is associated with several common autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), ophthalmic diseases such as uveitis and glaucoma, renal diseases including C3 glomerulopathy, atypical hemolytic uremic syndrome and IgA nephropathy, rare diseases such as central nervous system (CNS) and peripheral nervous system (PNS) in Alzheimer's (AD), and hematological diseases including paroxysmal sleep hemoglobinuria and thrombotic microangiopathy.
Despite the large number of diseases that require modulation targeting the complement system, only a few rare diseases are currently approved for clinical treatment targeting complement, such as paroxysmal sleep hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica.
Mallinckrodt's President and Chief Executive Officer, Mark Trudeau, stated, "We remain excited about the tremendous potential that exists for Silence's mRNAi GOLD™ platform to treat patients suffering from a range of complement-mediated diseases. We look forward to bringing our first complement candidate, SLN501, into the clinic in the first half of this year and making progress on our other two complement targets."