The complement system is designed to kill pathogens through a signal cascade that results in cell lysis, removal of the pathogens through phagocytosis, and alerting other immune system cells to help with infections. Signals come from three different pathways – classical, lectin and alternative – culminating at the C3 protein of the cascade.

Unfortunately the complement system also can be uncontrollably activated in various autoimmune diseases, causing inflammation and cellular destruction.

For instance, hereditary angioedema (HAE) is a rare genetic disorder caused by deficiency of C1 esterase inhibitor, which tempers the pathway, reducing swelling after an infection. With limited inhibitor activity, HAE patients can have extreme swelling that’s potentially life-threatening if it occurs around the throat.

The space has been a hotbed for acquisitions with Shire plc, of Dublin, recently acquiring Exton, Pa.-based Viropharma to gain access to Cinryze (C1 esterase inhibitor). Raleigh, N.C.-based Salix Pharmaceuticals Ltd. also got its hands on an HAE drug, Ruconest (conestat alpha), through its acquisition of San Diego-based Santarus Inc. (See BioWorld Today, Nov. 11, 2013, and Nov. 12, 2013.)

Alexion Pharmaceuticals Inc. has found two uses for its complement system drug, Soliris (eculizumab). The monoclonal antibody binds to C5, a protein toward the end of the cascade that promotes cell lysis and inflammation. Soliris is approved to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) who have red blood cells deficient in complement inhibitors. The deficiency causes the red blood cells to undergo complement-mediated destruction, leading to anemia.

More recently, Cheshire, Conn.-based Alexion expanded Solaris’ indication to include the treatment of another complement-mediated blood disorder, atypical hemolytic uremic syndrome (aHUS), which can cause abnormal blood clots in kidneys.

COMPLEMENTING THE CURRENT OFFERINGS

HAE, PNH and aHUS are just some of the alphabet soup of diseases that act through the complement system, providing plenty of opportunities for small companies to find a niche.

Last year Ipierian Inc. spun out True North Therapeutics Inc. to focus on TNT009, a monoclonal antibody targeting C1s, part of the classical pathway of the complement system. (See BioWorld Today, Sept. 5, 2013.)

The South San Francisco-based company is still performing preclinical experiments to determine the best indications to begin clinical testing of TNT009.

One possibility is cold agglutinin disease (CAD), an autoimmune disease characterized by cold-mediated antibodies that attack red blood cells, leading to anemia. In an article in Blood, True North showed the response from auto-antibodies in CAD patients’ serum in an ex vivo assay could be inhibited by a murine analog of TNT009.

But True North is keeping its options open testing the drug in other complement-mediated diseases in the neurology, renal and immunology fields. The company plans to wrap up its broad campaign and have TNT009 in phase I trials next year.

“As a relatively young company, we’re keeping our minds open,” True North’s CEO Nancy Stagliano told BioWorld Insight. “We need to follow a path that’s the most streamlined to get this molecule into the clinic.”

Stagliano said that hitting the start of the classical pathway of the complement system will make TNT009 as effective as possible. Leaving the immune responses in the lectin and alternative pathways in place also could make the drug safer, although that’s only theoretical at this point since TNT009 hasn’t been tested in humans yet.

Amyndas Pharmaceuticals S.A. is working downstream at C3 where the three pathways collide. Its compstatin tightly binds to C3 and with a long half-life could be self-administered subcutaneously every 12 hours. The Philadlephia-based company plans to have the drug in phase I trials by the end of the year testing its ability to temper the immune response that causes rejection of kidney transplants and, if all goes well, start a phase IIa trial next year.

Amyndas also plans to test the drug in PNH patients. “One-third of the patients are not responding to eculizumab therapy from Alexion,” Amyndas’ founder John Lambris told BioWorld Insight. He said inhibiting upstream at C3 instead of C5 could increase the number of PNH patients who respond.

Likewise, Novelmed Therapeutics Inc. is hoping to unseat Alexion with plans to test one of its antibodies against complement-system proteins in PNH patients in phase I trials this year.

SEEING AN ALTERNATIVE

Cleveland-based Novelmed has developed a portfolio of antibodies against complement system proteins, potentially treating other diseases, including age-related macular degeneration.

Mutations in genes of the complement system, including C2 and C3 have been associated with AMD. Alexion’s Soliris, which attacks downstream of there at C5, has been tested in dry AMD, although the biotech hasn’t prioritized the indication.

Ophthotech Corp., of New York, is testing Zimura, which also targets complement factor C5 in wet AMD in combination with anti-VEGF therapy as well as the dry form of AMD.

Roche has successfully tested lampalizumab, which targets factor D – a component of the alternative pathway of the complement system – in patients with geographic atrophy, an advanced form of dry AMD. Phase II data released last year showed a 20.4 percent reduction rate in the area of geographic atrophy after 18 months of treatment.

Editor’s note: This article was originally published in BioWorld Insight, the weekly news service that provides behind-the-scenes analysis and commentary on the biopharmaceutical marketplace. Subscribe by calling (770) 810-3144 or (800) 477-6307 if calling from the U.S. or Canada or email bioworld at salessupport@thomsonreuters.com.