While white blood cells are possibly the best-known heavy hitters of the immune system, the complement system—namely the protein C5—also plays a role in clearing unwanted cells or biological “invaders” from the body. However, as with cancer, when this system goes awry, it can have serious, detrimental results, resulting in inflammatory and autoimmune conditions such as Guillain Barré syndrome. At present, the one FDA-approved C5 inhibitor for such indications, Soliris (eculizumab), requires intravenous administration every two weeks, and some patients don’t respond to it. Akari Therapeutics is hoping to offer a new option with Coversin, a subcutaneously delivered C5 inhibitor derived from a protein in the saliva of the Ornithodoros moubata tick. Dr. Gur Roshwalb, CEO of Akari, discusses the therapeutic candidate and its implications with DDNews.
DDNews: The protein C5 usually splits into two variants that help to eliminate threats in the body. How does overproduction of C5’s variants damage the complement system to trigger inflammatory and autoimmune conditions?
Gur Roshwalb: The immune system has two fundamental tasks: identifying and then destroying foreign invaders. The complement system acts as a bridge between these two functions and works together with (i.e., in complement with) the immune system. For example, when the body develops an antibody to bacteria, that antibody can then trigger the complement system and at the end of this cascade, the complement system will create a cell membrane “bomb” (known as the membrane attack complex, or MAC) that blows a hole in the cell membrane of the antibody-targeted bacteria. This is known as the classical complement cascade. Unfortunately, the complement system is not specific, and if the antibody is against self, as in autoimmune diseases, this “bomb” will destroy our own cells.
DDNews: Coversin binds to C5 on a different site than eculizumab, correct? How do they compare in terms of mechanism of action and inhibition of complement C5 activity?
Roshwalb: Eculizumab binds to C5 and sterically inhibits the breakdown of C5 into C5a and C5b—these two end products, C5a and C5b, lead to the various effects of complement. As you noted, Coversin binds to a different epitope, but also sterically inhibits the breakdown of C5 into C5a and C5b. One feature of C5a worth noting is that C5a, as an anophylotoxin, promotes the generation of another protein called LTB4, and thus, decreasing C5a leads to a decrease in LTB4.
Coversin is a tick-derived salivary protein, and nature is very efficient. The epitope that Coversin binds to is conserved across mammalian species, and thus we can actually do animal studies (eculizumab only works on human C5). This has allowed Akari to do studies in more than 10 different animal models of disease, furthering our understanding of the role of complement inhibition and the potential in various disease states. Furthermore, the different binding site allows Coversin to work in patients who are eculizumab-resistant due to a polymorphism (first discovered in Japanese patients) that interferes with eculizumab binding. We are currently treating such a patient, and he has been under treatment for more than five months at this point.
What really differentiates the mechanism of action, however, is that not only does Coversin bind to C5 and inhibit the breakdown of C5 into C5a and C5b, but completely independently, it also binds to LTB4, thus further reducing the levels of LTB4, which acts as a neutrophil chemoattractant, bringing white blood cells to an area of inflammation. This is a really good example of nature being efficient—if reducing C5a is good, then adding LTB4 reduction directly is even better.
DDNews: Akari recently shared promising interim data from the ongoing Phase 1b trial featuring a once-daily dosing that has resulted in sustained complement inhibition, including 100-percent inhibition of complement C5 activity within 12 hours. Is once-daily dosing the ideal, or does your company have another goal in mind in terms of injection frequency?
Roshwalb: While we believe that once-daily dosing will be an advance for patients, we are also working on a once-weekly formulation that we hope to start testing in healthy volunteers in the third quarter of 2017.
DDNews: Akari has stated that it initially intends to advance Coversin in paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome and Guillain Barré syndrome (GBS), as well as patients who fail to respond to eculizumab. What kind of market need is there in these patient populations?
Roshwalb: There is a large market need, certainly in patients who fail to respond to eculizumab, like our currently treated PNH patient—for them, there is no other option. Even for patients who do respond to eculizumab, however, the potential for a once-daily subcutaneous injection can really make a difference in the quality of life. Patients no longer have to visit the clinic every two weeks for an IV, or hide from their work why they need to go to the doctor or take a morning off, or even worry about going on vacation and arranging for their next dose. Having an easy subcutaneous option empowers patients to feel in control of their disease; we have repeatedly heard from patients and key opinion leaders how important this is to them.
DDNews: Coversin has already received Orphan Drug Designation for treating GBS in the United States and the European Union, and recently got a positive opinion from the EMA for the treatment of PNH. What’s the timeline for hearing back on a final decision?
Roshwalb: It works differently in the U.S. and the EU. However, we have been confirmed for orphan designation for GBS in the U.S. and EU, and are awaiting the confirmation for PNH in the EU, which we expect shortly. While there are some pre-approval advantages (e.g., lower regulatory costs), the exclusivity benefit is only post-approval, and thus the orphan status will be confirmed (again) at approval.
DDNews: How are things progressing in terms of Akari’s development plan for Coversin?
Roshwalb: Very well, thank you. We have initiated our Phase 2 trial in PNH and look forward to potential topline results in several patients by year-end 2016 and starting our Phase 3 trial in mid-2017.
Gur Roshwalb, M.D., joined Akari’s management team as CEO in March 2013. Prior to that, he served as a vice president at Venrock from 2008 to 2013, working as an investment professional in the healthcare team that invested in private and public companies, and as a vice president and equity analyst at Piper Jaffray from 2004 to 2008. Roshwalb was in private practice and board certified in internal medicine in New York prior to his position at Piper.