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More coverage on Coversin
NEW YORK—Akari Therapeutics Plc recently shared preclinical and clinical data in two indications that showcase Coversin’s bifunctional activity in targeting inflammatory pathways. Coversin, the company’s lead drug candidate, is a C5 complement inhibitor under evaluation in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Coversin inhibits both C5 and leukotriene B4 (LTB4) activity.
As Akari explains on its website, “LTB4 plays an important early role in the initiation and amplification of inflammation: it attracts and activates white blood cells in areas of inflammation. The roles that LTB4 plays in the amplification of immune responses are still emerging, but LTB4 activity has been implicated in diseases as diverse as asthma and COPD, blistering skin disease, pulmonary arterial hypertension, thrombosis, diabetes and metastatic cancer.”
As for C5, it is part of the complement system, which is closely associated with the innate immune system. Akari notes that the complement system “acts by triggering one or all of three processes: inflammation, cell destruction by lysis or thrombosis through interactions with the coagulation system. Together with white blood cells and antibodies, it marks organisms recognized as pathogenic for destruction, and then assists in this process by recruiting white blood cells and mounting a direct lytic (destructive) attack on foreign cells or on the body’s own cells that appear to be foreign due to dysregulation of the complement system or some other homeostatic mechanism.”
“Many inflammatory diseases are difficult to treat because of the involvement of multiple interconnected inflammatory pathways,” says Clive Richardson, interim CEO of Akari. “The combined inhibition of C5 and LTB4 presents a potential novel therapeutic option. The bifunctional modality of Akari’s Coversin could enable the company to target a growing range of orphan diseases with unmet need where both complement and leukotriene pathways are believed to be implicated.”
The recent results shared by Akari included preclinical data from a rheumatoid arthritis (RA) mouse model, which was tested at Harvard Medical School in the lab of Dr. Andrew D. Luster. The tests looked at the effectiveness of Coversin with C5 and LTB4 binding activity (PASylated) compared to PAS LTB4-Coversin, which binds solely to LTB4, and Zileuton, an approved leukotriene inhibitor. The PASylated version is designed to enable weekly subcutaneous dosing. The PASylated forms of Coversin and Zileuton were administered starting day four of the study and onwards, following the appearance of arthritis symptoms. PAS-Coversin’s double mode of action seemed to be more effective than the other two treatments, as it began reversing symptoms by day 10.
“The effect of Coversin (PASYlated) used therapeutically in our mouse model of rheumatoid arthritis was impressive, with apparent total disease reversal,” Luster noted in a press release. “This highlights that the novel strategy offered by Coversin of simultaneously blocking both C5 and LTB4 may make it an effective anti-inflammatory, and offers the potential to provide an alternative therapy for RA patients who are unresponsive to current marketed therapies.”
In an ex-vivo study in four patients with bullous pemphigoid (BP), conducted by Dr. Christian Sadik of the Department of Dermatology at the University of Lubeck, it was found that the blister fluid from BP patients presented with higher concentrations of LTB4 than the serum of healthy patients. Similarly, the detection of C5a in blister fluid implicates local activation of C5.
“The combined inhibition of C5 and LTB4 presents a potential novel therapeutic option. We believe that the bifunctional modality of Coversin could enable us to target a growing range of orphan diseases with unmet need where both complement and leukotriene pathways are believed to be implicated,” Richardson commented. “In the first quarter of 2019, we anticipate announcing Phase 2 clinical data in two trials that focus on this bifunctionality: BP, a blistering skin disease, and atopic keratoconjunctivitis, a severe allergic eye condition. The trials will be run in conjunction with our existing clinical program for the complement-mediated diseases paroxysmal nocturnal hemoglobinuria and atypical haemolytic syndrome.”
At present, there are no existing approved therapies that target both C5 and LTB4, Richardson tells DDNews, though he notes that “Soliris inhibits C5 and Zileuton inhibits the leukotriene pathway.”
At the end of September, Akari announced that it had inked a Securities Purchase Agreement with Aspire Capital Fund LLC worth up to $20 million. Per the agreement, Aspire has committed to purchasing up to $20 million of Akari’s American depositary shares at the latter’s request at given times during a 30-month period. That period will begin on the date of a registration statement for the transaction, and the purchases will be based on the market price at the time of each sale. In conjunction with this transaction, Akari has issued 30 million ordinary shares at $0.02 per share to Aspire as a commitment fee, and sold 25 million ordinary shares to Aspire at $0.02 per share, in addition to establishing a Registration Rights Agreement.
Akari noted in a press release that it intends to use the resultant funds for general corporate purposes, ranging from R&D and clinical trial work to working capital.
“This transaction provides Akari with efficient and opportunistic access to up to $20 million of equity funding to advance the company through key clinical milestones,” Richardson commented. “These funds are expected to allow Akari to complete three Phase 2 trials studies and, on the basis of this data, initiate potential pivotal trials in Bullous pemphigoid, Atopic keratoconjunctivitis and thrombotic microangiopathies. In addition, Akari will continue to develop Coversin for treatment of patients with paroxysmal nocturnal haemoglobinuria.”