Akari Therapeutics plc's interim CEO and chief operating officer, Clive Richardson, told BioWorld that the company plans to enroll more seriously afflicted bullous pemphigoid (BP) patients in the phase II trial that has yielded positive results in three subjects treated with the firm's once-daily subcutaneous therapy, nomacopan (previously known as coversin), based on a protein originally discovered in the saliva of the Ornithodoros moubata tick. "Hopefully on the back of that expanded trial we would go to the FDA early next year and agree with them [on] what would be the pathway to a pivotal study," he said.

Wall Street liked Akari plenty, as shares of the firm (NASDAQ:AKTX), which has offices in New York and London, closed Tuesday at $3.88, up 53 cents or 15.8%, after trading as high as $5.04. BP, an orphan inflammatory skin disease that involves the formation of large, fluid-filled blisters on the skin, today is treated mainly with steroids and immunosuppressants; flares and relapses often afflict patients, not to mention the side effects of such therapies.

The phase II study enrolling up to nine mild to moderate BP patients is a six-week open-label single-arm experiment testing safety, with the main efficacy measure the commonly used Bullous Pemphigoid Disease Area Index (BPDAI). By days seven, 21 and 42 of treatment, the BPDAI global score fell by a mean of 31%, 45% and 52%, respectively. Measured at the same days, blisters/erosions dropped by a mean of 45%, 75% and 87%, respectively.

A second-generation complement inhibitor, nomacopan was discovered about 10 years ago by Akari's chief scientific officer, Miles Nunn, and acts on complement component C5, preventing release of C5a and formation of C5b9 (also known as the membrane attack complex, or MAC), while independently inhibiting leukotriene B4, or LTB4, activity, both elements that are co-located as part of the immune/inflammatory response. "The salivary glands of ticks are enormous," Richardson said. "They're probably the size of your lungs in proportion to their body area. Before they start sucking up your blood, they inject into you all these proteins that do various different things," including tamp down the immune system so the victim doesn't feel the puncture. Such proteins were screened to find nomacopan with its "clever" mechanism of action, tightly binding to separate sites, he said.

The compound also is being investigated in phase II and phase III studies in indications that include: atopic keratoconjunctivitis, a sight threatening surface of the eye condition; thrombotic microangiopathies including atypical hemolytic uremic syndrome and hematopoietic stem cell transplant-associated thrombotic microangiopathy; and paroxysmal nocturnal hemoglobinuria. "We think of it as a sort of platform molecule" that lends itself to engineering for various purposes, he said. In eye disease, the compound has been developed as an eye drop; in lung disorders, it can be nebulized.

But this week the stock booster was BP, a "horrible" disease with unmet need, Richardson said. The National Organization for Rare Disorders (NORD) describes BP as less commonly involving mucous membranes in the eyes, oral mucosa, esophagus and genital mucosa. The condition typically presents in older adults as a generalized, intensely itchy blistering skin condition, and the first symptom is usually redness and itching. Within weeks to months, thin-walled, tense blisters with clear fluid centers, or bullae, appear on the arms and legs, in the armpits, on the abdomen, and/or in the skinfolds of the groin. The blisters are usually tense and contain clear or blood-tinged fluid; they do not rupture easily with gentle contact. BP affects males and females in equal numbers, according to NORD, striking primarily the elderly, with an average age around 80 years old. Rare cases have been reported in infants and adolescents. Recently, researchers have learned of an association between BP and neurological disorders. About one-third to a half of all BP patients have neurological diseases such as dementia, Parkinson's disease, stroke, epilepsy and multiple sclerosis – conditions that normally occur before the onset of BP.

More sites open soon

Richardson said that, for some of the smaller, orphan indications, Akari might take the compound all the way to commercialization alone. "The most probable route would be to partner," however, he said. "One wants to keep one's options open."

Another player in BP was Fort Lee, N.J.-based Immune Pharmaceuticals Inc., which in October of last year disclosed more results from its positive, proof-of-concept phase IIa trial with the eotaxin-1-targeting, fully human monoclonal antibody bertilimumab in the indication, including pharmacokinetic (PK), pharmacodynamic and anti-drug antibody data. No anti-drug antibodies were observed in any subject at any timepoint, the company said, and the PK profile of bertilimumab in elderly BP patients proved similar to the profile observed in young, healthy volunteers and supported a once every other week dosing regimen. The mean serum concentration of autoantibodies to BP180 (type 17 collagen), important in the pathogenesis of BP, declined over the course of the study. In three subjects who experienced flares during the study, BP180 autoantibody levels rose during the episodes. (See BioWorld, Sept. 28, 2017.)

So far, so good. By December, though, the firm had engaged Extera Partners to lead the effort to secure a partnership for bertilimumab, and in February of this year Immune filed for Chapter 11 bankruptcy. Despite making significant progress toward a bertilimumab strategic transaction, the company said – partnering talks had yielded term sheets – officials were not able to negotiate terms for funding to provide several months' runway needed to clinch a deal. An expected $3 million in financing and the signing of a Ceplene (histamine dihydrochloride) pact, with a first payment of $2.5 million, failed to materialize.

In November, Immune had entered an agreement with New York-based Vector Therapeutics Inc. that gave the latter an option to acquire worldwide rights to Ceplene, a NOX2 inhibitor that enables low-dose aldesleukin to activate natural killer cells and T cells in order to prevent relapse in acute myeloid leukemia (AML) patients who have achieved first complete remission. The EMA confirmed the approval of Ceplene in July 2018 for the maintenance of first complete remission in patients with AML following the review of additional clinical studies.

Akari marches on. Richardson said six BP trial sites are open with two more to become operational shortly, as the firm explores the possibilities of a recombinant small protein (16,740 Da) taken from the lowly tick. "Sometimes we say [the firm's candidate] has had 300 million years of product development," he said.