DUBLIN – Swiss orphan drug developer AB2 Bio Ltd. has obtained dramatic clinical proof of concept for its recombinant interleukin-18-binding protein (IL-18BP) therapy (tadekinig alfa), in an exceptional case involving an infant girl at risk of death from severe systemic inflammation.

"The baby was really in a critical condition. She had massive systemic inflammation. She was not expected to live," Andrew Sleight, CEO of Lausanne, Switzerland-based AB2 Bio, told BioWorld Today. Therapy was initiated on a compassionate-use basis in June at the Children's Hospital of Philadelphia. She was discharged from the hospital in early August and by September she was reported to be in full remission.

AB2 Bio's assay, which selectively measures freely circulating IL-18, detected extremely high levels of the pro-inflammatory cytokine in the baby's serum. "We did expect her to respond to therapy, because she fulfilled the criteria of the assay," Sleight said.

Her phenotype corresponded with a gain-of-function mutation in a gene encoding nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4). The receptor, part of the inflammasome complex, normally needs to be activated by a danger signal – such as bacterial flagellin – to activate caspase-1 in turn. Its constituent activation leads to caspase-1-mediated processing of IL-1beta and IL-18 precursors into their active forms.

Ongoing work led by Scott Canna and Raphaela Goldbach-Mansky at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and by Richard Lifton and Barbara Irene Kazmierczak, both of Yale School of Medicine in New Haven, Conn., had previously linked several NLRC4 mutations with cases of severe autoinflammation, including macrophage activation syndrome, a frequently fatal complication.

Each group reported their findings in the October 2014 issue of Nature Genetics, in papers respectively titled: "An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome" and "Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation."

AB2 Bio is focused on rare inflammatory conditions that result from an excess of IL-18. "The science is driving the selection of disease," Sleight said. In healthy individuals, most IL-18 is bound to IL-18BP. Free IL-18 only becomes elevated when the inflammasome becomes activated in response to infection. Administering exogenous IL-18BP mops up the excess cytokine.

The company's edge lies in its assay, which works as a companion diagnostic, predicting those patients who are likely responders to its therapy. "The [other] assays that are available measure all IL-18, be it freely circulating or bound to IL-18-binding protein," Sleight said. AB2 Bio's assay is based on the standard Elisa format – it selectivity stems from the capture antibody it employs, which recognizes unbound IL-18 only.

The company's recombinant IL-18BP drug is midway through a phase II open-label trial in adult onset Still's disease, a debilitating inflammatory condition characterized by high spiking fevers, transient salmon-colored rash, sore throat, joint pain and swelling. The endpoints include patient- and physician-reported assessment, as well as impacts on inflammatory biomarkers, including C-reactive protein and ferritin.

AB2 Bio plans to begin a pivotal trial in the second half of next year, which should be completed in 2018. "Because the disease is genetic, potentially fatal and occurs in very young children we believe we have a very good chance to get breakthrough designation status," Sleight said. Other potential indications include chronic obstructive pulmonary disease, dry eye disease and prevention of ischemic reperfusion injury in kidney transplant patients.

London-based Glaxosmithkline plc previously conducted trials of GSK1070806, an anti-IL-18 monoclonal antibody, in patients with obesity and type 2 diabetes, but that program is no longer active. Novartis AG, of Basel, Switzerland, has developed Ilaris (canakinumab), which targets IL-1beta. another caspase-1-processed cytokine. It has FDA approval for treating systemic juvenile idiopathic arthritis and cryopyrin-associated periodic syndromes, a spectrum of autoinflammatory syndromes associated with mutations in NLRP3, the gene encoding the inflammasome protein NALP3.

The company was established in 2010 but has, until now, operated below the radar screen. It has already raised CHF30 million (US$29.6 million) from institutional investors, family offices and high-net worth individuals. "We have no venture capital investment in the company," Sleight said. The company will shortly close a "substantial" series B round, which, again, does not involve any VC money. In that respect, it is taking a leaf out of the playbook of company Chairman Andrea Pfeifer, who is CEO of Alzheimer's disease drug developer AC Immune SA, of Lausanne.