DUBLIN – Boehringer Ingelheim GmbH is bringing another drug mechanism to bear on nonalcoholic steatohepatitis (NASH), by exercising an option to in-license PXS4728A, a dual semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) inhibitor from Pharmaxis Ltd. for €27.5 million (US$31.4 million) up front with about $570 million more to come in milestones.
The total deal value is tied to approval of the product in two indications, with NASH and chronic obstructive pulmonary disease (COPD) in the frame at present. Up to €55 million is available for phase II and phase III trial starts and up to €140 million more is on the table for regulatory filings and approvals and reimbursement in a first indication. Similar sums are tied to development and regulatory milestones in a second indication. Pharmaxis, of Frenchs Forest, Australia, would also receive sales-based earn-outs and commercial milestones.
The deal is Ingelheim, Germany-based Boehringer's entry ticket to what is already a very crowded game. Around a dozen development programs are already under way, involving almost that number of targets and drug mechanisms. The wide variety of approaches that is being explored points both to the immaturity of the area from a drug development perspective and its increasing prevalence as a public health problem.
NASH is characterized by the presence of fat deposits in the liver in the absence of high levels of alcohol consumption. Obesity and type 2 diabetes are common co-morbidities, and the condition can lead to fibrosis and cirrhosis, but the precise pathophysiological mechanisms underlying this complex condition are not fully understood.
Right now, Intercept Pharmaceuticals Inc., of New York, is at the front of the pack, having reported positive phase IIb data for obeticholic acid (OCA), a bile acid analog, last year, which it has since supplemented with numerous subgroup analyses. (It is planning an NDA for the same drug in primary biliary cirrhosis in the current quarter.) OCA works as an agonist of farnesoid x receptor (FXR), and it demonstrated statistical significance in reducing the disease activity, although it has also elicited concerns over raised LDL cholesterol levels.
In its recent quarterly results statement, Conatus Pharmaceuticals Inc., of San Diego, said it was meeting FDA officials to discuss a registration pathway for emricasan, a pan-caspase inhibitor, on which it has reported more limited phase II subgroup data.
Also focusing on FXR is Foster City, Calif.-based Gilead Sciences Inc., which acquired a program in the area from Phenex Pharmaceuticals AG, of Ludwigshafen, Germany. (See BioWorld Today, Jan. 7, 2015.)
Gilead has a second NASH program, already in the clinic, a phase II antibody called simtuzumab, which inhibits lysyl oxidase-like-2 (LOXL2), an enzyme that alters the extracellular matrix by promoting the cross-linking of collagen fibers.
Genfit SA is targeting two nuclear receptor isoforms, peroxisome proliferator-activated receptors α (PPARa) and PPARδ, with GFT-505. A recent read-out from a phase IIb trial was mixed – the drug demonstrated efficacy but it failed to reach statistical significance because, the company said, of a high placebo response. (See BioWorld Today, March 27, 2015.)
Dublin-based Shire plc gained SHP626 (LUM002) through its acquisition of San Diego-based Lumena Pharmaceuticals Inc. 12 months ago for $260 million up front, plus milestones. The drug inhibits apical sodium-dependent bile acid transporter (ASBT), which is involved in recycling bile acids from the small intestine to the liver. It has yet to start a phase II trial.
Medicinova Inc., of La Jolla, Calif., recently gained FDA fast track designation for MN-001 (tipekulast), which has both anti-inflammatory and anti-fibrotic effects and acts on the 5-lipoxygenase/leukotriene pathway.
VAP-1 is an adhesion molecule, which is thought to play a role in immune cell trafficking and inflammation. It also has an oxidative deamination catalytic function.
VAP-1 inhibition has been explored fitfully in the past, but so far has yet to yield any compelling data. Biotie Therapies Oyj, of Turku Finland, has a VAP-1-targeting antibody program, originally pitched at rheumatoid arthritis and psoriasis. Roche Holding AG, of Basel, Switzerland, at one point held an option, which it failed to exercise.
Biotie is now positioning its anti-VAP-1 antibody, BT1023, as a treatment for fibrotic indications. Its academic collaborators recently reported that absence or blockade of VAP-1 reduced both recruitment of inflammatory cells to the liver and fibrosis. The data appeared in the Feb. 2, 2015, issue of the Journal of Clinical Investigation, in a paper, titled "Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis."
R-Tech Ueno Ltd., of Tokyo, recently moved RTU-1096, an oral VAP-1 inhibitor, into a phase I trial in healthy volunteers, with a view to developing it in atopic dermatitis and psoriasis.
Boehringer Ingelheim is also working with an oral agent. "With the acquisition of PXS4728A, we have secured the first small-molecule, oral VAP-1 inhibitor that has already shown promising early results in clinical development for NASH. We are convinced that due to its unique profile, PXS4728A could potentially provide benefits to patients with NASH – an area of high medical need, for which so far there are no treatments available at all," a company spokesman stated.