DUBLIN – Ablynx NV entered a broadly based alliance with Sanofi SA focused on the development of up to eight multispecific nanobodies across a range of immune-mediated conditions, in return for which it is getting €23 million (US$26.5 million) up front, €8 million in research funding and up to €2.4 billion in milestone payments. It also stands to earn tiered royalties on eventual product sales.

The two partners are disclosing neither the targets nor the specific indications involved. "It will be a combination of validated targets but also some new, more speculative targets as well," Ablynx CEO Edwin Moses told BioWorld.

There is, he said, some flexibility built into the agreement, which will enable Sanofi to select some indications at a later date. Those could extend beyond mainstream inflammatory and autoimmune indications, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis, to chronic diseases triggered by sterile inflammation, for example. Some of the programs included in the deal were already underway at Ghent, Belgium-based Ablynx. Others will be initiated de novo. The most advanced is two to three years from entering clinical development.

Immunology is not yet a major earner for Paris-based Sanofi, but it is a core part of its future growth strategy. It is building a franchise in the area on the back of the recent approvals of the interleukin-6 receptor (IL-6R) inhibitor Kevzara (sarilumab) in rheumatoid arthritis and the IL-4R alpha antagonist Dupixent (dupilumab) in atopic dermatitis. Both drugs emerged from Sanofi's longstanding alliance with Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. The deal with Ablynx is a next-generation successor.

"Sanofi are really determined to build on the progress they have made so far," Moses said. "Across these areas, Sanofi is signaling a desire to do something different from the rest of the pack."

Bispecific and multispecific antibodies have, over the past five years, become a mainstream topic in biologics drug development, although clinical success has so far been largely evasive. Most, but not all, of the activity is focused on oncology and immuno-oncology. In autoimmune disease, the most high-profile failure to date has been ABT-122 (TNF-alpha and IL-17), North Chicago-based Abbvie Inc.'s putative successor to its market-leading TNF-alpha inhibitor, Humira (adalimumab).

To stand any chance of commercial success, bi- and multispecific molecules have to offer substantial improvements over their monospecific predecessors, many of which are now becoming exposed to biosimilar competition. The "rules" for developing multispecific drugs are still unclear, however. Most companies rely on a combination of know-how and empirical grunt work. Although engaging two or more targets simultaneously may have a theoretical appeal, there can be numerous ways of doing so. Stoichiometric considerations may require one binding moiety to be present in higher quantities than another. Different targets may also need to be addressed with different potencies.

Ablynx has pioneered the development of nanobodies – small-sized, single-domain antibodies derived from camelidae (camels and llamas) – which act as building blocks for the development of biological drugs. It does not fashion multispecific molecules at the outset – it makes monospecific nanobodies, which it can snap together with amino acid linkers. That enables it to test various combinations and permutations of molecules, and it can drive additional variation into the mix by altering the linkers it employs. Once it settles on a particular structure, it can encode the entire molecule, including the appropriate linkers, in one piece of DNA.

Ablynx has one bispecific molecule undergoing clinical development at present. Its partner, Merck KGaA, of Darmstadt, Germany, recently reported that chronic plaque psoriasis patients who received the highest dose of the molecule, M-1095 (ALX-0761; IL-17A and IL-17F) achieved 90 percent skin clearance in a phase Ib trial.

In terms of its scale and scope, the present deal is more reminiscent of a wide-ranging immuno-oncology pact with Kenilworth, N.J.-based Merck & Co. Inc., which involves up to 17 programs. As part of that effort, a bispecific nanobody entered IND-enabling tox studies last month, an event that triggered a €2.5 million milestone to Ablynx. (See BioWorld Today, July 23, 2015.)

Ablynx also filed its first European marketing authorization application (MAA) this year, for caplacizumab, a nanobody that targets von Willebrand factor, for treating acquired thrombotic thrombocytopenic purpura, an often fatal blood clotting disorder. It is seeking conditional approval in Europe on the basis of phase II data. Phase III data are due later this year and will form the basis of an FDA BLA.

Shares in Ablynx (Brussels:ABLX) closed Thursday at €12.595, a gain of 7.8 percent.

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