Isis Enters Broad Collaboration With Ortho-McNeil, Inc. for the Discovery, Development and Commercialization of Antisense Drugs to Treat Metabolic Diseases
- Includes license of two antisense drugs in development targeting glucagon receptor and glucocorticoid receptor – Includes research collaboration to identify antisense drugs to inhibit additional targets to treat metabolic diseases.

Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) today announced a broad collaboration with Ortho-McNeil, Inc., a Johnson & Johnson
company, to discover, develop and commercialize antisense drugs to treat metabolic diseases, including Type 2 diabetes. As
part of the collaboration, Isis will grant to Ortho-McNeil worldwide development and commercialization rights to two of its
diabetes development candidates, ISIS 325568 and ISIS 377131, which selectively inhibit the production of glucagon receptor
(GCGR) and glucocorticoid receptor (GCCR), respectively. Additionally, Ortho-McNeil will provide funding to Isis to support the joint discovery of novel drugs to treat metabolic diseases, including diabetes and obesity. After the initial collaboration phase,
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) will continue development of these drugs.
Ortho-McNeil will pay Isis a $45 million upfront licensing fee, and will provide Isis with research and development funding over
the period of the collaboration. In addition to the licensing fee, Isis could receive over $230 million in milestone payments upon
successful development and regulatory approvals of ISIS 325568 and ISIS 377131, as well as royalties on sales. Isis could also
receive milestones and royalties on the successful development and regulatory approvals of additional drugs discovered as
part of the collaboration. The agreement is subject to clearance under the Hart-Scott-Rodino Antitrust Improvements Act. Prior
to closing of the transaction, Isis plans to purchase the equity in Symphony GenIsis, Inc. and reacquire the intellectual property
related to the GCGR and GCCR programs as well as regain full ownership of ISIS 301012, the Company’s lipid-lowering drug
targeting Apolipoprotein B-100.
“We look forward to working with Ortho-McNeil, Inc. and J&JPRD to advance our glucagon receptor and glucocorticoid receptor
drugs through the clinic and to develop additional drugs against other promising targets,” said Lynne Parshall, J.D., Executive
Vice President and Chief Financial Officer, Isis pharmaceuticals. “This collaboration represents another major step for us in capturing value from our achievements in creating a new drug discovery platform technology and discovering commercially attractive antisense drugs.”
“This collaboration has been enabled by the productivity of our metabolic drug discovery program, which has evaluated more
than 120 targets in animal models using antisense drugs,” said Jeffrey Jonas, M.D., Executive Vice President, Isis
Pharmaceuticals. “Both ISIS 325568 and ISIS 377131 have broad and exciting therapeutic profiles that include lowering of
blood lipids and body fat, in addition to significant glucose-lowering effects. These drugs have demonstrated robust effects in extremely diabetic and hyperlipidemic animals and have demonstrated a unique and preferential distribution to tissues such as liver and fat, thereby potentially minimizing the systemic side effects that would be expected with traditional approaches against the same gene targets. We are enthusiastic about our research collaboration, which should allow us to discover additional
drugs against novel targets, thereby adding to our strong pipeline in this therapeutic area.”
About glucagon receptor (GCGR), target of ISIS 325568
Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose. In Type 2 diabetes,
unopposed action of glucagon can lead to increased blood glucose levels. Reducing the expression of liver GCGR using
antisense inhibitors, and thereby reducing excessive liver glucose production, is expected to lower blood glucose levels and
help control Type 2 diabetes. In preclinical studies, antisense inhibitors of GCGR led to improved glucose control and reduced
levels of blood triglycerides without producing hypoglycemia.In addition, treatment with ISIS 325568 led to an increase in
circulating glucagon-like peptide, or GLP-1, which is a hormone that helps to preserve pancreatic function, thereby enhancing
insulin secretion.

About glucocorticoid receptor (GCCR), target of ISIS 377131
Glucocorticoid hormones have a variety of effects throughout the body, including promoting liver glucose production and fat
storage. Although inhibition of GCCR has long been recognized as an attractive strategy for development of therapeutics for
Type 2 diabetes, the side effects associated with systemic GCCR inhibition have challenged development of traditional drugs.
Antisense inhibitors of GCCR take advantage of the unique tissue distribution of oligonucleotides that allows the antisense
drugs to antagonize glucocortocoid action primarily in liver and fat tissue. Notably, antisense drugs do not reduce GCCR
expression in the central nervous system or adrenal glands — inhibition of GCCR expression in these two organs can lead to
systemic side effects. In preclinical studies, Isis has shown that ISIS 377131 has a broad therapeutic profile that includes
reduction of blood glucose levels, a dramatic and favorable effect on lipid levels including cholesterol and triglycerides, and a
reduction in body fat.