Pfizer Deal Puts Karo Bio in Pole Position for ROR-Gamma Race
By Catherine Shaffer
BioWorld International Contributing Writer
Pfizer Inc. has signed a collaboration agreement with Karo Bio AB, of Stockholm, Sweden, for the development of small-molecule modulators of retinoic acid-related orphan receptor (ROR-gamma), an enticing newer target with relevance for autoimmune disease.
ROR-gamma controls production and secretion of cytokine IL-17. Recent clinical studies using monoclonal antibodies to neutralize IL-17 have validated the pathway's significance for inflammation, heating up the race for a ROR-gamma drug.
"It's a tough race, with tough competition," said Karo Bio CEO Per Bengtsson. "We have Pfizer. They have stakes in this field, and strong ambitions."
Under the agreement, Karo Bio may receive up to $217 million in up-front and milestone payments, plus potential royalty fees.
ROR-gamma falls within Karo Bio's core competency of nuclear receptors, a field it's been focusing on for more than 20 years. Nuclear receptors, located inside the cell rather than on its surface, are involved in regulating functions in the body relevant to a broad range of diseases including dyslipidemia, diabetes, obesity, inflammation, osteoporosis and cancer.
Nuclear receptors control transcription of genes in the cell, resulting in different effects on tissues. They can be modulated by hormones, vitamins, fatty acids and other natural ligands.
According to Karo Bio, 48 receptors have been identified with potential relevance for human health, and approximately 10 percent of medicines have mechanisms that work through nuclear receptors.
The company has been studying ROR-gamma since 2010, with the goal of developing therapy for autoimmune diseases like rheumatoid arthritis, ulcerative colitis and multiple sclerosis based on inhibition of the receptor. It is considered difficult to drug because of its similarity to other targets and because its native ligand is unknown.
Karo Bio said it has identified potent and specific small-molecule modulators of ROR-gamma.
In March, Lycera Corp., of Plymouth, Mich., signed a deal with Merck & Co. Inc. to develop a new class of drugs targeting the T-helper 17 (Th17) cells via the ROR-gamma transcription factor. Th17 cells produce IL-17.
A number of other competitors are working on antibodies to target IL-17. In mid-2010, Genentech Inc. (now part of Roche AG) acquired rights to an IL-17 antibody program from Novimmune SA.
Novartis AG completed a Phase I/IIa study of an anti-IL17 antibody called secukinumab in patients with rheumatoid arthritis, psoriasis and uveitis in 2010, finding some symptom improvements in all patients. Results were published in the Oct. 6, 2010, edition of Science Translational Medicine.
Outside of ROR-gamma, Karo Bio's most advanced project is a drug for dyslipidemia, eprotirome, which is in development for heterozygous familial hypercholesteremia (HeFH). The drug is a thyroid hormone receptor agonist that is designed to have the risk-reducing effects for heart attack of natural thyroid hormone, without the undesirable side effects of high levels of natural thyroid.
The alpha receptor is believed to cause the unwanted side effects well known for all physicians: tachycardia and osteoporosis. Karo Bio has a beta selective agonist that, in addition, also is endowed with liver selective properties for better uptake in liver cells, as well as a short half-life for more rapid decay once it has passed the liver. The effects on the thyroid beta receptor in the liver mediates the beneficial effects on metabolism
The company began enrolling for a Phase III trial of eprotirome that will test the ability of the drug to lower levels of low-density lipoprotein cholesterol (LDL-C) to clinically meaningful levels in patients who are generally on statin therapy already. Data are anticipated in late 2013, with possible regulatory filing in 2014.
Karo Bio also has programs targeting glucocorticoid receptors, estrogen receptors and the Liver X receptor in various stages of development.
In October 2011, Karo Bio enrolled its first patient in a trial of perotirome for heterozygous familial hypercholesterolemia. The trial will include 630 patients with the condition, and it will evaluate safety and efficacy of perotirome for long-term treatment. An interim analysis is planned for the second quarter.
Because Pfizer will fund all costs for the ROR-gamma project, it will benefit Karo Bio in two ways. First, there's the up-front payment and milestones that will go straight to the company's bottom line. Second, Bengtsson noted that it will reduce overall costs for Karo Bio. "Currently, we are carrying costs for the program. We can allocate resources to other projects because we don't have to pay for it anymore."
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