Date: May 22, 2012 Author: Trista Morrison Source: BioWorld Today
by: Trista Morrison
Orphagen Pharmaceuticals Inc. knows its orphan nuclear receptor programs are too early stage for most venture capitalists. In fact, they’re too early even for most academics, CEO Scott Thacher told BioWorld Today.“If you want to get a publication in two years and you’re having trouble screening, you’re going to drop it,”Thacher said. “We went much earlier in the pipeline than is socially acceptable.”
There are 48 known nuclear receptors in the body, several of which are important drug targets, including the estrogen, androgen and glucocorticoid hormone receptors. But about half of the nuclear receptors have no known ligands, meaning there’s nothing that can bind to them and turn them on or off. Hence drugmakers call them “orphans,” and many are not even patented, Thacher said.
There are a few drug companies working to adopt orphan nuclear receptors. Karo Bio AB signed a deal with Pfizer Inc. last year for small-molecule modulators of retinoic acid-related orphan receptor (ROR-gamma) in autoimmune disease, while Bicoll GmbH and Genfit have found hits against an orphan nuclear receptor with anti-inflammatory properties. But overall, many drug companies see the field as too daunting.
“Everyone is willing to jump on a target once it’s got the seal of approval in multiple publications,” Thacher said. “Then you put five or ten chemists on the problem and you get an edge. But people aren’t working on unexplored targets.” Thacher left his position as a scientist at Allergan Inc. to found Orphagen in 2000. He decided to focus on orphan nuclear receptors that were tissue-selective, to minimize side-effect potential, and where academics had published some data suggesting the receptors had binding pockets where you might be able to put a molecule. He chose five receptors -- 12 years later, he has small molecules targeting three of them.
That’s a fairly long time horizon, considering the drugs are still preclinical. It’s too long for a venture fund. But Orphagen has funded itself through some angel investment, about $6 million worth of grants, and a partnership with Japan Tobacco Inc. for one of the three compounds. The receptor targeted in the Japan Tobacco deal has not been disclosed, but Thacher said it is a novel target in the immune system that should be applicable in autoimmune disease. Japan Tobacco is doing the “heavy lifting” in the program, Thacher said, but Orphagen provides support and gets fees and milestone payments.
Some of that money has helped Orphagen advance a program against steroidogenic factor 1 (SF1), which Thacher said turns off production of adrenal androgens and will be initially advanced for Cushing’s disease. But Thacher noted the drug could also potentially compliment or replace Zytiga (abiraterone, Johnson & Johnson) in prostate cancer. The program is preclinical, and Thacher estimated Orphagen will have a clinical candidate in one or two years.
The target for Orphagen’s third program is not disclosed, but Thacher said it is an orphan nuclear receptor that affects the central nervous system and may impact the circadian clock. Orphagen is doing proof-of-principle work in vivo and in vitro and expects to advance the drug for retinitis pigmentosa and mood disorders.
As far as what allowed Orphagen to unravel the mysteries of three orphan nuclear receptors, Thacher chalked it up to figuring out the assays and “just hard work and being willing to take the risk on a new target.” He said he’s been surprised not to have more competition in the field, but the fact that orphan nuclear receptors take so long to decipher, and that there’s no telling what indication they’ll be good for, means they “don’t fit the thinking” of many drug companies.
But now that Orphagen has done the leg work, other companies might follow Japan Tobacco into partnering with the San Diego start-up. “If you go into a target before everyone else and take some risk, people will come to you and will partner because they want to be first to market with a new class of compounds,” Thacher said.Orphagen is also looking at future funding through shared-risk arrangements and -- maybe eventually -- through venture capital.
