‘Cautious Optimism’ Voiced by Biotech, Pharma, and Academia at 2006 LRI Scientific Conference Forum

With the recent surge in knowledge about what causes and promotes lupus generated by LRI researchers and others, there appear to be-for the fist time ever-several candidate drug "targets" for lupus with enough potential to prompt biotechnology and pharmaceutical companies to take a closer a look.

The roster at the 2006 LRI Scientific Conference included:

Jeffrey Browning, PhD, Distinguished Scientist, Biogen Idec
Robert A. Eisenberg, MD, Chief of the Division of Rheumatology, University of
Keith Elkon, MD, Head of the Division of Rheumatology, University of Washington
Arthur Krieg, MD, Chief Scientific Officer, Coley Pharmaceutical Group
Flavius Martin, MD, Genentech
Peter Lipsky, MD, Chief, Autoimmunity Branch of NIAMS Intramural Research Program
Pennsylvania School of Medicine

"I think in lupus the most exciting thing is that we are now seeing the possibility of validated targets," said Arthur Kreig, MD, a rheumatologist who started a biotech company. Other panelists at the special panel discussion on Novel Therapeutics Based on Insights into Disease Pathogenesis, moderated by Peter Lipsky, MD, largely concurred.
So-called "targets" are molecules or processes in the body that researchers-many of them funded by the LRI-have identified as likely to be involved in lupus. They include B cells, T cells (including regulatory T cells), Toll-like Receptors, dendritic cells, interferons, as well as early "upstream" culprits in activating the immune response pathways in lupus.

Having targets is crucial because they give drug developers something to aim for with the goal of preventing, slowing, or halting the disease. The targets are the first step to safer and more effective medicines-and a cure.

We are living in a very exciting time because over the next few years we will be validating major categories of therapeutics," echoed Flavius Martin, MD. "The likelihood is that by 2011 we may have answers on which of these won't work, at which point the job is to sort out which will work-a much more complex issue, actually."

Dr. Lipsky noted, "It's been 40 years and all we have [approved] for lupus is aspirin, glucocorticoids (such as prednisone), and hydroxychloroquine. That's a rather unique circumstance."

A Dose of Provocative Realism

Audience at the 2006 LRI Scientific Conference

The challenges ahead are formidable but not insurmountable, the panelists agreed. While several drugs targets in lupus have been identified, for example, it remains to be seen whether they are right for translating into therapies for people with lupus, or whether they can specifically target and block steps in the misguided immune response without hitting multiple targets and even damaging other parts of the body.

Cost, risk, and time are all daunting obstacles. For biotechnology and pharmaceutical companies, a new medicine costs an estimated $1 billion to take from research stage to FDA approval.

"It's incredibly expensive," explained Dr. Kreig in an introductory talk on why more companies aren't developing lupus drugs. "A lot of programs fail. There's a lot of risk. Companies are not willing to make the investment unless there is very high confidence they will make their money back."

Dr. Kreig added that "if you start a program on drug development, your stock is going to go down 50 percent the next day," And the scenario for lupus drugs is even riskier. According to a recent review of some 450 clinical drug development programs, the probability of success (i.e. FDA approval) when starting a new Phase 1 drug program for any drug is a mere 6 percent; but for lupus it is 0 percent, as no new drug as been approved in decades.

Within a company, the view on drug development in lupus also is colored by the size of the company and its capacity to absorb risk, said Jeffrey Browning, PhD. "At a mid- to large pharmaceutical company, you are competing for a pool of money and that pool tends to go towards lower risk things or lifecycle management on existing drugs...[lupus] is trying to eke out an existence on the residue, so you need crisp endpoints."

Validation of a drug target alters that outlook dramatically, however. "If for lupus one company can validate a target, and show that they have something that makes a real difference in patient outcomes, all of the companies are going to go after that target. But until the target is validated, the risk of failure is very high," said Dr. Kreig.

Steep but Surmountable Path Ahead

Things are changing for lupus, however. The prospects for a validated lupus drug target improved dramatically with the issuance of the FDA Draft Guidance Document in spring 2005. Overnight, it became much more appealing to pursue lupus drugs, as the document clarifies the pathway for developing one.

It not only spells out what you need to show in order to have a drug approved but explains clinical endpoints and objective claims that can be used such as reduction in disease activity and complete clinical response/remission.

To actually get a drug approved, however, more people with lupus will have to participate in the trials that test for safety and efficacy-no easy feat given the highly variable course of the disease in and among patients, and disqualifying factors such as other medical problems and medicines that can muddle trial data.

Now Is the Time

Now is the time to prepare for that moment when one of the many lupus targets in the pipeline is validated, Dr. Lipsky and others pointed out. "Or it will all be for naught. We have to start planning now on how to run lupus clinical trials."

The size and flexibility of these trials have to be considered, for example. With the often overwhelming challenge in signing up sufficient participants that fulfill strict trial criteria, "the name of the game is industry rapidly going to small numbers of patients and over a small time frame," said. Dr. Browning.

"The ticket to getting more involvement [from industry] is the ability to run extremely focused 'proof of principle' trials with a hard end point," he said, " . . . to even look at just one snippet of biology and have a key insight and go from there."

"Perhaps smaller trials will give us enough information to further our understanding of the science and biology of the disease here before hundreds of millions of dollars are thrown at the subject," explained Robert Eisenberg, MD.

"But when moving along a failed pathway," inserted Dr. Lipsky, "you need to be able to modify the endpoint you're looking for sometimes rather than end the trial altogether."

Working Together

Success in developing new lupus drugs will require more explicit links and good faith interaction between industry and academia, the panelists pointed out. All parties will benefit from conferring on protocol design and strategies for modifying a trial goal even if the study has started-in the event that one outcome isn't showing promise but another is.

Academic researchers can help enormously in developing animal models for quickly testing a new agent, for example. And securing a patent and alerting industry to prospective agents early on, while still in the incubation stage but far enough along that industry can say "OK, that smells good."

And industry, for its part, can provide resources to support creative ideas in academia.
"Maybe the whole market concept might need to be tweaked some," said Dr. Eisenberg, "so you don't have small companies stick with something they have to and big companies kill things because they can't afford to take risks. Perhaps there should be another kind of economic model as to how to develop drugs for difficult diseases like lupus . . . the way that people have suggested new economic models for developing drugs for the third world."