Bringing Treatments to Market
The following article appeared in the Summer 2008 issue of the ICA Update. There’s more in every issue. Don’t miss any articles about new treatments, the research that will bring them, advice from top IC experts, and inspiration from others like you. Learn more about the ICA Update.
Ever wonder why it seems to take such a long time for new IC medications to become available? Here’s the scoop!
In the more than 100 years since IC was described, theories have spawned treatments, but treatments have spawned theories, and even medical mistakes have led to treatments and trials, explained IC researcher, clinician, and ICA Medical Advisory Board member David Burks, MD. We think of the first route as the “usual” one. Pentosan polysulfate (Elmiron) and hydroxyzine (Atarax) are examples of those.
The theory that there is a defective layer coating the bladder lining (called glycosaminoglycan or GAG) in IC prompted testing of the Elmiron to replace the layer. That went through clinical testing and was approved for marketing by the FDA in 1996.
The mast cell proliferation and swelling in the bladder wall seen in IC also looked a lot like an allergic reaction, so physicians began to try antihistamines, settling on the strong histamine 1 blocker hydroxyzine (Atarax). Though this treatment wasn’t tested in IC clinical trials aimed at FDA approval, it became a common treatment because it seemed to work for some patients.
Some autoimmune diseases are more common in IC patients than in the general population. This led to speculation that IC might be an autoimmune disease that destroys the bladder lining. The idea prompted clinical trials of immunosuppressive drugs such as cyclosporine, mycophenolate mofetil (CellCept), and bacille Calmette-Guérin (BCG).
One useful IC treatment that produced a theory is amitriptyline (Elavil), a tricyclic antidepressant. First developed for depression, this class of drugs also found a place in pain management, especially for chronic pain and nerve-generated (neuropathic) pain. This led to the theory that, for many IC patients pain may begin in the bladder and spread to the nearby nerves and spinal cord.
Unfortunately, none of the therapies tried and used in IC is a slam dunk. Some patients seem to benefit, some not. That’s why the NIDDK-sponsored Interstitial Cystitis Clinical Trials Group (ICCTG) and then its successor the Interstitial Cystitis Collaborative Research Network (ICCRN) aimed to put some of the most promising therapies to more rigorous, large scale tests, explained Harris Foster, MD. The group included a number of medical centers around the country and in Canada. Over several years they studied Elmiron, Atarax, BCG, CellCept, amitriptyline, and physical therapy.
The reason the group tested therapies that had already been studied, Dr. Foster explained, is that studies with small numbers of patients at one center don’t necessarily prove a therapy’s value. Another reason is that the therapies the group proposed to test had to be deemed safe enough and to show enough potential for the FDA, the trial’s data safety and monitoring board (DSMB), and each center’s institutional review board to allow the trial to go ahead.
“We started stepping outside of the box,” explained Dr. Foster, but on at least one occasion when the group proposed testing a promising therapy that had less evidence to back it up, the DSMB sent back the word, “We just don’t think this is worth it.”
The group’s Elmiron and Atarax study showed limited benefits, the CellCept study was stopped, and the BCG study results were definitely negative. Nevertheless, “negative studies, at least in some ways, are positive because they answer the question. I think that we, at least in my mind, put to rest the whole issue of BCG,” said Dr. Foster.
The ICCRN could yet hit a homer, however, in 2009. The group’s work on remaining trials will continue until May. Results of the pilot trial of physical therapy look promising, and the main trial is finishing up. The placebo-controlled trial of amitriptyline with and without diet modification and bladder retraining is complete and being analyzed.
But until we have a better idea about IC’s cause or causes, “coming up with an effective treatment for it is going to be the near-blind shooting match it’s been in the past,” said Dr. Burks. “But the effort to uncover a common cause of IC and its seemingly related conditions could mean it will be a long time, maybe even 5 to 10 years, before the research points to useful targets for treatments, speculated Curtis Nickel, MD.
“I think there needs to be a two-tracked approach,” said Dr. Foster — basic science as well as the clinical research focused on finding what makes a difference for patients.
Dr. Nickel and his pelvic pain research colleagues at 11 centers are determined to continue on that clinical track, despite lack of funding. Their clinical experience has told them that some treatments that don’t look good in trials really do work for some patients in the clinic, and likely not just because of placebo effect. “It’s because patients aren’t all alike,” he said. “What we have to do is identify which patients particular treatments are effective for. Then, while we wait for the basic science to come up with answers, we can direct therapy better at the individual patients rather than treating everybody the same.”
Meanwhile, he said, most new treatments will have to come from pharmaceutical company research.
And that’s not easy because reaping a profit from a drug for a relatively small population of patients is unlikely. That’s why some treatments being tested for IC, such as the allergy drug suplatast tosilate, are either approved or further along in tests for more common conditions. For an IC-only treatment, research investment may be just as high as for potential blockbusters, even though sales might amount to a few million dollars. For big pharmaceutical companies, “that’s chump change,” explained Michael Chancellor, MD. Compare that with sales of Lipitor, for example, which totaled some $13 billion in one year. Nevertheless, some established companies are testing new IC treatments. And some entrepreneurial researchers like Dr. Chancellor are taking a riskier route and starting up small companies to test treatment ideas. “It’s benchtop to bedside on a shoestring,” as he put it. For him, it’s the most promising way to try to jump that canyon between basic research and new treatments.
The new treatment he’s betting on is based on liposomes, microscopic particles that can dissolve fat, for bladder instillation. He was trying to find a way to instill one of the hot pepper like substances in the bladder, which wouldn’t dissolve in saline but would in alcohol — a bad idea for IC bladders. “Right down the hallway,” he said, “I had the world’s number one liposome expert.” He told Dr. Chancellor that liposomes would carry the substance, and the research took off. Dr. Chancellor and his team had found cannabinoid receptors, similar to the “hot pepper” receptors, in the bladder and also experimented successfully with these marijuana-like compounds in liposomes. But the liposomes seemed to work fine all on their own, so that’s the treatment Dr. Chancellor is focusing on to get approved for clinical use first.
Although recent safety concerns are making the FDA’s approval process even tougher and more expensive, government and universities are also doing more to stimulate the process. Today, Dr. Chancellor explained, nearly every university has an office of technology transfer that helps researchers spin off small tech companies. Providing much of the incentive for that trend is the Bayh-Dole Act of 1980, which entitles discoveries made with federal research grants to be transferred to the universities and small businesses where the discoveries were made.
To pull his promising liposome-based therapy even closer to the phased clinical testing trials for FDA approval that we’re so familiar with., it takes a combination of pilot research funds, like those Dr. Chancellor has had from the ICA Pilot Research Program and Fishbein Family IC Research Foundation, and then NIH grants to small startup firms and “angel investors” who take high financial risks. That’s where Dr. Chancellor’s work stands now — “getting the liposome to the phase where we could raise the venture capital money to have a company strong enough that we could be in an FDA trial in a year or a year and a half. This is the mission of Lipella Pharmaceuticals Inc. in Pittsburgh.”
Revised Monday, January 14th, 2013