The Pain Pipeline

The number-one item on doctors and patients' wish list? A better pain medication-one that isn't addictive, doesn't cause gastrointestinal problems, and targets the source rather than receptors in the brain.

Bruce A. Peacock (right) joined Adolor in May 2002 as CEO after serving as CEO of Orthovita, a biomaterials company. Previously, he served as senior vice-president for both Centocor and Cephalon. Bill K. Schmidt, PhD (left), Adolor's vice-president of scientific affairs, has 24 years of pharma R&D experience and previously served as president and CEO of NorthStar Research & Development, a biopharma start-up specializing in pain management.

Although it seems like a lot to ask for, that wish could soon become reality. A small Exton, Pennsylvania, company named Adolor-which, in Latin, means "without pain"-is creating a franchise of pharmaceuticals that target pain in a new way. (See "In Development," page 62.) In simple terms, its compounds target opioid receptors located outside the brain. By bypassing the central nervous system, Adolor's peripherally targeted drugs will not produce the sedation or addiction associated with current narcotic analgesics, all of which are pharmalogically similar to morphine.

Medications such as codeine and morphine work by stimulating mu opioid receptors, which are located in the stomach and intestines as well as in the brain. So, in addition to the narcotic effect, current analgesics also can cause nausea, and in long-term use, severe bowel problems. To avoid-and treat-those side effects, Adolor has focused its R&D on two first-in-class approaches: kappa opioid receptor agonists for pain management and mu opioid receptor antagonists to block current opioid analgesics' effects in the intestines. To be effective, both approaches require molecules that can't enter the brain. (See "The Barrier," page 64.)

Side Effects First

The company's lead candidate, alvimopan (ADL 8-2698), belongs to the second category-opioid receptor antagonist. Its mechanism of action is to bind with and block the gastrointestinal mu receptors stimulated by current pain medications. In Phase III trials, the compound is intended to treat post-operative ileus (POI), a debilitating condition that occurs after abdominal surgery, in which the gastrointestinal tract shuts down completely. A second target indication is for opioid bowel dysfunction (OBD)-constipation and cramping caused by prolonged use of current narcotics.

Recent results from a Phase III clinical trial show that of the 168 patients taking the drug, approximately half got relief for their condition within eight hours.

For POI, alvimopan is intended to restore GI function, allowing patients to have a bowel movement and consume food and water earlier without nausea and vomiting. The result may be faster, less painful recovery and shortened hospital stays. Phase II trials have shown that the medication nomalizes gastrointestinal function for patients taking narcotic analgesics.

But for that indication, patients may be able to take the product in conjunction with pain medication and avoid the condition altogether. Because the molecule fails to enter the central nervous system, it doesn't block the effect of the analgesic.

Alvimopan's market potential seems as great as its human potential. "If every patient who suffered a prolonged ileus as a result of a hospitalization procedure were to take alvimopan, the potential opportunity is in the area of $1 billion," says CEO Bruce Peacock.

GlaxoSmithKline apparently recognizes the opportunity, too. In April, it paid Adolor $50 million for a share of the US rights to the product. Adolor can also earn another $220 million in milestone payments and, if it's approved globally, additional royalties from non-US sales. The two companies will co-promote alvimopan in the United States, giving Adolor the opportunity to ultilize an experienced sales force.

Because the product does not treat pain, the company gave it a generic name that was distinct from current analgesics. The "mopan" stem is derived from "mo" for morphine, "p" for peripheral, and "an" for antagonist. That stem may be applied to any other peripherally restricted narcotic antagonist that follows.

If all goes as planned, Adolor hopes to file the ileus indication sometime in 2003

In development

Diamonds in the Rough

Adolor's greatest potential-for the company and patients-may be through its other novel approach: peripherally restricted kappa opioid receptor agonists. But kappa targets are not without problems, and Adolor is not the first company to try the approach. "Central kappa receptors have potential as therapeutic targets but have proven to be difficult," Peacock admits. "Almost all the compounds that have moved into human clinical testing as central kappa agonists have run into a significant dysphoric side effect."

Bill Schmidt, Adolor's vice-president of scientific affairs, was one of the scientists at DuPont 20 years ago when it attempted to develop a kappa receptor–based pain therapy. It never made it into human trials. "We stopped when we saw the adverse effects that similar compounds were having in clinical development," he says. Other major candidates were spiradoline, in development with Upjohn, and enadoline, being tested by Parke-Davis. Schmidt says, "Neither compound produced a convincing level of analgesic activity at doses that did not cause fairly significant adverse side effects, including very significant sedation, intense dysphoria, and psychotomimetic activity. Quite frankly, some of the patients were hallucinating."

The key was to develop a kappa targeting molecule that would not enter the brain. As evidenced by alvimopan's progress, Adolor may have mastered the peripheralization technology. Its lead candidates for pain management, ADL 10-1016 and ADL 10-0101 and are in Phase I and II , respectively, and the early data indicates that "0101" doesn't produce side effects in the brain or GI tract.

Human testing for efficacy has been limited to a handful of patients so far, but Peacock describes its analgesic effect as "very positive." "Right now," he comments, "we are ready to go back and say 'Let's do some more work and see if we can increase the dose.' Then our goal is to conduct studies with larger patient samples to continue to test the hypothesis that peripheral kappa agonists can generate analgesic relief. The preclinical work we've done gives us the confidence to move forward."

The Barrier

An upcoming issue of the journal Pain will publish a study conducted by Dr. Jim Eisenach of Wake Forest University Medical Center, in which he tested ADL 10-0101 in six chronic pancreatitis pain patients. The compound produced relief greater than any other drug the patients had experienced. And they had already taken maximally tolerated doses of morphine and other morphine-like compounds as well as adjuvant medications, such as antidepressants and anticonvulsant compounds, to treat their pain.

ADL 10-0116 is being evaluated as an oral medication, and ADL 10-0101 is being evaluated as an i.v. infusion, with the medication being given over a relatively short period of time (15–30 minutes). "In the future, 10-0101 might be developed as an oral medication," Schmidt elaborates. "There's no physical, chemical reason why it could not be. The reason that we chose an IV infusion for our first dose was that we wanted to model the blood level in comparison with the level of analgesic activity. And that's easier to do if you have full control of how much drug gets into the blood over a certain period of time."

Old is New Again

Also in development is a fourth compound, called loperamide (ADL 2-1294), a peripheral mu agonist that has been around for 30 years. It's the active ingredient in Imodium A-D, a widely used anti-diarrhea medicine. Adolor's scientists speculated that because loperamide has a similar effect on the GI system as narcotic pain medication-to block bowel function- it might also have a similar analgesic effect.

They were correct. Early studies have shown that the compound provides effective pain relief when applied locally. Santen Pharmaceuticals of Japan has licensed loperamide to develop it for the treatment of ophthalmic pain resulting from corneal abrasions and corneal surgery plans to begin Phase II studies next year.

The pain pipeline goes even broader with Adolor's preclinical work analgesics that stimulate a third type of opioid receptors known as delta, to which the company has a US patent. The R&D team also continues to modify its kappa receptor agonists to see whether they can be completely restricted to the GI tract-and thus treat the pain associated with irritable bowel syndrome. And, on a basic-research level, Adolor continues to look at other receptors and the signal transduction that occurs when molecules bind to them.

With $163 million in operating cash, the company is in good shape to in-license complementary compounds as well as see its proprietary products through development. "Although we're a young company, we have a wealth of experience in the folks we've employed," Peacock says. "So we think we would be a good company for in-licensing an analgesic product. We'd put a lot of focus on it, take it up, and run with it."

According to Peacock, the American Pain Society recently coined the phrase, "Pain: the fifth vital sign," to elevate awareness of pain treatment among healthcare professionals. "There is an increasing awareness that pain management is a legitimate medical concern and worthy of attention," he says. "We can meet that need with reformulations of existing products, as big pharmas have been doing. Or we can do it with new chemistry, new pharmacology, and new ideas about receptors that result in entirely new classes of compounds. I think the latter is the most exciting."