By David N. Leff

Would you believe there's an African cactus that can quell an uncontrollable urge to pee?

This is no tale told by an idiot, but a natural product just entering Phase II clinical trials in the U.S. and Europe, to treat urinary incontinence.

Nor is a leaky bladder a trivial or risible disorder; it's a chronic condition worldwide, and afflicts some 13 million Americans. Over half of them, 7 million men and women, especially the elderly, suffer from a specific subset of the disorder called urge incontinence. It accounts for half of all nursing home admissions.

The embarrassing and disabling condition is also a hallmark of multiple sclerosis and spinal cord injury.

Urinary incontinence costs society $1.1 billion a year for sanitary products alone. "Current treatment options," said physiologist Helmer Agersborg, "including drugs, devices and behavior modification, are unsatisfactory. The two commonest therapeutics," he added, "an antidepressant and an antispasmodic, have limited efficacy and numerous side effects.

"As a result of this under served demand," he told BioWorld Today, "the current drug market is estimated at less than $100 million per year."

Agersborg is chairman of a virtual company, Afferon Corp., based in Wayne, Pa., which plans to put a new spin on medical management of urge incontinence. His point of departure is an ultrapurified extract of that African plant, Euphorbia resinifera. The compound is called RTX — resiniferatoxin. Afferon imports the extract from Morocco, where it grows in the Anti-Atlas Mountains, and has it processed to FDA's Good Manufacturing Practice standards.

Two millennia ago, the dried latex of E. resinifera helped ease the royal pain of the arthritic Roman Emperor Augustus. In subsequent centuries, it remained a folk remedy.

That was then. This is now.

"I don't want people to confuse RTX with herbal or alternative medicine," said Agersborg, who is former president of Wyeth-Ayerst Research, in Philadelphia. His fledgling firm holds exclusive worldwide licenses to four U.S. patents issued to the National Cancer Institute. The lead patent protects the use of RTX and its chemical ilk in "a class of compounds having a variable spectrum of activities for capsaicin-like responses."

RTX is, in fact, a close chemical cousin of capsaicin — the fiery, pungent main ingredient of red chili peppers and derived hot sauces and salsas. (See BioWorld Today, Oct. 29, 1997, p. 1) The pharmaceutical resemblance of RTX to the botanical extract is no closer than that of an aspirin tablet to a strip of Hippocrates' willow bark.

From Red Pepper To Cactus Juice

Many urologists have instilled capsaicin by catheter (a common doctor's-office procedure) into the overactive bladders of patients with urge incontinence. Its therapeutic effects were acceptable; its side effects unacceptable.

"RTX exposure to the bladder for a 30-minute period," Agersborg recounted, "desensitizes hyperirritable afferent neurons in the bladder for extended periods. In patients with urge incontinence," he continued, "this activity blocks the premature bladder contractions, which cause an unpredictable loss of urine."

Several promising Phase I and early Phase II trials of RTX in such individuals found the drug to be upwards of 1,000 times more potent than capsaicin, but with none of its adverse effects. Moreover, its urge-curbing activity persisted for one to three months after treatment.

Afferon is this week launching more extensive Phase II studies of the compound in 120 patients at two urological centers in the U.S., and one in Belgium. Thirty participants are being enrolled at Jefferson Medical College, Philadelphia, and the University of Pittsburgh; 60 at the University of Louvain, Belgium.

Most of these will be patients with multiple sclerosis (MS), in whom urge incontinence is a clear-cut, readily measurable syndrome. "Urge," Agersborg explained, "is a situation in which there is an involuntary, unavoidable urine leakage, not due to physical activity."

He compared it with the more prevalent form, stress incontinence, triggered by such physical activities as laughing, running, straining. "Stress incontinence," he observed, "would be unlikely to respond to RTX treatment."

MS is a neurological disease in which certain neurons are denuded of their protective myelin sheath, and also impeded by plaques forming on the myelin. "MS is a disease of contracture, rigidity," Agersborg explained, "so the nerves, in response to the plaques, are firing at inopportune times. This may generate tremendous intention tremor — trembling that occurs during the performance of precise voluntary movements — such as trying to move an arm or a leg."

He went on to point out that "in the absence of spinal cord involvement, the urge involves a hyperactive locus in the bladder wall. This, in partial response to stretching, may trigger an involuntary contraction of the detrusor muscle," (which enwraps and squeezes the bladder). "We think our RTX treatment can deal with that as well."

The endpoint to be evaluated in these just-beginning clinical trials, he said, "is of course achieving urinary continence in incontinent patients. We will be measuring frequency of micturation and episodes of involuntary voiding." Among other factors under scrutiny will be the influence of RTX on bladder capacity.

Spinal cord injury, whether complete severing or mashing, Agersborg observed, "causes enough firing of neurons so that there is a constant barrage of neurological impulses that trigger the detrusor muscle contraction." Patients with such spinal insults will also comprise a sizable cohort in the upcoming trials.

Feb. 1 is the starting date for the Belgian studies. Those in Philadelphia began earlier in January; the Pittsburgh contingent by the end of this month.

In addition to the 60 Louvain patients, nearly all with MS, Afferon plans a 30-patient study in Belgium of simple urge incontinence, not connected to disease or trauma. By this, Agersborg does not mean plain enuresis, such as childhood bedwetting. "But we will assess urge in the middle of the night," he said.

Afferon is also exploring other possible uses for RTX, as in rhinitis, and migraine headache, in which the compound will be sprayed intranasally, and topically for diabetic and arthritic pain — coming full circle to Imperial Rome. *