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Word Up: Lexicon's Carcinoid Phase II Good, Phase III Starts

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By Randy Osborne
Staff Writer

A successful, earlier-stage trial with its oral, serotonin-reducing therapy for carcinoid syndrome helped Lexicon Pharmaceuticals Inc. figure out dosing in a Phase III study, the start of which made news at the same time that the company disclosed results from the Phase II experiment with LX-1032, or telotristat etiprate.

"Really, we narrowed it down in the first Phase II," said Arthur Sands, president and CEO of The Woodlands, Texas-based Lexicon. "This is confirmatory that 250 mg and 500 mg are the [right] doses," given three times daily, he said.

Although many investors are watching for Lexicon's Phase III trial in diabetes with a sodium-dependent glucose transporter, due to start in the first half of next year, the carcinoid syndrome study is the company's first-ever Phase III, and derives from the company's genomics program.

Carcinoid syndrome is a constellation of life-threatening symptoms that derive from a neuroendocrine tumor, usually in the small intestine, that can spread before physicians detect it – usually to the liver, where the tumor is inoperable, although sometimes to other places, such as the pancreas, in the case of Apple Inc.'s late, former CEO Steve Jobs.

When such tumors are what's called "functional" (as in Jobs' case), the sick cells keep the characteristics of the cells from which they derived, "so they're still cranking out the things they were good at when they were normal cells," Sands said. "Unfortunately for the patient, they're now amplified and creating neuroendocrine havoc," by way of super-high serotonin levels, he said.

Disease Easy to Misdiagnose for IBS

Patients show up with severe diarrhea, vascular flushing, and abdominal pain. Sometimes they are wrongly diagnosed with irritable bowel syndrome (IBS) or some other condition; a number cases slip through the cracks that way. The situation can worsen, leading to pulmonary hypertension and cardiovascular disease.

"Some of these patients will have such persistent GI symptoms and no solution. They'll go in for an exploratory laparotomy," in which a doctor visually inspects the entire small bowel and finds the small, white, thumbnail-sized culprits, Sands said. If removed before they spread, the tumors cause no further trouble and the disease is cured.

But abdominal surgery is "a big step for a patient," Sands noted, which is why about 10 percent of cases are missed. "No therapy, no agent has been able to tackle the tumor mass," he said. "Those are usually treated with chemotherapy embolization and dealing with each metastasis on its own."

Lexicon discovered and developed telotristat to knock down the skyrocketing levels of serotonin – and their associated peril – that carcinoid syndrome brings about. The drug does so by targeting tryptophan hydroxylase (TPH), a key enzyme in serotonin synthesis. Used in diagnosis is 5-HIAA, serotonin's breakdown product and a reliable biomarker.

The primary efficacy endpoint of the Phase II trial was the reduction of bowel movements from baseline in patients with metastatic carcinoid syndrome who were refractory to or could not tolerate the standard of care, therapy with a somastatin analogue: Basel, Switzerland-based Novartis AG's Sandostatin LAR (octreotide).

"We had two patients who couldn't tolerate [Sandostatin], and they responded very well to our drug" – the first time that has happened, Sands told BioWorld Today.

Patients showed a 46.4 percent median reduction from baseline at week 12, with the number of daily bowel movements steadily decreasing over time, and all changes from baseline were statistically significant (p < 0.001).

The bowel movement changes corresponded with an increased proportion of patients reporting adequate relief of their carcinoid symptoms, a global assessment which also improved over time, with 75 percent of the patients with data at week 12 reporting improvement.

Clinically relevant decreases from baseline appeared in key secondary endpoints, too, including statistically significant improvements in stool consistency (p < 0.001) and trends of reductions in abdominal pain (p = 0.09), as well as the number of cutaneous flushing episodes (p = 0.052). The median percentage reductions from baseline of urinary 5-HIAA, the biomarker, at weeks eight and 12 were 68.3 percent (p = 0.019) and 72.7 percent (p = 0.031), respectively.

Patients in the Phase II trial got ascending doses of 150 mg, 250 mg, 350 mg and 500 mg of telotristat three times daily for 14 days on each dose until they reached the maximal dose, which was then continued until the completion of 12 weeks of therapy.

Rising to the next-higher dose depended on tolerability and clinical response. Fourteen patients (93 percent) completed the trial, and 12 of those 14 patients were treated with 500 mg of thrice-daily drug during the last four weeks. The one patient who discontinued early withdrew from the 350-mg dose level for reasons not related to drug safety.

Lexicon presented data from the Phase II trial over the weekend at the North American Neuroendocrine Tumor Society meeting in San Diego.

Program Grew Out of Genomics Platform

The Phase III trial, also lasting 12 weeks, is a randomized, double-blind, placebo-controlled study to test telotristat in patients refractory to standard of care, enrolling about 105 subjects who are on background therapy with the somatostatin analogue. Two dose levels – 250 mg and 500 mg, both given three times daily – will be randomized 1-to-1-to-1.

After 12 weeks, patients will enter a 36-week open-label extension period where all patients will receive telotristat at the 500-mg dose, three times per day.

"This is the tip of the iceberg of applications for this target," Sands said, noting that Lexicon is developing a blood test for biomarker 5-HIAA (the current test uses urine).

Ongoing is a 360-patient trial in diarrhea-predominant IBS with an inhibitor, known as LX-1033, which acts locally on TPH rather than peripherally, like the carcinoid-syndrome drug. The 5HIAA diagnostic is being developed alongside it.

"A theory of IBS-D is now substantiated by genetics that people [with the disorder] have been found with mutations along the pathway of serotonin production and serotonin receptors," Sands said. "They don't have tumors, but they have an abnormal serotonergic axis." Some of those single-nucleotide polymorphisms have been pinpointed in the gene of Lexicon's target, TPH.

The locally acting TPH inhibitor for IBS-D hits the cells in the GI tract that make serotonin: enterochromaffin (EC), sometimes called Kulchitsky, cells, first identified by a Russian scientist. "They make 95 percent of the body's serotonin normally, which is one of the main modulators of motility in the GI tract," Sands said. It's the EC cells from which neuroendocrine tumors can derive, he added.

With telotristat, Lexicon also has an ongoing Phase II study in ulcerative colitis, enrolling 60 patients and due to report data in the first half of next year.

The importance of peripheral (as distinguished from brain) serotonin has long been known. London-based GlaxoSmithKline plc's Zofran (ondansetron) is a serotonin 5-HT3 receptor antagonist for chemo-induced nausea and vomiting.

Research by Lexicon with telotristat, taking aim at TPH, grew directly out of the company's genomics platform, Sands said. "We knocked out these enzymes in the early days in mice and realized this is a good, safe target," much more so than going after the receptor directly, he said. "It's a fascinating set of science and medicine."

Lexicon's shares (NASDAQ:LXRX) closed Friday at $2.69, up 12.6 percent, or 30 cents.