Lipid Therapeutics GmbH's ulcerative colitis treatment, LT-02, cleared its first major efficacy hurdle by hitting the primary endpoint in a Phase IIb trial.
The drug, a controlled-release formulation of the highly abundant phospholipid phosphatidylcholine, has a new mode of action, arising out of findings on the pathogenesis of the condition obtained by company founder Wolfgang Stremmel at the Heidelberg University Hospital, in Heidelberg, Germany.
Stremmel and colleagues reported seven years ago that the mucus obtained from rectal swabs of ulcerative colitis patients has a decreased phosphatidylcholine content, which is not the case in patients with Crohn's disease.
"This was an astonishing finding," Gerhard Keilhauer, CEO of Heidelberg-based Lipid Therapeutics, told BioWorld International.
The study appeared in August 2004 issue of the Scandinavian Journal of Gastroenterology, in a paper titled "Phosphatidylcholine and lysophosphatidylcholine in intestinal mucus of ulcerative colitis patients. A quantitative approach by nanoelectrospray? tandem mass spectrometry."
Although the precise cause of ulcerative colitis and of inflammatory bowel disease in general is not properly understood, the prevailing view is that it arises from inflammation of the mucosal wall of the colon. Stremmel's work suggested that an impaired mucosal barrier also is a factor. "The working hypothesis is the low amount of phosphatidylcholine precedes the inflammation," Keilhauer said.
The Phase IIb trial followed several investigator-initiated studies. It randomized 156 patients who were refractory to standard mesalazine treatment into one of three different dose arms of LT-02 or a placebo arm. All patients were permitted additional maintenance therapies, apart from biologic drugs, as long as they were stable on therapy before the trial and remained on therapy for its duration.
Those in the high-dose group, who took 0.8 grams of LT-02 four times daily, achieved a mean reduction of 51 percent in disease activity, as measured by the Simple Clinical Colitis Activity Index (SCCAI), a patient-based assessment that tracks basic features of the condition, such as frequency of daytime and of night-time bowel movements, urgency of defecation, bloody stool and general well being.
As is often the case in studies of gastrointestinal drugs, those in the placebo group exhibited a strong response, with a mean reduction of 33 percent. The difference was, however, statistically significant (p < 0.05). "It's a real clinical effect," Keilhauer said. "We see in all dose arms positive effects, but we clearly see the best effects in the high-dose [group]."
Patients who responded during the 12-week treatment period then completed an eight-week follow-up period without LT-02. Data from that part of the study have not yet been reported. "I think the patients might benefit for longer than 12 weeks," Keilhauer said. The full dataset will be presented at an upcoming scientific meeting.
Phosphatidylcholine also referred to by the general term lecithin is a major component of cell membranes and has a benign safety profile. "It's got GRAS status in the U.S., and it's a food additive everywhere. There are tons of the stuff being swallowed," Keilhauer said.
Administration of a controlled-release formulation is intended to ensure delivery of phosphatidylcholine to the colon, as any dietary intake of the compound is broken down by the digestive system.
Its action in ulcerative colitis may be twofold, according to Keilhauer. One line of thought, which is supported by animal data, suggests that phosphatidylcholine forms laminar bodies that provide a physico-chemical protection against bacterial attack of the mucosal wall. Studies in the literature suggested that phosphatidylcholine, which plays a role in signal transduction, may also have an anti-inflammatory effect.
Lipid Therapeutics already has a European partner for LT-02: Dr. Falk Pharma GmbH, of Freiburg, Germany. Although Lipid Therapeutics sponsored the Phase IIb study, it's now Dr. Falk's call on whether to move the program into Phase III. The field is relatively neglected. Only one new chemical entity gained approval in recent decades, the TNF-alpha inhibitor Remicade (infliximab), which is marketed by Johnson & Johnson, of New Brunswick, N.J., and Merck & Co., of Whitehouse Station, N.J.
Abbott, of Abbott Park, Ill., is also active in the space, however. It recently reported data from a Phase III study of its TNF-alpha inhibitor Humira (adalimumab) in patients who had not responded well to corticosteroids or immunosuppressants. After 52 weeks, 17.3 percent of those in the treatment arm achieved clinical remission, whereas 8.5 percent of those on placebo did (p = 0.004).
Privately held Lipid Therapeutics, which was formed in 2008, has received backing from two Heidelberg-based funds, EMBL Ventures GmbH and CD-Venture GmbH.