Atlantic Phase III Setback Might Prompt Pouchitis Endpoint Rethink
Executive Summary
Despite failing to meet the co-primary endpoints in a Phase III trial, Atlantic Healthcare believes alicaforsen enema could still be approved in orphan-designated pouchitis.
Post-hoc analyses of data sets from Phase III clinical trials that failed to meet primary endpoints might look like grasping at straws but in orphan indications there maybe some justification. Executives at Atlantic Healthcare PLC are now looking at subsets of data from the Phase III trial of Camligo, its alicaforsen enema formulation, in patients with debilitating antibiotic-refractory pouchitis.
The Phase III, multi-center, double-blind randomized controlled trial focused on the effectiveness of Camligo (alicaforsen enema) in treating 138 patients with chronic antibiotic-refractory pouchitis at 40 centers across the US, Canada and Europe. In the trial, patients were given either Camligo 240mg or placebo once daily for six weeks. The co-primary endpoints of the trial were the proportion of patients achieving endoscopic remission and a reduction in stool frequency at week 10.
A primary analysis, using an adaptation of the Mayo Score of Improvement in endoscopic remission and bowel frequency, confirms that the trial failed to meet these co-primary endpoints. However, the company notes, the data for the stool frequency do show an encouraging efficacy signal and remission in 34% of patients.
“We were surprised and disappointed that the trial did not achieve statistical significance, however, a re-evaluation of the endoscopy data, using new methods of analysis, indicates a statistically significant endoscopic response was achieved in a number of subgroups of patients,” Atlantic’s ceo Toby Wilson Waterworth told Scrip.
Indeed, alicaforsen enema provided on a named patient basis by leading centers in Switzerland, Sweden and Ireland backs up this cautious optimism. “It has been given to 350 ulcerative colitis or pouchitis sufferers on a named patient basis and we are seeing benefits – patients have been able to return to work or go on holiday for the first time in a long while,” he explained.
“In post-hoc analyses of the data it looks like patients with early stage disease do better with alicaforsen than those who have had the disease longer and may have developed scar tissue,” Chris Dunk, Atlantic’s director of clinical development, told Scrip. Moreover, the company noted a significant reduction in ulceration. “However, the endpoint for ulceration was binary – ulcers or not – and while we saw a reduction it did not result in a change in the disease score,” added Wilson Waterworth.
Pouchitis is a common adverse event after proctocolectomy with ileal pouch anal anastomosis, a surgical treatment that is required in up to 30% of patients with ulcerative colitis after a decade of disease, either as a consequence of medically refractive disease or development of dysplasia. Pouchitis may occur within 10 years in up to 50% of patients and is associated with impaired health-quallty of life and is estimated to impact the lives of approximately 200,000 patients in the US and Europe.
Pouchitis is a progressive disease characterized by inflammation, ulceration and increasingly uncontrolled, frequent and urgent emptying of the bowel up to 20 times a day. Some patients develop chronic pouchitis and either become dependent on antibiotics for symptom relief or have symptoms refractory to conventional therapies. With no approved treatments for the condition, a large unmet medical need exists.
The challenge for companies developing pouchitis treatments – in addition to Atlantic’s intercellular adhesion molecule-1 (ICAM-1) antisense oligonucleotide alicaforsen, the Takeda Pharmaceutical Co. Ltd. monoclonal antibody to the alpha4beta7 integrin Entyvio (vedolizumab) is being evaluated – is that there is a question mark over the reliability of outcome measures.
Indeed, in 2018, a multinational research team noted in a paper in Gastrointestinal Endoscopy that while current indices for evaluating pouchitis typically measure a composite of clinical, endoscopic and histologic items, none of them, including the most commonly used instrument, the Pouchitis Disease Activity Index (PDAI), was created using robust methodology for outcome measure development.
“The regulators are familiar with the challenge. Written scientific advice we got from the EMA said that even if we failed to achieve statistical significance but were able to show an underlying benefit they would encourage us to file for approval,” he told Scrip. Consequently, Atlantic Healthcare expects to meet with both the FDA and EMA by the end of the year to discuss a pathway to regulatory approval.
Beyond the orphan-designated pouchitis, Atlantic is developing alicaforsen enema in ulcerative colitis, which is in Phase II, and oral tablet formulations for the treatment of Crohn’s disease and ulcerative colitis both in Phase I.