Wyeth/Progenics Aim To Preempt Review Concerns To Expand Relistor Use

With FDA approval in hand, Wyeth and Progenics are building the Relistor database before the companies move to expand the opioid-induced constipation drug's use beyond its relatively limited initial population of patients with advanced illness.

FDA approved Relistor (methylnaltrexone) without mandating post-marketing requirements, but the firms are conducting additional studies of their own accord on concerns raised during Relistor's review process.

"Three hundred patients were sufficient for safety and efficacy [for approval], but being able to make definitive statements on quality of life - the numbers aren't there," Progenics VP of Corporate Affairs Richard Krawiec said in an interview.

Wyeth is currently conducting two Phase IV trials - one to gather more safety data and one to study health outcomes information. Each trial is slated to enroll 350 patients and should be completed by January 2010.

The subcutaneous formulation of the peripherally-acting mu-opioid receptor antagonist was approved April 24 for treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

Relistor received a first-cycle approval after a relatively smooth review marked only by an inadequate QT prolongation study that necessitated a second study (see following story). Relistor contrasts sharply with another peripheral mu opioid antagonist, Adolor/GlaxoSmithKline's Entereg (alvimopan), which was approved one month later for the larger post-operative ileus population. Entereg's May 20 approval capped a review featuring an action letter in 2006, an advisory committee in 2008, and one of the first risk evaluation and mitigation strategy programs required by FDA.

Isolating Distress Was "Problematic"

Progenics' choice of terminally ill OIC patients for Relistor's initial NDA earned it some degree of leniency from FDA. At a Pre-NDA meeting Aug. 15, 2005, FDA noted that the efficacy endpoints "lack adequate evaluation … compared to baseline. However, we do understand it is difficult to evaluate some of these endpoints in your proposed terminally ill population."

Progenics' initial proposed indication only specified patients receiving palliative care. But considering the patient population studied, "the term 'palliative care' may imply long-term care," clinical reviewer Ronald Orleans wrote in his Feb. 27 review. "Therefore, a more appropriate indication would be … in patients with terminal illness receiving palliative care." The approved indication specifies "advanced illness."

Orleans also recognized the difficulty of assessing this seriously ill population in a clinical trial setting. "The multiple endpoints and efficacy assessments used in this NDA measure constipation relief, but do not measure MNTX effects on decreasing the incidence of constipation-related complications," he stated.

"In patients who are suffering from a terminal illness requiring narcotic use, it seems to this reviewer that isolating the distress that is solely due to constipation is problematic," Orleans observed.

Two double-blind, placebo-controlled Phase III trials support Relistor's NDA. In both studies, patients had advanced illness with a life expectancy of less than six months. Diagnoses included incurable cancer, end-stage emphysema, Alzheimer's disease and HIV/AIDS.

In MNTX 301, patients receiving a single subcutaneous dose of either 0.15 mg/kg or 0.30 mg/kg of Relistor, followed by a four-week open-label period, were significantly more likely to have rescue-free laxations occurring within four hours of the dose versus placebo, the primary endpoint.

In the second trial, MNTX 302, patients received 0.15 mg/kg Relistor every other day as needed for two weeks. The trial had two primary endpoints: rescue-free laxation occurring within four hours of the first dose and laxation within four hours after at least two of the first four doses. Relistor exceeded placebo for both.

In both studies, laxation occurred within 30 minutes of Relistor administration in about 30 percent of patients.

Krawiec said Progenics was "very pleased with the numbers. These are extremely ill patients who had a wide variety of underlying diseases. To see a response in patients whose [GI tracts weren't functioning normally], to respond in 30 minutes or so, was very good."

Preparing To Launch

Wyeth plans to fully launch Relistor in late July, backed by a 1,700-person sales force, targeting the oncology, institutional, and general practice settings.

The firm will provide two doses to physicians and patients, Krawiec said. The two-dose sampling program will highlight the large percentage of patients who benefited from at least two doses.

Wyeth is buttressing its Relistor data package before it moves forward with launch and new indications for the drug, including quality-of-life data.

In April, Wyeth published a 1,066-person survey examining how OIC impacts care in patients with terminal illness. The survey, conducted in 2007, questioned 502 nurses from the Hospice and Palliative Nurses Association, and 310 end-stage cancer patients and 254 caregivers from the Nexcura cancer patient and caregiver database. The survey was not conducted at the request of FDA, the company said.

When asked about the most frustrating side effects of opioids, 80 percent of patients mentioned OIC. As a result, 43 percent of patients said they reduced the use or dose of opioids, while 19 percent stopped altogether.

In addition, 97 percent of nurses agree somewhat or strongly that OIC diminishes terminally ill patients' quality of life, and 90 percent of nurses agreed somewhat or strongly that OIC makes it more difficult to provide good end-of-life care.

Although the findings are not included in labeling, in both pivotal trials more Relistor patients described the change in constipation distress, bowel movement consistency and difficulty, and clinical impression of change as much, somewhat or slightly better compared with placebo. Patient-reported outcomes and quality-of-life measures have historically been difficult to get into labeling; a PRO draft guidance is pending.

More To Come From Relistor

Wyeth and Progenics are looking outside the terminally ill patient population to expand Relistor's use, Krawiec said. "The first indication for Relistor is for the palliative care setting, the patients with the greatest need. We're in the process of expanding the subcutaneous and oral formulations for a broader patient base."

The most advanced trial in this effort is a Phase III study with subcutaneous Relistor for OIC in patients with chronic, non-malignant pain, such as back pain, osteoarthritis and migraines, Krawiec said.

A Phase II trial for chronic pain patients with OIC is testing an oral formulation. Krawiec said the company hopes to move into pivotal studies later this year.

In addition to the subcutaneous and oral formulations of Relistor in OIC, Progenics and Wyeth are developing an intravenous version to be used in patients with post-operative ileus. A Phase III study evaluating POI patients following a ventral hernia repair, initiated in October 2007, should have data by 2009 (¹ Pharmaceutical Approvals Monthly March 2008, p. 18).

Two additional Phase III studies in POI patients following segmental colectomy failed their primary endpoints of a reduction in time to recovery of GI function, which "was puzzling as we had positive results in Phase II," Krawiec said.

The firms will study the results of both intravenous POI studies to determine whether and how to continue development.

GSK/Adolor's Entereg has the advantage of being first to market for POI (² Pharmaceutical Approvals Monthly June 2008, p. 25). However, Entereg is contraindicated in patients chronically exposed to opioids, and has the REMS concerning risk of myocardial infarction.

FDA lifted a clinical hold on Entereg's opioid bowel dysfunction program July 3, which had been in place until the agency could review additional safety information. GSK currently is evaluating whether to continue its partnership with Adolor concerning the OBD indication.

"We did one large Phase IIb and two Phase III studies with GSK," Adolor Senior VP David Jackson said. "There is a very good database to build a subsequent submission if that's going to go forward."

- Becky Jungbauer ([email protected])