Shire’s Motegrity: US FDA Panel Nod On CV Safety Comes With Concern About Neuropsych Events

In unanimously endorsing prucalopride for chronic idiopathic constipation, advisory committee seems reassured by extensive data on 5-HT4 agonist’s cardiovascular safety, but some members called for an epidemiological study to assess possible suicidality signal.

Shire PLC’s constipation drug Motegrity (prucalopride) won a US FDA’s advisory committee’s unanimous endorsement Oct. 18 on the strength of reassuring cardiovascular safety data, although some panelists called for further evaluation of a potential suicidality signal.

The Gastrointestinal Drugs Advisory Committee voted 10-0 that prucalopride’s risk-benefit profile supports approval for treatment of chronic idiopathic constipation (CIC). By the same voting margin, the panel backed the drug’s efficacy and cardiovascular safety. (See table.)

The endorsement appears to clear the way for US approval of a drug that first came to the European market nine years ago under the brand name Resolor. The application’s user fee goal date is Dec. 21.

However, if some panelists have their way, US approval could come with a request for an epidemiological, postmarketing study to further explore the risk of suicidal behavior.

Advisory Committee Votes

Do the clinical data provide substantial evidence of effectiveness of prucalopride for the treatment of adults with chronic idiopathic constipation (CIC)? Y – 10 , N – 0

Has the potential risk of cardiovascular adverse events with the use of prucalopride in adults with CIC been adequately addressed by the applicant? Y – 10 , N – 0

Does the risk-benefit profile of prucalopride support the approval of this application? Y – 10 , N – 0

Reasons To Be Comfortable With CV Safety …

FDA convened the advisory committee to consider the quantum of evidence on prucalopride’s cardiovascular safety given the history of cardiac-related concerns with other drugs in the class of selective serotonin type 4 (5-HT4) receptor agonists.

In 2000, Johnson & Johnson halted sales of Propulsid (cisapride) due to postmarketing reports of serious cardiac arrhythmias and deaths. In 2007, Novartis AG suspended US marketing of Zelnorm (tegaserod) after a pooled analysis from 29 placebo-controlled clinical trials showed a higher rate of ischemic CV events in patients taking the drug.

However, tegaserod’s current sponsor, US WorldMeds LLC’s Sloan Pharma subsidiary, is seeking to bring Zelnorm back for a more limited indication. On Oct. 17, the advisory committee endorsed the drug’s return to market, but the panel’s GI and cardiology experts differed on the most appropriate target population. (Also see "Zelnorm's Return: US FDA Panel Hands Down Split Decision On Constipation Drug's Target Population" - Pink Sheet, 17 Oct, 2018.)

From a CV safety perspective, advisory committee members said prucalopride’s mechanism of action, which is highly selective for the 5-HT4 receptor, set it apart from other drugs in the class that have a higher potential for off-target effects.

Panelists also said they were reassured by the extensive nonclinical testing, a thorough QT study, comparable rates of CV events in the clinical trial program, and the fact that no CV safety signal has emerged in the drug’s extensive postmarketing experience outside the US.

Prucalopride currently is marketed in 59 countries and has more than 280,000 patient-years of experience, with approximately one million treated patients, Shire said.

Committee members also took comfort in results from Shire’s population-based, pharmacoepidemiology study (SPD555-802), in which the incidence rates for major adverse cardiovascular events (MACE) with prucalopride and polyethylene glycol were compared using claims and electronic health records data from the UK and Sweden. The retrospective, noninterventional study was submitted in lieu of a dedicated, one-year CV safety study. (Also see "Shire’s Prucalopride Brings Real-World CV Safety Data To US FDA Panel, But Will It Be Enough?" - Pink Sheet, 16 Oct, 2018.)

Joel Weissfeld, a medical officer in FDA’s Division of Epidemiology, said that Study 802 provided reassuring evidence and satisfied the pre-NDA expectation of excluding a three-fold increased risk of MACE. However, he cautioned against overinterpretation of the results, citing “important problems” that make the study susceptible to confounding.

“The absence of biological plausibility for cardiovascular adverse events was very helpful here,” said panel member John Teerlink, a cardiologist at University of California-San Francisco. “The sponsor is to be congratulated on using pharmacovigilance studies to try to help inform the safety of these agents.”

… But Suicidality Events A ‘Residual Concern’

While CV issues were expected to predominate the safety discussion, a potential neuropsychiatric signal proved to be a greater concern for some panelists.

In the double-blind and open-label trials, there were two completed suicides and four attempted suicides among prucalopride-treated patients, compared to none in the placebo arms. Five of the patients had a clinical history of depression, anxiety, drug abuse or other psychiatric risk factors.

Sandeep Khurana, medical director of liver transplantation at Geisinger Medical Center, said his only concern about prucalopride’s risk-benefit profile related to the neuropsychiatric events, particularly given the lack of such events in the placebo arm.

“If we are to approve this then I think there should be some sort of a warning on it,” Khurana said. “Obviously that has to be discussed between the patient and physician prescribing it.”

Similarly, Steven Solga, a gastroenterologist at the University of Pennsylvania, cited the neuropsychiatric events as a “residual concern.”

“I don’t feel like we understand what not just this drug, but this class of drugs, do to serotonin on the brain.” – U-Penn’s Solga

“I don’t feel like we understand what not just this drug, but this class of drugs, do to serotonin on the brain. And unlike doing QTc studies and other cardiac and nonclinical data, I don’t know that we have the tools and the toolbox to answer these questions,” Solga said.

“It’s not going to hold back my ‘yes’ vote,” he said. “I don’t expect the sponsor to do studies we don’t know how to do, or the FDA to manage risk that we don’t know how to measure. But that is the area that I’m going to leave and wonder about for some time to come.”

Several panelists suggested the sponsor could conduct retrospective, observational study using the same UK and Swedish databases employed to assess MACE risk to further investigate the occurrence of suicidal behavior.

“It would just seem that given that there is a large database to study which was studied with respect to the MACE events, one might think that you can study this looking at maybe deaths related to suicide to look for a signal,” said Jennifer Lai, a gastroenterologist at the University of California-San Francisco.

“The reason I’m particularly worried is that while the general population of individuals with CIC … may be overall a low cardiac risk population, it is a population in which depression and other psychiatric disorders is probably much higher in prevalence than the general population,” Lai said.

Efficacy Suffices Despite Generalizability Questions

On the issue of efficacy, panelists said they were persuaded by the statistically significant results from five clinical trials and the numerically favorable results in a sixth trial (Study SPD555-401), which did not meet statistical significance.

Nevertheless, numerous panelists raised concerns about generalizability of the data to the US population. In particular, they bemoaned the small number of people of African descent who were studied in the clinical program.

Shire consultant Michael Camilleri, a gastroenterologist at Mayo Clinic, said the prevalence of CIC in African-Americans is about 20%, which is higher than that for the overall US adult population, Caucasians and Asians (about 15% each).

A total of 78 black patients were included in the intent-to-treat (ITT) and modified ITT populations in the six trials, according to FDA's briefing document. Black patients represented no more than 8% of the study population in any single trial, and one trial did not enroll any black patients.

“I’m hoping that the African-American gut motility is the same as the whites.” – Oklahoma University's Thadani

Panelists also questioned whether two US-only studies that were completed in 1999 were relevant to the current US population of CIC patients. In addition, they took note of the lack of long-term, controlled efficacy data, since the longest trial went out only 24 weeks.

Teerlink said his ‘yes’ vote on the efficacy question “does not relieve future sponsors of their responsibility of providing data to the FDA that provides information on longer-term effects and effects in subpopulations.”

“I do think it’s important to have more long-term evidence for chronic therapies, both from an efficacy and a safety standpoint,” he said.

Udho Thadani, a cardiologist at Oklahoma University, said he was persuaded by the positive results from five efficacy trials and the “positive direction” in the 401 study. “My only reservation, I’m hoping that the African-American gut motility is the same as the whites,” he said.