Valeant's Siliq Clears FDA Panel But Faces Prospect Of Post-Marketing Registry

Agency's advisors were divided on whether Valeant's proposal for voluntary registry would suffice or whether mandatory program under REMS was needed to better assess risk of suicide and suicidal behavior with psoriasis drug.

FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee unanimously recommended Valeant Pharmaceuticals International Inc.’s plaque psoriasis candidate Siliq (brodalumab) for approval July 19, but panelists were divided on whether a potential suicidality signal warranted a mandatory post-marketing registry as part of a Risk Evaluation and Mitigation Strategy or a voluntary program outside of a REMS.

Committee members voted 18-0 for approval of the interleukin-17 inhibitor; 14 supported approval only if risk management options beyond labeling were implemented to address suicidal ideation and behavior, while the other four panelists voted that labeling alone was sufficient to manage the risks.

"I think voluntary communication and voluntary registries have proven to be, and in this case will also be, completely useless,” committee chairman Bigby said.

Suicidal ideation and behavior was the primary focus of discussion during the meeting. There were six completed suicides in brodalumab's clinical development program, raising questions about whether there was a drug-related risk.

Committee Chairman Michael Bigby, a dermatologist at Harvard Medical School, praised the drug’s efficacy but noted that the six completed suicides cannot be ignored and the drug should be labeled with a boxed warning reflecting these cases.

Although Bigby voted that labeling alone is sufficient to manage risks, he said that if there is going to be a registry it should be mandatory. “I think voluntary communication and voluntary registries have proven to be, and in this case will also be, completely useless,” Bigby said. “The best way to make a problem go away is to not look very hard.”

Michael Irwin, a psychiatrist at the David Geffen School of Medicine at University of California-Los Angeles, concurred, calling a mandatory registry “a great idea.”

“Suicide monitoring as part of that seems to be really important,” Irwin said.

However, some panelists who supported risk management options beyond labeling favored Valeant's proposal for a voluntary registry conducted outside of a REMS. Valeant's proposed REMS consisted only of Medication Guide and health care provider communication plan to minimize the risk of suicidal behavior.

"I found the sponsor's presentation of their pharmacovigilance program and REMS program sufficient," said Michael Blaha, a cardiologist at Johns Hopkins. "My vote was for a voluntary … registry that was described and not a mandatory registry" which sounds "a lot more like a potential barrier to the use of the drug."

Access Is A Concern

Concerns about limiting patient access also were cited by panelists who favored a labeling-only approach to address the potential risk of suicidal ideation and behavior.

Lynn Drake, a dermatologist at Massachusetts General Hospital, emphasized the drug needs to be available to patients and noted that a REMS can have the unintended consequence of hindering patient access to the treatment.

“The insurance companies and/or other providers get spooked and won’t use [the drugs], or the insurance companies won’t cover them," Drake said. "We, in effect, deny patients access to the drug because of the burdensome approval process.”

Matthew Rudorfer, chief of the somatic treatments and psychopharmacology program at the National Institutes of Mental Health, also opposed a REMS, noting that he would not want to scare people away from an effective drug.

Panelists generally agreed that providers should be informed about the six completed suicides in the clinical development program. They also concluded there were no cardiovascular safety signals with the drug.

Should Psychiatric Patients Be Excluded?

Panelists also weighed whether to restrict use of the drug to patients who do not have a history of suicidal behavior.

Rudorfer said the clinical data have not shown the need to exclude patients with a history of depression from using the drug, despite the occurrence of suicides during clinical development. “I would rather not have patients who feel like they were afraid to tell their clinician how they are really feeling,” he said.

FDA reviewers previously reached different conclusions about exclusion criteria.

The agency's Division of Pharmacovigilance did not recommend excluding patients with a history of psychiatric disorders from brodalumab treatment because it has not been established that there is a drug-related risk of suicidal ideation and behavior, and a high proportion of patients with psoriasis have psychiatric disorders.

Conversely, the Division of Epidemiology recommended the drug should be limited to patients without a relevant past psychiatric history to reduce the number of suicidal ideation and behavior events among brodalumab users. (Also see "Valeant's Brodalumab Faces Conflicting FDA Views On Suicide Risk" - Pink Sheet, 15 Jul, 2016.)

Exceptional Efficacy

Valeant officials highlighted brodalumab's efficacy, with Chief Medical Officer Tage Ramakrishna noting that more than 50% of patients taking the drug had complete clearance of their psoriasis within a year. The drug also demonstrated superior efficacy to Janssen Biotech Inc.'s IL-12/23 antagonist Stelara (ustekinumab) in two studies, Valeant said.

The panelists agreed, with Bigby describing brodalumab as “clearly very efficacious.”

The Canadian drugmaker applauded the committee’s endorsement in a statement after the meeting.

"The positive recommendation by the FDA's advisory committee represents an important milestone toward our goal of delivering brodalumab to patients who suffer from moderate-to-severe plaque psoriasis," said CEO Joseph Papa. "Brodalumab has the potential to improve the lives of many patients suffering from this chronic, debilitating disease, and we greatly appreciated the opportunity to present our body of evidence to the panel.”

A Rare Bright Spot For Valeant

Brodalumab appears to have found some light at the end of a dark tunnel. It underwent a tumultuous past year, with its original sponsors – Amgen Inc. and AstraZeneca PLC– jumping the ship.

Amgen backed out in May 2015, just a few months after releasing positive efficacy data from three Phase III studies. The decision followed a pre-submission meeting with FDA at which the suicide safety signal in the clinical trials was discussed. (Also see "Amgen Bows Out Of Partnership With AstraZeneca On Phase III Brodalumab" - Pink Sheet, 22 May, 2015.)

AstraZeneca later transferred rights to the candidate to Valeant in an agreement valued up to $445m. (Also see "AstraZeneca Unburdens Itself Of Brodalumab" - Scrip, 1 Sep, 2015.)

Valeant has had countless other problems of its own over the past year, highlighted by an investigation into the drugmaker’s relationship with specialty online pharmacy Philidor Rx Services Inc. (Also see "Valeant: Another Fine Mess" - Scrip, 2 Mar, 2016.)

The user fee goal date for brodalumab is Nov. 16. The drug is also under review by the European Medicines Agency.