Human Genome Sciences escaped a boxed label warning and a Risk Evaluation and Mitigation Strategy for its lupus drug Benlysta (belimumab), despite FDA expectations late in the review process that both would be needed.

Just two months before FDA approved the first drug in more than 50 years to treat systemic lupus erythematosus, agency officials told HGS to prepare for a boxed warning on mortality.

During a Jan. 6 teleconference, “FDA informed HGS that substantial revisions are to be expected for the product labeling, including the addition of a boxed warning for mortality based on the imbalance of deaths observed in the clinical program,” the teleconference minutes state.

Yet, Benlysta was approved on March 9 without a boxed warning. Instead, the label’s Warnings and Precautions heading includes a section on mortality that reflects the total number, and imbalance, of deaths seen in the clinical program.

A Dozen Deaths Among Benlysta Patients

There were a total of 14 deaths across the placebo-controlled, double-blind treatment periods of three clinical studies, with only three of the deaths occurring in placebo patients. One additional death in a belimumab-treated patient occurred 15 weeks after study withdrawal. Causes of death included cardiovascular events, infections, suicide, respiratory failure and malignancy.

In a Feb. 17 memo, Division of Pulmonary, Allergy and Rheumatology Products’ Cross-Discipline Team Leader Sarah (Okada) Yim says the deaths “were consistent with the anticipated immunosuppressive effects of belimumab and an increase in the risk for serious infections.”

Nevertheless, she noted that while the absolute number of deaths in the clinical trials did not appear excessive, the exposure-adjusted incidence of death was approximately double in the belimumab treatment group compared to the placebo group.

Yet, it seems that concerns about the mortality imbalance did not reach the threshold warranting a boxed warning.

“The absolute number of deaths in the clinical program was not very large and the overall data are not conclusive to link belimumab to death with certainty,” writes DPARP Director Badrul Chowdhury in a March 9 summary review.

REMS Guidance Comes In The Nick Of Time

Benlysta also managed to avoid a REMS, thanks to the luck of timing.

The company first proposed a REMS, consisting solely of a Medication Guide, in November 2010. As late as Feb. 18, 2011, FDA requested HGS submit a revised MedGuide and REMS; the company complied on Feb. 23.

However, on Feb. 28 a Federal Register notice announced the availability of a new FDA draft guidance on MedGuide distribution requirements and REMS. The guidance states that MedGuides generally will be included as part of a REMS only when elements to assure safe use are needed (Also see "MedGuide-Only REMS Will Be The Exception, Not The Norm, As FDA Relaxes Policy" - Pink Sheet, 1 March, 2011.).

In light of this guidance, the review division and Office of Surveillance and Epidemiology concluded that a REMS was no longer required for Benlysta, and the agency simply approved the MedGuide as part of the drug’s labeling.

Benlysta was the second novel product approved after the guidance’s release to escape the burden of a MedGuide-only REMs. The first beneficiary was Forest Laboratories Inc.’s chronic obstructive pulmonary disease treatment Daliresp (roflumilast), approved on Feb. 28 (Also see "Forest/Nycomed's Daliresp Reaches The Market, But For Fewer Patients Than Expected" - Pink Sheet, 7 March, 2011.).

Suicide Events “Unexpected”

While HGS and its co-development and commercialization partner, GlaxoSmithKline PLC, were able to bring Benlysta to market with a clean label and no REMS burdens, they face a long list of post-marketing study requirements and commitments (see story, Also see "FDA’s Benlysta Approval: A Lesson In Overcoming Unvalidated Endpoints" - Pink Sheet, 1 June, 2011. ).

Primary among these is a required five-year, 5,000-patient, randomized, placebo-controlled study to evaluate belimumab’s long-term safety profile. Adverse events of special interest include mortality, malignancy, serious and opportunistic infections and depression/suicidality. The final study protocol must be submitted in September, with trial completion targeted for May 2022.

An increase in psychiatric adverse events, including depression and suicide, was “an unexpected safety finding” in the belimumab clinical program, DPARP Medical Officer Rosemarie Neuner writes in her Feb. 18 clinical review.

There were two completed suicides across the double-blind, placebo-controlled studies, and a third completed suicide during a safety extension study, all in belimumab-treated patients. In addition, there were four cases of suicide attempts or suicidal ideation, and a higher frequency of adverse event reports of depression and depressed mood, among belimumab-treated patients.

HGS’ original BLA submission did not include a formal assessment of the safety data for treatment-emergent suicide. The sponsor subsequently conducted, on its own initiative, a formal retrospective analysis using the Columbia-Classification Algorithm for Suicide Assessment, which did not reveal any new findings or patterns.

DPARP requested a consult from Gregory Dubitsky, a medical officer in the Division of Psychiatry Products. In an Oct. 29 review, Dubitsky said he found no convincing evidence of a psychiatric safety signal, but a definitive conclusion could not be reached due to limited data.

He urged HGS to recalculate reporting rates in the three placebo-controlled trials after combining similar preferred terms. He also recommended that future study protocols for belimumab prospectively incorporate suicidality screenings through use of the Columbia-Suicide Severity Rating Scale at baseline and each patient visit.

Despite its limitations, a 5,000-patient safety study is probably the largest that could feasibly be conducted, FDA concluded.

FDA determined that it would be impractical to require a safety study exceeding 5,000 patients due to the limited patient population, even though the sample size will limit the study’s power and the relative risk that can be ruled out.

“While there is always a tension between attributable risk, severity of safety issue and desire to define precisely the amount of risk, we must also be practical in determining a feasible study size,” Office of Drug Evaluation II Director Curtis Rosebraugh writes in his March 9 memo.

“It is also important to remember that we will not only be obtaining an upper bound of the 95% confidence interval, but we will also be determining a point estimate that will add to the body of safety knowledge. As such, and remembering that ‘the perfect should not be the enemy of the good,’ we have determined that this is probably the largest safety study that the sponsor could perform,” Rosebraugh writes.

By Sue Sutter

Human Genome Sciences Dodges Mortality Boxed Warning, REMS For Benlysta

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