FDA Panel to Weigh Efficacy Data for Belimumab

Food and Drug Administration review documents for the lupus drug belimumab (Benlysta) highlight a variety of agency concerns that appear to undermine the magnitude of the drug’s effects, leaving it up to a Nov. 16 Arthritis Advisory Committee to decide whether the drug’s benefit/risk ratio can still attain positive territory.

A primary issue is that the two phase III trials conducted by Human Genome Sciences enrolled patients who were on a stable systemic lupus erythematosus (SLE) treatment regimen for at least 30 days. Patients with severe lupus kidney disease or active CNS lupus were excluded since they were considered not to be on a stable regimen. Consequently, the most commonly involved organ systems in patients at baseline were musculoskeletal and mucocutaneous.

Therefore, the treatment effect was driven by those patients. "Improvement with belimumab shown in the clinical studies was largely due to the effects on these organ systems," the FDA’s review concludes.

Lupus that affects those two systems can be "debilitating in terms of impairing quality of life, but [those cases] are not generally fatal," the agency acknowledges.

With regard to the more deadly forms of the disease, the agency says, "the data are not adequate to demonstrate efficacy in organ involvement associated with poor outcome and mortality, such as kidneys, central nervous system, and blood vessels."

The company is seeking an indication to reduce disease activity in adults with active, autoantibody-positive, SLE who are receiving standard therapy.

Both pivotal phase III studies – 1056 and 1057 – were the subject of special protocol assessments. The former was a 76-week randomized, double-blind, placebo-controlled trial of 819 patients with active seropositive SLE on stable immunosuppressive medications. It was conducted primarily in North America and Europe. Study 1057 was essentially the same, except it was conducted for only 52 weeks in 865 patients primarily in the Asia Pacific and Latin America. Patients received either 1 mg/kg of belimumab, 10 mg/kg of the drug, or placebo.

SLE Responder Index (SRI) was the primary end point, as measured by the proportion of responders at week 52 with a response of at least a 4-point reduction in the SELENA-SLEDAI score compared to baseline; no worsening (an increase of less than 0.3 points from baseline) in physician global assessment; and no new BILAG A organ domain scores or two new BILAG B organ domain scores at 52 weeks compared to baseline.

Patients treated with belimumab 10 mg/kg had a statistically higher rate of response than placebo patients in both studies. The proportion of patients achieving success for each of the subcomponents was numerically higher in the belimumab groups than placebo in each study, although the differences reached statistical significance only in Study 1057.

Belimumab Efficacy May Be Short Lived

The longer-term data from Study 1056 throw into question the robustness of belimumab’s efficacy, the FDA says. In Study 1057, response improved over time and reached statistical significance at week 52. The same pattern occurred in Study 1056, but the statistical significance was lost by week 76 in the longer study.

"A potentially slower onset of benefit and a potential lack of durability need to be considered," since belimumab would be administered as a chronic treatment for SLE, the FDA says.

The agency also found troubling an inconsistent efficacy trend across geographical regions, particularly a numerically smaller difference in efficacy for patients in the United States and Canada, compared to other regions. The SRI for the North American patients in Study 1056 was 32% for placebo and 35% for belimumab 10 mg/kg. In comparison, the SRI for Latin American patients in Study 1057 was 49% in the placebo arm and 61% for the belimumab 10 mg/kg arm.

A post-hoc analysis of racial subgroups found a lack of demonstrated efficacy in patients of African American or African heritage. In Study 1056, 39% of these patients met the SRI, compared to 33% of belimumab 10 mg/kg patients; in Study 1057, those figures were 64% and 46%, respectively.

Sensitivity Analysis Addresses "Medication Failures"

Further complicating interpretation of the efficacy results was the large number of patients in the studies’ placebo arms who switched to protocol-prohibited or restricted background SLE medications. Per protocol, these "medication failures" were considered treatment failures.

Because these treatment failures "may have exaggerated the difference between placebo and belimumab for the primary endpoint analysis," FDA conducted a sensitivity analysis in which the medical team used its judgment to post-hoc assign some of the medical failures to a primary efficacy outcome.

The primary end point for subjects using statins or angiotensin-pathway antihypertensives was designated as a success for placebo subjects and a failure for belimumab recipients.

"Motivation for this imputation scheme was to take a very conservative approach for medication failure subjects who the clinical team did not feel would have unquestionably proceeded to be an efficacy failure had they not received the prohibited medication," the FDA’s briefing document explains.

Based on these assignments the sensitivity analysis found the results for study 1057 to be generally consistent with the primary efficacy analysis.

However, for Study 1056, the difference in treatment effect between the 10 mg/kg belimumab and placebo arms is only marginally statistically significant. This suggests that results of the primary efficacy analyses are "dependent on the disproportional occurrence of medication failures" in the placebo group of that study.

The apparently higher need for rescue medication in the placebo group can be taken as an unofficial signal of efficacy for belimumab, the agency acknowledges. But, the agency concludes, "the clinical importance of taking a prohibited medication relative to the clinical importance of the primary efficacy end point should be evaluated and kept in mind in interpreting the primary efficacy results."

Suicidality an Unexpected Addition to the Safety Issues

In addressing the safety issues that will be presented to the advisory panel, the FDA noted the somewhat unexpected increase in the risk for neuropsychiatric adverse events – suicide in particular. The safety database included 2,133 patients in the two phase III trials plus a randomized, placebo-controlled phase II study (L02).

Two suicides occurred among belimumab patients during the studies, with another in the safety extension of L02. Four cases of suicide attempts or suicidal ideation occurred in belimumab patients. Depression was the most serious adverse event in the psychiatric disorder category. '

Other safety issues to be discussed at the committee are the potential for death – a rate of 0.79 per 100 patient-years for belimumab patients versus 0.43 for those on placebo – as well as malignancies and infections, which have been recognized risks for the drug.

The advisory committee’s review of the efficacy and safety of belimumab comes in the context of Benlysta having the potential to be the first new drug for lupus in 50 years. The prescriber and patient communities are eager for a new therapy.

Elsevier Global Medical News and "The Pink Sheet" are both published by Elsevier.

Food and Drug Administration review documents for the lupus drug belimumab (Benlysta) highlight a variety of agency concerns that appear to undermine the magnitude of the drug’s effects, leaving it up to a Nov. 16 Arthritis Advisory Committee to decide whether the drug’s benefit/risk ratio can still attain positive territory.

A primary issue is that the two phase III trials conducted by Human Genome Sciences enrolled patients who were on a stable systemic lupus erythematosus (SLE) treatment regimen for at least 30 days. Patients with severe lupus kidney disease or active CNS lupus were excluded since they were considered not to be on a stable regimen. Consequently, the most commonly involved organ systems in patients at baseline were musculoskeletal and mucocutaneous.

Therefore, the treatment effect was driven by those patients. "Improvement with belimumab shown in the clinical studies was largely due to the effects on these organ systems," the FDA’s review concludes.

Lupus that affects those two systems can be "debilitating in terms of impairing quality of life, but [those cases] are not generally fatal," the agency acknowledges.

With regard to the more deadly forms of the disease, the agency says, "the data are not adequate to demonstrate efficacy in organ involvement associated with poor outcome and mortality, such as kidneys, central nervous system, and blood vessels."

The company is seeking an indication to reduce disease activity in adults with active, autoantibody-positive, SLE who are receiving standard therapy.

Both pivotal phase III studies – 1056 and 1057 – were the subject of special protocol assessments. The former was a 76-week randomized, double-blind, placebo-controlled trial of 819 patients with active seropositive SLE on stable immunosuppressive medications. It was conducted primarily in North America and Europe. Study 1057 was essentially the same, except it was conducted for only 52 weeks in 865 patients primarily in the Asia Pacific and Latin America. Patients received either 1 mg/kg of belimumab, 10 mg/kg of the drug, or placebo.

SLE Responder Index (SRI) was the primary end point, as measured by the proportion of responders at week 52 with a response of at least a 4-point reduction in the SELENA-SLEDAI score compared to baseline; no worsening (an increase of less than 0.3 points from baseline) in physician global assessment; and no new BILAG A organ domain scores or two new BILAG B organ domain scores at 52 weeks compared to baseline.

Patients treated with belimumab 10 mg/kg had a statistically higher rate of response than placebo patients in both studies. The proportion of patients achieving success for each of the subcomponents was numerically higher in the belimumab groups than placebo in each study, although the differences reached statistical significance only in Study 1057.

Belimumab Efficacy May Be Short Lived

The longer-term data from Study 1056 throw into question the robustness of belimumab’s efficacy, the FDA says. In Study 1057, response improved over time and reached statistical significance at week 52. The same pattern occurred in Study 1056, but the statistical significance was lost by week 76 in the longer study.

"A potentially slower onset of benefit and a potential lack of durability need to be considered," since belimumab would be administered as a chronic treatment for SLE, the FDA says.

The agency also found troubling an inconsistent efficacy trend across geographical regions, particularly a numerically smaller difference in efficacy for patients in the United States and Canada, compared to other regions. The SRI for the North American patients in Study 1056 was 32% for placebo and 35% for belimumab 10 mg/kg. In comparison, the SRI for Latin American patients in Study 1057 was 49% in the placebo arm and 61% for the belimumab 10 mg/kg arm.

A post-hoc analysis of racial subgroups found a lack of demonstrated efficacy in patients of African American or African heritage. In Study 1056, 39% of these patients met the SRI, compared to 33% of belimumab 10 mg/kg patients; in Study 1057, those figures were 64% and 46%, respectively.

Sensitivity Analysis Addresses "Medication Failures"

Further complicating interpretation of the efficacy results was the large number of patients in the studies’ placebo arms who switched to protocol-prohibited or restricted background SLE medications. Per protocol, these "medication failures" were considered treatment failures.

Because these treatment failures "may have exaggerated the difference between placebo and belimumab for the primary endpoint analysis," FDA conducted a sensitivity analysis in which the medical team used its judgment to post-hoc assign some of the medical failures to a primary efficacy outcome.

The primary end point for subjects using statins or angiotensin-pathway antihypertensives was designated as a success for placebo subjects and a failure for belimumab recipients.

"Motivation for this imputation scheme was to take a very conservative approach for medication failure subjects who the clinical team did not feel would have unquestionably proceeded to be an efficacy failure had they not received the prohibited medication," the FDA’s briefing document explains.

Based on these assignments the sensitivity analysis found the results for study 1057 to be generally consistent with the primary efficacy analysis.

However, for Study 1056, the difference in treatment effect between the 10 mg/kg belimumab and placebo arms is only marginally statistically significant. This suggests that results of the primary efficacy analyses are "dependent on the disproportional occurrence of medication failures" in the placebo group of that study.

The apparently higher need for rescue medication in the placebo group can be taken as an unofficial signal of efficacy for belimumab, the agency acknowledges. But, the agency concludes, "the clinical importance of taking a prohibited medication relative to the clinical importance of the primary efficacy end point should be evaluated and kept in mind in interpreting the primary efficacy results."

Suicidality an Unexpected Addition to the Safety Issues

In addressing the safety issues that will be presented to the advisory panel, the FDA noted the somewhat unexpected increase in the risk for neuropsychiatric adverse events – suicide in particular. The safety database included 2,133 patients in the two phase III trials plus a randomized, placebo-controlled phase II study (L02).

Two suicides occurred among belimumab patients during the studies, with another in the safety extension of L02. Four cases of suicide attempts or suicidal ideation occurred in belimumab patients. Depression was the most serious adverse event in the psychiatric disorder category. '

Other safety issues to be discussed at the committee are the potential for death – a rate of 0.79 per 100 patient-years for belimumab patients versus 0.43 for those on placebo – as well as malignancies and infections, which have been recognized risks for the drug.

The advisory committee’s review of the efficacy and safety of belimumab comes in the context of Benlysta having the potential to be the first new drug for lupus in 50 years. The prescriber and patient communities are eager for a new therapy.

Elsevier Global Medical News and "The Pink Sheet" are both published by Elsevier.

Food and Drug Administration review documents for the lupus drug belimumab (Benlysta) highlight a variety of agency concerns that appear to undermine the magnitude of the drug’s effects, leaving it up to a Nov. 16 Arthritis Advisory Committee to decide whether the drug’s benefit/risk ratio can still attain positive territory.

A primary issue is that the two phase III trials conducted by Human Genome Sciences enrolled patients who were on a stable systemic lupus erythematosus (SLE) treatment regimen for at least 30 days. Patients with severe lupus kidney disease or active CNS lupus were excluded since they were considered not to be on a stable regimen. Consequently, the most commonly involved organ systems in patients at baseline were musculoskeletal and mucocutaneous.

Therefore, the treatment effect was driven by those patients. "Improvement with belimumab shown in the clinical studies was largely due to the effects on these organ systems," the FDA’s review concludes.

Lupus that affects those two systems can be "debilitating in terms of impairing quality of life, but [those cases] are not generally fatal," the agency acknowledges.

With regard to the more deadly forms of the disease, the agency says, "the data are not adequate to demonstrate efficacy in organ involvement associated with poor outcome and mortality, such as kidneys, central nervous system, and blood vessels."

The company is seeking an indication to reduce disease activity in adults with active, autoantibody-positive, SLE who are receiving standard therapy.

Both pivotal phase III studies – 1056 and 1057 – were the subject of special protocol assessments. The former was a 76-week randomized, double-blind, placebo-controlled trial of 819 patients with active seropositive SLE on stable immunosuppressive medications. It was conducted primarily in North America and Europe. Study 1057 was essentially the same, except it was conducted for only 52 weeks in 865 patients primarily in the Asia Pacific and Latin America. Patients received either 1 mg/kg of belimumab, 10 mg/kg of the drug, or placebo.

SLE Responder Index (SRI) was the primary end point, as measured by the proportion of responders at week 52 with a response of at least a 4-point reduction in the SELENA-SLEDAI score compared to baseline; no worsening (an increase of less than 0.3 points from baseline) in physician global assessment; and no new BILAG A organ domain scores or two new BILAG B organ domain scores at 52 weeks compared to baseline.

Patients treated with belimumab 10 mg/kg had a statistically higher rate of response than placebo patients in both studies. The proportion of patients achieving success for each of the subcomponents was numerically higher in the belimumab groups than placebo in each study, although the differences reached statistical significance only in Study 1057.

Belimumab Efficacy May Be Short Lived

The longer-term data from Study 1056 throw into question the robustness of belimumab’s efficacy, the FDA says. In Study 1057, response improved over time and reached statistical significance at week 52. The same pattern occurred in Study 1056, but the statistical significance was lost by week 76 in the longer study.

"A potentially slower onset of benefit and a potential lack of durability need to be considered," since belimumab would be administered as a chronic treatment for SLE, the FDA says.

The agency also found troubling an inconsistent efficacy trend across geographical regions, particularly a numerically smaller difference in efficacy for patients in the United States and Canada, compared to other regions. The SRI for the North American patients in Study 1056 was 32% for placebo and 35% for belimumab 10 mg/kg. In comparison, the SRI for Latin American patients in Study 1057 was 49% in the placebo arm and 61% for the belimumab 10 mg/kg arm.

A post-hoc analysis of racial subgroups found a lack of demonstrated efficacy in patients of African American or African heritage. In Study 1056, 39% of these patients met the SRI, compared to 33% of belimumab 10 mg/kg patients; in Study 1057, those figures were 64% and 46%, respectively.

Sensitivity Analysis Addresses "Medication Failures"

Further complicating interpretation of the efficacy results was the large number of patients in the studies’ placebo arms who switched to protocol-prohibited or restricted background SLE medications. Per protocol, these "medication failures" were considered treatment failures.

Because these treatment failures "may have exaggerated the difference between placebo and belimumab for the primary endpoint analysis," FDA conducted a sensitivity analysis in which the medical team used its judgment to post-hoc assign some of the medical failures to a primary efficacy outcome.

The primary end point for subjects using statins or angiotensin-pathway antihypertensives was designated as a success for placebo subjects and a failure for belimumab recipients.

"Motivation for this imputation scheme was to take a very conservative approach for medication failure subjects who the clinical team did not feel would have unquestionably proceeded to be an efficacy failure had they not received the prohibited medication," the FDA’s briefing document explains.

Based on these assignments the sensitivity analysis found the results for study 1057 to be generally consistent with the primary efficacy analysis.

However, for Study 1056, the difference in treatment effect between the 10 mg/kg belimumab and placebo arms is only marginally statistically significant. This suggests that results of the primary efficacy analyses are "dependent on the disproportional occurrence of medication failures" in the placebo group of that study.

The apparently higher need for rescue medication in the placebo group can be taken as an unofficial signal of efficacy for belimumab, the agency acknowledges. But, the agency concludes, "the clinical importance of taking a prohibited medication relative to the clinical importance of the primary efficacy end point should be evaluated and kept in mind in interpreting the primary efficacy results."

Suicidality an Unexpected Addition to the Safety Issues

In addressing the safety issues that will be presented to the advisory panel, the FDA noted the somewhat unexpected increase in the risk for neuropsychiatric adverse events – suicide in particular. The safety database included 2,133 patients in the two phase III trials plus a randomized, placebo-controlled phase II study (L02).

Two suicides occurred among belimumab patients during the studies, with another in the safety extension of L02. Four cases of suicide attempts or suicidal ideation occurred in belimumab patients. Depression was the most serious adverse event in the psychiatric disorder category. '

Other safety issues to be discussed at the committee are the potential for death – a rate of 0.79 per 100 patient-years for belimumab patients versus 0.43 for those on placebo – as well as malignancies and infections, which have been recognized risks for the drug.

The advisory committee’s review of the efficacy and safety of belimumab comes in the context of Benlysta having the potential to be the first new drug for lupus in 50 years. The prescriber and patient communities are eager for a new therapy.

Elsevier Global Medical News and "The Pink Sheet" are both published by Elsevier.