Statistical Evaluation of Suicidal Risk
A PubMed and EMBASE database search was conducted with "suicide AND psoriasis" as search terms on March 15, 2016. The limit for the PubMed search was English in the title/abstract field. Limits for the EMBASE search were articles published after 2006. The populationbased cohort studies of psoriasis were selected to determine the suicidal risk of the general psoriasis patient population. The incidence rates of suicidality from the selected populationbased cohort/registry study are shown in Table 5.6. A metaanalysis was conducted to calculate the overall incidence rate of suicidality in the general psoriasis patient population. The metaanalysis using the random effects model shows that the overall incidence rate is 0.57 per 1,000 person year with 95% Cl (0.25,0.84) per 1,000 personyears.
The safety data for the clinical trials for brodalumab, secukinumab, and ixekizumab were obtained from published articles or conference presentations [29, 3334]. The number of suicide attempts or deaths and number of subjects and personyears at risk are shown in Table 5.7. Based on data from Tables 5.6 and 5.7, we can examine whether the suicidal risk in the treatment group in the clinical trials, particularly whether the suicidal risk in the AMAGINE2 and AMAGINE3 trials for brodalumab, are significantly higher than that for the general psoriasis paitient population.
TABLE 5.6
Incidence Rates of Suicidal Attempt from the PopulationBased Cohort or Registry Studies
Reference 
Patient 
Number of Subjects 
Number of Cases 
Incidence Rate per 1,000 Personyears 
Abuabara et al. (2010) [30] 
Severe psoriasis 
3,603 
1 
0.2 
Kurd etal. (2010) 
Mild psoriasis 
146,042 
Not reported 
0.93 
Severe psoriasis 
3,956 
Not reported 
0.92 

Singhal et al. (2014)[31] 
Psoriasis 
119,304 
1,141 
0.74 
Svedbom, et al. (2015) [32] 
Mild psoriasis 
34,355 
27 
0.17 
Severe psoriasis 
4,719 
3 
0.19 
TABLE 5.7
Number of Cases, Subjects, and Exposure for Several Phase 2,3 Trials for Brodalumab, Secukinmab, and Ixekizumab
Drug 
Clinical Trial 
Duration 
Dose 
Number of Subjects 
Exposure 
Number of Suicides 
Brodalumab 
AMAGINE2 & AMAGINE3 
54+ weeks 
210 mg Q2W 
975 
781.2 
2 
12 weeks 
210 mg Q2W 
1,234 
284.8 
1 

Secukinumab 
Pooled 7 clinical trials 
Vary 
S 1 dose 
39,28 
3225.0 
2 
Ixekizumab 
UNCOVER2 and UNCOVER3 
12 weeks 
Q2W 
7,29 
168.2 
1 
12 weeks 
Q4W 
734 
169.4 
1 
In Table 5.7, the risk of suicidal attempts at week 12 were comparable for the AMAGINE2 and AMAGINE3 210mg Q2W dose group and the UNCOVER2 and UNCOVER3 trials. Actually, the exposureadjusted incidence rate of suicidal attempt in the AMAGINE2 and AMAGINE3 trials was lower than that in the UNCOVER2 and UNCOVER3 trials at week 12. Most of the suicidal attempts occurred in the 210mg Q2W group with constant dose. One patient committed three suicidal attempts before week 52, and one additional suicide occurred after week 52 during the openlabel extension in the AMAGINE2 study [29]. The three suicidal attempts are strongly correlated. In the analysis, we count the three attempts as one incidence case. We can assess the probability of observing such numbers of suicidal cases given the incidence rates from the general patient population. We estimate the probability from the Bayesian perspective. Based on the metaanalysis for the suicidal incidence from populationbased cohorts in Table 5.6, the logit of the incidence rate X is distributed as
with jj> = 0.27 and a,, = 0.69. The null hypothesis to be tested is that H_{0}: the suicidal risk in the brodalumab clinical trials is similar to that of the general psoriasis patients. In the clinical trials, the number of suicidal attempt cases Y follows a Poisson distribution
where n is the personyears of exposure to the treatment and X is the incidence rate of suicidal attempt for the psoriasis patients. If the null hypothesis
TABLE 5.8
Probability of Observing the Number of Suicide Cases in the AMAGINE2 and AMAGINE3 Trials for Brodalumab
Duration 
Number of Subjects 
Exposure 
Number of suicides (y) 
P{Y>y) 
54+ weeks 
975 
781.2 
2 
0.067 
12 weeks 
1,234 
284.8 
1 
0.138 
is true, the probability of observing у number of suicidal attempts in the brodalumab clinical trial is
where f(k) is the density function of the background suicidal incidence rates based on Eq. (5.6).
Based on the background suicidal incidence rate estimated from the metaanalysis, the probabilities of observing a certain number of suicidal cases for the two clinical trials for brodalumab are shown in Table 5.8. At the study duration of 54+ weeks, there are 975 patients who receive a 210mg constant dose Q2W and the total exposure time is 781.2 personyear; the posterior mean probability of observing two suicidal subjects or more is P(Y > 2) = 0.067 The corresponding probability for the one case at week 12 is 0.138. Therefore, given the higher background risk of suicidal attempts among the psoriasis patients, it is possible that even though the use of brodalumab did not cause additional risk of suicide, we may still observe two or more suicidal attempts in the AMAGINE2 and AMAGINE3. In addition, multiple AEs are monitored in the safety analysis; the chance of an AE being statistically significant is even higher due to multiple testing. Note that the one subject at week 54 attempted suicide three times. If we count the three suicidal attempts as independent, we may observe four suicidal attempts by week 54. The probability of observing four or more cases is 0.0013. This may indicate a possibility of brodalumab causing suicide. However, this probability estimate is extremely conservative as the multiple suicidal attempts for the same individual are strongly correlated.
Furthermore, there may be some other causal factors related to the suicidal cases for brodalumab. First, antidepressant use might be a confounder that is associated with suicidal risk. Psoriasis patients are increasingly exposed to antidepressant drugs [35], and the use of antidepressants has been linked to suicidality and aggression [36]. Since May 2014, AMAGINE2 and AMAGINE3 started to collect information about the depression scale, but without further information, we cannot run a thorough analysis. In an earlier PLATO trial for Brilinta for cardiovascular diseases, the excessive use of aspirin has been shown to explain the regional difference of relative risk of cardiovascular death [37]. As a confounder, the excess use of antidepressants may explain the difference of suicidal attempts between the brodalumab and placebo groups. In the absence of a control group in the openlabel period, it is possible that the additional one reported suicide may be caused by another crisis not related to drug use. For example, worsening symptoms or recent economic crisis in the United States were associated with an increase in the suicidal rate [38].
Concluding Remarks
Although there are many systemic agents approved for the treatment of psoriasis, getting patients clear of their psoriasis is still a hurdle. Secukinumab (Cosentyx), an inhibitor of IL17, was approved for the treatment of moder atetosevere psoriasis in 2015. Two other inhibitors of IL17, brodalumab and ixekizumab, also are approved by the FDA for treatment of psoriasis. There has been no suicidality signal with secukinumab, nor with ixekizumab. Furthermore, antagonism of cytokine activity, and particularly of cytokines IL6, IL17, and IL23, has not been associated with neurological symptoms. For example, the antiIL6 receptor antibody tocilizumab has shown a positive impact in rheumatoid arthritis patients' qualityoflife scoring, which includes fatigue, anxiety, depression, and a number of other factors. More to the point, the antiIL17 antibody secukinumab, which targets the IL17 ligand (rather than the receptor), has not shown a link to suicide. Given the statistical analysis of realworld evidence, people may cast doubt on the claim that brodalumab increases the risk of suicide. Clearly more data are needed, and it would not be surprising if the FDA began a drug class review if the data in the brodalumab trials warranted it. They could cast quite a wide net given the complexity of this pathway, which overlaps with IL6, IL12, and IL23.