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 population-based 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 population-based cohort/registry study are shown in Table 5.6. A meta-analysis was conducted to calculate the overall incidence rate of suicidality in the general psoriasis patient population. The meta-analysis 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 person-years.

The safety data for the clinical trials for brodalumab, secukinumab, and ixekizumab were obtained from published articles or conference presentations [29, 33-34]. The number of suicide attempts or deaths and number of subjects and person-years 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 AMAGINE-2 and AMAGINE-3 trials for brodalumab, are significantly higher than that for the general psoriasis paitient population.

TABLE 5.6

Incidence Rates of Suicidal Attempt from the Population-Based Cohort or Registry Studies

Reference

Patient

Number of Subjects

Number of Cases

Incidence Rate per 1,000 Person-years

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

AMAGINE-2 & AMAGINE-3

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

UNCOVER-2

and

UNCOVER-3

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 AMAGINE-2 and AMAGINE-3 210-mg Q2W dose group and the UNCOVER-2 and UNCOVER-3 trials. Actually, the exposure-adjusted incidence rate of suicidal attempt in the AMAGINE-2 and AMAGINE-3 trials was lower than that in the UNCOVER-2 and UNCOVER-3 trials at week 12. Most of the suicidal attempts occurred in the 210-mg Q2W group with constant dose. One patient committed three suicidal attempts before week 52, and one additional suicide occurred after week 52 during the open-label extension in the AMAGINE-2 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 meta-analysis for the suicidal incidence from population-based 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 H0: 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 person-years 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 AMAGINE-2 and AMAGINE-3 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 210-mg constant dose Q2W and the total exposure time is 781.2 person-year; 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 AMAGINE-2 and AMAGINE-3. 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, AMAGINE-2 and AMAGINE-3 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 open-label 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 IL-17, was approved for the treatment of moder- ate-to-severe psoriasis in 2015. Two other inhibitors of IL-17, 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 IL-6, IL-17, and IL-23, has not been associated with neurological symptoms. For example, the anti-IL-6 receptor antibody tocilizumab has shown a positive impact in rheumatoid arthritis patients' quality-of-life scoring, which includes fatigue, anxiety, depression, and a number of other factors. More to the point, the anti-IL-17 antibody secukinumab, which targets the IL-17 ligand (rather than the receptor), has not shown a link to suicide. Given the statistical analysis of real-world 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 IL-6, IL-12, and IL-23.

 
Source
< Prev   CONTENTS   Source   Next >