Regulatory Decision Summary for Ikervis

Two Phase III pivotal efficacy studies, SICCANOVE and SANSIKA were submitted, however, only the SANSIKA study was directly relevant to the indication of severe dry eye disease (DED), since it was conducted in patients with severe DED. Both studies failed to show superiority of Ikervis compared to the drug vehicle in the primary efficacy endpoints at six months.

In the SICCANOVE study which included patients with moderate-to-severe DED, no significant difference was found between Ikervis and the drug vehicle in the co-primary endpoint at month 6 of mean change from baseline in clinical signs (corneal fluorescein staining [CFS]) and symptoms (mean change in global score of ocular discomfort).

Exploratory subgroup analyses suggested possible benefits of Ikervis in severe DED, therefore the SANSIKA pivotal trial was modeled to test this hypothesis. In the SANSIKA study involving patients with more severe DED (CFS = 4) at baseline, the primary efficacy endpoint failed to show superiority of Ikervis over the vehicle at 6 months, as shown by the rates of responder simultaneously on sign (CFS improvement by ≥2 grades) and symptoms [Ocular Surface Disease Index (OSDI) improvement by ≥30%].

In the response to the Notice of Non-Compliance, the Sponsor proposed that Health Canada consider only the improvement in clinical signs for approval of Ikervis, despite the failure of the primary composite endpoint. However, the key secondary endpoint of responder on sign alone (CFS improvement by ≥2 grades), and the additional secondary endpoint of responder on symptoms alone also failed. This failure on the main secondary endpoints of response on sign (CFS improvement by ≥2 grades) constitutes the basis for the non-approval of Ikervis with respect to improvement on signs only. In addition, all the remaining 14 secondary endpoints were negative, except possibly for mean CFS change from baseline, and HLA-DR cytology. However, both findings are not deemed statistically robust to be considered acceptable.

In summary:
1) both pivotal clinical trials failed on their respective primary endpoints;
2) the outcome of the submission effectively rests solely on one pivotal trial directly relevant to the indication;
3) the most important secondary endpoint of responder on signs in the relevant pivotal study was not statistically significantly superior (p = 0.35) for Ikervis over vehicle; and
4) 13 of the remaining 15 secondary endpoints were not in favor of Ikervis.

In conclusion, the Sponsor did not provide robust evidence to support the efficacy of Ikervis for the proposed indication and failed to address the major objections raised in the NON. The safety and efficacy of Ikervis was therefore not demonstrated for the proposed indication of treatment of severe keratitis in adult patients with dry eye disease, which has not improved despite treatment with tear substitutes. The benefit-risk profile for Ikervis is therefore not considered favourable.

A Notice of Non-Compliance / Withdrawal is recommended.