Efficacy, Safety, Patient Experience, and Tolerability of Risankizumab Administered by On-Body Injector for Moderate to Severe Crohn’s Disease

FORTIFY SS4 was conducted from June 17, 2021, to May 18, 2022, at 24 sites in the US. A total of 46 patients were enrolled in the study: 31 patients in the 180 mg OBI treatment arm and 15 patients in the 360 mg OBI treatment arm. Only patients who received rescue therapy prior to SS4 entry remained on 360 mg in SS4; therefore, fewer patients were in this treatment arm due to study design.

Patient Baseline Demographics and Disease Characteristics

A similar number of males and females (Table 1) were enrolled in FORTIFY SS4 [22 females (47.8%), 24 males (52.2%)]. Of the 46 patients enrolled, 21 (45.7%) were 18 to < 40 years old, 20 (43.5%) were between the ages of ≥ 40 and < 65 years, and 5 (10.9%) were ≥ 65 years old. Similar numbers of patients had a normal (14), overweight (15), and obese (14) body mass index (BMI), with two having an underweight BMI (and one missing data at Week 0). Average daily stool frequency (SD) was 2.2 (2.3), average daily abdominal pain (SD) was 0.5 (0.5), and CDAI (SD) was 113.3 (69.9).

Table 1 Baseline demographic and disease characteristics of the ITT populationPatient Disposition

In total, 46, 42, and 45 patients self-administered risankizumab using the OBI at Week 0 (in office), Week 8 (at home), and Week 16 (in office), respectively (Table S3). Three patients returned unused Week 8 kits and reported missing the dose (reasons captured were travel and feeling healthy). A fourth patient did not return a kit, and there was no confirmation of self-administration. At Week 16, 45 of 46 patients self-administered. One patient had the study drug interrupted due to a serious AE and did not self-administer with the OBI. No patient prematurely discontinued in FORTIFY SS4. Most self-administrations occurred in the abdomen, with 69.6% (32/46), 58.7%, (27/42), and 76.1% (35/45) injecting in the abdomen at Weeks 0, 8, and 16, respectively.

Successful Self-Administration

Self-administration, as observed by site staff, was assessed on a patient level at Weeks 0 and 16. At the Week 0 visit, 100% of patients (46/46) successfully self-administered risankizumab via OBI, including two patients who experienced a dosing failure (no drug administered) during their first self-administration attempt, and required a second OBI to successfully self-administer during a subsequent attempt. At Week 16, 100% of patients (44/44) successfully self-administered risankizumab via OBI, including one patient who again experienced a dosing failure and required a second OBI to successfully self-administer risankizumab. Five use-related hazards, as described below, were assessed by site staff for the patient for whom a second OBI at both Weeks 0 and 16 was required.

Achievement of No Potential Use-Related Hazards

Overall, the proportion of patients achieving zero use-related hazards with the OBI was high [44/46 (95.7%)] at both Week 0 and Week 16 [95.5% (42/44); Table S5]: 2 patients did not complete the case report form for use-related hazards at Week 16, and therefore only 44 patients were assessed at Week 16. Use-related hazards related to dosing failure were observed for two patients at Week 0 and one patient at Week 16 (for whom use-related hazards were also reported at Week 0). An additional patient had missing values for one of the assessed use-related hazards at Week 16, and was conservatively counted as having a use-related hazard. All use-related hazards assessed are shown in Table S6. For the patient with use-related hazards assessed at both Week 0 and 16, three use-related hazards (administration delayed due to device malfunction, door could not open/was damaged, administration was not completed because of device delivery error notification) were reported for the Week 0 injection, while two use-related hazards (door could not open/was damaged, administration was not completed because of device delivery error notification) were reported for the Week 16 injection. In both instances, the patient reported that the OBI door would not close. For this patient, as well as for the other patient who required a second OBI for successful risankizumab administration at Week 0, the root cause was determined to be incomplete cartridge insertion; these patients were able to complete all critical steps of the IFU with a second OBI. A use-related hazard of underdose was assessed for the second patient at Week 0. The root cause of this dosing failure was determined to be that the start button was pressed prior to securely placing the OBI on the skin, which resulted in dampness at the injection area of the OBI (i.e., ‘wet injection’). Inspection by the site staff revealed that the adhesive was not securely attached to the skin. Secure attachment led to the resolution of the damp sensation, and the device performed as intended.

Patient Rating of Acceptability

The mean (SD) SIAQ pre-dose (3 modules) domain scores were high prior to the initial administration of risankizumab via OBI (‘feelings about injection,’ 8.5 (2.0); ‘self-confidence,’ 8.5 (1.9); and ‘satisfaction with self-injection,’ 8.4 (1.9), indicating a positive feeling toward self-administered injections prior to OBI use. Post-dose (6 modules) domain scores were high (i.e., ≥ 8.5) after initial OBI use at Week 0 (positive feelings about self-administered injections = 9.0, self-image = 9.5, self-confidence = 8.8, pain and skin reactions during or after the injection = 9.3, ease of use of the self-injection device = 8.9, and satisfaction with self-injection = 8.5) and remained consistently high following at home injection at Week 8 and after final OBI-mediated risankizumab administration at Week 16 (Fig. 2).

Fig. 2figure 2

Post-module mean SIAQ domain scores over time, ITT4a, AOb. aITT4 Population includes all patients who received at least one dose of study drug in the substudy 4; bData are as observed. Scores range from 0 (worst experience) to 10 (best experience).#n = 31 except for ‘Ease of use of the self-injection device’ and ‘Satisfaction with self-injection’, n = 30; ^n = 15 except for ‘Pain and skin reactions during or after the injection,’ ‘Ease of use of the self-injection device,’ ‘Satisfaction with self-injection’, n = 14; $n = 14 except for ‘Self image,’ n = 13; §n = 46 except for ‘Pain and skin reactions during or after the injection,’ n = 45, ‘Ease of use of the self-injection device’ and ‘Satisfaction with self-injection,’ n = 44; ¶n = 39 except for ‘Self-image,’ n = 38

The proportion of patients achieving the top two response categories in both the pre- and post-modules of the SIAQ are presented in Table S7. Results from select individual questions in the post-module provided additional context to the ease of administration, satisfaction, and self-confidence in self-administration of the OBI (Table 2). For example, in response to the question ‘How difficult or easy was it to use the self-injection device?’, 93.2% (41/44) of patients answered ‘easy’ or ‘very easy’ at Week 0, followed by 97.7% (43/44) at Week 16. In response to ‘How difficult or easy was it to administer the injection without any help?’, 90.9% (40/44) answered ‘easy’ or ‘very easy’ at Week 0, followed by 93.2% (41/44) at Week 16. In addition, 97.7% (43/44) responded that it was ‘very easy’ or ‘extremely easy’ to ‘give yourself an injection’ at Week 0, followed by 93.2% (41/44) at Week 16, 90.9% (40/44) were ‘satisfied’ or ‘very satisfied’ with ‘your current way of taking your medication (self-injection)’ at Week 0, followed by 84.1% (37/44) at Week 16, 97.7% (43/44), were ‘very’ or ‘extremely’ confident to ‘give yourself injections at home’ at Week 0, followed by 95.5% (42/44) at Week 16, and 87% (40/46) were ‘very confident’ or ‘extremely confident’ in ‘giving your injection in the right way’ at Week 0, followed by 93.2% (41/44) at Week 16.

Table 2 Results from selected individual questions from the SIAQ post-module for self-administration of risankizumab via an OBI at Week 0 and Week 16 (ITT4 population)CDAI Clinical Remission

CDAI clinical remission (CDAI < 150) was stable over the 16-week OBI treatment period. For patients with available data (i.e., per AO analyses), 82.2% (37/45) of patients at Week 0 were in clinical remission and 84.2% (32/38) were in clinical remission at Week 16 (Fig. 3). Based on NRI analyses, 80.4% (37/46) of subjects at Week 0 were in clinical remission and 69.6% (32/46) were in clinical remission at Week 16.

Fig. 3figure 3

CDAI clinical remissiona, ITT4b, AOc. aCDAI clinical remission is defined as CDAI < 150; bITT4 population includes all patients who received at least one dose of study drug in the substudy 4; cdata are as observed; all available measurements were used for analysis and did not impute values for missing evaluations

Pharmacokinetics and Immunogenicity

Following risankizumab 180 mg SC and 360 mg SC administration via OBI at Weeks 0 and 8, serum trough concentrations were consistent between Week 0 (median at 5.99 and 8.01 µg/mL for 180 and 360 mg, respectively) and Week 16 (median at 5.48 and 7.35 µg/mL for 180 and 360 mg, respectively) time points for both dose arms, with dose-related differences between 180 and 360 mg, demonstrating that doses administered via OBI achieved the expected risankizumab exposures for these patients (Fig. 4).

Fig. 4figure 4

Risankizumab serum trough concentration by maintenance regimen at Weeks 0 and 16 in SS4. Risankizumab concentrations at scheduled pharmacokinetic assessments in the study. Horizontal bars in each box represent median, open circles represent arithmetic mean, whiskers extending from each box represent 1.5 times the inter-quartile range (25th to 75th percentiles)

Overall treatment-emergent ADA and NAb incidence in patients who received either 180 or 360 mg OBI during Weeks 0–16 was 2.2% (1/46) and 0%, respectively (Table S8). Following the use of OBI during the study, no patient developed de novo ADAs or NAbs, indicating no marked impact on immunogenicity by SC administrations via OBI (Table S8).

Safety

TEAEs were reported in 41.3% (19/46) of patients (Table 3). Most frequently reported AEs (by MedDRA 23.1 Preferred Term) included COVID-19 [4/46 (8.7%), all in the 180-mg risankizumab OBI arm] and hypokalemia [3/46 (6.5%), all in the 180-mg risankizumab OBI arm]. No other TEAE was reported in more than two subjects.

Table 3 Overview of TEAEs

Three patients reported a total of five serious AEs (SAEs), all in the 180 mg risankizumab OBI arm. One patient with history of stenosing ileal CD experienced two SAEs (reported terms, inflamed terminal ileum with small bowel perforation on day 97 after the baseline of SS4, and surgical removal of perforated ileal stricture on day 142 after the baseline of SS4); neither event was considered to be related to risankizumab or the OBI by the investigator. The second patient experienced an SAE of acute pancreatitis on day 138 after the baseline of SS4 that was judged not to be related to risankizumab nor the OBI by the investigator. The third patient experienced SAEs of Crohn’s colitis and intestinal obstruction on day 127 after the baseline of SS4; neither event was considered related to risankizumab or the OBI by the investigator.

Two patients (4.3%, 2/46) reported non-serious AEs of hypersensitivity, both dermatitis contact, which were assessed by the investigator as related to the OBI; one event was at Week 0 (180 mg risankizumab) and was mild in severity, while the other was at Week 8 (360 mg risankizumab) and was moderate in severity. Both events resolved, and both subjects self-administered with the OBI at the subsequent visits without further hypersensitivity AEs reported. An additional patient experienced a non-serious AE of rash (papular skin rash on back), that was moderate in severity and occurred approximately 4 weeks after the Week 16 OBI administration. The event was considered not related to the OBI and was assessed as having a reasonable possibility of being related to risankizumab per investigator’s opinion. There were two non-serious events of injection site reactions (180 mg risankizumab OBI). One patient reported events of injection site redness and injection site erythema (described as mild pain and discomfort that was related to the OBI adhesive pulling the hair) at the Week 0 visit. The other patient reported injection site pain at the Week 16 visit. Both events were mild, transient (resolved in 1 day), and neither was considered related to study drug or the OBI according to the investigator. No AEs were reported in other areas of safety interest.

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