RHAPSIDO Film-coated tablet Ref.[116560] Active ingredients: Remibrutinib

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: L04AA60

Mechanism of action

Remibrutinib is a selective Bruton's tyrosine kinase (BTK) inhibitor that forms a covalent bond with a cysteine residue in the BTK active site, leading to durable inactivation of BTK. The therapeutic effect of remibrutinib in CSU is achieved through inhibition of mast cell and basophil degranulation, including release of histamine and other proinflammatory mediators, mediated by pathogenic IgE or IgG directed against the FcεR1 or IgE.

Pharmacodynamic effects

Cardiac electrophysiology

The effects of remibrutinib on QTc interval prolongation were predicted using concentration-QTc analysis. The upper bound of the 90% confidence interval for the predicted mean change in QTcF was below 10 msec at the expected C_max at supratherapeutic exposures. Therefore, no clinically significant prolongation of QTcF interval is expected with therapeutic dosing of remibrutinib.

Clinical efficacy and safety

The efficacy and safety of remibrutinib were evaluated in two identical, multicentre, randomised, double-blind, placebo-controlled phase III studies (REMIX-1 and REMIX-2) in adult patients with inadequately controlled CSU despite treatment with second-generation H1 antihistamines.

In REMIX-1 and REMIX-2, patients were randomised in a 2:1 ratio to receive either remibrutinib 25 mg or placebo, respectively, twice daily via the oral route for 24 weeks during the double-blind treatment period and continued in a 28-week open-label treatment period during which all patients received remibrutinib 25 mg twice daily.

REMIX-1 and REMIX-2 enrolled a total of 925 adult patients diagnosed with CSU that was inadequately controlled despite treatment with a standard dose of a second-generation H1 antihistamine as defined by the presence of itch and hives for ≥6 consecutive weeks. All patients were required to have a weekly urticaria activity score (UAS7) ≥16 (range 0 to 42), a weekly itch severity score (ISS7) ≥6 (range 0 to 21) and a weekly hives severity score (HSS7) ≥6 (range 0 to 21) for 7 days prior to randomisation. In addition to all patients receiving a stable dose of a second-generation H1 antihistamine (background therapy), patients were allowed to use another second-generation H1 antihistamine on an "as-needed" basis (rescue therapy) in doses up to 4-fold the standard dose. Patients were excluded from these studies if they had evidence of clinically significant cardiovascular disease, a significant bleeding risk, coagulation disorders, ongoing, chronic or recurrent infection, chronic or acute hepatic disease with evidence of ongoing hepatitis C or B, history of renal disease, history of gastrointestinal bleeding or history of malignancy in the last 5 years.

Demographics and baseline characteristics were generally well balanced across all groups. In REMIX-1 and REMIX-2, the median age was 45 years (range: 18-79 years) and 41 years (range: 18-81 years), with 9.6% and 7.7% ≥65 years of age and 68.3% and 65.3% female patients, respectively. Patients had a mean UAS7 of 30.28 and 29.99, a mean ISS7 of 14.59 and 14.15, and a mean HSS7 of 15.69 and 15.84, respectively. At baseline, 63.4% and 59.1% of the patients had severe disease (UAS7 ≥28) and 35.1% and 38.7% had moderate disease (UAS7 >16 and <28), respectively. 51.7% and 46.6% of the patients had previous experience of angioedema in REMIX-1 and REMIX-2, respectively. 68.1% and 69.2% of patients were anti-IgE biologic naive in REMIX-1 and REMIX-2, respectively. The most common prior anti-IgE biologic used was omalizumab (19.5% and 19.0% in REMIX-1 and REMIX-2, respectively).

The reported mean duration of CSU at enrollment across treatment groups was 6.6 and 5.2 years in REMIX-1 and REMIX-2, respectively, with 39.4% and 29.5% of patients having had a duration of CSU >5 years.

The primary endpoint for the pivotal studies was:

• absolute change from baseline in UAS7 at week 12.

The secondary endpoints for the pivotal studies were:

• absolute change from baseline in ISS7 and HSS7 at week 12
• proportion of patients who achieved well-controlled disease (UAS7 ≤6) at weeks 2 and 12
• proportion of patients who achieved complete absence of itch and hives (UAS7 = 0) at week 12
• proportion of patients who achieved Dermatology Life Quality Index (DLQI) score = 0-1 (yes/no) at week 12
• number of weeks with sustained disease activity control (UAS7 ≤6) up to week 12
• number of angioedema-free weeks (weekly angioedema activity score [AAS7] = 0) up to week 12.

Clinical response

In both REMIX-1 and REMIX-2, the primary and all secondary endpoints were met and showed statistically significant and clinically meaningful improvements in itch and hives symptoms in patients treated with remibrutinib compared to patients given placebo. Results are presented in Table 2 and Figure 1.

Table 2. Efficacy results in REMIX-1 and REMIX-2 at week 12^a,b:

LS mean: Least squares mean, SE: standard error, CFB: change from baseline, CI: confidence interval, p-value: one-sided p-value, UAS7: weekly urticaria activity score, ISS7 score: weekly itch severity score, HSS7: weekly hive severity score, DLQI: dermatology life quality index, AAS7: weekly angioedema activity score.
^a All endpoints with nominal one-sided p<0.001
^b One endpoint from week 2 (all other endpoints are from week 12)

Figure 1. Mean change from baseline in UAS7 up to week 12 in REMIX-1 and REMIX-2 (observed data):

b.i.d. = twice daily

Subgroup analyses demonstrated a consistent treatment benefit with remibrutinib over placebo across subgroups including prior exposure to anti-IgE biologics and total IgE level.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Rhapsido in one or more subsets of the paediatric population in CSU (see section 4.2 for information on paediatric use).