Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Sanofi B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands
Pharmacotherapeutic group: not yet assigned
ATC code: not yet assigned
Bruton's tyrosine kinase (BTK) is an intracellular signalling molecule of the B-cell and innate immune cells. In B-cells, BTK signalling results in B-cell survival, proliferation, and maturation. In innate immune cells, BTK participates in inflammatory pathways that include, toll-like receptor signalling, Fc gamma receptor signalling, and the activation of the NLRP3 inflammasome.
Rilzabrutinib is a selective, covalent, reversible inhibitor of BTK, with a tailored residence time at BTK to reduce off-target effects. In ITP, rilzabrutinib mediates its therapeutic effect through multi-immune modulation by inhibiting B cell activation, interruption of FcγR mediated phagocytosis, and potentially amelioration of chronic inflammation associated with ITP.
In the "Thorough QT Study", co-administration of 400 mg rilzabrutinib and the CYP3A inhibitor (ritonavir) resulted in plasma exposure 8 times higher than rilzabrutinib alone. Under these conditions, there was no prolongation of the mean QTc interval to any clinically relevant effect. In this same study, a concentration dependent shortening in the QTc interval was observed with a maximum shortening of -10.2 ms (90% CI: -12.24, -8.16) following the supratherapeutic dose (combination of rilzabrutinib and ritonavir 100 mg)]. The shortening was smaller [-7.3 ms (90% CI: -9.33, -5.19)] at the rilzabrutinib 400 mg twice a day dose.
The safety and efficacy of rilzabrutinib in adult patients with primary persistent or chronic immune thrombocytopenia (ITP) was evaluated in a Phase 3, randomized, double-blind (DB), placebo-controlled, parallel-group study consisting of 24 weeks of blinded treatment, followed by an open-label (OL) period of 28 weeks and long-term extension (LTE) period during both of which all patients received rilzabrutinib (LUNA 3 Study). The patients enrolled in this study did not have a sustained response to either intravenous immunoglobulin (IVIg/anti-D) or corticosteroid (CS), or had a documented intolerance or insufficient response to any appropriate course of standard-of-care ITP therapy.
Patients were randomized 2:1 to rilzabrutinib or placebo and randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia.
Concomitant ITP medicinal products [oral CS and/or thrombopoietin receptor agonist (TPO-RA)] were allowed at stable doses at least 2 weeks before the start of the study and throughout the DB period. Rescue therapy was permitted.
Only patients that responded during the first 12 weeks of the DB period could continue the DB treatment until Week 24 before entering the OL period. Those who did not respond could enter the OL period at Week 13 or discontinue from the study. After completing the OL period, eligible patients could continue into the LTE period.
In the LUNA 3 Study, 202 patients were randomized and treated, 133 to the rilzabrutinib group and 69 to the placebo group. At baseline, the median age was 47 years (range: 18 to 80 years), 62.9% were female, 61.9% were Caucasian, and 31.7% Asian. Of the 202 patients, 15.8% (rilzabrutinib) and 21.7% (placebo) were 65 years of age and older while 4.5% (rilzabrutinib) and 4.3% (placebo) were 75 years of age and older.
At baseline, the majority (92.6%) of patients had chronic ITP, with a median time since ITP diagnosis of 7.69 years (range: 0.3, 52.2 years), and 27.7% had undergone splenectomy. The median platelet count was 15 300/μL, with almost half (48%) less than 15 000/μL. Twenty-four (11.9%) patients had 10 only one prior therapy and 178 (88.1%) patients had ≥2 prior therapies. The median number of prior therapies, including splenectomy, was 4 (range: 1 to 15). Prior ITP treatments varied, with the most common prior therapies being CS (95.5%), TPO-RAs (68.8%), IVIg or anti-D immunoglobulins (55.4%), and anti-CD20 monoclonal antibody/rituximab (35.1%.). In addition, at baseline 65.8% of patients received both CS and TPO-RAs. Baseline characteristics were generally similar across both groups.
During the DB period, the median duration of exposure was 98 days (range: 22 to 182) and 84 days (range: 17 to 173) for the rilzabrutinib group and placebo group, respectively. The cumulative duration of treatment exposure was 44.3 participant-years and 17.9 participant years for the rilzabrutinib group and placebo group, respectively. All rilzabrutinib treated patients received 400 mg twice a day. In addition, 39.8% of patients received rilzabrutinib without CS or TPO-RA, 25.6% received rilzabrutinib and CS, 18.8% received rilzabrutinib and TPO-RA, and 15.8% received rilzabrutinib and both CS and TPO-RA.
During the first 12 weeks of the DB period, 85 (63.9%) patients and 22 (31.9%) patients in the rilzabrutinib group and placebo group, respectively, achieved platelet count response (≥50 000/μL or between 30 000/μL and <50 000/μL and doubled from baseline). Among the patients who responded during the DB period, the median time to platelet response was 15 days and 50 days for the rilzabrutinib group and placebo group, respectively. Those who achieved platelet count response by week 13 were eligible to continue the DB period. Fifty-five (41.4%) and 55 (79.7%) patients in the rilzabrutinib and placebo groups, respectively, discontinued the DB period due to not achieving pre-defined criteria of platelet response and/or due to lack of response per investigator judgment. These individuals were counted as treatment failure in the primary endpoint analysis.
In the LUNA 3 Study, the primary endpoint was durable platelet response. A durable platelet response was the achievement of a weekly platelet count ≥50 000/μL for at least 8 out of the last 12 weeks of the 24-week DB period in the absence of rescue therapy, The proportion of patients achieving durable response was significantly higher in the rilzabrutinib group (23.3%) compared to the placebo group (0%) during the DB period (see Table 3 for study outcomes). A numerically higher percentage of patients that received rilzabrutinib with concomitant CS and/or TPO-RA had durable platelet response (27.5%) compared to those taking rilzabrutinib as monotherapy (17%).
Key secondary endpoints included persistence of platelet response, onset of clinical response, use of rescue therapy and patient reported outcome related to bleeding (see Table 3 for study outcomes).
Table 3. LUNA 3 Study outcomes during the 24-week DB period – adult ITT population:
| Study outcomes | Statistic | Rilzabrutinib 400 mg twice daily (N=133) | Placebo (N=69) |
| Durable platelet response1 | n (%) | 31 (23.3) | 0 (0) |
| 95% CI | 16.12, 30.49 | 0.00, 0.00 | |
| Risk difference (95% CI) vs placebo | 23.1 (15.95, 30.31) | ||
| p-value <0.0001 | |||
| Number of weeks with platelet response | |||
| ≥50 000/μL or between 30 000/μL and <50 000/μL2 | LS4 Mean (SE) | 7.18 (0.747) | 0.72 (0.350) |
| LS Mean difference (SE) vs placebo | 6.46 (0.782) | ||
| 95% CI | 4.923, 7.990 | ||
| p-value <0.0001 | |||
| ≥30 000/μL3 | LS Mean (SE) | 6.95 (0.749) | 0.64 (0.337) |
| LS Mean difference (SE) vs placebo | 6.31 (0.776) | ||
| 95% CI | 4.787, 7.831 | ||
| p-value < 0.0001 | |||
| Time to first platelet response2 | Median number of days to first platelet response (95% CI) | 36 (22, 44) | NR5 |
| Hazard ratio (95% CI) vs placebo | 3.10 (1.948, 4.934) | ||
| p-value < 0.0001 | |||
| Requiring rescue therapy | n (%) | 44 (33.1) | 40 (58) |
| Median number of days to first use of rescue therapy (95% CI) | NR5 | 56 (36, NR5) | |
| Hazard ratio (95% CI) vs placebo | 0.48 (0.309, 0.733) | ||
| p-value = 0.0007 | |||
| Change from baseline in IBLS score6 at week 25 | LS Mean (SE) | -0.040 (0.0169) | 0.047 (0.0226) |
| LS Mean difference (SE) vs placebo | -0.087 (0.0251) | ||
| 95% CI | -0.1358, -0.0373 | ||
| p-value = 0.0006 | |||
1 Defined as the proportion of participants able to achieve platelet counts ≥50 000/μL for ≥ two-thirds of at least 8 non-missing weekly scheduled platelet measurements during the last 12 weeks of the 24-week blinded treatment period in the absence of rescue therapy, provided that at least 2 non-missing weekly scheduled platelet measurements are ≥50 000/μL during the last 6 weeks of the 24-week blinded treatment period.
2 Platelet count ≥50 000/μL or between 30 000 μL and <50 000/μL and at least doubled from baseline in absence of rescue therapy.
3 Platelet count ≥30 000/μL and at least doubled from baseline in absence of rescue therapy.
4 LS: Least Square
5 NR: Not Reached
6 The ITP Bleeding Scale (IBLS) is a bleeding assessment questionnaire, with scores ranging from 0 to 2, with higher scores indicating higher presence of marked bleeding; average across anatomical sites.
After the DB period, 180 patients entered the OL period (115 patients from the rilzabrutinib group and 65 patients from the placebo group in the DB period) with a cumulative duration of treatment exposure of 75.6 participant-years. Of these 180 patients, 115 patients completed the 28-week OL period.
In the OL period, 14/65 (21.5%) patients from the placebo group achieved a durable response after being exposed to rilzabrutinib, and 10/84 (11.9%) patients in the rilzabrutinib group achieved a durable response despite not achieving durable response during the DB period.
The European Medicines Agency has deferred the obligation to submit the results of studies with rilzabrutinib in one or more subsets of the paediatric population in ITP (see section 4.2 for information on paediatric use).
Mean Cmax (%CV) and AUC24h (%CV) at steady state were estimated to be 150 ng/mL (56%) and 1 540 ng.h/mL (57.5%), respectively, for the ITP population. Accumulation, as reflected by the fold change in maximum median concentrations, was 1.3-fold following dosing at 400 mg twice daily. Rilzabrutinib exhibits approximately dose proportional increases in exposure over the dose range of 300 mg to 600 mg.
The absolute oral bioavailability of rilzabrutinib was 4.73%. The median time to peak rilzabrutinib plasma concentrations (Tmax) was 0.5 to 2.5 hours.
No clinically significant differences in rilzabrutinib AUC or Cmax were observed following the administration of a single 400 mg tablet with a high-fat meal, high-calorie meal as compared to dosing under fasting conditions. Resulting Tmax was delayed by 1.5 hours.
Volume of distribution at terminal phase (Vz) after intravenous administration is 149 L. The in vitro plasma protein binding of rilzabrutinib is 97.5%, mainly bound to human serum albumin, and the blood-to-plasma ratio is 0.786.
Rilzabrutinib is predominantly metabolized by CYP3A enzymes.
Rilzabrutinib is rapidly cleared from the plasma, with a t1/2 of approximately 3 to 4 hours. Following administration of a single 400 mg 14C-labeled rilzabrutinib dose, radioactivity was predominantly excreted in feces (~86%) and to a lesser extent in urine (~5%) and bile (~6%). Approximately 0.03% of rilzabrutinib is excreted unchanged in the urine.
Based on population PK analysis, gender, body weight (range 36-140 kg), race/ethnicity and age (range 12-80 years) had no meaningful effect on rilzabrutinib PK. The PK of rilzabrutinib in Chinese and Japanese populations is similar to the Caucasian population.
Rilzabrutinib exposure increased by approximately 1.5-fold in mild hepatic impairment (Child-Pugh Class A) and approximately 4.5-fold in moderate hepatic impairment (Child-Pugh Class B). Rilzabrutinib has not been studied in patients with severe (Child-Pugh Class C) hepatic impairment.
Patients with mild (60-90 mL/min) or moderate (30-60 mL/min) renal impairment participated in rilzabrutinib clinical trials. Population pharmacokinetic analysis suggest that mild or moderate renal impairment do not impact rilzabrutinib exposure.
Rilzabrutinib was shown in vitro to be a P-gp substrate, and to a lower extent potentially a substrate of BCRP. Rilzabrutinib was not a substrate for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or BSEP. Rilzabrutinib exhibited in vitro a potential to inhibit P-gp, OATP1B1, OATP1B3, and BSEP. However, PBPK simulations suggest that rilzabrutinib does not have any relevant effect on P-gp, BCRP, OATP1B1, and OATP1B3 substrate (see section 4.5).
Rilzabrutinib has a short duration of systemic exposure with a long duration of action on the target due to its slow dissociation from BTK. At therapeutic doses in healthy participants, durable BTK occupancy in peripheral blood mononuclear cells was observed over a 24-hour period.
In the 6-month repeat-dose toxicology study in rats, the oesophagus (haemorrhage), duodenum (haemorrhage), stomach (haemorrhage), brain (inflammation; neutrophilic inflammation), uterus (distended, pyometra), cervix (distended uterus), vagina (distended uterus), and ovaries (distended uterus) were identified as target organs. The no-observed-adverse-effect-level (NOAEL) was 150 mg/kg/day (AUC exposure margin of 4.5-fold) for males and 50 mg/kg/day (AUC exposure margin of 3.7-fold) for females. No rilzabrutinib-related changes, with the exception of the brain, were observed at the end of the 4-week recovery period. No evidence of neurodegeneration or cellular alteration in the brain was observed.
In a 9-month repeat-dose study in dogs, the stomach (increased intraepithelial lymphocytes with mucosal atrophy) and liver (Kupffer cell pigment, Kupffer cell hypertrophy and increase in ALT and AST) were identified as target organs. the NOAEL of this study was considered to be 30 mg/kg/day (AUC exposure margin of 0.4- to 0.5-fold). At the end of the 4-week recovery period, with the exception of Kupffer cell pigment, the liver and stomach findings had reversed.
Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.
Rilzabrutinib was not carcinogenic in a 6-month transgenic mouse study. In a 2-year rat carcinogenicity study, rilzabrutinib-related thyroid adenomas and carcinomas were observed for male rats at 100 mg/kg/day (AUC exposure margin of 2.4-fold). The non-carcinogenic dose was considered to be 30 mg/kg/day (AUC exposure margin of 0.64-fold) for males and 5 mg/kg/day (AUC exposure margin of 0.13-fold) for females. Transcriptomic analysis suggests that thyroid tumours in rats derive from rilzabrutinib-mediated perturbation of thyroid hormone maintenance. This nongenotoxic effect was discovered to be specific for rats with a mechanism not considered relevant to humans, therefore, the potential for thyroid tumours in humans is considered low. In this study, the non-neoplastic observation of erythrocytosis was noted for the mesenteric lymph nodes.
In the combined male and female rat fertility study, no rilzabrutinib-related effects were observed for any reproductive parameters. The NOAEL for fertility, reproductive performance, and early embryonic development was considered to be 300 mg/kg/day (HED 48 mg/kg/day), the highest dose evaluated.
In definitive rat and rabbit embryo-foetal toxicity studies, no rilzabrutinib-related foetal development and foetal external, visceral, or skeletal malformations were observed. The embryo-foetal development NOAELs were 300 and 100 mg/kg/day in rats and rabbits, respectively, which were the highest doses evaluated. Exposure ratios (AUC) at the embryo-foetal NOAEL compared to human clinical exposure at 400 mg twice daily, were 11.1- and 4.5-fold, in rats and rabbits, respectively. Skeletal variations of unknown relevance were observed at the same highest dose levels. Variations consisted in a shift in the number of thoracic and lumbar vertebrae (rats and rabbits) and an increase in the incidence of supernumerary rib pairs (rats). No such variations were observed at 150 and 30 mg/kg/day (resulting in 11.9- and 0.24-fold of clinical exposure at 400 mg twice daily, respectively) in rats and rabbits, respectively. In an exploratory rat embryo-foetal range-finding study, increased post-implantation loss and incidence of early resorption, and decreased foetal weight were observed at 500 mg/kg/day (AUC exposure margin of 21.8-fold). Foetal external, visceral and skeletal changes were observed at 500 mg/kg/day. No malformations were noted at ≤150 mg/kg/day (AUC exposure margin of 10-fold). In an exploratory rabbit embryo-foetal range-finding study, a slight increase in the incidence of early resorption was observed at 150 mg/kg/day (AUC exposure margin of 5.6-fold). Foetal visceral changes were observed at 150 mg/kg/day (AUC exposure margin of 5.6-fold).
In a pre-/postnatal developmental toxicity study investigating the effects of orally administered rilzabrutinib, the maternal (F0) systemic toxicity NOAEL was considered to be 50 mg/kg/day (HED 8.1 mg/kg/day). The NOAEL for F1 neonatal/developmental toxicity was considered to be 150 mg/kg/day (HED 24.2 mg/kg/day) and the NOAELs for F1 parental system toxicity, F1 reproductive toxicity, and F2 embryonic toxicity were considered to be 300 mg/kg/day (HED 48 mg/kg/day).
Rilzabrutinib did not show any phototoxicity potential in the in vitro 3T3 neutral red uptake phototoxicity test.
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