1 INDICATIONS AND USAGE

MULPLETA is indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure.

4 CONTRAINDICATIONS

None.

10 OVERDOSAGE

No antidote for MULPLETA overdose is known.

In the event of overdose, platelet count may increase excessively and result in thrombotic or thromboembolic complications. Closely monitor the patient and platelet count. Treat thrombotic complications in accordance with standard of care.

Hemodialysis is not expected to enhance the elimination of MULPLETA because lusutrombopag is highly bound to protein in plasma [see Clinical Pharmacology (12.3)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Lusutrombopag is an orally bioavailable, small molecule TPO receptor agonist that interacts with the transmembrane domain of human TPO receptors expressed on megakaryocytes to induce the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells and megakaryocyte maturation.

12.2 Pharmacodynamics

Platelet Response

Lusutrombopag upregulates the production of platelets through its agonistic effect on human TPO receptors.

The effect of lusutrombopag on platelet count increase was correlated with the AUC across the studied dose range of 0.25 mg to 4 mg in thrombocytopenic patients with chronic liver disease. With the 3 mg daily dose, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) × 109/L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days.

Cardiac Electrophysiology

At a dose 8 times the recommended dosage, MULPLETA does not prolong QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Lusutrombopag demonstrated dose-proportional pharmacokinetics after single doses ranging from 1 mg (0.33 times the lowest approved dosage) to 50 mg (16.7 times the highest recommended dosage). Healthy subjects administered 3 mg of lusutrombopag had a geometric mean (%CV) maximal concentration (Cmax) of 111 (20.4) ng/mL and area under the time-concentration curve extrapolated to infinity (AUC0-inf) of 2931 (23.4) ng.hr/mL. The pharmacokinetics of lusutrombopag were similar in both healthy subjects and the chronic liver disease population.

The accumulation ratios of Cmax and AUC were approximately 2 with once-daily multiple-dose administration, and steady-state plasma lusutrombopag concentrations were achieved after Day 5.

Absorption

In patients with chronic liver disease, the time to peak lusutrombopag concentration (Tmax) was observed 6 to 8 hours after oral administration.

Food Effect

Lusutrombopag AUC and Cmax were not affected when MULPLETA was co-administered with a high-fat meal (a total of approximately 900 calories, with 500, 250, and 150 calories from fat, carbohydrate, and protein, respectively).

Distribution

The mean (%CV) lusutrombopag apparent volume of distribution in healthy adult subjects was 39.5 (23.5) L. The plasma protein binding of lusutrombopag is more than 99.9%.

Elimination

The terminal elimination half-life (t1/2) in healthy adult subjects was approximately 27 hours. The mean (%CV) clearance of lusutrombopag in patients with chronic liver disease is estimated to be 1.1 (36.1) L/hr.

Metabolism

Lusutrombopag is primarily metabolized by CYP4 enzymes, including CYP4A11.

Excretion

Fecal excretion accounted for 83% of the administered dose, with 16% of the dose excreted as unchanged lusutrombopag, and urinary excretion accounted for approximately 1%.

Specific Populations

No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on age or race/ethnicity. Though lusutrombopag exposure tends to decrease with increasing body weight, differences in exposure are not considered clinically relevant.

Patients with Renal Impairment

A population pharmacokinetic analysis did not find a clinically meaningful effect of mild (creatinine clearance (CLcr) 60 to less than 90 mL/min) and moderate (CLcr 30 to less than 60 mL/min) renal impairment on the pharmacokinetics of lusutrombopag. Data in patients with severe renal impairment (CLcr less than 30 mL/min) are limited.

Patients with Hepatic Impairment

No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on mild to moderate (Child-Pugh class A and B) hepatic impairment.

The mean observed lusutrombopag Cmax and AUC0-τ decreased by 20% to 30% in patients (N=5) with severe (Child-Pugh class C) hepatic impairment compared to patients with Child-Pugh class A and class B liver disease. However, the ranges for Cmax and AUC0-τ overlapped among patients with Child-Pugh class A, B, and C liver disease.

Drug Interaction Studies

Clinical Studies

No clinically significant changes in lusutrombopag exposure were observed when co-administered with cyclosporine (an inhibitor of P-gp and BCRP) or an antacid containing a multivalent cation (calcium carbonate).

No clinically significant changes in midazolam (a CYP3A substrate) exposure were observed when co-administered with lusutrombopag.

In Vitro Studies

CYP Enzymes: lusutrombopag has low potential to inhibit CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). Lusutrombopag did not induce CYP1A2, CYP2C9, or CYP3A4.

UGT Enzymes: lusutrombopag did not induce UGT1A2, UGT1A6, or UGT2B7.

Transporter Systems: lusutrombopag is a substrate of P-gp and BCRP. Lusutrombopag has low potential to inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K, and BSEP.

14 CLINICAL STUDIES

The efficacy of MULPLETA for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure was evaluated in 2 randomized, double-blind, placebo-controlled trials (L-PLUS 1 (N=97) and L-PLUS 2 (N=215; NCT02389621)). Patients with chronic liver disease who were undergoing an invasive procedure and had a platelet count less than 50 × 109/L were eligible to participate. Patients undergoing laparotomy, thoracotomy, open-heart surgery, craniotomy, or organ resection were excluded. Patients with a history of splenectomy, partial splenic embolization, or thrombosis and those with Child-Pugh class C liver disease, absence of hepatopetal blood flow, or a prothrombotic condition other than chronic liver disease were not allowed to participate.

The patient populations were similar between the MULPLETA and placebo arms and consisted of 60% male and 40% female; median age was 60 years (range 19-88). The racial and ethnic distribution was White (55%), Asian (41%), and Other (4%).

Patients were randomized 1:1 to receive 3 mg of MULPLETA or placebo once daily for up to 7 days. Randomization was stratified by liver ablation/coagulation or other procedures and the platelet count at screening/baseline. In L-PLUS 1, 57% of patients underwent procedures other than liver ablation/coagulation and 43% underwent liver ablation/coagulation (RFA/MCT). In L-PLUS 2, 98% of patients underwent procedures other than liver ablation/coagulation and 2% underwent liver ablation/coagulation (RFA/MCT). Procedures other than liver ablation/coagulation (RFA/MCT) included liver-related procedures (transcatheter arterial chemoembolization, liver biopsy, and others), upper and lower gastrointestinal endoscopy-related procedures (endoscopic variceal ligation, endoscopic injection sclerotherapy, polypectomy, and biopsy), and other procedures (dental extraction, diagnostic paracentesis or laparocentesis, septoplasty, embolization of splenic artery aneurysm, bone marrow biopsy, removal of cervical polyp, and inguinal hernia repair (non- laparotomy based)).

In L-PLUS 1, the major efficacy outcome was the proportion of patients who require no platelet transfusion prior to the primary invasive procedure. In L-PLUS 2, the major efficacy outcome was the proportion of patients who require no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding (i.e., platelet preparations, other blood preparations, including red blood cells and plasma, volume expanders) from randomization through 7 days after the primary invasive procedure. In both trials, additional efficacy outcomes included the proportion of patients who require no platelet transfusion during the study, proportion of responders, duration of the increase in platelet count defined as the number of days during which the platelet count was maintained as ≥50 × 109/L, and the time course of platelet counts.

In both the L-PLUS 1 and L-PLUS 2 trials, responders were defined as patients who had a platelet count of ≥50 × 109/L with an increase of ≥20 × 109/L from baseline.

Table 2. L-PLUS 1 Trial: Proportion of Patients Not Requiring Platelet Transfusion Prior to Invasive Procedure and Proportion of Responders

Endpoint	Proportion (n/N) Exact 95% Confidence Interval	Treatment Difference (95% Confidence Interval) p value
MULPLETA (N=49)	Placebo (N=48)
A platelet transfusion was required if the platelet count was less than 50 × 109/L. † Cochran-Mantel-Haenszel test with baseline platelet count as stratum; p value and confidence interval calculated using Wald method. ‡ Platelet count reached at least 50 × 109/L and increased at least 20 × 109/L from baseline.
Not requiring platelet transfusion prior to invasive procedure*	78% (38/49) (63, 88)	13% (6/48) (4.7, 25)	64 (49, 79) <0.0001†
Responder‡ during study	76% (37/49) (61, 87)	6% (3/48) (1.3, 17)	68 (54, 82) <0.0001†

Table 3. L-PLUS 2 Trial: Proportion of Patients Not Requiring Platelet Transfusion Prior to Invasive Procedure or Rescue Therapy for Bleeding Through 7 Days After Invasive Procedure and Proportion of Responders

Endpoint	Proportion (n/N) Exact 95% Confidence Interval	Treatment Difference (95% Confidence Interval) p value
MULPLETA (N=108)	Placebo (N=107)
A platelet transfusion was required if the platelet count was less than 50 × 109/L. † Cochran-Mantel-Haenszel test with baseline platelet count as stratum; p value and confidence interval calculated using Wald method. ‡ Platelet count reached at least 50 × 109/L and increased at least 20 × 109/L from baseline.
Not requiring platelet transfusion prior to invasive procedure* or rescue therapy for bleeding from randomization through 7 days after invasive procedure	65% (70/108) (55, 74)	29% (31/107) (21, 39)	37 (25, 49) <0.0001†
Responder‡ during study	65% (70/108) (55, 74)	13% (14/107) (7.3, 21)	52 (41, 62) <0.0001†

The median (Q1, Q3) duration of platelet count increase to at least 50 × 109/L was 22 (17, 27) days in MULPLETA-treated patients without platelet transfusion and 1.8 (0.0, 8.3) days in placebo-treated patients with platelet transfusion in L-PLUS 1 and 19 (13, 28) days in MULPLETA-treated patients without platelet transfusion and 0.0 (0.0, 5.0) days in placebo-treated patients with platelet transfusion in L-PLUS 2.

MULPLETA is a registered trademark of Shionogi & Co., Ltd.

Manufactured for Shionogi Inc., Florham Park, NJ 07932.