6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hemorrhage [see Warnings and Precautions (5.1)]
Diarrhea [see Warnings and Precautions (5.2)]
Thrombocytopenia [see Warnings and Precautions (5.3)]
Prolonged QT Interval [see Warnings and Precautions (5.4)]
Major Adverse Cardiac Events [see Warnings and Precautions (5.5)]
Thrombosis [see Warnings and Precautions (5.6)]
Secondary Malignancies [see Warnings and Precautions (5.7)]
Risk of Infection [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

PERSIST-2 Trial

The safety of VONJO was evaluated in the randomized, controlled PERSIST-2 trial [see Clinical Studies (14)]. In PERSIST-2, key eligibility criteria included adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF with splenomegaly and a platelet count ≤100 × 109/L. Prior Janus associated kinase (JAK) inhibitor therapy was permitted. Patients received VONJO at 200 mg twice daily (n=106), 400 mg once daily (n=104), or best available therapy (BAT) (n=98). Forty-seven (44%) of the 106 patients treated with VONJO 200 mg twice daily had a baseline platelet count of <50 × 109/L The 400 mg once daily dose could not be established to be safe, so further information on this arm is not provided.

In PERSIST-2, among the 106 patients treated with VONJO 200 mg twice daily, the median baseline hemoglobin was 9.7 g/dL and the median drug exposure was 25 weeks. Fifty-four percent of patients were exposed for 6 months, and 18% were exposed for approximately 12 months. Accounting for dose reductions, the average daily dose (mean relative dose intensity) and median daily dose (median relative dose intensity) were 380 mg (95%) and 400 mg (100%), respectively, for patients receiving VONJO twice daily.

The median age of patients who received VONJO 200 mg twice daily was 67 years (range: 39 to 85 years), 59% were male, 86% were White, 3% were Asian, 2% were Native Hawaiian or Other Pacific Islander, 0% were Black, 9% did not report race, and 87% had an Eastern Cooperative Oncology Group performance status of 0 to 1.

Serious adverse reactions occurred in 47% of patients treated with VONJO 200 mg twice daily and in 31% of patients treated with BAT. The most frequent serious adverse reactions occurring in ≥3% patients receiving VONJO 200 mg twice daily were anemia (8%), thrombocytopenia (6%), pneumonia (6%), cardiac failure (4%), disease progression (3%), pyrexia (3%), and squamous cell carcinoma of skin (3%). Fatal adverse reactions occurred in 8% of patients receiving VONJO 200 mg twice daily and in 9% of patients treated with BAT. The fatal adverse reactions among patients treated with VONJO 200 mg twice daily included events of disease progression (3%), and multiorgan failure, cerebral hemorrhage, meningorrhagia, and acute myeloid leukemia in <1% of patients each, respectively.

Permanent discontinuation due to an adverse reaction occurred in 15% of patients receiving VONJO 200 mg twice daily compared to 12% of patients treated with BAT. The most frequent reasons for permanent discontinuation in ≥2% of patients receiving VONJO 200 mg twice daily included anemia (3%) and thrombocytopenia (2%).

Drug interruptions due to an adverse reaction occurred in 27% of patients who received VONJO 200 mg twice daily compared to 10% of patients treated with BAT. The most frequent reasons for drug interruption in ≥2% of patients receiving VONJO 200 mg twice daily were anemia (5%), thrombocytopenia (4%), diarrhea (3%), nausea (3%), cardiac failure (3%), neutropenia (2%), and pneumonia (2%).

Dosage reductions due to an adverse reaction occurred in 12% of patients who received VONJO 200 mg twice daily compared to 7% of patients treated with BAT. Adverse reactions requiring dosage reduction in ≥2% of patients who received VONJO 200 mg twice daily included thrombocytopenia (2%), neutropenia (2%), conjunctival hemorrhage (2%), and epistaxis (2%).

The most common adverse reactions in ≥20% of patients (N=106) were diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema.

Table 5 summarizes the common adverse reactions in PERSIST-2 during randomized treatment.

Table 5 Adverse Reactions Reported in ≥10% Patients Receiving VONJO 200 mg Twice Daily or Best Available Therapy During Randomized Treatment in PERSIST-2
a Grade by CTCAE Version 4.03
Adverse Reactions	VONJO (200 mg Twice Daily) (N=106)		Best Available Therapy (N=98)
Adverse Reactions	All Gradesa %	Grade ≥3 %	All Gradesa %	Grade ≥3 %
Diarrhea	48	4	15	0
Thrombocytopenia	34	32	23	18
Nausea	32	1	11	1
Anemia	24	22	15	14
Peripheral edema	20	1	15	0
Vomiting	19	0	5	1
Dizziness	15	1	5	0
Pyrexia	15	1	3	0
Epistaxis	12	5	13	1
Dyspnea	10	0	9	3
Pruritus	10	2	6	0
Upper respiratory tract infection	10	0	6	0
Cough	8	2	10	0