Vimseltinib

Vimseltinib is a selective small-molecule tyrosine kinase inhibitor of the colony stimulating factor 1 receptor (CSF1R), a receptor that supports the survival, proliferation and differentiation of macrophages and other myeloid cells. The CSF1/CSF1R signalling axis has a critical role in the development of tenosynovial giant cell tumour (TGCT).

Mechanism of Action

• CSF1R inhibition: vimseltinib holds the receptor in its inactive state. In enzyme and cell-based assays it inhibited CSF1R autophosphorylation, signalling triggered by CSF1 ligand binding, and the function and proliferation of cells that express CSF1R. In preclinical models in vivo it blocked downstream signalling in CSF1R-expressing cells.
• Anti-tumour effect: vimseltinib acts by depleting CSF1R-dependent macrophages and inflammatory cells.
• Effect on enzyme levels: CSF1R inhibition lowers the number of Kupffer cells in the liver, which reduces the clearance of serum enzymes and raises blood levels of AST, ALT and creatine phosphokinase (CPK).
• Exposure–response: higher exposure is associated with more oedema, pruritus and rash, and with larger rises in AST, ALT, CPK and creatinine, at all grades.

Pharmacokinetics

• Absorption: peak plasma concentration is reached at a median of 1 hour after a single 30 mg dose taken fasted. After a single dose Cmax is 283 ng/mL; at steady state Cmax is 747 ng/mL and AUC0-24h is 13.4 µg·h/mL. Steady state is reached after about 5 weeks (accumulation ratio 2.6) and is similar in patients and healthy volunteers. A high-fat meal has no clinically significant effect, and exposure is dose proportional.
• Distribution: apparent volume of distribution about 90 L; 96.5% bound to plasma proteins in vitro.
• Metabolism: there is no major circulating metabolite. Oxidation, N-demethylation and N-dealkylation are the main pathways; CYP enzymes are not expected to play a major role.
• Elimination: apparent clearance about 0.5 L/h and elimination half-life about 6 days after a single dose. After a radiolabelled oral dose about 43% was recovered in faeces (9.1% unchanged) and 38% in urine (5.1% unchanged).
• Special populations: no clinically relevant differences were seen with age (20–91 years), sex, race (Asian, Black or African American, White) or body weight (43–150 kg). Mild renal impairment (eGFR ≥60 mL/min) did not significantly change exposure.

• Tenosynovial giant cell tumour (TGCT): adults with symptomatic TGCT associated with clinically relevant deterioration of physical function, in whom surgical options have been exhausted or would cause unacceptable morbidity or disability.

• Hypersensitivity to vimseltinib or to any of the excipients.
• Pregnancy.

Safety data come from 184 patients with TGCT who received 30 mg twice weekly in two clinical studies, for a median of 13 months. The most frequent reactions were increased AST (92%), periorbital oedema (63%), increased cholesterol (53%), rash (51%), increased creatinine (43%), decreased neutrophils (36%), fatigue (30%), face oedema (28%), increased ALT (27%), pruritus (27%), peripheral oedema (22%) and hypertension (21%). Severe (grade 3/4) reactions included hypertension (9%), rash (3%), pruritus (3%) and decreased neutrophils (3%).

Very common (≥1/10): neuropathy (including peripheral neuropathy, paraesthesia, hypoaesthesia and peripheral sensory neuropathy); periorbital oedema (including eye and eyelid oedema or swelling), increased lacrimation; hypertension; rash (including erythematous, macular and pruritic rash, acneiform dermatitis and erythema), pruritus, dry skin; peripheral oedema, fatigue, face oedema, generalised oedema; laboratory findings: increased creatine phosphokinase (frequency based on laboratory data from the phase 1/2 study only), aspartate aminotransferase, cholesterol, creatinine, alanine aminotransferase and alkaline phosphatase, and decreased neutrophil count.

Common (≥1/100 to <1/10): dry eye, blurred vision.

The SmPC table lists no less frequent reactions. Serious reactions were peripheral oedema (0.5%) and increased CPK (0.5%). Treatment was stopped permanently because of a side effect in 7% of patients, most often for rash, periorbital oedema, neuropathy or pruritus. The dose was reduced or interrupted in 59%, most often for rash, periorbital oedema, increased CPK, pruritus, face or generalised oedema, fatigue or peripheral oedema.

Vimseltinib is not expected to depend on CYP enzymes for its metabolism; the interaction advice in the SmPC concerns transporters.

• P-glycoprotein (P-gp) inhibitors: itraconazole 200 mg once daily left peak exposure unchanged and raised total exposure by about 17–22%. No dose adjustment is needed.
• Proton pump inhibitors: rabeprazole 20 mg once daily (fasted) lowered peak and total exposure by about 21–26%, which is not clinically relevant. No dose adjustment is needed.
• BCRP substrates (for example rosuvastatin): vimseltinib inhibits BCRP in vitro, so levels of such medicines and their side effects may rise. No clinical studies have been done. Avoid the combination; if that is not possible, follow the dose advice in the SmPC of the other medicine.
• OCT2 substrates (for example metformin): vimseltinib inhibits OCT2 in vitro, with the same concern and the same advice: avoid, or follow the other medicine’s SmPC.
• P-gp substrates (for example digoxin, dabigatran): vimseltinib inhibits P-gp in vitro, with the same concern and the same advice.
• Hormonal contraceptives: it is unknown whether vimseltinib reduces the effectiveness of systemically acting hormonal contraceptives, so a barrier method should be added.
• Food: the capsules can be taken with or without food.

Treatment should be started by a healthcare professional experienced in the diagnosis and treatment of TGCT. The capsules are taken by mouth, with or without food. They are swallowed whole: patients must not open, break or chew them, and must not take a capsule that is broken, cracked or otherwise not intact.

Recommended Dose

• 30 mg twice weekly, at least 72 hours apart, for as long as benefit is observed or until unacceptable toxicity.

Dose Reductions

• If 30 mg is not tolerated, treatment is withheld temporarily. When the patient improves, it is restarted at a reduced dose: 20 mg twice weekly (first reduction), then 14 mg twice weekly (second reduction).
• Vimseltinib is discontinued in patients who cannot tolerate 14 mg.
• Interruptions or reductions may be needed according to individual safety and tolerability, for example for pruritus.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment. There are no clinical data in severe impairment, so it should not be used.
• Hepatic impairment: no adjustment in mild impairment (Child-Pugh A). There are no clinical data in moderate or severe impairment, so it should not be used.
• Body weight: a reduction to 14 mg twice weekly has not been used in patients of 115 kg or more, and efficacy has not been established at that dose.
• Children and adolescents: it should not be used from birth to pre-pubertal age because of safety concerns from preclinical data. Safety and efficacy from post-pubertal age to under 18 years have not been established, and no clinical data exist.

Missed Dose

• Less than 48 hours late: take the missed dose as soon as possible and return to the usual schedule.
• More than 48 hours late: do not take the missed dose; return to the usual schedule.

Embryo-Foetal Toxicity and Contraception

Animal studies showed foetal structural abnormalities and cardiac malformations, and vimseltinib is contraindicated in pregnancy. The pregnancy status of women of childbearing potential must be verified before starting and during treatment. Effective contraception is required during treatment and for 30 days after the last dose. The effect of vimseltinib on hormonal contraceptives has not been studied, so a barrier method should be added if they are used.

Liver and Muscle Enzyme Elevations

Vimseltinib has been associated with raised AST, ALT, alkaline phosphatase and CPK. In clinical studies these rises did not lead to liver injury or rhabdomyolysis, but this cannot be excluded because experience in this rare condition is very limited. Treatment should be avoided in patients with pre-existing raised transaminases, raised total or direct bilirubin, or active liver or biliary tract disease. Liver function is checked before starting, once a month for the first two months, every 3 months for the first year, and as clinically indicated afterwards.

Blood Pressure and Creatinine

Treatment was frequently associated with higher blood pressure and with raised creatinine; the reason for the creatinine rise is unknown.

Pruritus

Pruritus was reported in 27% of patients in the pooled safety population, and also after single doses in healthy participants. Dose interruptions or reductions may be needed.

Long-Term Safety

The long-term safety of vimseltinib has not been established. Because it depletes macrophages, its long-term effects on organs such as the liver, skin, central nervous system and bone marrow are uncertain.

Breastfeeding and Fertility

It is unknown whether vimseltinib passes into human milk, and a risk to the breast-fed child cannot be excluded; women should not breastfeed during treatment. Animal findings indicate that it may impair male fertility.

Excipients

The capsules contain lactose; patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. The 14 mg and 20 mg capsules contain sunset yellow FCF (E110), and the 20 mg capsule also contains tartrazine (E102); both may cause allergic reactions.

Effect on Driving

Vimseltinib has a minor influence on the ability to drive and use machines. Fatigue or blurred vision may occur.

Romvimza capsules need no special temperature conditions. Keep them in the original package, a blister inside a child-resistant wallet of 8 capsules, to protect them from moisture, and out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), as a medicinal product subject to restricted medical prescription. Treatment is started by a healthcare professional experienced in diagnosing and treating TGCT. Vimseltinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.