General Information

Zokinvy (lonafarnib) is a farnesyltransferase inhibitor. The accumulation of defective, farnesylated proteins leads to cellular instability and the process of premature aging.

Zokinvy is specifically indicated for patients 12 months of age and older with a body surface area (BSA) of 0.39 m2 and above:

• To reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS)
• For the treatment of processing-deficient Progeroid Laminopathies with either:
  • Heterozygous LMNA mutation with progerin-like protein accumulation
  • Homozygous or compound heterozygous ZMPSTE24 mutations

Zokinvy is supplied as a capsule for oral administration. The recommended dose of Zokinvy is as follows:

The recommended starting dosage of Zokinvy for patients with a BSA of 0.39 m2 and above is 115 mg/m2 twice daily with morning and evening meals, to reduce the risk of gastrointestinal adverse reactions.

An appropriate dosage strength of Zokinvy is not available for patients with a BSA of less than 0.39 m2.  

After 4 months of treatment, increase the dosage to 150 mg/m2 twice daily with morning and evening meals. Round all total daily dosages to the nearest 25 mg increment.

If a dose is missed, take the dose as soon as possible with food, up to 8 hours prior to the next scheduled dose. If less than 8 hours remains before the next scheduled dose, skip the missed dose, and resume taking Zokinvy at the next scheduled dose. 

Please see drug label for BSA chart and  dosing recommendations, as well as for various dose modifications.

Mechanism of Action

Zokinvy (lonafarnib) inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.

The accumulation of defective, farnesylated proteins which form tight associations with the nuclear envelope, leading to cellular instability and the process of premature aging in children and young adults with Progeria and processing-deficient Progeroid Laminopathies.

Side Effects

Adverse effects associated with the use of Zokinvy may include, but are not limited to, the following:

• vomiting
• diarrhea
• infection
• nausea
• decreased appetite
• fatigue
• upper respiratory tract infection
• abdominal pain
• musculoskeletal pain
• electrolyte abnormalities
• decreased weight
• headache
• myelosuppression
• increased aspartate aminotransferase
• decreased blood bicarbonate
• cough
• hypertension
• increased alanine aminotransferase

Clinical Trial Results

The FDA approval of Zokinvy was based on results from the Observational Cohort Survival Study, which retrospectively compared survival data from two Phase 2 studies in patients with HGPS to those from a natural history cohort. Study 1 was a Phase 2 open-label, single-arm trial that evaluated the efficacy of Zokinvy in 28 patients (26 with classic HGPS, one with non-classic HGPS, and one with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation with progerin-like protein accumulation). Patients received Zokinvy for 24 to 30 months. Patients initiated treatment with Zokinvy 115 mg/m2 twice daily. After 4 months of treatment, patients who tolerated treatment had an increase in dose to 150 mg/m2 twice daily. Among the 28 patients treated, 27 patients with HGPS (16 females, 11 males) were included in the survival assessment. The median age at treatment initiation for the 27 patients was 7.5 years (range: 3 to 16 years). The body weight range was 6.6 to 17.6 kg and the BSA range was 0.38 to 0.75 m2. Following completion of Study 1, 26 patients enrolled in a second Phase 2 open label, single-arm trial (Study 2) which consisted of two study phases. In the first phase of Study 2, patients received Zokinvy with additional therapies for about 5 years. In the second phase of Study 2, patients received Zokinvy 150 mg/m2 twice daily for a period of up to 3 years.

There were 35 treatment naïve patients with HGPS enrolled into the second phase of Study 2. Among the 35 treated patients (22 males, 13 females), 34 (97.1%) patients had classic HGPS and 1 (2.9%) patient had non-classic HGPS. The median age was 6 years (range: 2 to 17 years). The body weight range was 6.7 to 22 kg and the BSA range was 0.42 to 0.90 m2 . Throughout Study 1 and Study 2, Zokinvy was administered orally via capsules or the capsule contents were mixed with Ora Blend SF or OraPlus and administered orally as a suspension. The retrospective survival analysis was based on the mortality data from 62 treated patients (27 patients in Study 1 and 35 treatment-naïve patients in Study 2) and data from matched, untreated patients in a separate natural history cohort. The mean lifespan of HGPS patients treated with Zokinvy increased by an average of 3 months through the first three years of follow-up and 2.5 years through the last follow-up time (11 years) compared to untreated patients. 

 In patients with Progeria, Zokinvy reduced the incidence of mortality by 60% and increased average survival time by 2.5 years.