Drug Trials Snapshots: ZOKINVY
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The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
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Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the ZOKINVY Prescribing Information for complete information.
ZOKINVY (lonafarnib)
zoh-KIN-vee
Eiger BioPharmaceuticals, Inc.
Approval date: November 20, 2020
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
ZOKINVY is a drug used in patients one year of age and older with a certain body surface area to
- lower the risk of death in Hutchinson-Gilford Progeria Syndrome (HGPS), or
- to treat certain processing-deficient progeroid laminopathies.
HGPS and progeroid laminopathies are rare, inherited conditions that lead to premature aging and death because of certain gene mutations. The main cause of death from these conditions is a heart attack or stroke at a young age because of severe hardening of the arteries.
How is this drug used?
ZOKINVY is a capsule taken by mouth twice daily. The total daily dose is based on the patient’s size (body surface area).
What are the benefits of this drug?
ZOKINVY lowered the risk of death in patients with HGPS. The lifespan of HGPS patients treated with ZOKINVY increased by an average of three months through the first three years of follow-up and by an average of 2.5 years through the maximum follow-up time (11 years) compared to untreated patients.
What are the benefits of this drug?
The retrospective survival analysis was based on the mortality data from 62 treated patients (27 patients in Trial 1 and 35 treatment-naïve patients in Trial 2) and data from matched untreated patients from a separate natural history cohort.
Table 1. Survival Analysis Summary for Patients with HGPS
| Follow-up time censored at 3-years |
Last follow-up time | |||
|---|---|---|---|---|
| Summary | Untreated (n=62) |
ZOKINVY[1] (n=62) |
Untreated (n=62) |
ZOKINVY[1] (n=62) |
| Number of Deaths (%) | 12 (19.4) | 5 (8.1) | 25 (40.3) | 21 (33.9) |
| Mean Survival Time (years) [2] (95% CI) |
2.6 (2.4, 2.8) |
2.8 (2.7, 3.0) |
5.5 (4.3, 6.8) |
8.0 (6.9, 9.1) |
| Difference in Mean Survival Time (years) (95% CI) |
-- | 0.2 (0.0, 0.5) |
-- | 2.5 (0.8, 4.1) |
| Hazard Ratio for Risk of Death [3] (95% CI) |
-- | 0.30 (0.1, 0.9) |
-- | 0.40 (0.2, 0.8) |
[1] Includes 27 patients in Study 1 and 35 treatment-naïve patients in Study 2.
[2] Based on the area under the survival curves at the minimum of the largest observed time on each of the two groups,
[3] Based on a Cox regression model (with treatment as the only covariate) stratified by continent of residency.
Note: Treated patients were matched 1:1 to untreated patients (who were alive at the age when the treated patient began ZOKINVY) by mutation status (classic/unknow versus non-classic), sex and continent of residence using a fixed 50th percentile matching algorithm. In the fixed 50th percentile matching algorithm, candidate untreated patients were first sorted by decreasing last known age and the candidate in the 50th percentile was selected as the match. Follow-up time for a matched pair of treated and untreated patients began at the age of the treated patient at ZOKINVY initiation.
ZOKINVY Prescribing Information
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: ZOKINVY worked similarly in males and females.
- Race: Data not collected.
- Age: Most of the patients were children younger than 12 years of age, therefore differences in how well the drug worked between different age groups could not be determined.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Summaries of efficacy results by sex and age subgroups are presented below.
Table 2. Efficacy Results of Survival Time by Sex for Patients with HGPS (Fixed 50th Percentile Matching Algorithm)
| Summary | Follow-Up Time Censored at 3-Years | Follow-Up Time Censored at Last Follow-Up | ||
|---|---|---|---|---|
| Untreated | ZOKINVY | Untreated | ZOKINVY | |
| Male (N) | 33 | 33 | 33 | 33 |
| Number of deaths (%) | 9 (27.3) | 2 (6.1) | 13 (39.4) | 10 (30.3) |
| Mean survival time[1] (95% CI) | 2.5 (2.2, 2.8) | 2.9 (2.7, 3.0) | 5.98 (4.0, 8.0) | 8.1 (6.4, 9.7) |
| Difference in mean survival time (95% CI) | -- | 0.4 (0.1, 0.8) | -- | 2.1 (-0.5, 4.7) |
| Hazard ratio for risk of death[2] (95% CI) | -- | 0.2 (0.0, 0.9) | -- | 0.3 (0.1, 0.9) |
| Female (N) | 29 | 29 | 29 | 29 |
| Number of deaths (%) | 3 (10.3) | 3 (10.3) | 12 (41.4) | 11 (37.9) |
| Mean survival time[1] (95% CI) | 2.7 (2.4, 3.0) | 2.8 (2.5, 3.0) | 5.3 (4.1, 6.5) | 7.5 (6.3, 8.8) |
| Difference in mean survival time (95% CI) | -- | 0.1 (-0.3, 0.4) | -- | 2.2 (0.5, 3.9) |
| Hazard ratio for risk of death[2] (95% CI) | -- | 0.4 (0.1, 2.1) | -- | 0.3 (0.1, 0.8) |
Table 3. Efficacy Results of Survival Time by Age at Treatment Start for Patients with HGPS (Fixed 50th Percentile Matching Algorithm)
| Summary | Follow-Up Time Censored at 3-Years | Follow-Up Time Censored at Last Follow-Up | ||
|---|---|---|---|---|
| Untreated | ZOKINVY | Untreated | ZOKINVY | |
| >=12 years (N) | 5 | 5 | 5 | 5 |
| Number of deaths (%) | 5 (100.0) | 3 (60.0) | 5 (100.0) | 4 (80.0) |
| Mean survival time[1] (95% CI) | 1.0 (0.4, 1.5) | 1.6 (1.1, 2.0) | 1.0 (0.4, 1.5) | 1.6 (1.1, 2.0) |
| Difference in mean survival time (95% CI) | -- | 0.6 (-0.2, 1.3) | -- | 0.6 (-0.2, 1.3) |
| Hazard ratio for risk of death[2] (95% CI) | -- | 0.6 (0.1, 4.3) | -- | 0.6 (0.1, 4.3) |
| <12 years (N) | 57 | 57 | 57 | 57 |
| Number of deaths (%) | 7 (6.1) | 2 (2.0) | 20 (26.5) | 17 (24.5) |
| Mean survival time[1] (95% CI) | 2.7 (2.6, 2.9) | 2.9 (2.8, 3.0) | 6.0 (4.7, 7.2) | 8.5 (7.5, 9.6) |
| Difference in mean survival time (95% CI) | -- | 0.2 (-0.1, 0.4) | -- | 2.5 (0.9, 4.2) |
| Hazard ratio for risk of death[2] (95% CI) | -- | 0.2 (0.0, 1.0) | -- | 0.4 (0.2, 0.7) |
[1] Based on the area under the survival curves.
[2] Based on a Cox regression model (with treatment as the only covariate) stratified by continent of residency.
Note: Treated patients were matched 1:1 to untreated patients (who were alive at the age when the treated patient began ZOKINVY) by mutation status (classic/unknown versus non-classic), sex and continent of residence using a fixed 50th percentile matching algorithm. In the fixed 50th percentile matching algorithm, candidate untreated patients were first sorted by decreasing last known age and the candidate in the 50th percentile was selected as the match. Follow-up time for a matched pair of treated and untreated patients began at the age of the treated patient at ZOKINVY initiation.
FDA’s Statistical Review
What are the possible side effects?
ZOKINVY may cause serious side effects including kidney problems, eye problems (difficulty with night vision), fertility problems in females and males, and harm to an unborn baby if taken while pregnant.
The most common side effects are vomiting, diarrhea, infections, nausea, decreased appetite, fatigue, upper respiratory infection, abdominal pain, muscle and joint pain, and electrolyte abnormalities.
What are the possible side effects?
The table below summarizes adverse reactions that occurred in patients treated with ZOKINVY.
Table 4. Adverse Reactions in ≥5% of Patients in Trial 1 and Treatment Naïve Patients in Trial 2 Receiving ZOKINVY
| Adverse Reactions | ZOKINVY n=63 n (%) |
|---|---|
| Gastrointestinal disorders | |
| Vomiting | 57 (90%) |
| Diarrhea | 51 (81%) |
| Nausea | 35 (56%) |
| Abdominal pain1 | 30 (48%) |
| Constipation | 14 (22%) |
| Flatulence | 4 (6%) |
| General disorders and administration site conditions | |
| Fatigue | 32 (51%) |
| Pyrexia | 9 (14%) |
| Infections and infestations | |
| Infection2 | 49 (78%) |
| Upper respiratory tract infection3 | 32 (51%) |
| Rhinitis | 12 (19%) |
| Investigations | |
| Decreased appetite (anorexia) | 33 (53%) |
| Electrolyte abnormalities4 | 27 (43%) |
| Weight decreased | 23 (37%) |
| Myelosuppression5 | 22 (35%) |
| Increased aspartate aminotransferase | 22 (35%) |
| Decreased blood bicarbonate | 21 (33%) |
| Hypertension | 18 (29%) |
| Increased alanine aminotransferase | 17 (27%) |
| Dehydration | 3 (5%) |
| Musculoskeletal and connective tissue disorders | |
| Musculoskeletal pain6 | 30 (48%) |
| Nervous system disorders | |
| Headache | 23 (37%) |
| Cerebral ischemia7 | 7 (11%) |
| Ophthalmic | |
| Ocular changes8 | 15 (24%) |
| Psychiatric disorders | |
| Depressed mood | 3 (5%) |
| Respiratory, thoracic and mediastinal disorders | |
| Cough | 21 (33%) |
| Epistaxis | 13 (21%) |
| Skin and subcutaneous tissue disorders | |
| Rash | 7 (11%) |
| Pruritus | 5 (8%) |
| Mucositis | 5 (8%) |
1One patient with LMNA heterozygous mutation Progeroid Laminopathy.
ZOKINVY Prescribing Information
Were there any differences in side effects among sex, race and age?
- Sex: The occurrence of side effects was similar in males and females.
- Race: Data not collected.
- Age: Most of the patients were children younger than 12 years of age, therefore differences in side effects between different age groups could not be determined.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Summaries of adverse events by sex and age from both trials are presented below.
Table 5. Adverse Events by Sex
| Male (N=33) | Female (N= 30) | |
|---|---|---|
| At Least One TEAE, n (%) | 32 (97) | 30 (100) |
| Severe AE, n (%) | 13 (39) | 15 (50) |
| Death, n (%) | 3 (9) | 2 (7) |
Table 6. Adverse Events by Age Group
| 2-11 years (N=57) | 12-17 years (N=6) | |
|---|---|---|
| At Least One TEAE, n (%) | 56 (98) | 6 (100) |
| Severe AE, n (%) | 26 (46) | 2 (33) |
| Death, n (%) | 3 (5) | 2 (33) |
TEAE=treatment-emergent adverse event; AE=adverse event
Clinical Trial Data
WHO WAS IN THE CLINICAL TRIALS?
Who participated in the trials?
There were two clinical trials (Trial 1/NCT00425607 and Trial 2/NCT00916747) that enrolled 62 patients with HGPS and 1 patient with processing-deficient Progeroid Laminopathy. The patients were from 34 countries around the world, including the United States.
Figure 1 summarizes patients by sex who were in Trials 1 and 2.
Figure 1. Demographics by Sex (Trials 1 and 2)
Clinical Trial Data
Demographics by Race -Data Not Collected
Figure 2 summarizes the percentage of patients by age group in Trials 1 and 2.
Figure 2. Demographics by Age (safety population-Trials 1 and 2)
Clinical Trial Data
Demographics by Ethnicity -Data Not Collected
Who participated in the trials?
The table below summarizes demographics of patients in the clinical trials.
Table 7. Baseline Demographics of Enrolled Patients in the Clinical Trials
| Demographic Parameters | Trials 1 and 2 N=63 n (%) |
|
|---|---|---|
| Sex | ||
| Male | 33 (52) | |
| Female | 30 (48) | |
| Race-data not collected | ||
| Age | ||
| Mean (years) | 8.7 | |
| Median (years) | 8.5 | |
| Min, max (years) | 2, 17 | |
| Age group | ||
| 2-11 years | 57 (90) | |
| 12-17 years | 6 (10) | |
| Ethnicity-data not collected | ||
| Region | ||
| Unites States | 12 (19) | |
| Rest of the World1 | 51 (81) | |
1 Patients from 33 counties in Europe, Africa, Asia and Latin America.
Clinical Trial Data
How were the trials designed?
There were two trials that evaluated the benefit and side effects of ZOKINVY.
In Trial 1, patients received ZOKINVY twice daily for 24 to 30 months. Following completion of the treatment, most of the patients enrolled in Trial 2 and continued ZOKINVY with some other therapies for about 5 years. Another group of patients who were never treated with ZOKINVY also enrolled in Trial 2 and were treated with ZOKINVY for up to 3 years.
The benefit of ZOKINVY was evaluated by comparing the time to death in ZOKINVY-treated patients to patients who were not treated with ZOKINVY (called the natural history cohort).
How were the trials designed?
The safety and efficacy of ZOKINVY were evaluated in two clinical trials of patients with HGPS or Progeroid Laminopathy.
Trial 1 was an open-label, single-arm trial where patients received ZOKINVY for 24 to 30 months. Trial 2 was an open label, single-arm trial which consisted of two phases. In the first phase, Trial 2 enrolled patients from completed Trial 1 and they continued ZOKINVY with additional therapies for about 5 years. In the second phase of Trial 2, treatment naïve patients received ZOKINVY for up to three years.
The retrospective survival analysis was based on the mortality data from treated patients and data from matched untreated patients in a separate natural history cohort.
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.
PRESCRIBING INFORMATION