Drug Trials Snapshots: Kanuma
HOW TO USE THIS SNAPSHOT:
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.
LIMITATIONS OF THIS SNAPSHOT:
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 KANUMA Prescribing Information for complete information.
KANUMA (sebelipase alfa)
Kuh-new-muh
Alexion
Approval date: December 8, 2015
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
KANUMA is a treatment for patients with a rare disease known as Lysosomal Acid Lipase (LAL) deficiency. Patients with LAL deficiency have no or little LAL enzyme activity. This results in a build-up of fats within the cells of various tissues that can lead to liver, heart, and blood vessel disease and other complications.
LAL deficiency has two forms. The first type (referred to as Wolman disease) is seen in infants (around 2 to 4 months of age) and is often fatal in the first year of life. The second form (referred to as cholesteryl ester storage disease, or CESD) is milder with an onset in early childhood or later in life. Life expectancy of patients with CESD depends on the severity of the disease and complications from the disease.
How is this drug used?
KANUMA is given by a health care professional through a needle in the vein (intravenous). KANUMA is given once every week to patients who present with LAL deficiency in the first six months of life. It is given once every other week to other patients.
What are the benefits of this drug?
In patients with Wolman disease, six of nine (67%) treated with KANUMA were alive at 12 months of age. This was compared to a group from another study (called a historical control) of 21 infants who were not treated. In this untreated group, none were alive at 12 months of age.
In patients with CESD treated with KANUMA, there was an improvement in levels of low-density lipoprotein (LDL) cholesterol and other disease-related measures compared to placebo after 20 weeks of treatment.
What are the benefits of this drug (results of trials used to assess efficacy)?
The efficacy of KANUMA in infants was assessed by comparing the survival of 9 KANUMA-treated patients at 12 months of age with an untreated historical cohort of 21 patients.
The efficacy of KANUMA in children and adults was assessed by comparing low-density lipoprotein cholesterol (LDL-C) blood levels in KANUMA-treated patients with placebo-treated patients at Week 20.
Clinical Trial in Infants
Of the 9 KANUMA-treated infants, 6 survived beyond 12 months of age, compared to 0 of 21 patients in the historical cohort, all of whom died by 8 months of age. The median age of the 6 surviving KANUMA-treated patients was 18.1 months (range 12 to 42.2 months).
Following initiation of treatment with KANUMA 1 mg/kg once weekly, weight-for-age z-scores improved in 3 of 5 surviving patients with growth failure at baseline, and all 6 surviving patients demonstrated improvements from baseline in weight-for-age z-scores following dose escalation to 3 mg/kg once weekly.
Efficacy in Children and Adults
At the completion of the 20-week double-blind period of the trial, a statistically significant improvement in percent change from baseline in LDL-c was observed in the KANUMA-treated group as compared to the placebo group (mean difference and 95% C.I.: -22%, [-33%, -15%]; p<0.0001). LDL-c of less than 130 mg/dL was achieved in 13 of 32 (41%; 95% C.I.: [24%, 58%]) KANUMA-treated patients and in only 2 of 30 (7%; 95% C.I.: [0%, 16%]) placebo-treated patients with baseline LDL-c of 130 mg/dL or greater. A statistically significant improvement in percent change from baseline at 20 weeks was also observed in the KANUMA-treated group compared to the placebo group for other parameters related to LAL deficiency, including decreases in non-HDL-c (mean difference and 95% C.I.: -21%, [-30%, -15%]; p<0.0001) and triglycerides (mean difference and 95% C.I.: -14%, [-28%, -1%]; p=0.0375), and increases in HDL-c (mean difference and 95% C.I.: 20%, [12%, 26%]; p<0.0001). The effect of KANUMA on cardiovascular morbidity and mortality has not been established.
Patients treated with KANUMA had larger reductions from baseline in alanine aminotransferase (ALT) values and liver fat content (measured by MRI), compared to patients treated with placebo. The significance of these findings as they relate to progression of liver disease in LAL deficiency has not been established.
Open-label Extension
Pediatric and adult patients who participated in the randomized, placebo-controlled trial were eligible to continue treatment in an open-label extension. Sixty-five of 66 patients (98%) entered the open-label period in which all patients received KANUMA at a dosage of 1 mg/kg once every other week. During the open-label extension, patients treated with KANUMA for up to 36 weeks demonstrated improvements in lipid parameters, including LDL-C and HDL-C levels, and ALT.
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
Subgroup analyses were conducted for sex, race, and age for the CESD trial in children and adults.
- Sex: KANUMA worked similarly in males and females.
- Race: The majority of patients in the trials were white. Differences in response to KANUMA among races could not be determined.
- Age: KANUMA worked similarly in all age groups studied.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
The table below summarizes the responses to KANUMA and placebo, by subgroups in the trial in children and adults.
Table 3. Subgroup Analysis of Mean Percent Reduction from Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 20-Trial in Children and Adults with CESD*
|
KANUMA |
Placebo (N=30) |
95% CI** | |||
|---|---|---|---|---|---|
| LDL-C % Change from Baseline (Mean) | N | LDL-C % Change from Baseline (Mean) |
N |
||
| Overall/All patients | -28.5 | 36 | -6.4 | 30 | -31.3,-12.9 |
| Sex | |||||
| Male | -26.3 | 18 | -5.7 | 15 | -36.2, -5.1 |
| Female | -30.6 | 18 | -7.0 | 15 | -34.6, -12.6 |
| Age Group | |||||
| "< 12" | -17.0 | 14 | -0.8 | 10 | -33. 6, 1.2 |
| 12 - 17 years | -32.2 | 9 | -8.9 | 14 | -36.2, -10.3 |
| >= 18 years | -38.2 | 13 | -9.5 | 6 | -46.9, -10.5 |
| Race | |||||
| White | -29.5 | 27 | -6.0 | 28 | -32.3, -14.9 |
| Black or African American | -46.4 | 1 | - | 0 | _ |
| Asian | -3.6 | 3 | - | 0 | _ |
| Other | -34.0 | 5 | -12.0 | 2 | -60.3, 16.3 |
*Based on clinical trial data
** 95% Confidence Interval for the mean difference of the percentage change from baseline in LDL concentration between KANUMA and Placebo
What are the possible side effects?
The most common side effects observed in patients treated with KANUMA are diarrhea, vomiting, fever, rhinitis, anemia, cough, headache, constipation, and nausea.
KANUMA may cause severe allergic reactions including a life-threatening reaction called anaphylaxis.
What are the possible side effects (results of trials used to assess safety)?
The tables below summarize adverse reactions for each trial separately.
Table 4. Most Common Adverse Reactions* in Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life**
| Adverse Reactions | KANUMA N=9 |
|---|---|
| n (%) | |
| Diarrhea | 6 (67) |
| Vomiting | 6 (67) |
| Fever | 5 (56) |
| Rhinitis | 5 (56) |
| Anemia | 4 (44) |
| Cough | 3 (33) |
| Nasopharyngitis | 3 (33) |
| Urticaria | 3 (33) |
*Reported in more than 30% of patients receiving KANUMA
** KANUMA Prescribing Information
Table 5. Most Common Adverse Reactions* in Children and Adult Patients with CESD**
| Adverse Reactions | KANUMA N = 36 |
Placebo N = 30 |
|---|---|---|
| n (%) | n (%) | |
| Headache | 10 (28) | 6 (20) |
| Fever | 9 (25) | 7 (23) |
| Oropharyngeal pain | 6 (17) | 1 (3) |
| Nasopharyngitis | 4 (11) | 3 (10) |
| Asthenia | 3 (8) | 1 (3) |
| Constipation | 3 (8) | 1 (3) |
| Nausea | 3 (8) | 2 (7) |
* Reported in at least 8% of pediatric and adult patients receiving KANUMA and at a higher incidence than in patients receiving placebo
**KANUMA Prescribing Information
Were there any differences in side effects among sex, race, and age? Subgroup analyses were conducted for sex, race, and age for the CESD trial in children and adults.
- Sex: The risk of side effects was similar in males and females.
- Race: The majority of patients in the trials were white. Differences in side effects among races could not be determined.
- Age: The risk of side effects was similar in all age groups studied.
Were there any differences in side effects in the clinical trials among sex, race and age groups?
The table below summarizes treatment emergent adverse events (TEAEs) in children and adult patients with CESD by subgroup.
Table 6. Subgroup Analysis of TEAEs in Children and Adult Patients with CESD
| Subgroup | KANUMA (n=36) | Placebo (n=30) | ||||||
|---|---|---|---|---|---|---|---|---|
| n (%) | Total number of patients (n) |
n (%) | Total number of patients (n) |
|||||
| Overall/All patients | 31 (86) | 36 | 28 (93) | 30 | ||||
| Sex | ||||||||
| Male | 16 (89) | 18 | 14 (93) | 15 | ||||
| Female | 15 (83) | 18 | 14 (93) | 15 | ||||
| Age Group | ||||||||
| < 12=""> | 14 (100) | 14 | 10 (100) | 10 | ||||
| 12 - 17years | 8 (89) | 9 | 13 (93) | 14 | ||||
| >= 18 years | 9 (69) | 13 | 5 (83) | 6 | ||||
| Race | ||||||||
| White | 22 (82) | 27 | 26 (93) | 28 | ||||
| Black or African American |
1 (100) | 1 | - | 0 | ||||
| Asian | 3 (100) | 3 | - | 0 | ||||
| American Indian or Alaska Native |
- | 0 | - | 0 | ||||
| Native Hawaiian or Other Pacific Islander |
- | 0 | - | 0 | ||||
| Other | 5 (100) | 5 | 2 (100) | 2 | ||||
*Based on Clinical trial data
WHO WAS IN THE CLINICAL TRIALS?
Who participated in the clinical trials?
The FDA approved KANUMA based on evidence from 2 clinical trials of 75 patients with LAL deficiency. One trial enrolled 9 infants 1-6 months of age with Wolman disease, and the other trial enrolled 66 children and adults 4 years to 58 years of age with CESD. The trials were conducted in the United States and 16 other countries around the world.
Figures 1 and 2 summarize how many patients, by sex, were enrolled in the clinical trials. The two trials are shown separately.
Figure 1. Baseline Demographics by Sex—Clinical Trial in Infants*
*Based on clinical trial data
Figure 2. Baseline Demographics by Sex—Clinical Trial in Children and Adults with CESD*
Figure 2 and Table 1 summarize the number and percentage of patients by race in the clinical trial in infants.
Figure 2. Baseline Demographics by Race—Clinical Trial in Infants*
*Based on clinical trial data
Table 1. Baseline Demographics by Race—Clinical Trial in Infants*
| Race | Number of Patients | Percentage |
|---|---|---|
| White | 4 | 44% |
| Black or African American | 1 | 11% |
| Asian | 1 | 11% |
| Other | 3 | 33% |
*Based on clinical trial data
Figure 3 and Table 2 summarize the number and percentage of patients by race in the clinical trial in children and adults.
Figure 3. Baseline Demographics by Race—Clinical Trial in Children and Adults with CESD*
*Based on clinical trial data
Table 2. Baseline Demographics by Race—Clinical Trial in Children and Adults with CESD*
| Race | Number of Patients | Percentage |
|---|---|---|
| White | 55 | 83% |
| Black or African American | 1 | 2% |
| Asian | 3 | 5% |
| Other | 7 | 11% |
*Based on clinical trial data
Figure 3 summarizes the number and percentage of patients by age group in the clinical trial in children and adults.
Figure 3. Baseline Demographics by Age—Clinical Trial in Children and Adults with CESD*
Who participated in the trials?
The tables below summarize baseline demographics for the each trial separately.
Table 7. Baseline Demographics- Clinical Trial in Infants with Wolman Disease*
| Demographic Parameters | KANUMA (N=9) n (%) |
|---|---|
| Sex | |
| Male | 5 (56) |
| Female | 4 (44) |
| Age (Months) | |
| Mean years (SD) | 3.4 (1.6) |
| Median (months) | 3.0 |
| Min, Max (months) | 1.1, 5.8 |
| Race | |
| White | 4 (44) |
| Black or African American | 1 (11) |
| Asian | 1 (11) |
| Other | 3 (33) |
| Ethnicity | |
| Not Hispanic or Latino | 6 (67) |
| Unknown | 3 (33) |
| Region | |
| United States | 1 (11) |
| Europe | 6 (67) |
| Asia | 1 (11) |
| Africa | 1 (11) |
*Based on clinical trial data
Table 8. Baseline Demographics – Clinical Trial in Children and Adults with CESD*
| Demographic Parameters | Trial 2 (N=66) |
Total (N=66) |
|
|---|---|---|---|
| KANUMA (N= 36) n (%) |
Placebo (N= 30) n (%) |
||
| Sex | |||
| Male | 18 (50) | 15 (50) | 33 (50) |
| Female | 18 (50) | 15 (50) | 33 (50) |
| Age | |||
| Mean years (SD) | 16.9 (11.6) | 15.2 (10.2) | 16.1 (11.0) |
| Median (years) | 13.5 | 13.0 | 13.0 |
| Min, Max (years) | 4, 55 | 4, 58 | 4, 58 |
| Age Group | |||
| < 12=""> | 14 (39) | 10 (33) | 24 (36) |
| >=12 - < 18=""> | 9 (25) | 14 (47) | 23 (35) |
| >= 18 years | 13 (36) | 6 (20) | 19 (29) |
| Race | |||
| White | 27 (75) | 28 (93) | 55 (83) |
| Black or African American | 1 (3) | 0 | 1 (2) |
| Asian | 3 (8) | 0 | 3 (5) |
| Other | 5 (14) | 2 (7) | 7 (11) |
| Ethnicity | |||
| Hispanic or Latino | 6 (17) | 4 (13) | 10 (15) |
| Not Hispanic or Latino | 30 (83) | 26 (87) | 56 (85) |
*Based on clinical trial data
How were the trials designed?
There were two trials that evaluated the benefits and side effects of KANUMA.
The first trial was done in 9 infants with Wolman disease. All babies were treated with intravenous KANUMA once every week. The benefit was evaluated by measuring how many infants were alive at the age of 12 months. This was compared to a historical cohort, which is a group of Wolman disease patients from another study with similar clinical characteristics who were not treated with KANUMA.
The second trial was done in 66 children and adults with LAL deficiency. All participants in the trial were treated with intravenous KANUMA or placebo once every other week. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed. The benefit of KANUMA was measured at 20 weeks although some patients continued to receive KANUMA for up to 36 weeks.
The trial measured improvement in LDL cholesterol levels and compared KANUMA to placebo at Week 20.
How were the trials designed?
A multi-center, open-label, single-arm clinical trial of KANUMA was conducted in 9 infants with Wolman disease who had growth failure or other evidence of rapidly progressive disease prior to 6 months of age. The age range at entry was 1 to 6 months. Patients received KANUMA at 0.35 mg/kg once weekly for the first 2 weeks and then 1 mg/kg once weekly. Due to suboptimal clinical response, doses in all 6 surviving patients were escalated to 3 mg/kg once weekly, between week 4 and 88 (median 11 weeks) after starting treatment at 1 mg/kg. The recommended dosage for these patients is 1 mg/kg to 3 mg/kg once weekly.
Efficacy of KANUMA was assessed by comparing the survival of 9 KANUMA-treated patients at 12 months of age with an untreated historical cohort of 21 patients with a similar age at disease presentation and similar clinical characteristics.
The safety and efficacy of KANUMA were assessed in 66 pediatric and adult patients with CESD in a multi-center, double-blind, placebo-controlled trial. Patients were randomized to receive KANUMA at a dosage of 1 mg/kg (n=36) or placebo (n=30) once every other week for 20 weeks in the double-blind period. Sixty-two of the 66 (94%) patients had LDL-C of 130 mg/dL or greater at study entry. The majority of patients (58%) had LDL-C above 190 mg/dL at study entry, and 24% of patients with LDL-C above 190 mg/dL remained on lipid lowering medications.
The efficacy of KANUMAa was primarily based on the percent change from baseline in LDL-C at Week 20 in patients treated with KANUMA compared to patients treated with placebo. The trial had an open-label extension with KANUMA treatment for up to 36 weeks.
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.