Drug Trials Snapshot: CRENESSITY
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic 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 healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the CRENESSITY Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
CRENESSITY (crinecerfont)
(kreh neh' si tee)
Neurocrine Biosciences Inc.
Approval date: December 13, 2024
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
CRENESSITY is a corticortopin-releasing factor type 1 receptor antagonist to be used together with glucocorticoids (steroids) to control androgen levels in adults and pediatric patients aged 4 years and older with classic congenital adrenal hyperplasia.
How is this drug used?
CRENESSITY is available as an oral capsule and as oral solution that is taken twice daily.
Who participated in the clinical trials?
The FDA approved CRENESSITY based on evidence from two clinical trials of 182 adults and 103 children with classic congenital adrenal hyperplasia. The adult trial was conducted at 54 sites in 16 countries in North America, Europe, and Asia. The pediatric trial was conducted at 37 sites in 10 countries in North America and Europe. Of the 285 participants, 127 (45%) were from the United States. Findings from both clinical trials established CRENESSITY’s safety and efficacy.
How were the trials designed?
CRENESSITY was evaluated in two randomized, double-blind, placebo-controlled clinical trials of 182 adults and 103 children aged 4 years and older with classic congenital hyperplasia due to 21-hydroxylase deficiency who were taking supraphysiologic daily glucocorticoid doses.
How were the trials designed?
In the adult trial, 122 subjects received CRENESSITY 100 mg twice daily and 60 subjects received placebo twice daily for 24 weeks. During the first four weeks of CRENESSITY treatment, subjects maintained a stable glucocorticoid regimen except for stress dosing as needed. After the first four weeks, the glucocorticoid dose was reduced to physiologic replacement levels, and then further adjusted, if needed, to achieve control of serum androstenedione by Week 24. The primary efficacy measure was the percent change from baseline in the total glucocorticoid daily dose while maintaining androstenedione control (i.e., ≤120% of baseline or ≤ upper limit of normal for age and sex) at 24 weeks.
In the second trial, children and adolescents (mean age 12 years, range 4 to 17 years) received a weight-based dose (50 mg twice daily for those weighing 20 to <55 kg and 100 mg twice daily for those weighing ≥55 kg) of CRENESSITY (69 subjects) or placebo (34 subjects) for 28 weeks. During the first four weeks of the trial, glucocorticoid dose remained stable. After the first four weeks, the glucocorticoid dose was adjusted based on androstenedione levels. The primary measure of efficacy was the change from baseline in serum androstenedione at Week 4. A key secondary efficacy endpoint was the percent change from baseline in in the total glucocorticoid daily dose while maintaining androstenedione control (i.e., ≤120% of baseline or ≤ upper limit of normal for sex and age or, if pubertal, pubertal stage) at 28 weeks.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female participants were enrolled in the combined clinical trials used to evaluate the efficacy of CRENESSITY.
Figure 1. Baseline Demographics by Sex, Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes how many participants by race were enrolled in the combined clinical trials used to evaluate the efficacy of CRENESSITY.
Figure 2. Baseline Demographics by Race, Efficacy Population
Source: Adapted from FDA Review
Figure 3 summarizes how many participants by age were enrolled in the combined clinical trials used to evaluate the efficacy of CRENESSITY.
Figure 3. Baseline Demographics by Age, Efficacy Population
Source: Adapted from FDA Review
Figure 4 summarizes how many participants by ethnicity were enrolled in the combined clinical trials used to evaluate the efficacy of CRENESSITY.
Figure 4. Baseline Demographics by Ethnicity, Efficacy Population
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics of Efficacy Trials
| Demographic | Subgroup | Adult Trial | Pediatric Trial | ||
|---|---|---|---|---|---|
| CRENESSITY N=122 n (%) | Placebo N=60 n (%) | CRENESSITY N=69 n (%) | Placebo N=34 n (%) | ||
| Sex | Female | 61 (50) | 29 (48.3) | 34 (50.7) | 16 (47.1) |
| Male | 61 (50) | 31 (51.7) | 35 (49.3) | 18 (52.9) | |
| Age category, years | 2 to <12 | NA | NA | 31 (44.9) | 16 (47.1) |
| 12 to 17 | NA | NA | 38 (55.1) | 18 (52.9) | |
| 18 to 25 | 40 (32.8) | 27 (45.0) | NA | NA | |
| 26 to 35 | 43 (35.2) | 21 (35.0) | NA | NA | |
| ≥36 | 39 (31.9) | 12 (20.0) | NA | NA | |
| Race | Other or unknown | 8 (6.6) | 3 (5.0) | 16 (23.2) | 9 (26.5) |
| Asian or Pacific Islander | 5 (4.1) | 0 (0) | 8 (7.0) | 2 (5.8) | |
| Black or African American | 2 (1.6) | 0 (0) | 3 (4.3) | 0 (0) | |
| White | 107 (87.7) | 57 (95.0) | 42 (60.9) | 23 (67.6) | |
| Ethnicity | Hispanic or Latino | 6 (4.9) | 8 (13.3) | 8 (11.6) | 3 (8.8) |
| Not Hispanic or Latino | 116 (95.1) | 52 (86.7) | 52 (75.4) | 25 (73.5) | |
| Unknown | NA | NA | 9 (13.0) | 6 (17.0) | |
Source: Adapted from FDA Review
Abbreviations: NA, not applicable
What are the benefits of this drug?
In both adults and in children, CRENESSITY allowed for a statistically significant decrease in glucocorticoid daily dose while maintaining androstenedione control. In the adult trial, CRENESSITY resulted in a 27% lower glucocorticoid daily dose at Week 24, while androstenedione levels were controlled, compared to a 10% lower daily glucocorticoid dose in the group that received placebo. In the pediatric trial, CRENESSITY resulted in an 18% lower glucocorticoid daily dose at Week 28, while androstenedione levels were controlled, compared to a 6% increased glucocorticoid daily dose in the group that received placebo.
In the adult study, CRENESSITY lowered serum androstenedione levels at Week 4 by 299 ng/dL, while glucocorticoid daily dose remained stable, compared to an increase in serum androstenedione of 46 ng/dL in the group that received placebo. In the pediatric study, CRENESSITY lowered serum androstenedione levels at Week 4, while glucocorticoid daily dose remained stable, by 197 ng/dL compared to an increase of 71 ng/dL in the group that received placebo.
The FDA granted CRENESSITY Fast Track, Breakthrough Therapy, Orphan Drug and Priority Review designations.
What are the benefits of this drug (results of trials used to assess efficacy)?
Table 2. Efficacy Results, Efficacy Population
| Trial | Primary Efficacy Endpoint | Placebo Change (SEM) | CRENESSITY Change (SEM) | Difference (95% CI) | p-Value |
|---|---|---|---|---|---|
| Adult | Percent change from baseline in glucocorticoid daily dose at Week 28 | -10.3 (3.2) | -27.3 (2.4) | -17.0 (‑23.8, -10.2) | <0.0001 |
| Pediatric | Change from baseline in serum androstenedione (ng/dL) at Week 4 | 71 (56) | -197 (40) | -268 (‑403, ‑132) | 0.0002 |
Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; SEM, standard error of mean
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: CRENESSITY worked similarly in males and females.
- Race: The number of patients of races other than White was small. Therefore, differences between races in how well CRENESSITY worked could not be determined.
- Age: CRENESSITY worked similarly in patients regardless of age.
- Ethnicity: CRENESSITY worked similarly in Hispanic or Latino and Not Hispanic or Latino patients.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 3. Efficacy Results by Sex, Race, Age, and Ethnicity, Efficacy Population
| Group | Subgroup | Adult Trial | Pediatric Trial |
|---|---|---|---|
| Treatment Effect Mean (95% CI)* | Treatment Effect Mean (95% CI)* | ||
| Sex | Female | -14.7 (-23.7, -4.96) | -369.28 (-585.65, -164.73) |
| Male | -19.4 (-28.6, -10.80) | -174.54 (-366.39, 23.94) | |
| Age category, years | 2 to <12 | NA | -238.87 (-406.78, -51.93) |
| 12 to 17 | NA | -297.15 (-464.48, -134.15) | |
| 18 to 25 | -16.5 (-24.1, -8.93) | NA | |
| 26 to 35 | -15.6 (-23.3, -7.90) | NA | |
| ≥36 | -16.4 (-24.4, -8.33) | NA | |
| Race | Other1 | -16.2 (-31.7, -0.61) | -225.03 (-424.09, -51.64) |
| White | -16.1 (-23.0, -9.19) | -193.00 (-305.81, -74.72) | |
| Ethnicity | Hispanic or Latino | -16.3 (-28.1, -3.73) | -198.77 (-346.20, -46.73) |
| Not Hispanic or Latino | -16.9 (-23.8, -10.00) | -188.96 (-294.27, -86.26) |
Source: Adapted from FDA Review
* Credible intervals include the relevance of outcomes from other subgroups.
1 Due to small number of participants Black or African American and Asian or Pacific Islander were combined with Other category of race.
Abbreviations: CI, credible interval; NA, not applicable
What are the possible side effects?
A serious allergic reaction with symptoms of throat tightness and swelling and skin rash occurred in a patient after three days of treatment with CRENESSITY.
There is a risk of sudden adrenal insufficiency or adrenal crisis if patients decrease their glucocorticoid dose below the dose required for cortisol replacement. Any adjustment of daily glucocorticoid dosage after initiation of CRENESSITY should be performed under the supervision of a health care provider. Use glucocorticoid stress doses in cases of increased cortisol need (e.g., acute illness, serious trauma, surgical procedures).
The most common side effects of CRENESSITY in adults include tiredness, headache, dizziness, joint pain, back pain, decreased appetite, and muscle pain. The most common side effects of CRENESSITY in children include headache, stomach pain, nasal congestions, and nose bleeds.
What are the possible side effects (results of trials used to assess safety)?
In addition to risk of adrenal insufficiency and allergic reactions, thoughts of suicide (i.e., suicidal ideation) and decreased levels of neutrophils (a white blood cell that helps to fight infection) were observed in the clinical trials of CRENESSITY.
In the adult trial, 2.5% (3 of 122) of CRENESSITY-treated patients reported suicidal ideation without method, intent, or plan on the Columbia-Suicide Severity Rating Scale compared to 1.7% (1 of 59) in the placebo arm. Low neutrophil counts (i.e., <2 x 103 cells/mcL) occurred in 14% (17 of 120) of CRENESSITY-treated patients compared to 5% (3 of 58) in the placebo group. Very low neutrophil counts (i.e., <1 x 103 cells/mcL) were more common in placebo-treated patients (1.7%) compared to CRENESSITY-treated patients (0.8%).
In the pediatric trial, 6% (4 of 67) of CRENESSITY-treated patients reported suicidal ideation without method, intent, or plan on the Columbia-Suicide Severity Rating Scale compared to 0% (0 of 31) in the placebo arm. Low neutrophil counts (i.e., <2 x 103 cells/mcL) occurred in 37% (25 of 68) of CRENESSITY-treated patients compared to 16% (5 of 32) in the placebo group and very low neutrophil counts (i.e., <1 x 103 cells/mcL) affected 4% of CRENESSITY-treated subjects, compared to no subjects in the placebo group.
The most common adverse reactions (i.e., those occurring in at least 4% of CRENESSITY-treated subjects) in the adult and pediatric trials are shown in Table 4.
Table 4. Adverse Reactions (≥4%) in Adult and Pediatric Trial Participants Treated With CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects, Safety Population
| Adverse Reaction | Adult Trial | Pediatric Trial | ||
|---|---|---|---|---|
| CRENESSITY N=122 n (%) | Placebo N=59 n (%) | CRENESSITY N=69 n (%) | Placebo N=33 n (%) | |
| Fatigue | 30 (24.6) | 9 (15.3) | 5 (7.2) | 0 |
| Headache | 10 (8.5) | 19 (15.6) | 17 (24.6) | 2 (6.1) |
| Dizziness | 10 (8.2) | 2 (3.4) | NA | NA |
| Arthralgia | 9 (7.4) | 0 | NA | NA |
| Back pain | 7 (5.7) | 2 (3.4) | NA | NA |
| Decreased appetite | 5 (4.1) | 1 (1.7) | NA | NA |
| Myalgia | 5 (4.1) | 2 (3.3) | NA | NA |
| Abdominal pain1 | NA | NA | 6 (8.7) | 0 |
| Nasal congestion | NA | NA | 5 (7.2) | 1 (3.0) |
| Epistaxis | NA | NA | 3 (4.3) | 0 |
Source: Adapted from FDA Review
1 Abdominal pain includes: abdominal pain, abdominal pain upper, and abdominal pain lower
Abbreviations: NA, not applicable
Were there any differences in side effects among sex, race and age?
- Sex: Side effects from CRENESSITY were similar in females and males.
- Race: The number of patients of race other than White was small; therefore, differences among races in sides effects from CRENESSITY could not be determined.
- Age: Side effects from CRENESSITY were similar across different age groups.
- Ethnicity: The number of patients that were Hispanic or Latino was small; therefore, differences among ethnicities in sides effects from CRENESSITY could not be determined.
Table 5. Adverse Reactions by Sex, Race, Age, and Ethnicity, Safety Population
| Group | Subgroup | Adult Trial | Pediatric Trial | ||
|---|---|---|---|---|---|
| CRENESSITY N=122 n/Ns (%) | Placebo N=59 n/Ns (%) | CRENESSITY N=69 n/Ns (%) | Placebo N=33 n/Ns (%) | ||
| Sex | Female | 53/61 (86.9) | 25/29 (86.2) | 28/34 (82.4) | 12/15 (80.0) |
| Male | 48/61 (78.7) | 23/30 (76.7) | 30/35 (85.7) | 15/18 (83.3) | |
| Age category, years | 2 to <12 | NA | NA | 26/31 (83.9) | 14/15 (93.3) |
| 12 to 17 | NA | NA | 32/38 (84.2) | 13/18 (72.2) | |
| 18 to 25 | 31/40 (77.5) | 20/27 (74.1) | NA | NA | |
| 26 to 35 | 35/43 (81.4) | 18/21 (85.7) | NA | NA | |
| ≥36 | 35/39 (89.7) | 10/11 (90.9) | NA | NA | |
| Race | Other or unknown1 | 14/15 (93.3) | 3/3 (100) | 23/27 (85.2) | 9/10 (90.0) |
| White | 87/107 (81.3) | 45/56 (80.4) | 35/42 (83.3) | 18/23 (78.3) | |
| Ethnicity | Hispanic or Latino | 4/6 (66.7) | 7/8 (87.5) | 7/8 (87.5) | 3/3 (100) |
| Not Hispanic or Latino | 97/116 (83.6) | 41/51 (80.4) | 45/52 (86.5) | 19/24 (79.2) | |
| Unknown | NA | NA | 6/9 (66.7) | 5/6 (83.3) | |
Source: Adapted from FDA Review
1 Due to small number of participants Black or African American and Asian or Pacific Islander were combined with Other category of race.
Abbreviations: NA, not applicable, Ns, total number of patients for each specific subgroup
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.