Effective Date

Date of Origin 

07-01-2025            

07-01-2025

Crenessity™

(crinecerfont)

Capsule

Oral solution

Adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH)

1

Congenital Adrenal Hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders. It is potentially life-threatening in its classic (severe) form and may be asymptomatic or cause female infertility in its nonclassic (mild) form. The most common type of CAH is 21-hydroxylase deficiency and is synonymous with classic CAH terminology, CAH indicates CAH due to 21-hydroxylase deficiency. More than 95 percent of cases of CΑН are caused by autosomal recessive deficiency of 21-hydroxylase, due to mutations of the СΥΡ21Α2 gene. CAH is a disease of multiple hormonal imbalances. Mutations in CYP21A2 (the gene encoding 21-hydroxylase, a cytochrome P-450 enzyme) result in lack of 21-hydroxylase, which is required for the production of cortisol and aldosterone in the adrenal cortex. A deficiency of this enzyme has cascading effects. Reduced cortisol leads to overproduction of pituitary corticotropin. This downstream deficiency results in diminished or absent production of cortisol and aldosterone and overproduction of pituitary corticotrophin and adrenal androgens.(2,3,6)

Today, the classic form is the most common cause of atypical genitalia in 46,XX newborns and of primary adrenal insufficiency during childhood. Clinical manifestations depend on the severity of the deficiency and adequacy of treatment but most commonly include risk for adrenal crisis, virilizаtiοn including atypical genitalia (in 46,XX iոfantѕ), abnormal growth during ϲhilԁhоoԁ, early puberty, adult short ѕtature, menstrual dysfunction, and iոfеrtility. Unlike the therapeutic approaches to other forms of adrenal insufficiency, therapeutic goals in CAH are twofold: first, to replace deficient hormones, and second, to reduce excessive androgen levels. Although the overwhelming majority of patients with CAH survive the disease, thanks to advances in genetics, metabolomics, and treatment strategies, existing therapies have failed to prevent multiple coexisting conditions, and deaths due to adrenal crisis still occur.(4,6)

The Endocrine Society guidelines recommend the following:(2)

• All newborn screening programs are recommended to incorporate screening for CAH due to 21-hydroxylase deficiency (currently available in all 50 states).
• Screening laboratories are recommended to employ a second-tier screen by liquid chromatography–tandem mass spectrometry in preference to all other methods (e.g., genotyping) to improve the positive predictive value of CAH screening.
• In the newborn and in early infancy, we recommend using fludrocortisone and sodium chloride supplements to the treatment regimen.
• Growing individuals with classic CAH should receive maintenance therapy with hydrocortisone and should avoid chronic use of more potent or long-acting glucocorticoids, which can have adverse side effects.
• Patients with CAH (and parents of minors) should seek mental health treatment to address any congenital adrenal hyperplasia-related psychosocial problems.
• In individuals with CAH, we suggest genotyping only when results of the adrenocortical profile after a cosyntropin stimulation test are equivocal, or cosyntropin stimulation cannot be accurately performed (i.e., patient receiving glucocorticoid), or for purposes of genetic counseling. Genotyping at least one parent aids in the interpretation of genetic test results because of the complexity of the CYP21A2 locus.
• In growing individuals with classic CAH, we recommend maintenance therapy with hydrocortisone. In all individuals with classic CAH, we recommend monitoring for signs of glucocorticoid excess, as well as for signs of inadequate androgen normalization, to optimize the adrenal steroid treatment profile.
• In all individuals with classic CAH, we recommend monitoring for signs of mineralocorticoid deficiency or excess.
• In adults with classic CAH, we recommend using daily hydrocortisone and/or long-acting glucocorticoids plus mineralocorticoids, as clinically indicated.

In summary, the standard of treatment for CAH is glucocorticoid and mineralocorticoid replacement which account for the deficiencies of cortisol and suppression of adrenal androgen production. While hydrocortisone (HC) is the most commonly used glucocorticoid in children with CAH, in adult patients synthetic glucocorticoids (e.g., prednisone or dexamethasone) are more frequently used as they may have benefits in terms of androgen control given their longer half-life. The most commonly used mineralocorticoid is fludrocortisone (9α-fludrocortisone). The usual daily dose varies between 0.05 and 0.2 mg and is usually taken in the morning. However, these supraphysiologic doses can cause severe side effects such as weight gain, diabetes, osteoporosis, and cardiovascular issues, significantly impacting patients’ quality of life.(6,7)

Crenessity is a non-steroidal therapy designed to target and block the corticotropin-releasing factor type 1 (CRF1) receptor. By selectively blocking CRF binding to CRF1 receptors in the pituitary gland, Crenessity directly reduces ACTH and reduces downstream production of androgens. This improved androgen control and allows for glucocorticoid dose reductions, enabling a transformational approach to managing CAH. Patients receiving Crenessity should continue glucocorticoid replacement therapy for the adrenal insufficiency associated with CAH, but lower doses may be required based on the efficacy of the medication. Effects can be seen as soon as 4 weeks after starting the medication.(1)

Efficacy

Pediatric Patients with Classic Congenital Adrenal Hyperplasia (CAH)

The efficacy of Crenessity to improve androgen control and enable a reduced glucocorticoid dose while maintaining androgen control in pediatric patients with classic CAH was evaluated in a Phase 3 randomized, double-blind, placebo-controlled study (NCT#04806451). This study enrolled 103 pediatric subjects 4 to 17 years of age with classic CAH due to 21-hydroxylase deficiency and inadequate androgen control on supraphysiological glucocorticoid doses. Subjects were randomized to receive either Crenessity twice daily or placebo for 28 weeks. During the first 4 weeks of Crenessity treatment, subjects were maintained on a stable glucocorticoid regimen (hydrocortisone dose equivalents adjusted for body surface area) except for stress dosing, as needed. A hydrocortisone dose of 11 mg/m^2/day is roughly equivalent to 10 mg/day for a 6-year-old, 14 mg/day for a 10-year-old, and 16 mg/day for a 12-year-old.(1)

The primary efficacy endpoint was the change from baseline in serum androstenedione at Week 4. The goal was to achieve a glucocorticoid dose of 8 to 10 mg/m^2/day (hydrocortisone dose equivalents adjusted for body surface area) by Week 28 while maintaining androstenedione control. The mean age was 12 (range 4 to 17) years and 41% were Tanner Stage 1 or 2. With respect to concurrent glucocorticoid use at baseline, 92% of patients were receiving hydrocortisone alone and 8% were receiving prednisone. At baseline, subjects were receiving a mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents of 16 (4) mg/m^2 /day, and had a mean (SD) androstenedione level of 431 (461) ng/dL and mean (SD) serum 17-hydroxyprogesterone level of 8682 (6847) ng/dL prior to the morning glucocorticoid dose. At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean reduction from baseline in serum androstenedione in the Crenessity group was statistically significantly different at -197 ng/dL compared to the increase of 71 ng/dL in the placebo group.(1)

Adult Patients with Classic Congenital Adrenal Hyperplasia (CAH)

The efficacy of Crenessity to reduce androgen levels and enable a reduced glucocorticoid dose while maintaining androgen control in adults with classic CAH was evaluated in a randomized, double-blind, placebo controlled study (NCT#04490915). This study enrolled 182 adults with classic CAH due to 21-hydroxylase deficiency on supraphysiological glucocorticoid doses and with androgen concentrations in the normal range or with inadequate androgen control. The mean age was 31 (range 18 to 58) years, 51% were male. At baseline, the mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents was 32 (9) mg/day, with mean (SD) androstenedione levels of 620 (729) ng/dL prior to the morning glucocorticoid dose. Subjects were randomized to receive Crenessity 100 mg twice daily or placebo for 24 weeks. During the first 4 weeks of Crenessity treatment, subjects maintained a stable glucocorticoid regimen except for stress dosing as needed. During weeks 4 to 12, the glucocorticoid dose was reduced as frequently as every 2 weeks without regard to androstenedione levels, with the goal to achieve a glucocorticoid dose of 8 to 10 mg/m^2 /day in hydrocortisone dose equivalents adjusted for body surface area by Week 12. From Weeks 12 to 20, the glucocorticoid dose was further adjusted, if needed, to achieve androstenedione control by Week 24.(1) 

The efficacy of Crenessity was assessed by the least-squares (LS) mean (SEM) percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (greater than or equal to 120% of baseline or greater than or equal to the upper limit of normal [ULN]) after 24 weeks. The LS mean percent change from baseline in daily glucocorticoid dose was greater in the Crenessity group at -27% compared to -10% in the placebo group. At Week 24, there was a greater percentage of subjects achieving a reduction to a physiologic glucocorticoid daily dose (less than or equal to 11 mg/m^2 /day hydrocortisone equivalents) while androstenedione was controlled (greater than or equal to 120% of baseline or greater than or equal to the ULN) with Crenessity compared to placebo (63% vs 18%). At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean change from baseline in serum androstenedione in the Crenessity group was statistically significantly different at -299 ng/dL compared to the LS mean increase from baseline in the placebo group of 46 ng/dL.(1)

Safety

Crenessity is contraindicated in patients with a history of hypersensitivity to crinecerfont or any excipients of Crenessity.(1) 

1

Crenessity precribing information. Neurocrine Biosciences, Inc. December 2024.

2

Society E. Congenital Adrenal Hyperplasia Guideline resources. Endocrine Society. Published December 8, 2022. https://www.endocrine.org/clinical-practice-guidelines/congenital-adrenal-hyperplasia-guideline-resources

3

Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med. 2020;383(13):1248-1261. doi:10.1056/NEJMra1909786

4

Auchus RJ, Hamidi O, Pivonello R, et al. Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia. N Engl J Med. 2024;391(6):504-514. doi:10.1056/NEJMoa2404656

5

Yau M, Gujral J, New MI. Congenital adrenal hyperplasia: diagnosis and emergency treatment. Endotext - NCBI Bookshelf. Published April 16, 2019. https://www.ncbi.nlm.nih.gov/books/NBK279085/#:~:text=Diagnosis%20of%20the%2021%2DOHD,diagnostic%20of%20classical%2021%2DOHD.

6

Yau M, Khattab A, Yuen T, New M. Congenital adrenal hyperplasia. Endotext - NCBI Bookshelf. Published November 3, 2022. https://www.ncbi.nlm.nih.gov/books/NBK278953/

7

Auer MK, Paizoni L, Nowotny H, et al. Synthetic glucocorticoids instead of hydrocortisone do not increase mineralocorticoid needs in adult patients with salt wasting congenital adrenal hyperplasia. The Journal of Steroid Biochemistry and Molecular Biology. 2023;230:106271. doi:10.1016/j.jsbmb.2023.106271

Crenessity

crinecerfont cap

100 MG ; 50 MG

M ; N ; O ; Y

N

Crenessity

crinecerfont oral soln

50 MG/ML

M ; N ; O ; Y

N

Crenessity

crinecerfont cap

50 MG

60

Capsules

30

DAYS

Crenessity

crinecerfont cap

100 MG

60

Capsules

30

DAYS

Crenessity

crinecerfont oral soln

50 MG/ML

120

mLs

30

DAYS

Crenessity

crinecerfont cap

100 MG ; 50 MG

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Crenessity

crinecerfont oral soln

50 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Crenessity

crinecerfont cap

100 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Crenessity

crinecerfont cap

50 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Crenessity

crinecerfont oral soln

50 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

PA

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The requested agent is eligible for continuation of therapy AND ONE of the following:

1. 1. 1. The patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR
      2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed OR
   2. BOTH of the following:
      1. The patient has a diagnosis of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency as confirmed by ONE of the following:
         1. Positive infant screening with secondary tier 2 confirmatory testing OR
         2. Elevated serum 17-hydroxyprogesterone level (17OHP) above the upper limit of normal (ULN) OR
         3. Cosyntropin (ACTH) stimulation test OR
         4. Genetic testing for mutation in the СΥΡ21Α2 gene consistent with CAH AND
      2. If the patient has an FDA labeled indication, then ONE of the following:
         1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
         2. There is support for using the requested agent for the patient’s age for the requested indication AND
2. The patient is currently treated with glucocorticoid replacement therapy (e.g., hydrocortisone, prednisone, prednisolone, dexamethasone) AND
3. The patient will continue glucocorticoid replacement therapy (e.g., hydrocortisone, prednisone, prednisolone, dexamethasone) in combination with the requested agent AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist, geneticist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. The patient is currently treated with glucocorticoid replacement therapy AND
4. The patient will continue glucocorticoid replacement therapy in combination with the requested agent AND
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist, geneticist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   3. BOTH of the following:
      1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication

Length of Approval:  up to 12 months