NEUROCRINE 1037
`Neurocrine Biosciences, Inc. v. Spruce Biosciences, Inc.
`PGR2021-00088
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`The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. XX, No. XX
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`changesfrom baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone
`(170OHP), androstenedione, and testosterone.
`Results: Eighteen participants (11 women, 7 men) wereenrolled: cohort 1 (n = 8), cohort
`2 (n=7), cohort 3 (n=8), cohort 4 (n=8). Mean age was 31 years; 94% were White.
`Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and
`androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants,
`73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had
`median 26% to 65% decreases in androstenedione/testosterone ratios.
`Conclusion: Crinecerfont treatment for 14 days lowered ACTH and afforded clinically
`meaningful reductions of elevated 17OHP androstenedione, testosterone (women), or
`androstenedione/testosterone ratio (men) in adults with 21O0HD. Longerterm studies
`are required to evaluate the effects of crinecerfont on clinical end points of disordered
`steroidogenesis and glucocorticoid exposure in patients with 21OHD.
`
`Key Words: congenital adrenal hyperplasia, 21-hydroxylase deficiency, 17-hydroxyprogesterone, crinecerfont,
`NBI-74788
`
`
`Congenital adrenal hyperplasia (CAH)refers to a group of
`rare autosomalrecessive disorders that result in disordered
`
`adrenalsteroidogenesis, including impaired cortisol synthesis.
`Excess adrenal androgen production occurs in patients with
`CAHdue to 21-hydroxylase deficiency (21OHD), a popula-
`tion that accounts for approximately 95% of all CAH cases
`(1). The cortisol deficiency removes normalnegative feedback
`inhibition on the hypothalamus andthe pituitary gland,re-
`sulting in increased secretion of corticotropin-releasing factor
`from the hypothalamus and adrenocorticotropin (ACTH)
`from the pituitary. Chronic ACTH drive leads to excess pro-
`duction of adrenal androgens(2,3).
`The “classic” form of CAH due to 21OHD, which is
`associated with more severe enzymedeficiency, occurs in
`approximately 1:15 000 births (4). The androgen excess
`during fetal life leads to virilization of 46,XX newborns;
`210HDis the leading cause of atypical genitalia in the
`female infant. Continued androgen excess during child-
`hood and adolescence causes sexual precocity, virilization,
`and accelerated somatic growth with advanced boneage,
`whichresults ultimately in below-predicted adult height (5,
`6). During adulthood, hirsutism and irregular menses are
`common in women, and men and women with 21OHD
`suffer from reducedfertility and psychiatric disorders (7).
`In addition,all patients with 21OHDareatrisk for adrenal
`crises that can result in death if untreated.
`
`Glucocorticoid (GC) therapy, the current standard of
`care, is used to replace the endogenouscortisol deficiency(8).
`However, supraphysiologic GC doses and nonphysiologic
`timing (eg, evening dosing) are usually needed to reduce
`the elevated ACTHsecretion and excess androgen produc-
`tion. This chronic exposure to supraphysiologic GC doses
`can lead to serious complications including growth sup-
`pression in children, reduced bone mineral density with
`
`increased fracture risk, and metabolic disorders such as
`obesity, insulin resistance, and hypertension, which can in-
`crease cardiovascular risk (1, 2, 8-11). Thus, the challenge
`of treating 21OHDis to balance adequate control of an-
`drogens with the risks of excessive and prolonged GC ex-
`posure; undertreatment and overtreatment with GCs both
`cause side effects and complications.
`Anantagonist of the corticotropin-releasing factor type
`1 receptor (CRF1R) may offer a new approachfortreating
`this disorder. CRF1R antagonism can reduce ACTH se-
`cretion, which in 21OHD could decrease the down-
`stream production of androgens and reduce symptoms of
`hyperandrogenism, while also potentially allowing for GCs
`to be administered at more physiologic doses. Thus, this
`approach could help to mitigate the negative consequences
`of long-term supraphysiological GC treatment. The poten-
`tial efficacy of CRF1R antagonism was demonstrated in
`an exploratory study of a CRF1R antagonist (NBI-77860)
`in 8 female patients with 21OHD (12) that found mean-
`ingful reductions in ACTH and 17-hydroxyprogesterone
`(17OHP)after single-dose administration.
`Crinecerfont, an orally administered, nonsteroidal
`CRF1R antagonist, is currently being studied for the treat-
`mentof classic 21 OHD.This phase 2 study (NCT03525886)
`of crinecerfont was conducted to evaluate its safety, toler-
`ability, and effects on ACTH,adrenal androgens, and an-
`drogen precursors in adults with classic 21OHD.
`
`Materials and Methods
`
`Study Design and Participants
`
`This phase 2, open-label study used a sequential-cohort de-
`sign to evaluatethe safety, tolerability, and efficacy of 4 dif-
`ferent crinecerfont dosing regimens, each dosed for 14 days
`
`
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`in adults with classic 21OHD. The study was performed
`at 6 centers in the United States and conducted in accord-
`
`including
`ance with Good Clinical Practice guidelines,
`International Conference on Harmonization requirements
`and the United States Code of Federal Regulations for clin-
`ical trials; see the supplementary material for details (13).
`The protocol and patient consent forms were reviewed and
`approvedbythe institutional review boardateach site.All
`participants provided written and informed consent prior
`to any study-related procedures.
`Key inclusion criteria were as follows: male or female,
`aged 18 to 50 years; medically confirmed classic 21OHD
`by hormonal and/or molecular testing; body mass index be-
`tween 18 and 45 kg/m” (inclusive); serum 17OHPgreater
`than or equal to 30.3 nmol/L (2 1000 ng/dL), serum cor-
`tisol less than 138 nmol/L (< 5 pg/dL), and plasma ACTH
`greater than or equal
`to 4.4 pmol/L (220 pg/mL) at
`screening before morning GC dose; receiving a stable GC
`regimenforat least 30 days before baseline.
`Key
`exclusion criteria were
`as
`follows: known
`or suspected diagnosis of other
`forms of CAH (eg,
`11B-hydroxylase deficiency); prior or current medical con-
`dition requiring daily GC therapy (other than 21OHD));
`clinically significant unstable medical condition, chronic
`disease, or malignancy; clinically significant illness within
`30 days before screening; clinically relevant laboratory
`abnormality (eg, hematologic, coagulation, renal, liver en-
`zymes); pregnancyorlactation; corrected QTinterval using
`the Fridericia formula of greater than 450 msec (men) or
`greater than 470 msec (women); history of significant car-
`diac abnormality or arrhythmia; recent or current sub-
`stance abuse or dependence; risk of suicidal or violent
`behavior; and dexamethasonetherapy for 30 days before
`screening and throughoutthe study.
`The sequential-cohort design comprised 4 open-label
`crinecerfont dosing regimens, as follows: cohort 1 (50 mg
`once daily at bedtime); cohort 2 (100 mg once daily at
`bedtime); cohort 3 (100 mg once daily in the evening);
`cohort 4 (100 mg twice daily, morning and evening)
`(Fig. 1). The study medication was taken with 8 ounces
`(236 mL) of Ensure Plus (16 g protein, 47 g carbohy-
`drate, 11 g fat; Abbott Laboratories) (cohorts 1 and 2) or
`patients’ regular evening meals (cohort3) or their regular
`morning and evening meals (cohort 4). Each regimen was
`administered for 14 consecutive days while continuing
`their normal daily GC regimen, which was maintained
`stable over the 14 days. Participants who enrolled in co-
`hort 1 (50 mg once daily at bedtime) or cohort 2 (100 mg
`once daily at bedtime) were allowed to enter cohort 3
`(100 mg once daily in the evening) if no safety concerns
`were raised. Participants were allowed to enter cohort 4
`(100 mg twice a day) from anyearlier cohort or de novo.
`
`Study drug (crinecerfont) was provided by Neurocrine
`Biosciences,
`Inc. Participants who reenrolled into a
`new cohort underwent additional screening if their GC
`regimen changedsince their last study visit; otherwise, a
`new day —7 to —6 baseline sampling could be performed
`after the day 49 final follow-upvisit.
`
`Procedures and Assessments
`
`All participants were admitted to the study center from
`day —7 to -6 forserial blood sampling to establish baseline
`ACTH, 17OHP, androstenedione, and testosterone concen-
`tration profiles. Serial blood sampling schedules at baseline
`were time-matchedfor similar serial sampling on days 1/2
`(cohorts 1 and 2) and days 14/15 (all cohorts). On day 1,
`participants received the first dose of study medication at
`22:00 (cohorts 1 and 2) or 19:00 (cohorts 3 and 4) and
`continued their assigned regimen until day 14. Participants
`in cohort 4 received the final dose of study medication on
`the evening of day 14. During treatmentin cohort 1 (50 mg
`once daily at bedtime) and Cohort 2 (100 mg once daily
`at bedtime), serial sampling started at 15 minutes prior to
`crinecerfont dosing and continued for 24 hours postdose
`(at 1,2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours) (see Fig.
`1). During treatmentin cohort 3 (100 mg oncedaily in the
`evening) and cohort 4 (100 mg twice a day), serial sampling
`started at 15 minutes predose and continued for 27 hours
`postdose(at 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15, 17, 19, 23, 24,
`and 27 hours).
`During these overnight study admissions, the partici-
`pants’ usual morning GC doses were delayed until after
`the 10:00 blood sample collection on day 2 and after the
`14:00 blood sample collection on day 15. For analysis,
`the time frame between 06:00 and 10:00 was defined as
`
`the “morning window”and included samples obtained at
`8, 10, and 12 hours postdose in cohorts 1 and 2 and at 11,
`13, and 15 hours postdose in cohorts 3 and 4. Analyses
`focused on the average (mean) of the 3 morning window
`time points to evaluate the effect of crinecerfont on the
`early morning surge of ACTH andthe resulting rise in
`adrenal steroid production, which are difficult to con-
`trol with physiologic GC regimens (1, 12). Blood samples
`were sent to a central laboratory for analysis of plasma
`ACTH; serum 17OHP, androstenedione,
`testosterone,
`and cortisol; and crinecerfont pharmacokinetics. See the
`supplementary material for details (13).
`Treatment-emergent adverse events (TEAEs), including
`serious adverse events and TEAEs leading to discontinu-
`ation, were assessed throughout
`the study. Additional
`safety assessments included vital signs, 12-lead electrocar-
`diogram,clinical laboratory tests, Brief Psychiatric Rating
`Scale, and Columbia-Suicide Severity Rating Scale.
`
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`Study Periods
`(Repeat for Each Dose Cohort)
`2
`
`
`
`DosingPeriod 14Days
`
`Follow-UpPeriod&Final
`
`StudyVisit
`
`Cohort 4:
`Cohort 4:
`100 mg
`twice a day
`100 mg BID
`Cohort 3: > Cohort 3:
`-
`100 mg once
`daily in evening
`100 mg QPM
`
`Cohort 2:
`100 mg once
`daily at bedtime
`
`Cohort 2:
`
`100 mg QHS
`Cohort 1:
`50 mg QHS
`
` Crinecerfont Dose Escalation
`
`PD
`2
`=
`o
`@
`0
`
`wi
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`s
`Zz
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`x
`a
`N
`of
`f
`Nights Evening of
`-7to-6
`Night?
`
`f
`Days
`-27to-7
`
`{
`2-5 Weeks
`Postdose
`
`Cohort 1:
`50 mg once
`daily at bedtime
`
`Serial Blood Sampling Schedule: Cohorts 1 and 2
`Crinecerfont Dosing:
`22:00 (Days 1 and 14)
`Aa
`A
`A
`A
`A
`0
`1
`2
`3
`4
`Hours postdose
`
`A
`6
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`7
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`5
`
`A
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`12)13 14
`
`A
`16
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`15
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`17
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`18
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`19
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`A
`20
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`21
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`22
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`23
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`A
`24
`
`A
`11
`10
`9
`06:00 to 10:00
`.
`.
`
`(Morning Window)
`
`Serial Blood Sampling Schedule: Cohorts 3 and 4
`Crinecerfont Dosing:
`19:00 (Day 14)
`aAadbakaAaabaaAaaA A
`0
`41
`2
`3
`4
`5
`6
`7
`
`A
`9
`
`8
`
`a
`a
`14
`1112 13
`06:00 to 10:00
`(Morning Window)
`
`Hours postdose
`
`a
`15)
`
`A
`17
`
`18
`
`A
`19
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`16
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`20
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`21
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`22
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`aA
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`25
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`27
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`Figure 1. Study design. Blue triangles denote samplecollection. In all cohorts, sampling for the 24-hour baseline period (day —7 to -6) matched the
`sampling schedule during crinecerfont treatment. For the baseline and day 1 visits, participants received their prescribed glucocorticoid dose after
`sample collection at 10:00 (end of the morning window); for the day 14 visit, glucocorticoid was administered after sample collection at 14:00. GC,
`glucocorticoid.
`
`Statistical Analyses
`
`Descriptive statistical methods were used to summarize the
`data. The analysis population included all 18 participants
`whoreceived at least one dose of study drug. All partici-
`pants had a baseline and at least one postbaseline pharma-
`codynamic assessment. Three participants (one each from
`cohorts 1, 2, and 3) were considered to have a protocol
`deviation for inadvertently receiving GC dosing before
`morning window blood sample collection. However, a sen-
`sitivity analysis indicated that the inclusion/exclusion of
`these data did not materially alter the results. Therefore,all
`18 participants were included in the pharmacodynamic/ef-
`ficacy analyses. Sample size was based on practicalclinical
`considerations for a rare disease, without formalstatistical
`powercalculations.
`Efficacy analyses were based on assessments collected
`on days —7/-6 (“baseline”), days 1/2 (“day 1”), and days
`14/15 (“day 14”); for simplicity, the 24- and 27-hour
`postdose periods are referred to as “24-hour sampling
`period.” Key end points for ACTH, 17OHP, androstene-
`dione, and testosterone concentrations were based on
`available values both in the morning window and the
`24-hour sampling period. Analyses based on these values
`included the following: median change from baseline to
`day 14 (morning window and 24-hourperiods); median
`
`percent change from baseline to day 14 (morning window);
`and percentage of participants with 50% orgreater re-
`duction (ie, “responders”) (12) from baseline to day 14
`(morning window). Changes (in men) for androstene-
`dione/testosterone ratios were also analyzed, including
`achieving a target of less than 0.5 (14). Reduction into
`the normal range during the morning window wasalso
`analyzed in participants whose androstenedioneortestos-
`terone (women only) at baseline exceeded 1.2 times the
`upper limit of normal. Mean values are presented with
`the standard deviation. Median values are presented with
`the interquartile range, defined as the absolute difference
`between the 75th and 25th percentiles (Q3-Q1).
`
`Results
`
`Participants and Crinecerfont Exposure
`
`A total of 18 participants were enrolled in the study. Three
`participants enrolled in 3 cohorts each; 7 participants en-
`rolled in 2 cohorts each. The median time between cohorts
`was 183 days (range, 49-343 days). Crinecerfont exposure
`0-24
`over 24 hours (area under the curve [AUC],
`,,) increased
`with dose across cohorts. In the 100-mg cohorts, mean
`plasma exposure of crinecerfont was similar irrespective
`of meal type (liquid dietary supplement vs usual evening
`
`
`
`
`
`
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`meal) or timing (once daily at bedtime vs once daily in the
`evening) [AUC,,,: 77.4 mol x h/L vs 72.0 pmol x h/L].
`Crinecerfont dosed at 100 mg twice daily was observed
`to result in approximately twice the exposure [AUC,,,:
`138.5 pmol x h/L] compared to the exposure observed
`with 100 mg oncedaily (once daily at bedtime or once daily
`in the evening).
`Of the 18 enrolled participants, 61% were female and
`94% were White; mean age was 31 + 9.3 years (Table 1).
`A prior hysterectomy was reported in one female partici-
`pant whoenrolled in cohorts 2 and 4. For GC therapy at
`baseline, 56% of participants were receiving hydrocortisone
`alone, and 44% were receiving prednisone (or equivalent)
`with or without hydrocortisone. Mean baseline total daily
`GC dosein hydrocortisone equivalents was 26 + 9.1 mg/day
`(14 + 4.8 mg/day/m? when adjusted for body surface area),
`with 1 mg of prednisolone, methylprednisolone, or pred-
`nisone considered equivalent to 4 mg of hydrocortisone.
`Baseline samples from the morning window indicated that
`mean and median values for androstenedione, 17OHP,tes-
`tosterone (in men and women), and androstenedione/testos-
`terone ratios (in men) were abovethe upperlimit of normal
`(see Tables 1 and 2), indicating inadequate disease control.
`
`Effects of Crinecerfont on Adrenal Androgens
`and Precursors
`
`At baseline, the 24-hour plasma/serum concentration pro-
`file of ACTH, 17OHP, and androstenedione demonstrated
`the expected early morning increases starting around
`04:00 and peaking around 08:00 to 10:00 in the morning
`(Fig. 2). Treatment with crinecerfont for 14 days led to
`substantial median reductions for ACTH, 17OHP, and
`androstenedione relative to baseline, especially during the
`morning window, across all cohorts (see Fig. 2). The de-
`crease in androstenedione was most pronouncedfor cohort
`4 (100 mgtwice a day).
`In all cohorts, median ACTH, 17OHP, androstenedione,
`testosterone (in women), and androstenedione/testosterone
`ratio (in men) were reduced from baseline to day 14 whether
`based on samples collected during the morning window
`(06:00-10:00) or the 24-hour sampling period (see Table 2).
`For ACTH and 17OHP, median percent decreases from base-
`line were generally similar across cohorts, ranging from—53%
`to -66% (Fig. 3). Dose-related decreases in androstenedione
`were also observed, ranging from a 21% reduction in cohort
`1 (50 mg oncedaily at bedtime) to a 64% reduction in cohort
`4 (100 mg twice a day). Median percent reductions for tes-
`tosterone (in women) ranged from —32 % (cohort 1) to -74%
`(cohort 3) (see Supplementary Fig. $1) (13).
`In male participants, testosterone derives from both the
`adrenals and testes, which complicates the assessment of
`
`testosterone changes in men; however, the androstenedione/
`testosterone ratio increases as the adrenal contribution to
`
`circulating androgensrises (1). While androstenedione de-
`clined similarly in male and female participants, testos-
`terone did notfall proportionately in the male participants
`(see Fig. 3 and Supplementary Fig. $1)(13). Consequently,
`the median androstenedione/testosterone ratio (in men)
`during the morning window declined from 26% to 65% in
`a dose-dependentfashion across the 4 cohorts, and median
`24-hour androstenedione/testosterone ratios also declined
`
`by 33% (cohort 1) to 59% (cohort3).
`In cohort 4 (100 mg twice a day), a majority of parti-
`cipants had a 50% or greater reduction from baseline to
`day 14 in ACTH, 17OHP, androstenedione, testosterone
`(women), and androstenedione/testosterone ratio (men);
`2 of 3 male participants achieved an androstenedione/tes-
`tosterone ratio of less than 0.5 (Table 3). Among female
`participants, 73% (8/11) had a 50% orgreater reduction
`from baseline in testosterone concentrations. Fourof 8 par-
`ticipants in cohort 4 achieved 50% or greater reductionsin
`ACTH, 170OHP,and androstenedione(Fig. 4).
`
`Safety
`
`TEAEsare summarized in Table 4. The majority of TEAEs
`were mild or unrelated to the study drug, with no deaths,
`severe TEAEs, or discontinuations due to TEAEs. The
`most common TEAEs(reported in 2 2 participants overall)
`were headache, upper respiratory tract infection, fatigue,
`contusion (bruising), insomnia, nasopharyngitis, pyrexia,
`and nausea. Oneserious TEAEofcholelithiasis, occurring
`34 days after the last dose of the study drug, was assessed
`as unlikely related to the study drug by the investigator.
`There were no safety concerns with respect to routineclin-
`ical laboratory values, vital signs, electrocardiograms, or
`neuropsychiatric assessments.
`
`Discussion
`
`Since Wilkins et al described life-saving cortisone
`therapy for 21OHDin the early 1950s (15), GCs have
`been the mainstay of treatment, both to replace the
`cortisol deficiency and to reduce the production of
`adrenal-derived androgens. With routine access to GCs,
`the introduction of newborn screening, and improved
`health care delivery, most children with 210OHDsurvive
`well into adulthood (1). Supraphysiologic GC dosing,
`however, is often needed to attenuate the excess adrenal-
`derived androgen production.This lifelong treatment of
`excessive GC dosing is associated with a high burden of
`comorbidities and reduced quality of life in adults with
`210HD(7, 16, 17).
`
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`Table 1. Baseline characteristics
`
`Cohort 1: 50 mg once Cohort 2: 100 mg once Cohort 3: 100 mg once Cohort 4: 100 mg_All participants
`
` daily at bedtime (n= 8) daily at bedtime (n=7) daily in evening (n= 8) twice a day (n = 8) (N = 18)
`
`
`
`Demographics
`Women, n (%)
`White, n (%)*
`Age, mean (SD), y
`Body mass index, mean
`(SD)
`Glucocorticoid treatment,
`n(%)
`Hydrocortisone
`Prednisone or equivalent
`Hydrocortisone + pred-
`nisone or equivalent
`Glucocorticoid total daily
`dose, mean (SD)
`Hydrocortisone equiva-
`lent, mg/day
`Hydrocortisone equiva-
`lent, mg/m7/day
`Adrenal androgens and
`precursors, mean (SD)?
`170HP, nmol/L
`ACTH,pmol/L
`
`Men
`
`Women
`
`Androstenedione,
`nmol/L
`
`Men
`Women
`Testosterone-women,
`nmol/L
`
`Testosterone-men,
`nmol/L
`
`4 (50)
`7 (88)
`31 (9.4)
`29 (5.5)
`
`3 (38)
`4 (50)
`1 (13)
`
`25 (11.1)
`
`14 (6.6)
`
`7 (66)
`
`o (116)
`
`230 (126)
`
`10s (70)
`
`1 (8.5)
`
`14 (10)
`7.7 (6.4)
`1.8 (1.5)
`
`12 (5.8)
`
`5 (71)
`7 (100)
`33 (9.7)
`29 (2.7)
`
`4 (57)
`3 (43)
`0 (0)
`
`26 (6.9)
`
`14 (2.5)
`
`53 (42)
`
`310 (229)
`
`533 (78)
`
`221 (207)
`
`26 (26)
`
`61 (5.7)
`12 (13)
`3.1 (1.6)
`
`12 (0.5)
`
`3 (38)
`7 (88)
`31 (10.5)
`29 (4.7)
`
`(50)
`(38)
`(13)
`
`6 (9.0)
`
`4 (4.9)
`
`3 (64)
`
`‘in (177)
`
`197 (177)
`
`232 (213)
`
`17 (19)
`
`18 (23)
`14 (14)
`3.7 (3.7)
`
`4 (5.6)
`
`5 (63)
`8 (100)
`29 (8.2)
`31 (2.8)
`
`5 (63)
`(25)
`(13)
`
`1 (61)
`7 (94)
`1 (9.3)
`9 (4.1)
`
`(56)
`7 (39)
`(5.6)
`
`26 (8.0)
`
`26 (9.1)
`
`13 (3.6)
`
`14 (4.8)
`
`78 (74)
`
`343 (260)
`
`428 (303)
`
`292 (253)
`
`9 (24)
`
`40 (27)
`22 (23)
`3.4 (3.7)
`
`70 (67)
`
`236 (183)
`
`304 (213)
`
`217 (195)
`
`8 (20)
`
`28 (24)
`14 (15)
`3.0 (2.4)
`
`13 (3.8)
`
`13 (4.5)
`
`2.2 (2.1)
`3.5 (2.7)
`9 (2.8)
`5.0 (0.3)
`1.2 (1.0)
`Androstenedione/testos-
`terone ratio-men
`
`Abbreviations: 17OHP, 17-hydroxyprogesterone; ACTH,adrenocorticotropin.
`“Included oneparticipant whoalsoself-identified as Hispanic or Latino.
`Based on values from the morning windowtimepoints (06:00, 08:00, 10:00). Normalrangesare as follows: ACTH,2.2 to 13.2 pmol/L (10-60 pg/mL); 170HP
`adult men,less than 6.7 nmol/L (< 220 ng/dL); 17OHPfollicular women,less than 2.4 nmol/L (< 80 ng/dL); 17OHPluteal women,less than 8.6 nmol/L (< 285 ng/
`dL); 17OHP postmenopausal women,less than 1.5 nmol/L (< 51 ng/dL); androstenedione adult men, 2.3 to 7.3 nmol/L (65-210 ng/dL); androstenedione adult
`women,2.8 to 8.4 nmol/L (80-240 ng/dL); total testosterone women,0.3 to 2.1 nmol/L (8-60 ng/dL); total testosterone men, 10.4 to 41.6 nmol/L (300-1200 ng/
`dL). For androstenedione/testosterone men, target ratio was less than 0.5. In cohort 3,results for testosterone womenare based on 4 participants who had avail-
`able baseline morning window values.
`
`These limitations of current treatment regimensillustrate
`the unmetneed for adjunctive therapies that can reduce an-
`drogen production without the need for supraphysiologic
`GC dosing. The major finding of this study is that treat-
`ment with crinecerfont (at 50-200 mg/d for 14 days) af-
`fordssignificant, consistent, and dose-dependentreduction
`of ACTH, 17OHP, and androstenedione in adults with in-
`adequately controlled 21OHD. Crinecerfont also signifi-
`cantly lowered testosterone in most female participants
`and reduced androstenedione/testosterone ratios in male
`
`participants. Moreover, these reductions were achieved in
`
`the early morning hours—the most challenging window to
`achieve disease control with physiologic GC exposure(1,
`18)—despite a protocol-imposed delay of the first morning
`GC dose to 14:00, which was implemented to observe the
`isolated effects of crinecerfont in the absence of concurrent
`
`GC action. Importantly, the evaluation of multiple dosing
`regimenspermitted a dose-related response to be observed;
`the greatest effect was seen for the 100-mg twice-daily
`dose, for which all participants experienced a decrease
`in ACTH, 17OHP, and androstenedione. Although the
`treatment duration was limited to 14 days, crinecerfont
`
`
`
`zZz0zAvenuqe4ZOuoysanBAqOLZg6E9/6rZGe6pP/weUl}9/0LZ101/!op/a|o1e-eoueApe/weo[/Woo'dno‘olaepese//:sdyyWoypapeojumog
`
`
`
`
`
`6
`
`

`

`The Journalof Clinical Endocrinology & Metabolism, 2021, Vol. XX, No. XX
`
`7
`
`Table 2. Effects of crinecerfont on adrenal androgens and precu rsors??
`
`
`
`Median (IQR) Cohort 3: 100 mg once—Cohort 4: 100 mg twice aCohort 1: 50 mg once Cohort 2: 100 mg once
`
`
`
`daily at bedtime (n = 8)
`daily at bedtime (n = 7)
`daily in evening (n = 8)
`day (n = 8)
`
`ACTH, pmol/L
`33 (103)
`At baseline
`Change from baseline to -24 (48)
`day 14
`170HP, nmol/L
`162 (77)
`At baseline
`Change from baseline to -81 (43)
`day 14
`Androstenedione, nmol/L
`9.9 (27)
`27 (41)
`6.4 (13)
`11 (19)
`7.2 (38)
`7.8 (51)
`7.5 (6.5)
`9.4 (12)
`At baseline
`
`Change from baseline to -3.8 (4.8)|-0.9 (4.2) -5.8 (12) -3.5 (8.5) -8.1 (13) -4.8 (9.7) -14 (33) -4.2 (16)
`
`
`
`
`
`day 14
`Testosterone-women,
`nmol/L?
`
`2.0 (2.0)
`2.2 (4.6)
`1.9 (6.2)
`3.0 (7.3)
`1.9 (0.5)
`2.4 (0.3)
`1.4 (1.9)
`1.9 (2.5)
`At baseline
`
`
`Change from baseline to -0.4 (1.2) -0.2 (1.0)|-1.8 (0.8)|-1.3 (0.6) -2.6 (5.7) 1.5 (4.9) -1.7 (3.0) -0.6 (1.3)
`
`
`
`day 14
`Testosterone for men,
`nmol/L’
`
`9.9 (4.3)
`12 (7.0)
`8.9 (7.3)
`11 (8.7)
`11 (0.4)
`12 (0.7)
`8.9 (6.3)
`12 (8.4)
`At baseline
`
`
`
`
`
`
`Change from baseline to 0.7 (3.0)—-0.6 (4.4)2.2 (7.9) 2.7 (5.8) -0.5(0.1) 1.3 (1.7) 0.9 (3.6) 0.8 (1.2)
`
`day 14
`Androstenedione/testos-
`terone ratio for men®
`
`3-2 (3:7)
`3.9 (5.4)
`0.5 (0.9)
`0.6 (1.1)
`4.3 (1.1)
`5.0 (0.4)
`1.0 (1.4)
`0.9 (1.2)
`At baseline
`
`
`
`Change from baseline to -0.3 (0.8) -0.3 (0.8)=-1.7(1.3)—-1.7 (1.7) -0.5 (0.6)——-0.3 (0.6) -3.6 (3.7)|-2.4 (2.7)
`day 14
`
`
`
`
`
`Morning
`24-h
`Morning
`24-h
`Morning
`24-h
`Morning
`24-h
`window‘
`period?
`window‘
`period?
`window‘
`period?
`window‘
`period?
`
`
`98 (104)
`-85 (101)
`
`28 (26)
` -18 (29)
`
`68 (86)
`-45 (57)
`
`22 (25)
`-5.8 (15)
`
`20 (69)
`-7.6 (48)
`
`43 (83)
`-34 (42)
`
`16 (21)
`-9.2 (16)
`
`69 (89)
`-20 (43)
`
`299 (452)
`-135 (281)
`
`114 (260)
`-38 (104)
`
`197 (292)
`-102 (208)
`
`89 (150)
`-59 (94)
`
`327 (425)
`-171 (330)
`
`103 (175)
`-41 (74)
`
`Abbreviations: 17OHP, 17-hydroxyprogesterone; ACTH,adrenocorticotropin; GC,glucocorticoid; IQR, interquartile range (Q3-Q1).
`“Normalranges are as follows: ACTH, 2.2-13.2 pmol/L (10-60 pg/mL); 17OHP adult men, less than 6.7 nmol/L (< 220 ng/dL); 17OHPfollicular women,less
`than 2.4 nmol/L (< 80 ng/dL); 17OHPluteal women, less than 8.6 nmol/L (< 285 ng/dL); 17OHP postmenopausal women,less than 1.5 nmol/L (< 51 ng/dL);
`androstenedione adult men, 2.3 to 7.3 nmol/L (65-210 ng/dL); androstenedione adult women, 2.8 to 8.4 nmol/L (80-240 ng/dL); total testosterone women, 0.3
`to 2.1 nmol/L (8-60 ng/dL); total testosterone men, 10.4 to 41.6 nmol/L (300-1200 ng/dL). For androstenedione/testosterone men,target ratio was less than 0.5.
`»Aside from GCincreases foundin 3 participants with a protocol deviation (received GC dosing before blood sample collection in cohorts 1, 2, and 3 [each n = 1]),
`no clinically meaningful changesin cortisol levels were found.
`‘Based on values from the morning windowtimepoints (06:00, 08:00, 10:00).
`4Based onvalues from all time points in serial blood sampling period: cohorts 1 and 2 (from 23:00 to 22:00 [following day]); cohorts 3 and 4 (from 20:00 to
`22:00 [following day]).
`‘n values for testosterone and androstenedione/testosterone were as follows: females (cohort 1, n = 4; cohort 2, n = 5; cohort 3, n = 3; cohort 4, n = 4); males (co-
`hort 1, n = 4; cohort 2, n = 2; cohort 3, n = 5; cohort 4, n = 3).
`
`was well tolerated, with the majority of adverse events as-
`sessed as mild and/or unrelated and without evidence of
`relationship to dose. Thus, these data demonstrate that
`crinecerfont shows promise as adjunctive treatment to
`control androgen excess in 21OHD.If such improvements
`are sustained during chronic treatment, GC dosing might
`be reduced to physiologic replacement schedules, which in
`turn could mitigate the long-term adverse health outcomes
`observed in adults with 21OHD(19).
`Oneprior published study evaluated a single bedtime dose
`of the CRF1R antagonist NBI-77860 in 8 adult women with
`210OHDat doses of 300 mg and 600 mg (12). A majority of
`
`participants (50%-75%) experienced a substantial 50% or
`greater reduction in ACTH and/or 17OHP during the early-
`morning window as described in this study. A significant
`pharmacokinetic-pharmacodynamiccorrelation was observed,
`as most participants with peak drug concentrations of greater
`than 500 ng/mL showed a goodresponse to treatment. In a
`secondtrial, 6 days of treatment with abiraterone acetate, a
`17-hydroxylase/17,20-lyase (CYP17A1) inhibitor, normalized
`androstenedione on day7 in all 6 adult women with 21OHD
`at a dose of 250 mg/d (20). A third study of nevanimibe, a
`cholesterol acyltransferase enzyme (SOAT1 or ACAT1) in-
`hibitor, found reductions in 17OHP but not androstenedione
`
`
`
`
`
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`
`7
`
`

`

`8
`
`The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. XX, No. XX
`
`A.Plasma ACTH, pmol/L
`
`120
`100
`
`380
`
`c<
`3
`@ 60
`=
`
`Cohort 2 (n=7)
`Morning Window
`
`-® Baseline
`-® Day 14
`
`ac GC Dose
`
`
`
`rr
` Dose(Day 14)
`Crinecerfont
`
`
`w/e GC Dose
`
`
`
`Cohort 4 (n=8)
`Morning Window
`
`-® Baseline
`~® Day 14
`ac GC Dose
`
`Crinecerfont
`Dose (Day 14)
`
`
`
`100
`
`c 80
`
`& 3
`
`=
`
`60
`
`407
`20
`
`
`
`
`0
`SASAggcs s € s EES LS ss
`
`Cohort 1 (n=8)
`Morning Window
`
`-® Baseline
`-® Day 14
`
`rinecerton’
`Crinecerfont
`Dose (Day 14)
`
`4 GC Dose
`
`ac GC Dose
`
`
`
`
`0 ©
`weQyy RS €
`
`Ss cs es es
`
`ss
`
`120
`
`Ss
`
`Median
`
`Cohort 3 (n=8)
`Morning Window
`
`-® Baseline
`%
`GC Dosee- Day 14
`
`
`
`
`
`Crinecerfont
`Dose (Day 14)
`
`
`
`120
`100
`
`0
`
`“0
`20
`
`c 80
`
`& 3
`
`=
`
`B. Serum 170HP, nmol/L
`
`Cohort 1 (n=8)
`Morning Window
`
`
`
`-® Baseline
`-® Day 14
`
`
`Dose (Day 14)
`
`350
`300
`
`Cohort 3 (n=8)
`Morning Window
`
`-® Baseline
`-@ Day 14
`
`
`Dose (Day 14)
`
`400
`350
`300
`
`400
`
`350
`300
`
`Cohort 2 (n=7)
`Morning Window
`g
`
`
`ac GC Dose
`
`-® Baseline
`-® Day 14
`
`
`
`
`Cohort 4 (n=8)
`Morning Window
`
`
`-® Baseline
`‘Gc Dose™ Pay 4
`
`
`
`Figure 2. Twenty-four-hour profiles. For cohorts 1 and 2, crinecerfont dosing was at 22:00 on day 14; predose sampling wasat 21:45. For cohorts 3
`and 4, crinecerfont dosing wasat 19:00 on day 14; predose sampling was at 18:45. 170HP, 17-hydroxyprogesterone; ACTH, adrenocorticotropin; GC,
`glucocorticoid.
`
`compared to placebo without a dose-response relationship
`(21). Studies of slow-release hydrocortisone (22, 23) and
`continuous subcutaneous hydrocortisone infusion (24) have
`demonstrated improved biomarker control, but GC exposure
`
`remained above physiologic levels (> 20 mg/d)in these studies.
`In contrast, we found that crinecerfont lowered ACTH and
`consequently afforded meaningful
`reductions in 17OHP
`and androstenedione in adults with 21OHD. Additionally,
`
`& 250
`& 250
`B 200
`B 200
`s
`ae GC Dose
`= 150
`Crinecerfont
`Crinecerfont
`
`1004Dose (Day 14)
`50
`0 & QDHO ODD:
`S
`SH
`YF
`QD
`DOD
`QD
`O©
`S$
`FALLAKVEE FEE EES LG
`
`& 250
`B 200
`= 150
`Crinecerfont
`Crinecerfont
`
`
`1007Dose (Day 14)
`50
`0
`MQggs FFE EFSF SS ESE S
`
`
`
`
`
`
`
`Zz0zAvenuqeZOuoysonBAqOLZg6E9/6rZGe6pP/weUl}9/0LZ10L/!op/a|ore-eoueApe/teo[/woo'dno‘olepese//:sdyyWoypapeojumog
`
`8
`
`8
`
`

`

`
`
`
`
`zz0zAvenuqe4ZOuoysonBAqOLZg6E9/6rZ4e6p/WeUI}9/0LZ10L/!op/a|ore-eoueApe/so[/Woo'dno‘olepese//:sdyyWo.papeojumog
`
`The Journalof Clinical Endocrinology & Metabolism, 2021, Vol. XX, No. XX
`
`9
`
`C. Serum androstenedione, nmol/L
`
`Cohort 2 (n=7)
`Morning Window
`
`-& Baseline
`-® Day 14
`
`Crinecerfont
`Dose (Day 14)
`
`
`
`5
`30
`25
`
`&>
`
`20
`oO
`= 15
`10
`
`
`
`
`
`GC Dose
`MQqags FFE EF FSS EF
`SF
`
`Cohort 4 (n=8)
`Morning Window -® Baseline
`
`
`
`
`c 25
`5 20o
`S 1
`10 Crinecerfont
`Dose (Day 14)
`
`5 0
`
`ESE SES SES BS
`
`5 0
`
`5
`30
`
`Cohort 1 (n=8)
`Morning Window
`
`-® Baseline
`~® Day 14
`
`Cohort 3 (n=8)
`Morning Window -@ Baseline
`~@& Day 14
`
`Crinecerfont
`Dose (Day 14)
`
`a GC Dose
`
`
`
`
`
`5
`30
`
`c&D
`
`S
`oO
`=
`
`5
`30
`c 25
`5 20
`s 15=
`
`Figure 2. Continued.
`
`ACTH
`
`170HP
`
`Androstenedione -64%
`
`
`
`-100
`
`ant
`ar
`
`64%
`[84%]
`
`66%
`[30%]
`
`[53%]
`
`[35%]
`
`-64%
`[16%]
`
`& Cohort 1: 50 mg oncedaily at bedtime (n=8)
`™ Cohort 2: 100 mg oncedaily at bedtime (n=7)
`I Cohort 3: 100 mg once daily in evening (n=8)
`1 Cohort 4: 100 mg twicea day (n=8)
`
`
`
`
`
`
`
`MedianPercentChange[03-01]
`
`Fig