A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of SPR001 (Tildacerfont) in Reducing Supraphysiologic Glucocorticoid Use in Adult Subjects with Classic Congenital Adrenal Hyperplasia

CAH is an inherited genetic disorder that affects the adrenal glands, a pair of
walnut-sized organs above the kidneys. The disease affects the production of
steroid hormones by the adrenal glands, which include *glucocorticoids* such as
cortisol, which regulate the body*s response to illness or stress. People with
CAH often have abnormal levels of certain adrenal sex hormones, which can have
negative effects on overall health. The current standard of care for CAH is the
use of glucocorticoids (GCs). These can have significant side effects and do
not always work well in treating CAH. A non-steroidal treatment option that
helps control adrenal hormone levels may benefit CAH patients. This study
involves the use of an investigational drug, tildacerfont (SPR001).
Investigational means that the study drug has not been approved for use as a
prescription or over-the-counter medicine. The purpose of this study is to see
if tildacerfont can reduce the amount of GC (e.g., hydrocortisone) that
patients need to take and reduce the level of certain hormones in their body.

Because this is a scientific study, it is also important to collect information
about patients with CAH who are not receiving tildacerfont. Therefore,
tildacerfont will be compared to *placebo*, which is a medication that looks
like investigational drug but does not contain any tildacerfont or any other
active compound.

This study has been transitioned to CTIS with ID 2023-503771-13-00 check the CTIS register for the current data.

The purpose of this study is to see if tildacerfont can reduce the amount of GC
(e.g., hydrocortisone) you need to take and reduce the level of certain
hormones in your body.

This is a study with a 2-part treatment period that will evaluate the potential
of tildacerfont to reduce GC burden in adult subjects with classic CAH who are
have A4 <=2.5x ULN and are on supraphysiologic doses of GC therapy (>=30 mg/day
and <=60 mg/day in HCe).
The first 24 weeks of the treatment period will be a randomized, double-blind,
and placebo-controlled study in which subjects are randomized in a 1:1 ratio to
receive either placebo or tildacerfont at 200 mg once daily (QD).
The 52-week Open-Label Period (day after Week 24 to Week 76) will provide
subjects who complete the Placebo-Controlled Treatment Period with 52 weeks of
open-label treatment with tildacerfont 200 mg QD. An optional Open-Label
Extension Period will provide an open-label treatment with tildacerfont at 200
mg QD for up to 240 weeks.
During the 30-day Follow-up period, subjects will maintain the GC dose regimen
and mineralocorticoid regimen (as applicable) established during the course of
the study until the 30-day follow-up visit unless the Investigator determines
that the subject*s clinical status necessitates a dosing change. After
completion of the study, GC therapy will be managed at the discretion of the
subject's treating physician.

The drug product is a small-molecule CRF1 receptor antagonist and will be
supplied as yellow, round, convex tablets containing 50 mg of drug substance.
Placebo will be supplied as tablets that look identical to drug product but
contain no drug substance.

At the beginning of the Placebo-Controlled Treatment Period, subjects will be
randomized in a 1:1 ratio to receive either placebo or tildacerfont at 200 mg
QD for 24 weeks. During the Open-Label Extension Period, all subjects will
receive open-label tildacerfont at 200 mg QD for 52 weeks. Study drug will be
taken orally between 6 PM and midnight, with an evening meal. The evening meal
should contain <50% fat content. Study drug may be consumed up to 30 minutes
after completing the evening meal, if necessary.

Subjects will also receive a subject-specific standardized oral 3-times-daily
(TID) HC or twice-daily BID prednisolone regimen provided by the Sponsor. On
the mornings of clinic visits, subjects should delay taking any morning dose of
GC medication until after the 8 AM (±1 hour) laboratory assessments have been
completed. On all other days during the study, subjects should take their GC
medication at the usual time(s). Mineralocorticoid may be taken at any time of
day, but its timing relative to laboratory assessments should be consistent
throughout the study. During times of clinically significant physical stress
such as intercurrent illness with fever, surgical procedures, or significant
trauma, stress dosing with extra GC (in the form of HC) for prevention of
adrenal crisis will be allowed according to *sick day guidelines*. Study drug
will be discontinued in subjects who meet individual treatment-stopping
criteria such as having clinically significant liver chemistry or QTcF values
at any time during the Treatment Period. During the Open-Label Extension
Period, it may be possible to decrease the tildacerfont dose from 200 mg QD to
100 mg QD in subjects assessed by the Investigator as having ongoing issues
with study drug tolerability, upon discussion with the Medical Monitor.

The Sponsor believes that the benefit-to-risk profile of this study is
favorable. Given the serious nature of CAH and the limitations and risks of
chronic steroid therapy, new treatment modalities are needed for patients with
CAH. Given 1) the acceptable overall safety and tolerability profile of
tildacerfont in healthy volunteers and subjects with CAH; 2) the ability to
monitor the observed risk of LFT elevation, which is reversible and occurred at
higher exposures than those expected in this study; and 3) the evidence of
reductions in ACTH, 17-OHP, and A4 at multiple dose levels tested in previous
Phase 2 studies, the Sponsor believes that the benefit-to-risk profile favors
the continued clinical investigation of tildacerfont, including this
investigation of tildacerfont*s potential to reduce GC use and of extended
treatment with tildacerfont for up to 1 year in subjects with CAH. An optional
Open-Label Extension Period will provide an open-label treatment with
tildacerfont at 200 mg QD for up to 240 weeks.