Multi-center, randomized, comparator-controlled, single-blind, parallel-group study to
investigate the pharmacodynamics, pharmacokinetics and safety of an intrauterine
system releasing BAY 1007626, as compared with Mirena and Jaydess, in a combined
proof-of-concept and dose-finding study in healthy pre-menopausal women treated for
90 days

There is a continuing need for innovation in the field of safe and reliable
contraception. At present, there is a trend towards more widespread use of
long-acting reversible contraceptive (LARC) methods. Levonorgestrel-releasing
intrauterine systems (IUSs) are in wide use because of their high efficacy,
cost effectiveness and convenience compared with short-acting methods. However,
such systems are frequently associated with an increased incidence of bleeding
and spotting during the first few months of treatment, and long-term use can
lead to amenorrhea (although many women regard this as a positive effect) and
to systemic effects such as inhibition of ovulation, occasional development of
ovarian cysts and also partial androgenic activity.

BAY 1007626 is a synthetic hormone with progesterone-like effects, a so-called
progestin. It is being developed for use in a new intrauterine delivery system
for reversible, long-acting contraception. This new LARC is intended to show
equal contraceptive efficacy (based on surrogate marker endometrial histology),
reduce the initial bleeding and spotting, and result in a lower incidence /
frequency of systemic effects on ovarian activity (ovulation inhibition)
compared with Levonorgestrel-releasing intrauterine systems (LNG-IUSs, such as
Mirena).

In animal studies, BAY 1007626 showed a high plasma clearance and therefore low
systemic exposure. The phase I study 15728 confirmed that BAY 1007626 has a
higher plasma clearance and lower systemic exposure compared to Mirena. The
hypothesis is that low systemic exposure should result in fewer systemic
adverse events in humans (e.g., ovulation inhibition, ovarian cysts), even at
relatively high release rates, and would thus make possible a high local
(uterine) progestin exposure resulting in an improved bleeding profile compared
with that of Levonorgestrel-releasing IUSs.

The primary objective of this study is to investigate local and systemic
effects of BAY 1007626 on:
- Number of bleeding and spotting days,
- Endometrial histology,
- Ovulation (as surrogate for systemic effects).

The secondary objective of this study is to assess the effects of BAY 1007626
on:
- Endometrial thickness,
- Serum levels of hormones: estradiol (E2), progesterone, luteinizing hormone
(LH), follicle-stimulating hormone (FSH),
- Cervix function (Insler score),
- Bleeding pattern characterization,
- Safety and tolerability of BAY 1007626,
- PK of BAY 1007626 following intrauterine application, in comparison with
Jaydess and Mirena.

The study will be conducted in a multi-center, randomized,
comparator-controlled, parallelgroup, single-blind design in healthy women aged
18-40 years. Six different types of IUS will be used: four with different
release rates of BAY 1007626 and two comparators (Jaydess and Mirena). Each of
these will be applied for 90 days. The subjects will additionally be required
to use non-hormonal contraception, as this is the first study for investigation
of contraceptive effects as measured by local endometrial effects. It is
planned that a total of 176 subjects will take part in the study: 33 in each of
the BAY 1007626 and the Mirena treatment arms, and 11 in the Jaydess treatment
arm.

The frequency and pattern of bleedings as well as endometrial histology will be
assessed for all women:

- The number of bleeding and spotting days will be evaluated using an
electronic diary.
- Endometrial histology will be evaluated in endometrial biopsy specimen to be
taken in the pre-treatment cycle and around the end of treatment phase as well
as during follow-up. The histology of the specimen will be evaluated by blinded
reading involving three pathologists.

The evaluation of ovarian activity under treatment will be assessed in all
women as follows:

- In the dense visit subgroup a thorough analysis, requiring a high frequency
of study visits, will be done. Here ovarian activity will be assessed based on
twice weekly measurement of size of follicle-like structures (FLS) by TVUS and
serum progesterone and estradiol concentrations using the 6-step grading of
ovarian activity according to Hoogland. The dense visit subgroup will consist
of 12-18 subjects per treatment arm for BAY 1007626 and Mirena and of all 11
subjects receiving Jaydess. As these investigations will require a twice weekly
visit schedule they will be limited to a small number of preselected study
sites.

- In the weekly visit subgroup (N = 15-21 subjects per treatment arm, except
for the Jaydess arm) ovulation will be assessed by analysis of progesterone
serum concentrations. A progesterone serum concentration above 5 nmol/L has
been defined as indicating ovulation.

The effects on cervical mucus (Insler score) will be evaluated only in the
dense visit group population. The aim is to have in this subgroup, at the end
of the study, at least 10 evaluable women from each of the treatment arms
receiving the various dose levels of BAY 1007626 or Mirena and 8 of those
receiving Jaydess.

Pharmacokinetics (PK) of BAY 1007626 will be evaluated using sparse sampling
and a population PK approach in the women with weekly visit schedule. A more
detailed PK profile will be obtained in the women of the dense visit subgroup.

Further safety data i.e. a panel of safety laboratory parameters, vital signs
(blood pressure, heart rate and body weight) as well as 12 lead ECG will be
collected in all women.

The new product to be tested is a *New Progestin Intrauterine System* (NP IUS).
The active drug substance is BAY 1007626. The two comparators are standard,
commercially available products ((Jaydess / Mirena).

BAY 1007626 has not been administered to women released from an IUS, yet.
However, 50 women beyond child bearing age received BAY 1007626 administered
either subcutaneously or intravenously. The following temporary side effects
with BAY 1002076 were observed in this first human study:

• Headache
• Changes in laboratory values which did not give rise to any concern about the
safety (e.g. kidney function test, lipid metabolism)
• Exhaustion
• Hot flushes
• Blood in the urine
• Injection site reaction

Some other side effects such as diarrhoea, vomiting and breast discomfort only
occured in single volunteers.

Based on the aforementioned clinical study and several studies in e.g. animals,
BAY1007626 is assessed as sufficiently well characterized and as safe for a
first clinical study in women of child-bearing potential with a treatment
period of 90 days.

There is no human experience so far from BAY 1007626 IUS users. As reported for
intrauterine contraceptives (Mirena® and Jaydess®) comparable side effects can
be expected such as
infrequent bleeding, pelvic inflammation, expulsion of the IUS, perforation of
the womb and ovarian cysts.

Both Mirena® and Jaydess® are levonorgestrel releasing intrauterine systems for
contraception available on the market. The following side effects have been
reported with Mirena® and Jaydess® respectively.

Very common side effects (>=1/10 study subjects have experienced these side
effects):

- Mirena®: headache, abdominal / pelvic pain, bleeding changes including
increased and decreased menstrual bleeding, spotting, infrequent or very light
bleeding or absent of menstrual bleeding, inflammation of the vulva and vagina
(vulvovaginitis), genital discharge.
- Jaydess®: headache, abdominal/pelvic pain, acne/greasy skin, bleeding changes
including increased and decreased menstrual bleeding, spotting, infrequent or
very light bleeding or absent of menstrual bleeding, ovarian cyst, inflammation
of the vulva and vagina (vulvovaginitis)

Common side effects (>=1/100 to < 1/10 study subjects have experienced these
side effects):
- Mirena®: ovarian cyst, painful periods, depression/ depressed mood, migraine,
back pain, nausea, acne, increased growth of hair on the face and body, painful
breasts, intra-uterine contraceptive device expelled, upper genital tract
infection.
- Jaydess®: depressed mood/depression, migraine, nausea, hair loss, upper
genital tract infection, painful menstruation, breast pain/discomfort, device
expulsion, genital discharge.

Uncommon side effects (>=1/1,000 to < 1/100 study subjects have experienced
these side effects):
- Mirena: hair loss
- Jaydess®: excessive body hair.

Rare side effects (>=1/10,000 to < 1/1,000 study subjects have experienced these
side effects):
- Mirena®: perforation of the womb
- Jaydess®: perforation of the womb.

Side effects of unknow frequency:
- Mirena®: allergic reaction (symptoms may include rash, hives (urticaria) and
angioedema (characterised by sudden swelling of e.g. the eyes, mouth, throat),
increased blood pressure.