Effects of a New Progesterone Receptor Modulator,

7/29/2019 Effects of a New Progesterone Receptor Modulator,

1/19

Effects of a New Progesterone

Receptor Modulator, CDB-4124, on

Fibroid Size and Uterine Bleeding

report by

Ronald D Wiehle, MD, PhD,1 Jay Goldberg, MD, MSCP,2 Teresa Brodniewicz, MD,3

Katarzyna Jarus-Dziedzic, MD, PhD3 and Zoulikha Jabiry-Zieniewicz, MD, PhD3

1. Repros Therapeutics, Inc.; 2. Jefferson Medical College, Philadelphia; 3. MTZ ClinicalResearch Ltd, Warsaw


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Introduction

Currently available medical treatments for

symptomatic fibroids are limited, include:

Non-steroidal anti-inflammatory drugs (NSAIDs),

Oral contraceptives, and

Gonadotropin-releasing hormone (GnRH) agonists


3/19

NSAIDsOral

contraceptives

do not reduce bulk

symptoms

Fibroid-related menorrhagia

and dysmenorrhea


4/19

GnRH agonists

Reducing bleeding

and bulk symptoms

Systemic menopausal side effects, including :

hot flashes,

vaginal dryness,

mood swings,

and a decrease in bone density


5/19

A new compound, 17-acetoxy-21-methoxy-

11-[4-N,N-dimethylaminophenyl]-19-

norpregna-4,9-diene-3,20-dione (CDB-4124),

exhibits strong progesterone antagonist

activities in receptor binding, in vitro activity,

and uterine selectivity.

The current study is the first human trial ofCDB-4124


6/19

Materials and Methods

Trial Design

The study was approved by the Institutional

Review Board of the Klinika Pozocnictawa i

Ginokologii Akamiij Medycnej w Warszwie

This was a phase I/II study, with single-dose

pharmacokinetic (PK) sampling conducted in

subjects randomized to the CDB-4124


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CDB-4124 12.5mg, 25mg, or 50mg comparedwith placebo (PLA) and Lucron (Lupron Depotleuprolide acetate, 3.75mg) im

Samples

30 females with symptomatic uterine fibroids

that were measured by transvaginalultrasound.

The treatment lasted for three months.


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Eligibility Criteria

All women were pre-menopausal and aged between 18 and50 years.

No surgical interventions for uterine fibroids were neither

planned nor anticipated during the 4.5-month study period.

At least one fibroid was identifiable and measurable bytransvaginal ultrasound.

Women of child-bearing potential had to be willing to use

effective non-hormonal contraception during the study period

and for a minimum of 30 days after discontinuation of thestudy drug.

Subjects had a negative pregnancy test at screen and baseline

visits.


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All women had a regular or steady menstrual cyclelasting for 2436 days.

No patient with endometriosis, moderate to severevaricose veins, any significant cardiovascular, renal, orhepatic disease, past or present history ofthrombophlebitis, thromboembolic disorders, cerebralapoplexy, or known or suspected carcinoma of thebreast or reproductive organs was allowed to enroll.

The body mass index (BMI) of the women had to bebetween 18 and 35.

All subjects gave their informed consent to participate.


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Procedures

All Subject

Complete 14days to PK

sampilng

CDB4124

(Back 1-4 of

mens cyrcle)

Lupron and

PLA

(Not Return)

four oral

capsules

Collecting ACTH

hormon and

pregnancy test

blood collected

ABCLaboratories

(Columbia,

MO)

Visit 1

Visit four time

for EvaluateFibroid


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Assays Assays of serum hematology,

hormones, bone resorption test (c-telopeptide [CTX]),

bone formation test (n-mid-osteocalcin), and

white blood cell (WBC),

red blood cell (RBC),

hybrid capture tube (HCT),

hemoglobin (HGB),

melanin-concentrating hormone (MCH),

Mean corpuscular volume (MCV),

mean corpuscular hemoglobin concentration (MCHC),

Differential platelets,

prothrombin time (PT),

sodium (Na),

potassium (K),

chlorine (Cl),

carbon dioxide (CO2)/bicarbonate (HCO3),

glucose, phosphorous, uric acid, creatinine, blood urea nitrogen

(BUN), total protein, albumin, cholesterol, triglycerides, aspartate

aminotransferase (SGOT), serum glutamic pyruvate transaminase (SGPT),

alkaline phosphatase, total/direct bilirubin, lactate dehydrogenase (LDH),

and routine urinalysis with microscopic exam.


12/19

Results

Demographics

The populations studied were between 40 and 49years of age, were 162166cm in height, and had

a BMI of 2329. There were two differencesworth highlighting

CDB-25 subjects were slightly older and heavierthan the rest of the treatment groups.

Fibroids were predominantly intramural in alltreatment groups except CDB-12.5, in whichsubserosal fibroids predominated.


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Pharmacokinetics

CDB-4124 was rapidly absorbed, reaching

peak plasma levels in 0.5 to two hours.

No statistically significant differences were

found between the 12.5 and 25mg doses, but

a significant difference was seen with the

50mg dose.


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Uterine Bleeding


15/19

Fibroid Size


16/19

Safety and Adverse Events

After three months of treatment, the overall

incidence rate of treatment-emergent adverse

events was lower among the CDB-4124 subjects

compared with Lupron and PLA subjects (83.3versus 100%, respectively).

The Lupron subjects had the highest incidence of

headache and vaginitis, the largest increase incholesterol, and the only statistically significant

mean change in bone resorption CTX.


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There were two serious adverse events: both

subjects were from the CDB-50 group and

both underwent elective hysterectomy due to

uterine bleeding.


18/19

Discussion

There was a statistically significant mean

reduction in tumor size at visit 5 and follow-up

compared with baseline for CDB-25, CDB-50,

and Lupron subjects.

A dose of 12.550mg per day appears to be

appropriate for clinical studies and the higher

dose was effective within one month.


19/19

Although this was a phase I/II trial in which PK

and safety were the primary objectives, the

encouraging safety and efficacy results in this

first human trial of CDB-4124 as a treatmentfor symptomatic uterine fibroids provide

evidence of its potential.

Documents

Effects of a New Progesterone Receptor Modulator,