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Esmya® clinical R & D

About PEARL (PGL4001’s Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata) studies

Clinical Research & Development

About PEARL (PGL4001’s Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata) studies

PEARL I, PEARL II, PEARL III and III extension, PEARL IV are Phase III clinical trials conducted mainly in Europe, all of them have been completed to date. These four studies included pre-menopausal adult women with symptomatic uterine fibroids characterised by heavy menstrual bleeding and eligible for surgery7,42,43,44,45,.

October 2008 – August 2010

PHASE III study-
(PEARL I)

a randomized, parallel-group, double-blind, placebo-controlled, phase 3 trial involved 241 patients. The primary objectives of PEARL I were to demonstrate superior efficacy of ulipristal acetate versus placebo, to reduce excessive uterine bleeding and to reduce total fibroid volume prior to surgery.

pearl_charts_I

 

October 2008 – August 2010

PHASE III study-
(PEARL II)

a randomized, parallel-group, double-blind, double-dummy, phase 3 trial comparing ulipristal acetate versus the injectable Gonadotropin Releasing Hormone (GnRH) agonist (leuprolide acetate) involved 307 patients.

pearl_charts_II

July 2010 – January 2014

PHASE III –
(PEARL III +PEARL III Extension)

PEARL III and its extension were long-term Phase III, multicentre, double-blind, open-label trials of UPA, open-labelled and placebo-controlled toward the double-blinded administration of progestin (norethisterone acetate [NETA]) after each course to explore any effect on histological endometrial changes and on timing and magnitude of the next menstruation, off-treatment.

pearl_charts_PEARL_III_Extension

 

June 2012- January 2015

PHASE III –
(PEARL IV)

PEARL IV was a Phase III, multicenter, randomised, double-blind, parallel-group, long-term study investigating the efficacy and safety of UPA 5 mg (ESMYA®) and 10 mg daily for the treatment of uterine fibroids.

Pearl_iv

References

  • 480 Reference 7 - Donnez J, et al. Fertil Steril 2016;105(1):165-173. e4 [PEARL IV PART 2]
  • 2910 Reference 42 – Donnez J., et al. “Ulipristal acetate versus placebo for fibroid treatment before surgery.” N Engl J Med. 2012 Feb 2;366(5):409-20. [PEARL I]
  • 2909 Reference 43 – Donnez J., et al. “Ulipristal acetate versus leuprolide acetate for uterine fibroids.” N Engl J Med. 2012 Feb 2;366(5):421-32. [PEARL II]
  • 2908 Reference 44 – Donnez J, et al. Long-term treatment of uterine fibroids with Ulipristal Acetate. Fertil Steril 2014;101(6):1565-1573. [PEARL III]
  • 2907 Reference 45 – Donnez, J. et al. “Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids”. Fertil Steril 2015; 103(2):519-27 [PEARL IV, Part 1]

PEARL I

Ulipristal Acetate versus Placebo for Fibroid Treatment before Surgery43

Publications
Jacques Donnez, M.D., Ph.D., Tetyana F. Tatarchuk, M.D., Ph.D., Philippe Bouchard, M.D., Lucian Puscasiu, M.D., Ph.D., Nataliya F. Zakharenko, M.D., Ph.D., Tatiana Ivanova, M.D., Ph.D., Gyula Ugocsai, M.D., Ph.D., Michal Mara, M.D., Ph.D., Manju P. Jilla, M.B., B.S., M.D., Elke Bestel, M.D., Paul Terrill, Ph.D., Ian Osterloh, M.Sc., M.R.C.P., and Ernest Loumaye, M.D., Ph.D., for the PEARL I Study Group

N Engl J Med 2012; 366(5): 409-420

Study objectives
To demonstrate superior efficacy of Ulipristal Acetate (UPA) with concomitant iron administration versus placebo with concomitant iron administration, to reduce excessive uterine bleeding and to reduce total fibroid volume prior to surgery.

Design of PEARL I study
A Phase III, randomised, parallel-group, double-blind, placebo-controlled, multicentre study in patients with symptomatic uterine fibroids.

pearl_charts_I

All patients had Hb<=10.2g/dL at screening and received concomitant administration of iron.

Efficacy

  • Uterine bleeding was controlled in over 90% of women receiving Esmya® 5mg (UPA 5mg). Bleeding (PBAC score of <75) was controlled in 91% and 92% of patients in the Esmya® 5mg and UPA 10mg groups, respectively, vs. 19% in those receiving placebo, at week 13.
  • More than 73% of patients, receiving UPA, reached amenorrhoea (PBAC score of ≤ 2) within 2 months. The rates of amenorrhoea were 73%, 82%, and 6% for Esmya® 5mg, UPA 10mg* and placebo, respectively.
  • Amenorrhoea occurred within 10 days for 50% of patients receiving Esmya® 5mg  and 70% for those receiving UPA 10mg.
  • Significant reduction in fibroid volume by week 13. The median changes in total fibroid volume reduction were -21%, -12% and +3% for the 3 groups, respectively (P=0.002 for Esmya® 5mg vs. placebo, P=0.006 for UPA 10mg vs. placebo).
  • Significant pain reduction, as measured by VAS scale, and improved Quality of Life.

Safety and tolerability

  • The rate of the occurrence of adverse events was similar across the three groups.
  • Headache and pain, discomfort or tenderness in the breasts were the most common adverse events associated with UPA, but did not occur significantly more frequently than with placebo.
  • Non-physiological endometrial changes (PAEC) were observed more frequently in patients receiving ulipristal acetate than in patients receiving placebo, but these changes had resolved by the time of the follow-up assessment 6 months after the end of the treatment period.

References

  • 2909 Reference 43 – Donnez J., et al. “Ulipristal acetate versus leuprolide acetate for uterine fibroids.” N Engl J Med. 2012 Feb 2;366(5):421-32. [PEARL II]

PEARL II

Ulipristal Acetate versus Leuprolide Acetate for Uterine Fibroids43

Publications
Jacques Donnez, M.D., Ph.D., Janusz Tomaszewski, M.D., Ph.D., Francisco Vázquez, M.D., Ph.D., Philippe Bouchard, M.D., Boguslav Lemieszczuk, M.D., Francesco Baró, M.D., Ph.D., Kazem Nouri, M.D., Luigi Selvaggi, M.D., Krzysztof Sodowski, M.D., Elke Bestel, M.D., Paul Terrill, Ph.D., Ian Osterloh, M.R.C.P., and Ernest Loumaye, M.D., Ph.D., for the PEARL II Study Group

N Engl J Med 2012; 366(5): 421-432

Study objectives
To demonstrate non-inferior efficacy of Ulipristal Acetate (UPA) versus Gonadotrophin Releasing Hormone (GnRH) agonist in reducing, prior to surgery, excessive uterine bleeding caused by uterine fibroids. The co-primary safety objectives were to show a superior safety and tolerance of UPA versus GnRH agonist in terms of serum oestradiol levels at end of treatment (week 13) and the proportion of patients with moderate-to-severe hot flushes during treatment.

Design of PEARL II study
A Phase III, randomised, parallel-group, double-blind, double-dummy, active comparator-controlled, multicentre study comparing UPA versus once-monthly injections of GnRH agonist leuprolide acetate 3.75mg.

pearl_charts_II

Efficacy

  • Uterine bleeding was controlled in 90% of the women receiving Esmya® 5mg. This compares with bleeding controlled in 98% of those receiving UPA 10 mg and 89% of those receiving GnRH agonist.
  • Excessive bleeding was controlled significantly more rapidly in patients receiving Esmya® 5mg or UPA 10mg, than in those receiving GnRH agonist (P<0.001, both comparisons).
  • Median times to amenorrhoea were 7 days for patients receiving Esmya® 5mg. This compares to 5 days for those receiving UPA 10mg, and 21 days for those receiving GnRH agonist.
  • All treatments reduced the volume of the 3 largest fibroids. Median reductions at week 13 were 36%, 42% and 53% for the Esmya® 5mg, UPA 10mg and GnRH agonist groups, respectively.
  • For patients who did not undergo a hysterectomy or myomectomy, UPA showed a more sustained effect on the reduction of myoma volume up to 6 months after treatment cessation compared to GnRH agonist.

Safety and tolerability

  • Median oestradiol levels at week 13 were maintained at approximately 60-65 pg/mL in both the UPA groups but had decreased to post-menopausal levels (25.0 pg/mL) with GnRH agonist.
  • Significantly lower incidence of moderate to severe hot flashes with Esmya® 5mg or UPA 10mg (< 11%) when compared to GnRH agonist (40%) (P<0.001 for both comparisons).
  • Mean endometrial thickness at week 13 was significantly different between the UPA and GnRH agonist groups (p < 0.001 for both comparisons) with means of 9.4mm and 10.1 mm in the Esmya® 5mg and UPA 10mg respectively, compared to 5,1 mm in the GnRH agonist group.

References

  • 2909 Reference 43 – Donnez J., et al. “Ulipristal acetate versus leuprolide acetate for uterine fibroids.” N Engl J Med. 2012 Feb 2;366(5):421-32. [PEARL II]

PEARL III + PEARL III extension

Long-term treatment of uterine fibroids with Ulipristal Acetate44

Publications
Jacques Donnez, M.D., Francisco Vázquez, M.D., Janusz Tomaszewski, M.D., Kazem Nouri, M.D., Philippe Bouchard, M.D., Bart C. J. M. Fauser, M.D., David H. Barlow, F.R.C.O.G., Santiago Palacios, M.D., Olivier Donnez, M.D., Elke Bestel, M.D., Ian Osterloh, M.R.C.P., and Ernest Loumaye, M.D., PEARL III and the PEARL III extension study;

Fert and Sterility 2014;101:1565-1573

Study objectives
To investigate the efficacy and safety of ulipristal acetate (UPA) for long-term treatment of symptomatic uterine fibroids.

Design of PEARL III study + extension
PEARL III and its extension were long-term Phase III, multicentre, open-label trials of UPA, open labelled and placebo-controlled toward the administration of progestin after each ulipristal acetate treatment course.

pearl_charts_PEARL_III_Extension

Efficacy

  • Uterine bleeding control was sustained in the majority (80-90%) of women treated with repeated courses.
    • ~80% achieved amenorrhoea during 1st treatment course, increasing to ~90% with repeated treatment courses.
    • Amenorrhoea was achieved after a median of 4, 2, 3 and 3 days respectively for treatment courses 1, 2 , 3 and 4.
  • Pain levels were reduced and maintained at the lower leverls during all treatment courses.
  • Quality of life scores indicated substantially reduced QoL at baseline, but mean scores were within the range of healthy participants at the end of each treatment course and the improvement was largely maintained at the 3-month follow-up after the final treatment course ‡§.
  • Median reduction from baseline in fibroid volume of the 3 largest fibroids was -45%, -63%, -67% and -72% for treatment courses 1, 2, 3 and 4 respectively.

Safety and tolerability

  • The majority of adverse events were mild or moderate in nature and did not increase with successive treatment courses.
  • Headache and nasopharyngitis were the most common adverse events reported during the study, but the incidences decreased after each treatment course.
  • Severe AEs occurred in only 3.8% of women during the 1st course of treatment. Only one (Treatment Emergent Adverse Event) TEAE led to treatment withdrawal.
  • Transient increases in endometrial thickness occurred in < 19% of woman after each treatment course.
  • No cases of endometrial hyperplasia or adenocarcinoma were reported at any timepoint for any woman.
  • All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology.

 † Amenorrhoea defined as no bleeding for a continuous period of ≥35 days (1 day of spotting allowed). 
‡ Quality of Life was measured by general EQ-5D questionnaire and the Uterine fibroid symptom and health-related quality of life (UFS-QoL) questionnaire.
§ Pain was measured with the short-form McGill pain questionnaire.

References

  • 2908 Reference 44 – Donnez J, et al. Long-term treatment of uterine fibroids with Ulipristal Acetate. Fertil Steril 2014;101(6):1565-1573. [PEARL III]

PEARL IV

Efficacy and Safety of repeated use of ulipristal acetate in uterine fibroids4 (PEARL IV part 1)
Long-term medical Medical Management Of Uterine Fibroids5 (PEARL IV part 2)

Study objectives
To investigate the efficacy and safety of repeated 12-week courses (3 months) of 5 or 10 mg daily of UPA (ulipristal acetate) for intermittent treatement of symptomatic uterine fibroids.

Design of PEARL IV

  • A multicentre, randomised, double-blind, Phase III clinical study of UPA 5 mg or 10 mg daily for the long-term management of symptomatic uterine fibroids
  • 4 courses of 12-week treatment with ulipristal acetate
  • 451 patients recruited
  • The main pivotal study on the intermittent use of Esmya®

Pearl_iv

Adapted from Donnez 2015, in press5 UPA, ulipristal acetate

PEARL IV: Primary efficacy endpoint

  • percentage of subjects in amenorrhoea at the end of all four UPA courses7

PEARL IV: Secondary endpoints

 

Subjects
in amenorrhoea
Percentage
of subjects in amenorrhoea at the end of each treatment course
Time
to amenorrhoea
Median time to amenorrhoea during each individual treatment course
Subjects
with controlled bleeding
Percentage of subjects with controlled bleeding in the last 56 days of each individual
treatment course
Percentage of subjects with controlled bleeding at the end of all 4 treatment courses
Myoma
volume
Change from baseline in the volume of the three largest myomas and uterus
QoL Change from baseline in quality of life (UFS-QoL and EQ-5D)
Pain Change from baseline in pain (VAS)

EQ-5D, EuroQol 5-dimensional health status questionnaire
UFS-QoL, Uterine Fibroid Symptom and Quality of Life Questionnaire
UPA, ulipristal acetate
VAS, visual analogue scale

PEARL IV: Key inclusion criteria

 

Premenopausal women aged 18−50 years
At least one uterine fibroid 3−12 cm diameter (none >12 cm diameter)
Regular menstrual cycles 22−35 days duration (FSH <= 20 mIU/mL)
Body mass index 18–40 kg/m2
Uterus volume upper limit equivalent to 16 weeks pregnancy
Excessive uterine bleeding (PBAC >100)

FSH, follicle-stimulating hormone
PBAC, pictorial blood assessment chart

PEARL IV: Baseline characteristics

 

Characteristic (full analysis set) Esmya® (UPA 5 mg/day)
(N=228)
UPA 10 mg/day (N=223)
Mean age, years (SD) 41.6
(5.4)
41.4
(5.1)
Ethnic origin, n (%) White 211
(92.5)
214
(96.0)
Black 12
(5.3)
8
(3.6)
Other 4
(1.8)
1
(0.4)
Not reported 1 (0.4) 0
Mean weight, kg (SD) 69.2
(12.7)
70.0
(12.8)
Mean BMI, kg/m2 (SD) 25.2
(4.1)
25.3
(4.5)

Adapted from Donnez 2015, in press 5

Efficacy

  • Amenorrhoea†1 was achieved by 71.8%, 74.1%, 73.3%, and 69.6% in the Esmya® 5 mg group and 82.6%, 82.2%, 78.3%, and 74.5% in the 10 mg group, for treatment courses 1, 2, 3, and 3 respectively.
    • Amenorrhoea was achieved after a median of 4-6 days for both groups across the treatment courses.
  • The percentage of patients with controlled bleeding†2 in the last 56 days for individual treatment courses ranged from 73.3% to 93.4% across both treatment groups.
  • Pain levels were reduced and maintained at the lower levels during all treatment courses and even during the off-treatment periods levels did not return to baseline.
  • Quality of life scores indicated substantially reduced QoL at baseline, but mean scores were within the range of healthy participants at the end of each treatment course, and even during the off-treatment periods and the improvement was largely maintained at the 3-month follow-up after the final treatment course ‡§.
  • Clinically significant reduction of ≥ 25% volume of the three largest fibroids was reported after each treatment course. In both groups, the percentage of subjects with a clinically significant reduction increased from course 1 to course 4. In the 5-mg group, the percentages increased from 62.3% after course 1 to 78.1% after course 4. Similarly, in the 10-mg group, the percentages increased from 66.5% to 80.5%.
  • Further examination showed that at the end of four treatment courses, 73.5% of all subjects had a fibroid volume reduction of ≥ 25% and were in amenorrhea.

Safety and Tolerability

  • The majority (97.6%) of adverse events were mild or moderate in nature and did not increase with successive treatment courses (≤ 11% in both cases).
    • Headache and hot flushes were the most common adverse events reported during the study, but the incidences decreased after each treatment course.
  • Breast pain/discomfort was observed in ≤ 3% of subjects, with a decrease in frequency for each successive treatment course (≤ 1% by treatment course 4).
  • During the study, the median endometrial thickness remained between 7 and 8 mm. The percentage of subjects with endometrial thickness ≥ 16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses.
  • The frequency of nonphysiological changes did not increase with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were reversible after treatment cessation.
  • There were no significant changes in laboratory parameters during the study.

†1 Amenorrhoea was defined as no bleeding for a continuous period of ≥35 days (1 day of spotting allowed).
†2 Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 d of bleeding during the last 56 d of a course of treatment.
‡ Quality of Life was measured by general EQ-5D questionnaire and the Uterine fibroid symptom and health-related quality of life (UFS-QoL) questionnaire.
§ Pain was measured with the short-form McGill pain questionnaire

References

  • 478 Reference 5 - Lerner D., et al. Impaired work performance among women with symptomatic uterine fibroids. J Occup Environ Med 2008; 50: 1149-1157.
  • 480 Reference 7 - Donnez J, et al. Fertil Steril 2016;105(1):165-173. e4 [PEARL IV PART 2]
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