Biodrugs 2003; 17 (4): 288-289ADIS R&D PROFILE 1173-8804/03/0004-0288/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Urofollitropin – FerringFERRING hFSH, hFSH – Ferring, Human Follicle-Stimulating Hormone –Ferring, Bravelle™

Ferring Pharmaceuticals (US) is developing a highly purified form of urofollitropin [human follicle-Abstractstimulating hormone, hFSH, FERRING hFSH™, Bravelle™] for use in ovarian stimulation in fertility treat-ments. The highly purified human-derived follicle-stimulating hormone (HP-FSH), administered by eitherintramuscular (IM) or subcutaneous (SC) injection, was in phase III trials in the US and in May 2002 the productreceived US FDA approval for use in conjunction with human chorionic gonadotropin for infertility patientsundergoing ovulation induction. The product will be marketed as Bravelle™. Ferring Pharmaceuticals has alsosubmitted a New Drug Application for additional indications for Bravelle™ in infertility treatment, which iscurrently under review by the US FDA.

Bravelle™ is produced from the urine of menopausal women and has been shown to be as effective asOrganon’s recombinant FSH product, Follistam®. Preclinical studies have shown that Ferring Pharmaceuticals’hFSH can be mixed in the same syringe as purified human menopausal gonadotropin (hMG) to reduce thenumber of daily injections required in ovarian stimulation protocols without altering the bioactivity of FSH orluteinising hormone. In addition, Ferring Pharmaceuticals’ hFSH administered SC or IM showed positive resultscompared with SC Repronex® in a randomised, open-label study in patients undergoing in vitro fertilisation.[1]

Ferring Pharmaceuticals has teamed up with the American Infertility Association and RESOLVE: theNational Infertility Association to improve access to infertility treatment in the US, with the recent launch of the‘Bravelle™’ HEART (Helping Expand Access to Reproductive Therapy) Programme. The programme isintended to provide urofollitropin treatment at significant cost savings to patients and their physicians.[2]

Serono is also developing a highly purified urofollitropin product.

Table I. Features and properties

WHO ATC code G03G-A (Gonadotrophins)

EphMRA ATC code G3G (Gonadotrophins, Including Other Ovulation Stimulants)

Originator Ferring Pharmaceuticals: Denmark: US

Highest development phase Phase registered (US)

Properties

Mechanism of action Ovarian follicle stimulants

Route IM

Adverse events Occasional injection site pain

doses (once daily for 7 days) of 150IU were administered SC to 161. Profile patients and IM to 12 patients. For single SC versus IM doses,

mean Cmax was 5.9 versus 7.0 mIU/mL, tmax was 21.3 versus17.8h, AUC was 379.3 versus 343.4 mIU h/ml and t1/2 was 42.91.1 Pharmacokineticsversus 43.4h. SC administration gave significantly greater bio-availability (22%) and higher peak concentrations and AUC atThe pharmacokinetics of subcutaneous (SC) and intramuscularsteady state than IM injection. Results were also more consistent(IM) urofollitropin (Ferring Pharmaceuticals) were evaluated in

healthy premenopausal female volunteers. Single and multiple for the SC route. Mean pharmacokinetic parameters at steady state

Urofollitropin 289

for SC versus IM administration were: Cmax = 14.8 versus 11.5mIU/mL, tmax = 9.6 versus 11.3h, AUC = 234.7 versus 192.1 mIUh/mL and t1/2 = 24.8 versus 24.4h.[3]

Numerous bioassays using low, medium and high doses ofFerring Pharmaceuticals’ hFSH and purified hMG combined in

Table II. Drug development history

May 2001 Phase III for female infertility in the US (SC)

May 2001 Phase III for female infertility in the US (IM)

May 2002 Registered for female infertility in the US (SC)

May 2002 Registered for female infertility in the US (IM)0.9% sodium chloride in the same syringe showed that the bioac-tivity of FSH and LH remained unchanged.[1]

pregnancy rates for IM and SC urofollitropin were 9/36 (25%) and7/37 (18.9%), respectively, compared with 11/38 (28.9%) forrFSH. Ongoing pregnancy rates were similar.[5]

1.2 Adverse Events

In the EMBRACE I trial, urofollitropin + menotropins(Bravelle™ + Repronex®) in various ratios mixed in the sameIn an open-label study in 177 women undergoing in vitrosyringe and administered as a single daily SC dose was effectivefertilisation treatment, purified urofollitropin administered IM orfor controlled ovarian hyperstimulation in a study involving 108SC was as well tolerated as SC follitropin-β in patients undergoingwomen aged 18–33 years undergoing in vitro fertilisation. Thecontrolled ovarian hyperstimulation for in vitro fertilisation. Bothmean total number of oocytes retrieved was 13.6–16.7. The con-urofollitropin groups experienced significantly less injection sitetinuing pregnancy rate was 41–47%.[6]pain than follitropin-β recipients.[4] IM and SC urofollitropin and

SC recombinant fSH (Follistim®) were safe and well tolerated in In the EMBRACE II trial, urofollitropin + menotropinsan open-label study in 111 women.[5]

(Bravelle™ + Repronex®) in various ratios mixed in the sameIn the Evaluation of Mixed Protocols with Bravelle™ and syringe and administered as a single daily SC dose was effective

Repronex® to Assess Clinical Efficacy (EMBRACE) I trial, for controlled ovarian hyperstimulation in 110 women aged 34–40urofollitropin + menotropins (Bravelle™ + Repronex®) in various years undergoing in vitro fertilisation. The mean total number ofratios mixed in the same syringe and administered as a single daily oocytes retrieved was 9.6–11.5 and live birth rates ranged fromSC dose for controlled ovarian hyperstimulation in 108 women 42–45%.[7]

aged 18–33 years undergoing in vitro fertilisation was associatedwith adverse event rates of 49–74%, and serious event rates of3–6%.[6] In the EMBRACE II trial, urofollitropin + menotropins

References(Bravelle™ + Repronex®) in various ratios mixed in the same1. Ferring Pharmaceuticals Inc. Ferring Pharmaceuticals presents data on new infer-syringe and administered as a single daily SC dose for controlled

tility treatments at the Pacific Coast Reproductive Society Meeting [online].ovarian hyperstimulation in 110 women aged 34–40 years under- Media Release: 22 Apr 2002. Available from URL: http://www.ferringusa.comgoing in vitro fertilisation was associated with adverse event rates

2. Ferring Pharmaceuticals Inc. The American Infertility Association, RESOLVE andof 44–58%, and serious event rates of 0–5%.[7]

Ferring team up to improve access to infertility treatment [online]. MediaRelease: 11 Nov 2002. Available from URL: http://www.ferringusa.com

3. Fein SHS, Cheng L, Nardi RV. An open-label, parallel group, single centre1.3 Therapeutic Trials pharmacokinetic study in normal female subjects comparing FERRING

hFSH™ SC and IM. Fertil Steril 2001; 75 (Suppl. 1): 12

4. Dickey RP, Thornton M, Nichols J, et al. Comparison of the efficacy and safety of ahighly purified human follicle-stimulating hormone (Bravelle™) and recombi-1.3.1 Women’s Healthnant follitropin-β for in vitro fertilization: a prospective, randomised study.Infertility: Purified urofollitropin administered IM or SC was as Fertil Steril 2002 Jun; 77: 1202-8

effective as SC follitropin-β in a study involving 177 patients5. Nardi RV, Feigenbaum S, Miller P, et al. A randomized, open-label, parallel group,

undergoing controlled ovarian hyperstimulation for in vitro fer- multi-center efficacy study in oligoanovulatory infertile patients comparingFERRING hFSH™ SC, FERRING hFSH™ IM, and Follistim® SC for ovula-tilisation. There were no significant differences among groups intion induction. Fertil Steril 2001; 75 Suppl. 1: 13-4

the number of oocytes retrieved per patient (13–14%), clinical6. Marrs RP, Check JH, Schnell VL, et al. Evaluation of mixed protocols with(32–46%) and continuing (30–45%) pregnancy rates and live birth

Bravelle™ (hFSH) and Repronex® (hMG) to assess clinical efficacy (EM-rates (25–38%).[4]

BRACE I) in patients (18–33 years) undergoing in vitro fertilization. FertilSteril 2003 Apr; 79 Suppl. 2: 14-5In a multicentre, open-label study in 111 oligoanovulatory

7. Keye Jr WR, Surrey MW, Van Voorhis BJ, et al. Evaluation of mixed protocolswomen, Ferring Pharmaceuticals’ urofollitropin (150IU SC or IMwith Bravelle™ and Repronex® to assess clinical efficacy (EMBRACE II) in

for 5 days then ≤450 IU/day for ≤7 days) had comparable efficacy patients (34–40 years) undergoing in vitro fertilization. Fertil Steril 2003 Apr;79 Suppl. 2: 6-7to the same dose of rFSH (Follistim®) administered SC. Clinical

© Adis Data Information BV 2003. All rights reserved. Biodrugs 2003; 17 (4)