fsh gonadotrophins : which is better???

Performance of commercially available HP-FSH: a meta-analysis

Hesham Al-Inany

Cairo University

Conflict of interest

•Dr.Al-Inany has worked as a co-investigator For Serono project 14742

•Received Speaker’s honoranium in Ferring & IBSA symposiums

• Sponsored by Organon for ASRM ,2007

IVF/ICSI cycles

• Multifollicular development by gonadotrophins is still an integral component for ovarian stimulation in IVF / ICSI cycles (Keck et al, 2005)

How To Choose!!

• Two of the most commonly used classes of drugs are the highly purified follicle stimulating hormone and recombinant follicle stimulating hormone.

But

Research

is not all the same

EVIDENCE

The Evidence Pyramid

Why such meta-analysis!!

• Published meta-analysis was in favor of recombinant FSH over Metrodin-HP

• So why to re-examine this issue again!!

First: Manufacturer Improvement

• The technological developments of gonadotrophins over the last ten years have shown improvements in specific activity, purity, degradation and impurities (Bassett & Driebergen , 2005)

• This has been reflected on HP-FSH

FSH purific a tio n p ro c e s s e s

Polyclonal antibodies extraction(Lualdi et al. USP 6,162,905)

Urine

Solvent/Salt precipitations

Affinity chromatography (1)

Affinity chromatography (2)

Purified FSH

Ion exchange chromatography

(Loumaye et al.; Hum Rep Up.; 1998)

(Wolfenson et al. USP 7,022,822) (Olijve et al.; Mol. Hum Rep.; 1996)

Urine

Solvent/Salt precipitations

Ion exchange chromatography(1)

Purified FSH

Ion exchange chromatography(2)

Hydrophobic Interaction chrom.

Ion exchange chromatography(3)

Ion exchange chromatography (1)

Rec. Mammalian cell line

Ion exchange chromatography(2)

Affinity chromatography

Reverse Phase HPLC

Size exclusion chromatography

Purified FSH

Purified FSH

Ion exchange chromatography (1)

Ion exchange chromatography(2)

Hydrophobic Interaction chrom.

Size exclusion chromatography

Rec. Mammalian cell line

Pre vio us p ro c e s s e s

Pro c e s s e ng ine e ring s tra te g ie s

Current

Second: Why commercially available Gonadotrophins!!

•Metrodin-HP® has been withdrawn from the market and no more available.

• The evidence should be revaluated in view of currently available HP-FSH

Two subunits (alpha 92 aa; beta 111 aa)

is composed of a large number of different isoforms that differ in electric charge

FSH is a c o m p le x m o le c ule …

ALPHA BETA

Clinically oriented value

• FSH isoforms could be of importance for clinical efficacy as it may affect the developmental competence of oocytes. (Nayudu et al., 2002)

Third: questioning Metrodin-HP

• FSH isoforms in Metrodin-HP has been documented to be of lower activity than expected (Andersen et al., 2004).

But more importantly

•Currently available HP-FSH are not only of higher purity

• But also of higher glycosylated content

•Clinical outcome varies according to glycosylation of FSH (Grudzinskas, 2007)

A Highly Glycosylated FSH

•Naturally released at time of enhanced need …e.g Pubertal age

• In COH : Stronger stimulation due to extended half-life, higher biopotency

Accordingly

• The awareness of the role of FSH glycosylation stimulated us to revisit the evidence

Aim

• To compare commercially available HP-FSH with recombinant FSH in women undergoing IVF/ICSI.

Search strategy

• Extensive electronic (e.g. MEDLINE, EMBASE, CENTRAL) and hand searches were performed to locate trials from conference proceedings (e.g. ASRM & ESHRE).

Outcomes

Primary : ongoing pregnancy/ live birth rate rate of OHSS

Secondary outcomes clinical pregnancy, multiple pregnancy miscarriage rates, treatment durationnumber of ampoules,number of oocytes retrieved

Dichotomous Data e.g pregnancy

• Analysis using the Peto-modified Mantel-Haenszel method

•Odds ratio (OR) and 95% confidence intervals (CI) presented.

Contineous Data e.g dose units

• Analysis using the Inverse Variance method

•Weighted mean difference (WMD) and 95% confidence intervals (CI) presented.

• 5 Randomized Controlled Trials comparing HP-FSH versus rFSH• 3 full-text papers• 2 conference abstract

Search Results

Results

• HP-FSH (188/ ) vs. rFSH (143/ )

• ( O.R = 1.26, 95% CI = 0.96 to 1.66)

Clinical Pregnancy Rate

(P = 0.09)

Review: HP-FSH versus rFSHComparison: 03 Pregnancy Outcomes Outcome: 03 Clinical Pregnancy Rate

Study Peto OR Weight Peto ORor sub-category 95% CI % 95% CI

Grudzinskas 2006 14.99 1.09 [0.54, 2.20] Dickey 2002 17.41 1.34 [0.70, 2.58] Mohamed 2006 17.73 1.13 [0.59, 2.15] Baker 2007 18.44 1.17 [0.62, 2.21] Selman 2002 31.43 1.47 [0.90, 2.38]

Total (95% CI) 100.00 1.26 [0.96, 1.66]Total events: 188 (HP-FSH), 143 (rFSH)Test for heterogeneity: Chi² = 0.74, df = 4 (P = 0.95), I² = 0%Test for overall effect: Z = 1.68 (P = 0.09)

0.2 0.5 1 2 5

Favours rFSH Favours HP-FSH

Ongoing Pregnancy/Live-birth Rate

• HP-FSH (137/ ) vs. rFSH (102/ )• ( O.R = 1.25, 95% CI = 0.92 to 1.70)

(P = 0.16)

Review: HP-FSH versus rFSHComparison: 03 Pregnancy Outcomes Outcome: 07 Ongoing pregnancy/ live-birth rate

Study Peto OR Weight Peto ORor sub-category 95% CI % 95% CI

Mohamed 2006 19.76 1.07 [0.54, 2.15] Dickey 2002 20.00 1.40 [0.70, 2.80] Baker 2007 22.44 1.00 [0.52, 1.92] Selman 2002 37.81 1.45 [0.88, 2.40]

Total (95% CI) 100.00 1.25 [0.92, 1.70]Total events: 137 (HP-FSH), 102 (rFSH)Test for heterogeneity: Chi² = 1.08, df = 3 (P = 0.78), I² = 0%Test for overall effect: Z = 1.41 (P = 0.16)

0.2 0.5 1 2 5

Favours rFSH Favours HP-FSH

WMD = -0.27, 95% CI = -0.52 to -0.02

Treatment DurationReview: HP-FSH versus rFSHComparison: 02 Ovarian Stimulation Outcome: 01 Treatment duration

Study WMD (fixed) Weight WMD (fixed)or sub-category 95% CI % 95% CI

Mohamed 2006 24.15 -0.70 [-1.20, -0.20] Grudzinskas 2006 25.13 0.20 [-0.29, 0.69] Selman 2002 50.73 -0.30 [-0.65, 0.05]

Total (95% CI) 100.00 -0.27 [-0.52, -0.02]Test for heterogeneity: Chi² = 6.29, df = 2 (P = 0.04), I² = 68.2%Test for overall effect: Z = 2.14 (P = 0.03)

-4 -2 0 2 4

More with rFSH More with HP-FSH

(WMD = -329.80, 95% CI = -483.82 to -175.77)

Amount of GonadotrophinsReview: HP-FSH versus rFSHComparison: 02 Ovarian Stimulation Outcome: 02 Total dose (IU)

Study WMD (fixed) Weight WMD (fixed)or sub-category 95% CI % 95% CI

Mohamed 2006 9.83 -2320.00 [-2811.14, -1828.86]Selman 2002 22.03 -660.00 [-988.13, -331.87] Baker 2007 30.75 -74.00 [-351.76, 203.76] Grudzinskas 2006 37.38 178.00 [-73.91, 429.91]

Total (95% CI) 100.00 -329.80 [-483.82, -175.77]Test for heterogeneity: Chi² = 85.84, df = 3 (P < 0.00001), I² = 96.5%Test for overall effect: Z = 4.20 (P < 0.0001)

-1000 -500 0 500 1000

More with rFSH More with HP-FSH

How to explain

• FSH receptors in human are variants, so it could be logic that FSH-HP would be more suitable than recombinant in all patients

Secondary outcomes

• the number of oocytes retrieved (WMD = -0.51, 95% CI = -1.06 to 0.04) was not significantly different between the two groups.

• In addition, there were no significant differences with regards the clinical pregnancy rate (O.R = 1.26, 95% CI = 0.96 to 1.66) or the other secondary outcomes.

• it should be noted that there was significant statistical heterogeneity between the included trials.

•More RCTs to ensure adequate power for our findings

Limitations

Future of HP-FSH

• It is well known that Patency of recombinant FSH will end by 2008

•Companies currently producing HP-FSH are in the process of manufacturing recombinant FSH

•Would this put an end to HP-FSH!!!

Our findings

• Support continuing the production of urinary FSH-HP even if the profit margin for companies is small

Cost-effective analysis should be performed according to regional prices in order to ascertain if a change in policy should be enforced.

Conclusion

•HP-FSH has been demonstrated to be non-inferior to rFSH with regards the clinical outcomes and patient safety.

• In addition it was shown to be superior in stimulation efficacy than rFSH, with less numbers of ampoules and treatment days needed to attain similar results.

Further research

•We have recently demonstrated that hMG is also not inferior to recombinant FSH

hMG (363/ 1453) vs. rFSH (324/ 1484)

(P < 0.04; O.R = 1.20, 95% CI = 1.01 - 1.42)

Al-Inany et al., RBM Online, (in press)

• HP-FSH (188/ ) vs. rFSH (143/ )

• ( O.R = 1.26, 95% CI = 0.96 to 1.66)(P = 0.09)

Review: HP-FSH versus rFSHComparison: 03 Pregnancy Outcomes Outcome: 03 Clinical Pregnancy Rate

Study Peto OR Weight Peto ORor sub-category 95% CI % 95% CI

Grudzinskas 2006 14.99 1.09 [0.54, 2.20] Dickey 2002 17.41 1.34 [0.70, 2.58] Mohamed 2006 17.73 1.13 [0.59, 2.15] Baker 2007 18.44 1.17 [0.62, 2.21] Selman 2002 31.43 1.47 [0.90, 2.38]

Total (95% CI) 100.00 1.26 [0.96, 1.66]Total events: 188 (HP-FSH), 143 (rFSH)Test for heterogeneity: Chi² = 0.74, df = 4 (P = 0.95), I² = 0%Test for overall effect: Z = 1.68 (P = 0.09)

0.2 0.5 1 2 5

Favours rFSH Favours HP-FSH

The question

• If pharmaceutical companies has to choose between hMG or HP-FSH !!

• The answer should be through conducting a large RCT comparing HP-FSH vs HP-hMG

• If both were not different , then it is the FSH isoforms and higher glycosylation rather than hCG that affect folliculogenesis.

Thank You