Fertility Market Poised For Growth Spurt After Fallow Decade

Late-stage pipeline is dominated by follicle stimulating hormones, split between “biobetters” and biosimilars. Next-generation oxytocin antagonists are leading candidates for the next novel entities in infertility.

The female infertility market could see a growth spurt like it hasn’t seen in almost 10 years if the range of follicle stimulating hormones in Phase III prove successful.

At least five recombinant FSH candidates to support assisted reproductive technology are in advanced clinical trials, after almost a decade of low FDA approval activity. The last advance in follitropins came with the 2004 approvals of ready-to-use pen injector formulations of recombinant follitropin alfa/beta products from Merck Serono SA (Gonal-F RFF) and Organon USA Inc. (Follistim AQ). The recombinant FSH products were originally approved on the same day in 1997.

At least two of the near-term FSH candidates are being developed as biosimilars to Gonal-F, but two offer new modifications of the FSH molecule – “biobetters.”

The market for controlled ovarian stimulation products used as part of in vitro fertilization procedures has been dominated for decades by three companies: Serono (now Merck Serono, the pharmaceuticals business of the German firm Merck KGAA), Organon (now Merck & Co. Inc.), and Ferring Pharmaceuticals AS.

The companies have pursued development of the hormone products, originally derived from the urine of postmenopausal women, along two pathways: highly purified urinary-derived hormones (the urofollitropins) and recombinant follitropin.

Serono’s urine-derived Pergonal, which contains both FSH and luteinizing hormone, inaugurated the ovulation induction market in the 1970s. The company then introduced the first urofollitropin – Metrodin – in 1986, followed in 1996 by another highly purified urofollitropin, Fertinex. The following year, 1997, saw the approval of recombinant FSH, Gonal-F. The company, now Merck Serono, built its recombinant Gonal-F franchise by introducing a revised formulation containing methionine and polysorbate 80 (Gonal-F RFF) and then a pen injector pre-filled multidose liquid product, which were approved in quick succession in 2004.

Merck Serono, however, has removed itself as a significant player in infertility R&D and has recast its R&D operations to focus on immuno-oncology (Also see "Merck KGAA Ramps Up Immuno-Oncology R&D To Close Ground On Rivals" - Pink Sheet, 23 Jul, 2013.). A pipeline overview released in May 2013 does not list any fertility or other women’s health products in development.

And while Merck KGAA is committed to biosimilars, the company’s strong position in branded fertility biologics positions it as a defender, not a challenger, in the emerging generic biologics field. Its fertility portfolio also includes Ovidrel (choriogonadotropin alfa), the only available recombinant version of human chorionic gonadotropin (used after FSH to trigger the release of mature eggs), and the gonadotropin-releasing hormone antagonist Cetrotide (cetrorelix acetate) (used to stop luteinizing hormone surges that can result in premature ovulation).

Ferring joined the market in 1996 by acquiring Lederle Laboratories’ Repronex, a menotropins product equivalent to Pergonal. Ferring built on the same starting materials as Repronex to introduce the purified urofollitropin Bravelle, approved in 2002, and a purified menotropins product, Menopur, in 2004.

Organon had been in the controlled ovarian stimulation segment since FDA’s 1994 approval of the menotropins Humegon. The company bypassed the highly purified urofollitropins battle in favor of developing its recombinant Follistim line. Organon was acquired by Schering-Plough Corp., which in turn was acquired by Merck, which is now looking to the next step in follitropin evolution.

“Biobetters” Offer Longer Dosing, Less Costly Production

The biobetter sponsors span the range of companies, from venerable big pharma Merck to the young German biotech Glycotope GMBH, established in 2001.

Merck’s corifollitropin is a long-acting FSH administered as a single subcutaneous injection, an advantage over the marketed rFSH products, which are injected daily for six to up 19 days.

Corifollitropin, which was approved in the EU in February 2010 as Elonva, uses carboxyl terminal peptide technology licensed from Washington University. CTP is a short, naturally occurring amino acid sequence that is attached to a protein to keep proteins in the body for longer periods by preventing the combination from being eliminated. In CTP-follitropin, or corifollitropin, the alpha subunit is identical to natural FSH while the beta-subunit is a fusion of the c-terminal peptide of chorionic gonadotropin to the beta-subunit of FSH.

After announcing results of the Phase III PURSUE trial at the American Society for Reproductive Medicine annual meeting in October 2012, Merck said it was on track for a 2013 corifollitropin NDA filing. The PURSUE trial enrolled 1,390 women in the U.S. and met its primary endpoint of non-inferiority in vital pregnancy rates between a single corifollitropin injection and seven daily injections of rFSH. Adverse events, including ovarian hyperstimulation syndrome, were in the same range for both FSH products. The corifollitropin U.S. database also includes the ENGAGE study, conducted by Schering-Plough, and an ongoing follow-up study of frozen-thawed embryo transfer (the Merck P06029 study).

Glycotope’s FSH-GEX product is a “glycooptimized” formulation of recombinant FSH that the company hopes will offer the safety advantages of recombinant protein production as well as the fully human glycosylation profile of urine-derived FSH. “While urinary versions of FSH carry human glycosylation, the in general better safety of recombinant products makes them the product of choice for most patients, despite a non-human glycosylation profile and higher production costs,” Glycotope said.

The fully human sugar structures produced with the company’s GlycoExpress platform of glycooptimized human cell lines reduce immunogenicity associated with recombinant products. “Superior production yields” could help bring the economics of FSH-GEX production closer to the urinary-derived FSH than the costly recombinant products, Glycotope maintains. The German firm is also developing its own device to administer FSH-GEX.

Phase II started in Europe in January 2013, comparing FSH-GX to Gonal-F. The trial is expected to enroll 240 women undergoing ART, with final data collection targeted for April 2014, according to NIH’s clinicaltrials.gov database. Glycotope hopes to start Phase III in early 2014.

Biosimilar In Intent, But Not Regulatory Pathway

Allergan PLC and the emerging Swiss biotech Finox AG are developing versions of Gonal-F that they describe as biosimilars, although both companies have said they plan to use the 505(b)(2) NDA pathway instead of the new 351(k) abbreviated pathway for biosimilars. Sponsors have generally been wary of the 351(k) pathway (Also see "Biosimilars: Does Low BsUFA Fee Revenue Suggest Sponsor Interest Has Stalled?" - Pink Sheet, 8 Apr, 2013.). The European biosimilar pathway is more established, and is becoming even clearer for FSH. The European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a guideline on recombinant human FSH biosimilar development on Feb. 21, 2013; it comes into effect on Sept. 1.

Follitropin has occupied an unusual regulatory niche in the U.S. The available products are of biological origin – purified from human urine or recombinant – but have been approved under NDAs, not BLAs. The 505(b)(2) NDA pathway, established by the 1984 Waxman-Hatch amendments to the FD&C Act, considers “naturally derived or recombinant active ingredients” to be eligible for 505(b)(2) filings, which can reference approved NDAs or published literature to reduce the regulatory burden.

The 505(b)(2) pathway functioned as a sort of proto-biosimilar pathway for relatively simple recombinant proteins like fertility hormones, growth hormones and hyaluronidase. “An application for a drug product containing an active ingredient(s) derived from animal or botanical sources or recombinant technology where clinical investigations are necessary to show that the active ingredient is the same as the active ingredient in a listed drug” is eligible for a 505(b)(2) NDA, according to a draft FDA guidance issued in 1999.

Finox’s biosimilar rFSH Afolia is the most clinically advanced of the biosimilar rFSH candidates. In the U.S, the pivotal Phase III FIN3002 trial kicked off in May under a Special Protocol Assessment with FDA. The company submitted an MAA in Europe on Oct. 30, 2012 under the name Bemfola, based on the Phase III FIN3001 study.

Afolia/Bemfola “has been developed according to EMA biosimilar guidelines and FDA requirements for the 505b2 pathway,” Finox says. To meet U.S. regulations, the FIN3002 study is more than twice as large as the FIN3001 trial that sufficed for European approval: 1,106 patients, randomized 1:1 to Afolia or Gonal-F, versus 410 women randomized 2:1 in favor of Bemfola.

The emerging company is, however, seeking a U.S. partner to “support further drug development within the ongoing Phase III study” as well as a partner for a European launch Finox hopes for in 2013. Finox is targeting 2015 for the U.S. NDA submission.

Finox touts its delivery advantage over the Gonal-F RFF pen injector. Afolia has a “substantially more attractive injector device,” the company maintains: a single-use, once-daily disposable pen injector with a more streamlined, three-step self-injection process.

Actavis CEO Paul Bisaro told a Goldman Sachs conference June 12 that “our first biosimilar product will be FSH and … obviously we’ll be the premier female health care company so we’ll be in a good position to sell that product from a branded perspective.” The biosimilar FSH is “moving into Phase III,” he said. Actavis has predicted global launches starting in 2015-2016.

Actavis predecessor Watson licensed the rFSH project from Itero Biopharmaceuticals Inc. in 2010 (Also see "Watson Biosimilar Tie Up With Itero Plays Into Women's Health Expertise" - Pink Sheet, 19 Jul, 2010.). The technology was transferred to the biologics manufacturing facility it acquired with the purchase of Eden Bioscience earlier in 2010 for scale-up. Actavis says “device design and dosing” have been “confirmed” and notes that it has met with FDA to discuss the rFSH.

“We believe we've done the chemistry well so that we've characterized the product very, very effectively,” Actavis told a May 30 Sanford Bernstein conference.

“We have a unique delivery device that will be coming with it that we've not disclosed. And that's progressing beautifully. It's in the clinic now …. the acceptance of it has been very good,” Actavis continued.

“It will be treated as a biosimilar,” Actavis said May 30. “But it is a 505(b)(2).” The company previously had been cagy about what regulatory pathway it would use for the rFSH (Also see "Are Potential Biosimilar Sponsors Still Hesitant About The Pathway Despite Expected Growth?" - Pink Sheet, 4 Mar, 2013.).

Actavis sees FSH as representing a $2 billion market. “The market for FSH is about equal U.S. to ex-U.S.,” the company noted, but with a “very different pricing structure” and “very different utilization.” The company said that “three times as many infertility cycles are done outside the United States as there are in the United States.” Actavis is “going to go after both of those with a biosimilar.”

Ferring Branches Out Into Recombinant FSH

Ferring has focused on what it calls “traditional highly purified and sterilized urinary-derived products” in its fertility portfolio, but the company’s 2005 acquisition of Bio-Technology General (Israel) Ltd. brought recombinant DNA development and manufacturing capability. Ferring has been working on a recombinant FSH – FE 999049 – that completed a Phase II trial in Europe in March comparing FE 999049 to Gonal-F. The dose-response trial enrolled 265 women, according to clinicaltrials.gov.

“FE 999049 is a recombinant FSH produced from a host cell line of human fetal retinal origin while follitropin alfa [Gonal-F] is derived from a Chinese hamster ovary (CHO) cell line,” according to a poster presented at the European Society of Human Reproduction and Embryology annual meeting in London July 7-10. Organon’s Follistim rFSH line is also derived from CHO cells.

Results of Ferring’s randomized, double-blind, multiple-dose Phase I PK/PD study “strongly indicate that the source of recombinant FSH is of importance with respect to the exposure and elimination after subcutaneous administration, as well as for the pharmacodynamic response. Equivalent IU doses of FE 999049 and follitropin alfa do not lead to similar pharmacokinetic and pharmacodynamic profiles,” an abstract of the poster published in journal Human Reproduction in June states. “Follicle development, inhibin B, estradiol and progesterone responses were all greater with FE 999049.”

Ferring patent applications show the company also has been working on adding sialylated glycan structures to rFSH to increase the product’s stability. Preservatives like phenol or benzyl alcohol are known to have a destabilizing effect on rFSH, but the addition of sodium or potassium salts may neutralize the destabilizing effect of preservatives, according to the applications.

Supporting Implantation In IVF

Assisted reproduction is a process that typically involves multiple drugs. While the FSH pipeline is the most active, some new products used later in the process to support embryo transfer and implantation success are moving through development.

Teva Pharmaceutical Industries Ltd., which has tagged fertility as “a meaningful new area of specialization for the company,” received a “complete response” letter in 2011 for a vaginal progesterone product for luteal phase support of implantation during IVF. Its once-weekly micronized progesterone vaginal ring Milprosa offers a convenience advantage over the daily use of available 8% progesterone vaginal gel.

Teva’s clinical program in response to the FDA action letter appears to be reaching maturity, with Phase III data rolling out throughout the year. A Phase III study published in March in the journal Fertility and Sterility enrolled 1,297 women ages 18 to 42 years old, potentially responding to FDA’s request for a study in women over age 34 in its “complete response” letter.

The next novel molecules in infertility treatment could come from the class of oxytocin antagonists now in early to mid-stage development. Ferring and GlaxoSmithKline PLC are developing next-generation oxytocin antagonists to reduce embryo and blastocyst implantation failure due to uterine contractions.

The dampening of uterine contractility by oxytocin antagonists also has a tocolytic benefit for pregnant women in preterm labor. Ferring’s first-generation peptide oxytocin antagonist atosiban (Tractocile) is approved as a tocolytic in Europe, but not the U.S., and GSK has tested its non-peptide selective oxytocin receptor antagonist retosiban for preterm labor.

Atosiban is active at both oxytocin and vasopressin receptors, leading to adverse effects. Ferring says that its second-generation peptide oxytocin antagonist barusiban (FE 200440) has “higher selectivity and potency at the oxytocin receptor level,” as well as low affinity for the vasopressin V1a receptor. The greater selectivity “could lead to a faster onset of action and a longer duration of action following parenteral administration,” the company says.

Ferring’s Phase II BASIC study of barusiban to reduce implantation failure due to uterine contractions in ART procedures started in November 2012 in Europe, Australia and Canada. The trial is set to enroll 300 women and is estimated to reach completion in early 2014, according to clinicaltrials.gov.

GSK’s oxytocin antagonist GSK-557296 finished a Phase I adaptive-design dose-selection study in 36 women in March. The study was the first clinical trial in women; the compound reached Phase II in men with premature ejaculation.

Will Pharmacogenetics Reveal The Future Of Infertility Drug R&D?

The late-stage pipeline for infertile women undergoing ART is still dominated by new iterations of human hormones like FSH. The next breakthroughs in the field are likely to come on the device and diagnostic sides, including information technology tools to improve fertility monitoring (Also see "Using Quantified-Self Data To Enhance Fertility And Pregnancy" - Medtech Insight, 16 Apr, 2013.). Actavis touts Diafert, a non-invasive immunoassay kit for the assessment of egg quality during IVF, as a highlight of its acquisition of Uteron Pharma SA; the test is expected to gain approval in the EU this year and in the U.S. in 2014 (Also see "Watson Continues Expansion Of Women’s Health Biz With Uteron Buy" - Pink Sheet, 23 Jan, 2013.).

But basic biology studies could identify new opportunities to improve infertility treatment. European Society of Human Embryology and Reproduction meeting in July featured multiple presentations on the role of anti-Mullerian hormone levels in fertility, for example. Other potential pharmacogenetic approaches could emerge from research looking at the role of kisspeptin signaling, DNA methylation of the GRB10 gene, VEGF gene polymorphism, or herpes virus-associated ubiquitin-specific protease gene polymorphism genotypes, to list only a few of the presentations at the ESHER meeting.

This early-stage research covers a broad range, but currently offers only embryonic hints of what new treatments might someday emerge. In the near term, improvements in convenience and cost of the currently used hormonal preparations look to be the next step in fertility drugs.

[Editor’s note: This is part of Pharmaceutical Approvals Monthly’s series reviewing R&D activity in women’s health. Previous stories have included female sexual dysfunction, osteoporosis, menopausal symptoms, endometriosis, uterine fibroids, and contraception.]