Introduction

Since the very early years (1969–1978) of human IVF, Patrick Steptoe and Robert Edwards were utilizing a range of pharmaceutical agents for ovarian stimulation, ovulation induction, and luteal phase support (e.g., urinary gonadotrophins, chorionic gonadotrophin, clomiphene citrate, progesterone)[1,2]. However, in spite of their efforts with these agents, their breakthrough pregnancy following ovarian stimulation was sadly an ectopic[3]. After this setback, the pioneering team decided to revert to natural cycle IVF, and the first IVF birth, Louise Brown, marked the end of the beginning of human IVF[4]. However, soon after there was broad recognition from the first IVF groups around the globe that “ovarian stimulation promised more oocytes and therefore more pregnancies, and (would) allow a better scheduling of oocyte collection[5].”

While there has been, over the years, a forward and backwards debate in the literature and international conferences on the issue of mild stimulation/natural cycle regimens versus conventional controlled ovarian stimulation protocols[6,7], data from both country registries and multicenter initiatives now demonstrate that the number of oocytes recovered is directly correlated with the cumulative live birth rate when vitrified embryos are also considered[8,9]. Today, we are fortunate to have a large armament of pharmaceutical agents to utilize in ART protocols. However, drug choice, dosing regimens, and modes of administration are highly variable and dependent on patient, clinical, and geographical variables. Injectable gonadotrophins have evolved from crude, and then more refined, urinary preparations[10], to highly purified recombinant human (r-h) gonadotrophins; the latter being available in pen devices, which allow a wide range of doses to be utilized (more background on the evolution can be found in Ludwig et al. and Lunenfeld[11,12]).

Drug development is a highly complex and regulated process, which is both costly and has a high failure rate. It has been stated that to get one drug approval an average of 8.5 compounds need to be put through clinical development[13]. Additionally, in reproductive medicine the ART treatment process is in itself highly complex and subject to multiple variables emanating from the patient, clinical, and laboratory procedures. Often the primary drug-related (pharmacodynamic) endpoint can be remote from the desired treatment endpoint. For example, the most important pharmaceutical drug utilized in an ART treatment is follicle-stimulating hormone (FSH), which is responsible for the growth and development of the ovarian follicle from which a mature oocyte will be aspirated. However, the desired treatment outcome is a healthy baby, which is dependent primarily on upstream (patient) as well as downstream laboratory and clinical procedures[14]. Thus, there is an important disconnect between FSH drug action and ART treatment outcome, which raises additional challenges for the drug developers, especially when dealing with different regulatory authorities (e.g., the United States FDA routinely demand clinical pregnancy as a primary endpoint for gonadotrophins).

The ART therapeutic area, while growing at around 10% in treatment cycles per year[15], is still, in medical terms, relatively small. It is estimated that the total number of ART treatment cycles worldwide is around two million[16]. This compares, for example, with the therapeutic area of diabetes where in the United States alone, 9.4% of the population have diabetes and 1.5 million are diagnosed each year, with need of insulin therapy.

Additionally, as far as ovarian stimulation is concerned, the period of treatment is relatively short (i.e., for FSH with/without LH median 11 days)[17].

The following sections will give a brief overview of the drug development process: challenges and potential opportunities specific to ART, modes of delivery for gonadotrophins, gonadotropin-releasing hormone (GnRH) analogs, and luteal phase supporting drugs, with some insights on in-development or recently launched therapeutics.

Drug Development Can Be a Long and Risky Business

It has been estimated that developing a new prescription medicine that enters the clinic costs the pharmaceutical industry around $2.6 billion USD[13,18]. DiMasi and colleagues[18] used information provided by 10 pharmaceutical companies on 106 randomly selected drugs that were first tested in human subjects anywhere in the world from 1995 to 2007. This represents a 145% increase from the previous study carried out 10 years previously. Additionally, although the average time taken to bring a drug through clinical trials has actually decreased, the rate of success has gone down by almost one-half, to just 12%. This study has naturally had its critics and some commentators refer to a previous study carried out by the Office of Health Economics[19], which provided an estimate of $1.5 billion USD (at 2011 prices).

However, all authors agree that costs have dramatically increased requiring clinical trials of increasing complexity, which are a crucial part of the drug development process. Such trials (ranging from phase I, II, III to postapproval IV) have to be conducted to demonstrate drug safety and efficacy so that approval for clinical use can be obtained from regulatory bodies. The cost of carrying out clinical trials varies according to therapeutic area, size of the pharmaceutical company, and whether the test molecule is a chemical compound or a biologic (e.g., FSH) and also between different development phases. In the United States, the highest cost of clinical trials is in the respiratory system therapeutic area ($115 million USD), while for the endocrine area, the clinical trial costs are estimated to be around $59.1 million USD including the regulatory review phase. Table 3.1 gives some examples of the research and development time for some of the FSH and GnRH antagonist drugs used in the reproductive medicine field. The fastest was for a recombinant form of natural human follicle stimulating hormone (hFSH) (from patent to registration: 9 years) compared with 30 years for orally active GnRH antagonist. The reasons for these widely differing time frames are many and some will be discussed in this chapter.

Another important element to consider that is particularly relevant to the ART therapeutic area is the rise in importance of “biotech” companies and how they are today feeding “big pharma” with innovative candidate products to replenish their drug pipelines. In the last months of 2018/2019, three big pharmaceutical companies splashed out almost $100 billion USD in deals, which brought biotechs little-known outside Silicon Valley or Cambridge, Massachusetts, under their wings (Financial Times, January 11, 2019). The characteristics of these two players are summarized in Table 3.2.

Biologic drugs, examples of which in ART are the recombinant (a core strength of biotech companies) and urinary gonadotrophins, are produced using a biological source. Increasingly, these complex glycoproteins are derived using genetically engineered cells[10]. The glycoproteins naturally exist in a range of forms (isoforms) due to subtle differences in the carbohydrate moieties, which are attached to the protein backbone. In spite of the inherent variability in the isoform profile between different marketed recombinant and urinary gonadotrophin FSH preparations, they all essentially have the same therapeutic features, reflected in similar daily dosing regimens and length of treatment.

An important milestone in gonadotrophin development was the first birth following stimulation of follicular growth in a hypopituitary hypogonadal woman (WHO group I) with recombinant human FSH (r-hFSH) as well as recombinant human luteinizing hormone (r-hLH) and then recombinant human chorionic gonadotropin (r-hCG) to induce final follicular maturation and ovulation[20], signaling that the era of all recombinant gonadotrophins had truly commenced.

Over a 25-year period, there have been numerous attempts to demonstrate the benefit of “LH activity” in ART patients. However, these have not translated into regulatory approval for the clinical use of a r-hLH/r-hFSH combination product. While there seems to be some physiological rationale as to the potential benefit of LH in low responders/women of advanced maternal age, the largest randomized controlled trials (RCTs) to date demonstrated no benefit of LH supplementation in terms of oocytes or pregnancy outcomes[21].

Recently, r-hFSH preparations have become available in the European Union (EU) – the so-called “biosimilars” – which bear essentially the same active pharmaceutical ingredient (API) to be used at the same dose, via the same route for the same indications as the reference medicinal product, in this case follitropin alfa (Gonal-f, Merck KGaA, Darmstadt), which was first registered in 1996[22].

In 2005, the European Medicines Agency put forward a stringent regulatory framework for biosimilars development, which became the foundation for other regulatory bodies around the world including the United States FDA who initiated such a pathway in 2015[23]. The biosimilars have biologic activity comparable to their corresponding reference drugs and are often more cost-effective. To stimulate innovation and new market entrants, the regulatory pathway allows for the biosimilar to extrapolate and “piggyback” on the branded biological to get approval for all the original drug’s indications. Even so, it can still take somewhere between 5 and 9 years to develop a biosimilar at a cost of $100–250 million USD[24]. This compares with a development time of about 2 years and a cost of $1–2 million USD for a small-molecule generic. Bringing a biosimilar to the market is not for the fainthearted!

The Use and Delivery of FSH Biologics in Reproductive Medicine

Until the general availability of recombinant gonadotrophins, all urinary preparations were available in a lyophilized form, either in a glass ampoule (which needed to be snapped open by the patient or nurse) or in a vial with a rubber stopper to allow a needle to be pushed through for the next step. Additionally, the very first products (first-generation urinaries) had low specific activity and required to be injected intramuscularly until the availability of highly purified urinary FSH[25]. These formulations also required reconstitution steps, and the use of different syringes/needles than those for injection, which undoubtedly played a role in increasing the potential for injection errors, which could affect pregnancy outcome[26,27,28].

A major step forward, though, as far as patient convenience, ease of use, and facilitating the teaching process of drug administration for the health-care professional, was the availability of recombinant gonadotrophins as a liquid formulation and finally in prefilled pen devices[29,30,31].

In a variety of country and multinational studies[32,33], it was documented that over half the patients interviewed reported ovarian stimulation had an impact on their day-to-day lifestyle, in particular regarding whether the correct daily dose had been administered correctly. Thus, the availability of a delivery device which provides patients with attributes that assist in minimizing the impact on their daily life and simplifies the ease of teaching for health-care professionals (in particular nurses) is the desired goal. A recent multicenter study, which was designed to assess such product specific features of a range of self-administered FSH injection devices used in ART, clearly demonstrated important differences between injection devices, which were shared across users in a number of European countries[31]. Overall, for both patients and nurses, the ideal FSH injection device would be a highly accurate, multiuse pen injector, with a dial-back function which is easy to use and/or teach. These attributes are present with one of the recently available biosimilar FSH devices (Ovaleap, Theramex, UK).

It has been well documented that the most frequent cause for patients to drop out from IVF treatment is the physical or psychological burden of the treatment process[34]. Daily injections can be far more distressing for a patient than health-care professionals realize[35]. Another approach was taken by one drug manufacturer (Organon, now Merck, Sharp, and Dohme [MSD]) to address these patients’ concerns; namely to reduce the burden (number) of injections required by utilizing a recombinant fusion molecule (corifollitropin alfa). The initial design for this molecule was conceptualized in the early 1990s by Irving Biome’s research group in St. Louis, Missouri, United States[36]. Here, human FSH is coupled to the CTP of hCG, which naturally extends FSH’s half-life in human serum (to around 70 hours compared with that of follitropin alfa or beta of around 36–40 hours). Because of the extended absorption and longer half-life of corifollitropin alfa, the frequency of FSH administration may be reduced, resulting in more injection-free days for patients undergoing controlled ovarian stimulation (COS).

The first live birth after ovarian stimulation using r-hFSH-CTP was reported by Beckers and colleagues[37] and the molecule was registered in the EU for use in ART in 2010. Two dose forms are available: 100 µg for women with body weight ≤60 kg and 150 µg FSH-CTP for women with body weight>60 kg.

Following its introduction in the EU (2010), corifollitropin alfa did not really live up to initial expectations. In September 2013, Merck & Co (MSD outside of United States) announced that a new drug application was accepted for review by the United States FDA. Just 10 months later in July 2014, Merck & Co announced the receipt of a complete response letter from the United States FDA. In the Merck & Co annual report[38], it was stated that the company had “made a decision to discontinue development of corifollitropin alfa injection in the United States for business reasons.”

The reasons for the drug’s lackluster performance are probably numerous; the first being that longer-acting drugs are more suited for chronic disease conditions. The impact of reducing the number of injections during a COS cycle was, I believe, limited due to the fact that other injections (daily GnRH antagonist injections) still had to be administered, so there were in effect only 3–4 injection-free days compared to standard daily treatment. Additionally, as an injection of corifollitropin alfa was developed to be active for just seven days, if the appropriate follicular response had not been achieved by that time, daily FSH injections would then need to be administered, thus a patient may have to learn two injection techniques for FSH in one treatment cycle. The use of this novel drug also led to different follicular growth dynamics, which may not have fitted some clinical units’ procedures.

Finally, it must also be remembered that, due to the long elimination half-life after subcutaneous injection of 36–40 hours[39] of standard r-hFSH, it is feasible to reduce injection frequency to every three days if desired[40]. Alternate-day FSH regimens have been previously described both for ovulation induction and ART[41], but never really caught on, probably due to concerns around injection compliance.

MSD is now focusing development efforts in applying corifollitropin alfa in a chronic condition: the treatment of male hypogonadism[42]. In this condition, it is first necessary to restore testosterone levels back into the normal range with hCG alone for 3–6 months[43], before moving to combination therapy with 2–3 times weekly FSH injections for up to 18 months if spermatogenesis is the desired outcome.

A major learning from this is that, while the drug treatment burden can be an important barrier, the available pen device systems for daily administration probably provide sufficient confidence to the vast majority of patients when faced with a relatively short FSH treatment duration of around 11 days.

Another recombinant human FSH (follitropin delta; Rekovelle Ferring Pharmaceuticals) with different pharmacokinetic properties compared to existing FSH products, was granted marketing authorization by the European Commission in December 2016. In view of its longer elimination half-life (30 hours versus 24 hours for follitropin alfa[44]), due to follitropin delta’s higher overall sialic acid content, the product is dosed based on AMH and weight (kg) of the IVF patient[45]. This product is again available in a multidose pen device for daily injections of the same individualized dose based on the measurement of AMH from only one validated assay system and weight. While follitropin delta is an effective follicular stimulant, it was concluded by the French Haute Autorité de Santé to provide no clinical added value compared with the long-established comparator product follitropin alfa[46].

There are also other companies (Glycotope GmbH, Berlin, Germany) active at the time of writing working on the development of yet another injectable FSH (FSH-GEX; follitropin epsilon), which also has different pharmacodynamic properties from follitropin alfa. Follitropin epsilon has undergone phase I and II trials[47]. Glycotope is currently seeking development and commercialization partners for a number of its pipeline products; one of which is FSH-GEX and therefore we will have to await further information on the clinical utility of this molecule.

The Introduction of Orally Active GnRH Analogs and Gonadotrophin Receptor Agonists

The “holy grail” of fertility drug development research has been to have a generation of orally bioavailable gonadotropin mimetics: how simple it would then be for our patients!

Our knowledge about the receptor-activating sites of gonadotrophin and GnRH analogs has greatly increased, and the search for small, non‐peptide molecules that induce signal transduction without binding to the extracellular domains of membrane proteins has been ongoing for over 20 years. A standard approach has been to use high-throughput screening using cell-based assays of large chemical libraries to find small-molecule (<500 Da) agonists of the receptor. In a classic 2000 review article, Millar and colleagues[48] provided a comprehensive snapshot of the development and commercialization of GnRH peptide analogs with agonistic as well as antagonistic properties. A number of these were just becoming commercially available, including the daily subcutaneous GnRH antagonists, still with us today in ART treatment regimens (cetrorelix, ganirelix). Millar and colleagues also presented a first glimpse of what was in the patent pipeline from a number of commercial laboratories and pharmaceutical companies – in particular Abbott and Takeda – the emergence of nonpeptide GnRH antagonists. Eighteen years later, the United States FDA approved for the first time an orally active nonpeptide GnRH antagonist, elagolix. The drug (Orilissa, brought to the market by AbbVie and in cooperation with Neurocrine Biosciences) is approved for the management of moderate severe pain associated with endometriosis. It is estimated that up to 10% of all women may have endometriosis, with an incidence of around 24–50% in women who experience infertility and in more than 20% who have chronic pelvic pain[49]. Endometriosis may be a lifelong problem, and therefore has the potential to seriously disrupt quality of life and cause significant emotional distress. According to one market analyst, elagolix is projected to become a “blockbuster” with projected sales of $1.35 billion USD by 2022[50].

However, not all in the medical community share the enthusiasm for this new introduction, especially at the projected treatment cost (in the United States the manufacturer AbbVie has priced elagolix at around $10 000 USD a year). In a recent mini review entitled “Elagolix for endometriosis: all that glitters is not gold’’, Vercellini and colleagues[51] concluded that it is currently not clear whether its use will translate into major benefits for women with endometriosis. They argue that elagolix should not be considered differently to existing GnRH agonists currently in the therapeutic armamentarium.

Irrespective of these arguments, the almost three-decade-long research and development leading to a market introduction of the first orally active GnRH antagonist is certainly an important milestone[52]. Only time will tell if this innovation will become widely used in routine clinical practice.

The development and clinical introduction of an orally active gonadotrophin, however, still eludes us. The first scientific report of a bioactive low molecular weight (LMW) gonadotrophin was in 2002[53]. This molecule was described to act as an FSH receptor antagonist, and could be a potential compound for female contraception. Soon after, other researchers reported small-molecule modulators of the FSH receptor[54] and other compounds (thiazolidinones) with a high affinity for the FSH receptor[55].

The chapter author also reported in 2004/5 on our company’s research efforts (Serono International) of the quest for an orally bioavailable gonadotrophin mimetic[56,57]. There was a two-pronged approach to the research: one in the discovery of a potential small molecule (a pyrazolyl tyrosineamide), which could activate the (LH) gonadotrophin receptor and the second avenue through research into biochemical pathways controlling ovarian function, and enzymes, which, when inhibited by specific chemical inhibitors, were able to mimic or amplify gonadotrophin actions. The first avenue of research initially yielded some promising results in a male rat model, but early tests failed to demonstrate ovulatory activity in female animals. The second line of research continued to make progress and a review was published by Nataraja and colleagues[58]. There were, however, a number of important lessons learned following years of intensive research efforts; e.g., first, the immortalized cell-based assay used to screen compounds do not necessarily reflect the compound’s ability to stimulate follicle development, and second, finding a molecule with a high potency in vitro does not always correlate with best efficacy in vivo.

There was also another promising lead in the search for an LMW compound with nanomolar potency on the LH receptor. Org 43553 is a hydrogen chloride salt of tert-butyl 5-amino- 2-methylthio-4-(3-(2-(morpholin-4-yl)-acetamido)-phenyl)-thieno[2,3-d]-pyrimidine-6-carboxamide, which was synthesized by the Schering Plough Research Institute at that time in Oss, Netherlands (see Figure 3.1).

Figure 3.1 X-ray structure of Org 43553: an LMW compound with nanomolar potency on the LH receptor and hCG

Source: van de Lagemaat et al [59]

Van de Lagemaat and colleagues[59] reported on Org 43553, which demonstrated oral bioavailability and ovulation induction in various animal models as well as testosterone stimulation in male rats. This paper describes succinctly the necessary pathway and testing procedures for a novel small molecule, which is first required prior to use in the human. The data presented provided a solid proof of concept of in vivo physiological LH receptor activation. Additionally, the paper refers to first results in a human clinical study[60], which demonstrated ovulation (by transvaginal ultrasound (TVUS) and elevated progesterone levels) following administration of a single dose of 300 mg.

However, 14 years later, there is still no sign of this novel small molecule coming to the clinic.