Emerging drugs for acromegaly.

Review

Emerging drugs for acromegaly Sylve`re St€ormann† & Jochen Schopohl

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Waterloo on 11/25/14 For personal use only.

Klinikum der Universita¨t Mu¨nchen, Medizinische Klinik und Poliklinik IV, Mu¨nchen, Germany 1.

Background

2.

Medical need

3.

Existing treatment

4.

Market review

5.

Current research goals

6.

Scientific rationale

7.

Competitive environment

8.

Potential development issues

9.

Conclusion

10.

Expert opinion

Introduction: Acromegaly is a rare disease that severely impacts patients’ health all the while, being a slowly progressing illness. In the past decades, advancements in treatment modalities, especially development of new drugs, as well as focused guidelines has improved management of acromegaly. Still, many patients are considered not sufficiently treated and there remains an ongoing need for further development. Areas covered: This article reviews new medical treatments currently under clinical investigation (such as pasireotide, oral octreotide and somatoprim) and under experimental development (such as octreotide implants, CAM2029 and ATL-1103). Expert opinion: As it seems unlikely that one single agent may achieve cure in 100% of cases, there is an urgent need for new agents that help patients where current medication fails. Imperatively, this means we have to improve our understanding of the underlying pathogenetic and molecular mechanisms. Keywords: acromegaly, antisense drugs, lanreotide, octreotide, pasireotide, pegvisomant, somatoprim, somatostatin analogs, temozolomide Expert Opin. Emerging Drugs (2014) 19(1):79-97

1.

Background

Acromegaly is a rare disease resulting from an excess of growth hormone (GH). It has an estimated prevalence of approximately 40 -- 70 patients per million and an incidence of 3 -- 4 new cases per million per year [1-6]. Newer studies postulate a much higher prevalence with 125 [7] or as much as 1034 patients per million inhabitants [8]. Due to slow disease progression and often non-specific symptoms, diagnosis is often delayed by several years after first onset of symptoms [9,10]. In spite of progress made in better understanding the disease and minimizing the delay, clinical, biochemical and tumor size characteristics at diagnosis of acromegaly patients have not significantly changed over the past decades [11]. Clinical signs of acromegaly are diverse and affecting multiple organ systems (Table 1). Presenting symptoms are often non-specific and easily dismissed as sporadic or marginal occurrences by primary care physicians and other treating physicians alike. Typical first symptoms may be [severe] cephalgia, fatigue, excessive sweating and hypertension [12]. However, the excess GH also leads to coarsening of facial features as well as enlarged hands and feet over time that leads to a typical appearance. Still, acromegaly may remain hard to detect visually and the development of new diagnostic tools may facilitate recognition of acromegalic patients [13]. Other typical complaints of acromegalic patients are joint pain, paresthesia due to carpal tunnel syndrome, thickened skin, snoring (as a sign of obstructive sleep apnea) and macroglossia [11]. As GH antagonizes insulin, acromegaly is associated with diabetes [14]. In almost all cases, the GH excess is due to hypersecretion from a benign adenoma of the pituitary gland [15]. In rare cases (< 1% [16]), the GH excess is caused by an ectopic hypersecretion of GH itself [17] or more commonly GH-releasing hormone (GHRH), mostly from pancreatic or bronchial tumors [18]. More than 70% of somatotroph tumors are macroadenomas at diagnosis [19], which can account for signs and 10.1517/14728214.2014.875529 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

79

€ rmann & J. Schopohl S. Sto

Table 1. Clinical features of acromegaly. Tumor compression

Bone


Metabolic

Soft tissue

Reproductive system

Organ manifestations

Psychopathology

Visual field defects Headaches Pituitary insufficiencies Enlargement of hand and feet Arthropathy Prognathism Supraorbital ridge Vertebral fractures (independently of bone mineral density) Impaired fasting glycemia Diabetes Hypertension Swelling of soft tissue and thickening of the skin Carpal tunnel syndrome Hypogonadism (e.g., as consequence of tumor compression or as effect of prolactin co-secretion) Heart: cardiomegaly, cardiomyopathy, left ventricular hypertrophy Lungs and respiratory tract: sleep apnea Skin: hyperhidrosis (especially of the hands) Thyroid: goiter Prostate: prostatic hyperplasia Tongue: macroglossia Liver: hepatomegaly Spleen: splenomegaly Kidneys: renomegaly Colon: polyps Depression Reduced vitality Sense of inferiority

symptoms of compression of adjacent structures, such as pituitary insufficiency and visual field defects. Diagnosis of acromegaly comprises baseline biochemical parameters and dynamic testing [20,21]. Criteria for active disease are a random GH level > 1 µg/l, a failure to suppress GH secretion below 0.4 µg/l after an oral glucose load and elevated IGF-I [21], a growth factor that is synthesized in the liver and extrahepatic tissues and mediates most of the growth-promoting actions of GH [22]. Upon diagnosis of GH excess pituitary imaging is imperative to establish the source and therefore diagnosis of pituitary adenoma. Pituitary function should be assessed as well as visual field defects. Further diagnostic tests may be necessary to evaluate possible complications [14]. Diagnostic evaluation and treatment planning should always be performed in a specialized center. 2.

Medical need

Acromegaly is a slowly progressing and insidious disease with a slow onset of symptoms. The excess GH leads to changes of 80

internal organs, joints and bones causing multiple defects and systemic complications that may be present at the diagnosis of the disease [14,23]. Many studies have shown an increased mortality due to untreated acromegaly [2,4,24-31], with a mean weighted standardized mortality rate of 1.72 (1.62 -- 1.83, 95% CI) [27] and an average 10-year reduction in life expectancy [22,32]. By restoring normal GH levels and normalizing IGF-I the elevated mortality of the condition returns to normal levels [29]. Furthermore, acromegaly leads to severe impairment of quality of life [33], which can be explained by increased anxiety levels, the chronic nature of the disease, the burden of comorbidities and, potentially, the burden of therapy [34]. Even though surgical intervention may cure acromegaly, in many cases, remnant adenoma tissue causes continuing disease activity. There are potent medical treatment options available that have been shown to be effective in numerous studies (for a concise review see Melmed 2009 [22], Heaney & Edling 2013 [35] or Jallad & Bronstein 2013 [36]), there is a need for better biochemical control of disease activity. A recent German study analyzed the long-term outcome in 1344 patients with acromegaly and found biochemical control in only 72% of patients [37]. Similar rates have previously been found in Spain (76%) and Finland (also 76%) [38,39]. Applying strict criteria of cure [21] about 20 -- 30% of patients are insufficiently treated and are in urgent need for alternative treatment options. However, biochemical control does not by itself lead to improvement of all complications of the disease [40,41]. Complications such as arthropathy may persist or even progress despite adequate control of the GH excess [42]. Therefore, treatment of acromegaly is focused on not only biochemical control but also other end points such as tumor shrinkage, improvement of symptoms, as well as improvement and control of chronic complications, which have to be taken into consideration. 3.

Existing treatment

Acromegaly can be cured by surgical removal of the tumor causing the GH excess. In cases where surgery fails or is not possible medical options are available. In certain cases radiotherapy may also be necessary. Surgical treatment Surgery is the first treatment used for most patients, regardless of the cause [15]. In somatotroph pituitary adenoma, transsphenoidal resection is the primary treatment recommended to achieve cure. Results of the surgical approach vary greatly and remission rates overall have been reported between 46 and 85% [43]. A detailed look at outcomes considering tumor size yields postoperative biochemical remission in 70 -- 90% of microadenomas and 40 -- 60% of macroadenomas [44]. This is comparable to previous rates of success [45] using older consensus guidelines on criteria of cure [20]. Several factors that are predictors of surgical success have 3.1

Expert Opin. Emerging Drugs (2014) 19(1)

Emerging drugs for acromegaly

been identified [15]: tumor size and growth pattern [46,47], preoperative GH levels [48] and maybe most importantly (as it can be influenced) the surgeon’s experience [49,50]. Young age is considered a poor prognostic factor [46,51]. It is safe to assume as a conservative estimate that approximately one-half of patients with newly diagnosed acromegaly can expect to be cured by surgery [22]; this may increase as surgical technique further improves [52]. Radiotherapy A few decades ago radiotherapy was the preferred treatment option in acromegaly [24]. Irradiation of the pituitary is still a viable option in patients where surgical cure is not possible and medical treatment insufficient [34,53]. The success rate of treatment is difficult to quantify because of varying techniques, doses and biochemical definitions of cure [54], but current evidence suggests that conventional radiotherapy is able to achieve biochemical remission of disease in approximately 50 -- 60% of patients after 10 years [55]. The effects of radiotherapy are not immediate and it usually takes several years until biochemical remission is achieved and maximum response is to be expected after 10 -- 15 years [53,56,57]. Therefore, interim medical treatment is necessary for disease control. Its main disadvantage is the high risk of hypopituitarism, which may affect multiple axes [53,54,56]. This risk has been assessed as high as 80% after 10 -- 15 years [54]. Stereotactic radiosurgery may be more advantageous and it has been hinted at less frequent adverse events and faster response [54,55,58,59], but long-term data are still lacking. Radiotherapy offers the advantage of being a permanent therapy and it has to be performed only once [60].


3.2

Medical treatment Currently there are three substance classes available for treatment of acromegaly: somatostatin analogs (SSA), GH receptor antagonists, and dopamine agonists. Medical therapy plays an important role as surgical cure is only achieved in a fraction of patients [61]. Advances in drug delivery systems have had a strong impact on therapeutic strategies in many domains, including medical treatment of acromegaly [62]. As overall remission rates from surgery range between 46 and 85% [43] and some patients are not eligible for or refuse surgery, in practice approximately half of all acromegaly patients require long-term medical treatment. 3.3

Somatostatin analogs Somatostatin demonstrates important auto- and paracrine effects on different cell systems and mediates its effects through the somatostatin receptor family (SSTR) [63]. There are five somatostatin receptor subtypes (SSTR1 to SSTR5) that are expressed in numerous tissues throughout the central and peripheral nervous systems, in the endocrine pancreas and in the gut, and various other tissues [64]. One of the effects of the endogenous isoforms of somatostatin is the suppression of GH secretion in the pituitary. More than 90% of 3.3.1

GH-secreting tumors express SSTR2 and SSTR5 [19,65]. Synthetic somatostatin receptor ligands (SRL) bind to the somatostatin receptor subtypes with varying affinity and can effectively suppress GH excess in acromegalic patients [25,53]. Currently there are two SSA marketed: octreotide and lanreotide. Both exist as long-acting formulations that are usually injected every 4 weeks [66,67]. Therapy with SSA reportedly achieves biochemical control in approximately 60% of cases [68] and also lead to shrinkage of tumor volume [21,68], which has been reported in 60 -- 75% of cases [46,69]. However, in more recent studies with unselected patient cohorts lower rates of biochemical control have been reported [70]. The reasons for non-response are not yet fully understood, but predictors of response have been identified: patients’ gender, age, initial GH and IGF-I levels, tumor mass, as well as adequate expression of somatostatin receptor types 2 and 5 [71]. As true resistance seems to be rare, it is important to evaluate response of patients to long-term treatment with adequate dosing. Numerous studies comparing the currently available SSA octreotide and lanreotide have been published and subsequently been evaluated in systematic reviews [72,73]. In conclusion, both agents are comparable in terms of their efficacy. The SSA are usually well tolerated and safe to use. Somatostatin physiologically assumes numerous other functions such as inhibition of pancreatic secretions, gastrointestinal peptide secretions, as well as modulation of gastrointestinal functions (bowel motility, gallbladder contractility) [74]. These explain the various side effects of SSA such as nausea, diarrhea, abdominal pain, biliary sludge, cholelithiasis and impaired insulin secretion [75,76]. However, due to their different affinities toward the five somatostatin receptor subtypes, the adverse events reported are varying in degree. While octreotide and lanreotide both are similar in terms of systemic side effects [77] such as lower insulin secretion and gastrointestinal malaises, other agents currently in clinical trials show these adverse events more or less pronounced. As GH leads to insulin resistance, the biochemical control achieved by SSA leads to a reduced insulin resistance. However, they also exert a direct effect on insulin secretion by suppressing islet b-cell secretion. On the other hand, SSA also show beneficial effects on complications and clinical features of acromegaly, such as improvements of the cardiovascular system, sleep apnea and lipid profile, among others [23,78]. Octreotide is a cyclic octapeptide analog of somatostatin and was the first analog to be used in clinical protocols [79]. It has a high binding affinity toward SSTR2 and SSTR5 [19]. Binding affinity is higher toward SSTR2. It is currently marketed as a depot formulation (Sandostatin LAR) containing octreotide acetate encapsulated within microspheres that when added to diluent forms a suspension administered as an intramuscular injection every 4 weeks [78]. Lanreotide is a synthetic octapeptide with a high affinity to SSTR2 and SSTR5 [80]. Similarly to octreotide the binding affinity toward SSTR2 is higher than toward SSTR5. It is


81



currently marketed as a gel in an aqueous solution as a long-acting depot formulation in a prefilled syringe that is injected subcutaneously (Somatuline Autogel). As the octreotide depot formulation, it is typically applied once every 4 weeks. However, it is approved for an extended dosing interval of 6 or even 8 weeks as studies have shown it to be equally efficacious [81,82]. Another advantage of the lanreotide depot formulation is its approval for self- or partner injection. Multicenter studies showed the patients’ acceptance of self- or partner injection and that it allows for disease control without the need for health professionals to inject the drug [67,83,84]. In some patients who were very well controlled with SSA the drug could be withdrawn with sustained remission in long-term follow-up [85,86]. Other patients who could not be biochemically controlled with conventional doses have shown positive responses to higher doses of SSA in studies [87-91]. Pegvisomant Pegvisomant is a competitive GH receptor antagonist that binds to GH receptor but prevents conformational changes of the receptor that are needed for signal transduction. It is a recombinant GH that is mutated at position 120 where the amino acid arginine replaces glycine, which exerts an antagonistic effect [92]. Eight additional alterations of the modified GH increase the binding affinity toward the GH receptor [93]. Furthermore, the covalent attachment of polyethylene glycol (PEG) leads to improved pharmacokinetic and pharmacodynamics profile prolonging its half-life to about 100 h [94,95]. Upon binding to the GH receptor pegvisomant does not transduce intracellular signaling and is then internalized [96-101]. It has proven very effective in medical treatment of acromegaly, achieving normalization of IGF-I in 89 -- 97% of cases in initial reports [102,103]. Recent studies report lower success rates ranging around 70 -- 90% [104,105]. Due to the lowered IGF-I levels and thus a loss of negative feedback on GH secretion, it leads to elevated GH levels [103]. In clinical practice, as shown in a large study with 1288 patients, normalization is sustained in 63% of patients [106]. This is in part due to the severity of the disease in patients treated with pegvisomant and probably also due to insufficient dosing. In general, it is applied daily as a subcutaneous injection, but other treatment patterns are in clinical use as well [107,108]. Pegvisomant is well tolerated and safe to use [106]. A common side effect is a temporary elevation of liver enzymes that is observed in about 25% of patients [109,110]. Due to its lack of effect on the pituitary concerns have been raised that pegvisomant may lead to tumor growth [103]. Current evidence suggests that tumor growth rate appears to be comparable to other treatment modalities [61,111]. 3.3.2

Dopamine agonists Somatotroph adenomas of the pituitary express not only somatostatin receptors but also dopamine D2 receptors as well [112]. Oddly, while dopamine agonists increase GH release in healthy individuals, they inhibit GH secretion in 3.3.3

82

acromegalic patients [36]. Normalization of IGF-I is only achieved in 20 -- 33% of patients after surgery [113-115]. In cases where dopamine agonist therapy proves effective, tumor shrinkage may be observed as well, especially in patients with higher baseline prolactin levels [115]. It is a viable option for patients with mild IGF-I elevation that is safe and cost-effective. Hyperprolactinemia due to prolactin co-secretion of the adenoma has been proposed as a predictive factor of dopamine agonist responsiveness in acromegaly [113], but reports are conflicting and it is advisable to try dopamine agonists regardless of prolactin levels [114]. In patients with Parkinson’s disease treated with ergotderived dopamine agonists an increased frequency of cardiac valve regurgitation was shown [116]. It has to be noted that cabergoline in Parkinson’s disease is typically given in a 15- to 20-fold dosage. Recent studies could show that cabergoline does not increase the risk for cardiac valvulopathy [117,118]. Nevertheless, echocardiographic monitoring should be performed regularly. Combination treatments The combination of substances of the aforementioned drug classes can lead to better disease control than with either medication as a monotherapy [119]. For example, several studies investigated the rate of IGF-I normalization in patients not controlled by octreotide monotherapy when cabergoline was added to the therapeutic regimen. The cabergoline adjunction normalized IGF-I in about 50% of cases [115]. Recently, the combination of cabergoline and pegvisomant has been examined, but data are still scarce. From a current perspective it may be a viable option to reduce treatment cost in less severe cases of acromegaly. The combination of SSA and pegvisomant shows synergistic effects: SRL lower GH levels, which in turn reduce the need for competitive GH receptor antagonists [35]. Furthermore, this combination combines the beneficial effects of each substance (tumor shrinkage, high IGF-I normalization rates). A recent retrospective study showed that combination therapy of SSA and pegvisomant was more likely to be prescribed for patients with relatively severe/aggressive disease [105]. The combination of cabergoline or SSA with pegvisomant could lead to use lower doses of this latter drug [120,121]. 3.3.4

4.

Market review

Acromegaly is a costly disease that burdens health care payers [122-127]. In recent studies, the mean annual cost of therapy is estimated around e10,000 [124], with a peak annual cost of almost US$70,000 in selected patients [128]. While mean costs may be of use for stakeholders, it does not adequately reflect the individual patient’s course of disease. The cost of transsphenoidal surgery is often redeemed by its success, and thus absence of further treatment cost. In practice, however, acromegaly necessitates life-long medical treatment in most cases.



1600 1400

Sales im millions US$


1200

1000 800 600 400

200 0 2004

2005

2006

2007

2008

2009

2010

2011

2012

Sandostatin® (octreotide)

$827

$896

$915

$1.027

$1.123

$1.155

$1.291

$1.443

$1.512

Somatuline® (lanreotide)

$67

$73

$87

$118

$151

$174

$213

$256

$336

$135

$147

$157

$183

$197

Somavert® (pegvisomant)

Figure 1. Market share development. Development of market shares of Sandostatin (octreotide), Somatuline (lanreotide) and Somavert (pegvisomant) from 2004 to 2012 in million US dollars. Octreotide and lanreotide are also used in the treatment of neuroendocrine tumors. Market share data on Somatuline are published in Euros; for comparison market share values were converted to US dollars according to annual exchange rates as published by the European Central Bank. Pegvisomant sales data prior to 2008 are not available.

In terms of economic value from a manufacturer’s perspective, the currently available medical treatment options can be subdivided into profitable and less-profitable drugs. Dopamine agonists such as bromocriptine and cabergoline have limited efficacy in the treatment of acromegaly and there are tolerability concerns that may limit compliance, but they are comparatively inexpensive and do lead to good biochemical control in some cases. In terms of market share measured as net sales dopamine agonists play only a negligible role. The gross sales are performed by SSA octreotide and lanreotide, as well as the GH receptor antagonist pegvisomant. Treatment costs of these drugs range from US$25,000 to 70,000 per year [128]. It must be noted though that most data on costs are largely influenced by currency and country of analysis. For example, expenses in the United States surmount European expenditure [124,128]. Comparing prices of different doses lanreotide is less expensive than octreotide in European countries [125,127], whereas the situation is reversed in the US [128]. It is not possible to evaluate sales for SSA used solely for the treatment of acromegaly as they are also prescribed for other indications such as gastroenteropancreatic cancer and neuroendocrine tumors. In 2012, the total revenue of Sandostatin (Novartis, octreotide), Somatuline (Ipsen, lanreotide) and Somavert (Pfizer, pegvisomant) grossed over US$2 billion.

Figure 1 illustrates the progression of sales from 2004 to

2012. Most of the market share is held by Novartis with over US$1.5 billion in sales [129]. Over the past 8 years, Sandostatin achieved a mean growth of +7.9%. Ipsen’s share of the market accounts for approximately US$340 million in sales [130] (market data given in Euros were converted using the mean annual exchange rate as provided by the European Central Bank). Somatuline has continually grown its sales with a mean growth of +22.6% over the past 8 years and a notable increase of +31.3% from 2011 to 2012. With almost US$200 million Somavert holds a significant amount of market share [131]. It has also grown steadily by an average +10.0%. In total there has been continuous growth of +11.0% over the past 8 years. According to a market study by Global Business Intelligence Research, acromegaly and GH deficiency are the two major revenue generating therapy areas in endocrinology and are expected to grow further in subsequent years. Geographically Somatuline is predominantly sold in European countries where its market share reaches approximately 35%, leaving 60 and 5% to Sandostatin and Somavert, respectively. In the United States, Somatuline was commercially introduced in 2007 and claims 20% of the total market share. Sandostatin still holds 75% of the market in the US and Somavert also 5%.


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The high cost of specific acromegaly treatment is often juxtaposed to the cost of treating comorbidity [33,132]. In a thorough British analysis of cost-effectiveness of pegvisomant for the treatment of acromegaly the authors come to the conclusion that despite being a very effective treatment it does not ‘represent good value for money’ [120]. For higher acceptance, they conclude, medication cost should be reduced. In light of new advancements in drug development with new compounds soon to challenge the established products as well as patents to expire there is some cost reduction to be expected. As of yet, no price adjustments have been announced. 5.

Current research goals

Further development of existing treatments as well as new drugs is mainly focused on eliminating the shortcomings of the status quo: Current medical treatment options achieve biochemical control of acromegaly only in a fraction of patients [37,133,134] and there are tolerability issues that may be critical in individuals leading to reduced compliance, especially with daily injections of pegvisomant [135]. Also, except for dopamine agonists all medical treatment options require regular injections. It could be shown that as much as one out of six patients is lost to follow-up [136], and as much as one out of five patients is inadequately controlled regardless of receiving medication or not [37]. Therefore, research targets these goals: . Improve biochemical control of acromegaly . Reduce side effects . Improve ease of use/drug application

6.

Scientific rationale

Pituitary somatotroph adenomas are benign, monoclonal tumors that arise from highly differentiated anterior pituitary cells that excessively secrete GH [22]. The pathogenetic mechanisms of pituitary tumorigenesis are not fully understood but there is evidence of various genetic and epigenetic causes resulting in cell cycle dysregulation, signaling defects as well as disinhibition of antiproliferative factors [22,137]. Understanding of these deficiencies is fragmented and there is no clear differentiation between causative and permissive attributes of these factors. Retinoblastoma-associated protein (Rb) is a tumor suppressor protein that is inactivated by phosphorylation through cyclin-dependent kinases (CDK). This leads to the release of E2F transcription factors and subsequent progression of the cell cycle [138]. Disruptions in this pathway are present at different stages and represent anomalies previously shown in animal models and tumor biopsies leading to pituitary tumorigenesis [137]. Comparatively common mutations affect gsp oncogenes that inactivate GTPase of the a-subunit of the stimulatory 84

G-protein (GNAS), a membrane-located and GHRH receptor-associated protein of somatotroph cells [139-141]. This GTPase inactivation results in a continuously activated adenylyl cyclase system that physiologically mediates GH transcription upon GHRH receptor binding, thus imitating excessive signal transduction. As a consequence, GH secretion is upregulated and cell proliferation is initiated. This mutation has been identified in approximately 30 -- 40% of acromegalic patients, albeit geographic variation exists [137,141]. Pituitary adenomas are benign tumors with low mitotic activity and seldomly become malignant. The exact reasons for this are unknown to date, but it is believed that proliferative constraints such as chromosomal instability, DNA damage, cell cycle disruption as mediated by CDK and senescence act as suppressors of malignant transformation [137,142-147]. Physiologically GH secretion is controlled by three endogenous hypothalamic hormones: the stimulatory GHRH, the hunger-stimulating peptide and hormone ghrelin that also stimulates GH secretion and the inhibitory somatotropin release-inhibiting factor (SRIF) [74]. GH in turn binds to GH receptors that are ubiquitously expressed in various tissues [148]. IGF-I is a ubiquitously expressed autocrine, paracrine and endocrine effector, primarily secreted by the liver [149]. IGF-I is the principal mediator of GH effects and exerts negative feedback regulation of GH synthesis and secretion [22]. Over the past decades, understanding of the underlying signaling mechanisms in GH receptor binding has greatly evolved. The GH receptor is ubiquitously distributed, albeit predominantly expressed in the liver and cartilage. A common pathway of its signaling cascade is a conformational change of GH receptor dimers upon binding of GH, which leads to phosphorylation of JAK2 molecules as well as the cytoplasmatic domain of the GH receptor [22,150]. This leads to binding of signal transducers and activators of transcription (STAT) proteins [151]. This pathway leads to transcription of IGF-I [22]. Other pathways involve the IRS and Shc families of proteins that regulate cell proliferation genes and glucose metabolism [22]. Suppressors of cytokine signaling (SOCS) can suppress intracellular GH signaling [152]. A JAK2-independent pathway involving an Src family tyrosine kinase activates extracellular regulated kinases (ERK), which are associated with cell growth and tumorigenesis [153-156]. These pathways may potentially serve as targets for new agents. For a schematic overview of the hypothalamic--pituitary-somatotropic axis and the mechanism of GH binding to its receptor (Figure 2).

7.

Competitive environment

In the past couple of years various new compounds from pharmacological research have emerged and reached preclinical and clinical trials (Table 2). While the main focus lies on new SSA with improved efficacy while maintaining good tolerability, other therapeutic agents such as antisense



Ghrelin SRIF GHRH (“somatostatin”) (“somatoliberin”)

+

+

–

GH GH


IGF-I

Organs Muscle Bone Fat

GH

GHR

JAK2

Phosphorylation Intracellular signaling

STAT

IRS

SHC

Figure 2. Physiology of the hypothalamic--pituitary--somatotropic axis. Growth hormone (GH) is secreted by the pituitary gland and affects many tissues of the human body. IGF-I is primarily secreted by the liver upon GH receptor binding and is the principal mediator of growth hormone effects. Intracellular signaling of GH receptor binding that leads to IGF-I expression is mediated via the JAK2 pathway.

drugs are explored as well. Two new drugs are likely to be approved for the treatment of acromegaly in near future. 7.1

Somatostatin analogs Pasireotide (SOM230)

7.1.1

Pasireotide is a SSA targeting somatostatin receptor type 1, 2, 3 and 5. Thus, it has a broader binding profile than octreotide and lanreotide (mainly sst2 and 5). Furthermore, its binding affinity toward SSTR5 is much higher than in octreotide or lanreotide, whereas SSTR2 binding affinity is less pronounced. In rat primary cell cultures, it showed superior suppression of IGF-I in comparison to octreotide [157]. Preclinical data also showed a significant inhibition of ACTH and corticosterone secretion. It has subsequently been developed for multiple indications, among others acromegaly, neuroendocrine tumors and Cushing’s disease. In clinical trials, pasireotide was efficacious showing good biochemical response in 34% of patients with acromegaly after 3 months of

treatment [158]. Furthermore, in 39% of patients the tumor volume shrank by > 20%. Pasireotide was well tolerated by all study subjects with a similar safety profile as octreotide [158,159]. In contrast, pasireotide leads to a more pronounced dysregulation of glucose homeostasis [160] and to significant decreases in insulin with hyperglycemia [161]. Further studies to evaluate the efficacy of various antidiabetic drugs to counter hyperglycemia in pasireotide treatment showed superiority of GLP-1 analogs, DPP-4 inhibitors and insulin secretagogues [162,163]. While initially developed as subcutaneous injection to be applied b.i.d., Novartis soon introduced a depot formulation (long acting release, LAR) injected intramuscularly once every 4 weeks. The LAR formulation has passed clinical Phase I and II trials. A randomized, double-blind Phase III trial tested pasireotide LAR in 358 subjects in 27 countries for the treatment of acromegaly and was completed [164]. In the pasireotide LAR patient group, 31.3% of subjects achieved the


85


primary end point of GH suppression below 2.5 µg/l and normalization of IGF-I compared to 19.2% in the octreotide LAR group. Hyperglycemia occurred in 28.7 and 8.3% of patients in the pasireotide and octreotide group, respectively. Pasireotide LAR is currently under clinical investigation in a randomized, double-blind, parallel-group, head-to-head Phase III trial in 186 patients with inadequately controlled acromegaly. Octreotide capsules (Octreolin) Peroral delivery of hydrophilic drugs is considered one of the greatest challenges in biopharmaceutical research [165]. Recently, the Israel-based company Chiasma has developed a drug delivery mechanism that relies on its proprietary transient permeability enhancer (TPE) technology [166]. It leads to a transient and reversible loosening of epithelial tight junctions in the small intestine. In conjunction with resistant capsules that bypass the stomach’s acidic environment drugs such as peptides (as is somatostatin) can be delivered through the small intestine’s epithelial tight junctions. According to Chiasma molecules of up to 20 kDa molecular weight can be delivered into systemic circulation by an oral route. It is planned to develop multiple drugs using TPE technology (press release, Chiasma). Octreolin is the first of these drugs and contains as active ingredient octreotide acetate for the treatment of acromegaly [166]. In preclinical testing, octreotide capsules showed similar pharmacokinetic profiles as obtained from subcutaneous 0.1 mg octreotide injections, albeit with a slightly longer half-life and more pronounced coefficient of variation [166,167]. Toxicology studies in cynomolgus monkeys showed no macro- or microscopic findings of the gut. Currently, the capsules are in Phase III clinical trial with 150 patients in an open-label study. Completion of the trial and regulatory filings are expected in 2013 (press release, Chiasma). Roche has licensed the product for worldwide commercialization. A non-interventional questionnaire study among patients receiving parenteral treatment with SSA (OCT-ACM-001) has been commissioned by Chiasma as well. Its purpose is to strengthen the rationale for oral octreotide by data.


7.1.2

Somatoprim (DG3173) Somatoprim is a heptapeptide SSA that binds with high affinity to sstr2, sstr4 and sstr5 and shows a very low insulin suppression in contrast to other SSA [168-170]. Initially developed by Ipsen, it is now under active development by licensee Aspireo Pharmaceuticals, an Israeli company. In vitro as well as in vivo testing showed a dose-dependent GH lowering effect [168,170], which could later be confirmed in Phase I and II clinical trials. In an interim analysis, a beneficial side effect profile was shown in contrast to octreotide (press release, Aspireo Pharmaceuticals). A Phase IIa study was completed in 2013. 7.1.3

86

Octreotide C2L formulation Ambrilia Biopharma developed an octreotide acetate (C2L) prolonged-release microsphere formulation using patented technology under license from Brookwood Pharmaceuticals (SurModics). So far three Phase III clinical trials have been conducted to assess safety and efficacy of C2L, which showed significant decreases in serum IGF-I and GH levels, comparable to Sandostatin LAR. No serious AEs were reported during those trials. Owing to a longer bioavailability in comparison to Sandostatin LAR longer treatment intervals were also tested and yielded promising results. However, due to a legal dispute with SurModics, Ambrilia could not afford to continue development and decided to terminate the third Phase III clinical trial as part of ongoing measures to reduce costs. As of 2011, Ambrilia has filed for bankruptcy; no further development of C2L has been reported. 7.1.4

Intravail octreotide acetate Aegis Therapeutics reported high bioavailability of its oral octreotide formulation in April 2011, supposedly surpassing bioavailability by injection (press release). However, data were obtained in preclinical trials on Swiss Webster mice [171] and so far no information on Phase I clinical trials is available. In May 2012, the US patent office awarded Aegis Therapeutics a patent for their pharmaceutical composition of octreotide using their Intravail and ProTek technology that makes it suitable for all routes of administration including oral, buccal, metered nasal spray or injection (press release, Aegis Therapeutics). 7.1.5

Camurus octreotide (CAM-2029) Camurus developed a liquid crystal depot formulation of octreotide called CAM-2029 for the treatment of acromegaly and gastroenteropancreatic neuroendocrine (GEP--NE) tumors, including carcinoid cancer and vasoactive intestinal peptide (VIP)-producing tumors (press release, Camurus). Camurus highlights the less painful subcutaneous application of readyto-inject syringes as well as the possibility to store the medication at room temperature as major advantages over currently available SSA. In Phase I clinical trials with 32 acromegaly and carcinoid tumor patients and 70 healthy volunteers respectively, the drug showed significant suppression of IGF-I over 1 month with good tolerability. Phase II clinical trials are currently underway. In 2011, Camurus granted Novartis an exclusive option to license the FluidCrystal Injection depot technology to develop, manufacture and commercialize CAM2029 (press release, Camurus). 7.1.6

Octreotide implant (VP-003) Endo Health Solutions developed hydrogel implants that provide stable doses of octreotide comparable to 20 mg of commercially available depot octreotide throughout a period 7.1.7




of 6 months. Two Phase II open-label randomized studies in a total of 45 patients with acromegaly showed good tolerability of 84 mg implants. Patients received stable octreotide doses with sufficient suppression of IGF-I and GH over 6 months [172]. Adverse events were mild and less frequent when compared to conventional octreotide therapy given once every 28 days. Two Phase III clinical trials confirmed previous findings of safety and efficacy in a total of 158 acromegalic patients. While the longer treatment intervals are promising for patients, a drawback is that the implants have to be inserted and removed in a surgical procedure. However, breakage of implants seemed not to lead to serious side effects [173]. In 2010, orphan drug status was granted in the USA. Initially, the launch of this new product was anticipated in 2011, but the FDA requested additional preclinical studies, including a carcinogenicity study. Due to these requirements the launch is now expected for 2016/2017.

expression of IGF-I. In vitro studies showed a dose--response relationship that was later confirmed in in vivo studies in mice. Suppression of IGF-I was observed over 10 weeks of dosing. In cynomolgus monkeys, ATL-1103 given twice weekly over a period of 6 weeks suppressed IGF-I levels by 35% in comparison to placebo [178]. In a Phase I clinical trial with 36 healthy adult male subjects, the drug showed a significant decrease of IGF-I as well as a significant reduction in GH-binding protein (GHBP) by 16% after 3 weeks (press release, Antisense Therapeutics). The drug is currently undergoing safety and efficacy testing in Phase II clinical trials. Results of a first Phase II trial in 24 acromegalic patients in Spain and the UK are expected by the end of 2013. Antisense Therapeutics further plans to develop this drug for other indications as well, such as diabetic retinopathy and age-related macular degeneration.

Glide octreotide acetate (GP02) Developed by Glide Pharma, GP02 is the first product to use the company’s sold dose injector (SDI), a needle-free drug application system. It relies on a pointed implant containing active pharmaceutical material that is injected through the skin. In preclinical studies, healthy volunteers preferred the injector system over conventional syringes with needles. In a Phase I trial, octreotide SDI was bioequivalent to subcutaneous injections of octreotide (press release, Glide Pharma). According to its licensee’s pipeline (Paladin Labs), octreotide SDI is currently in Phase II trials.

7.4.1

7.1.8

7.2

Chimeric ligands BIM-23A760

7.2.1

The chimeric ligand BIM-23A760, a compound with high binding affinity toward sst2 and sst5, as well as dopamine D2 receptors, was considered one of the most promising upcoming treatment innovations in acromegaly developed by Ipsen. Preclinical data showed a very good suppression of GH secretion in vitro [174], but failed to show any significant effect in Phase IIb clinical trials as the drug produced a metabolite with dopaminergic activity that gradually accumulates and interferes with the activity of the parent compound in vivo [175]. Consequently, Ipsen decided to discontinue its development (press release, December 2010). Other such chimeric molecules have also showed promising results but have not been developed further so far [174,176,177]. 7.3

Antisense drugs ATL-1103

7.3.1

Antisense Therapeutics, an Australian-based company, has developed a second-generation antisense oligonucleotide. It is designed as nucleotide sequence that perfectly fits mRNA of a protein that is usually part of the GH receptor. By binding to the mRNA the transcription of the gene and thus the GH receptor is effectively inhibited, which in turn inhibits

7.4

Other antineoplastic drugs Temozolomide

The alkylating agent temozolomide is primarily targeted at malignant tumors and has an indication for glioblastoma multiforme and other tumors of the CNS [179,180]. Temozolomide has proven useful in several cases of prolactinomas [181-183] and has therefore been incorporated into current guidelines [184]. The efficacy of temozolomide is diminished by a specific DNA repairing protein that is encoded by the O-6-methylguanine-DNA methyltransferase (MGMT) gene [185]. In practice, a silenced expression of MGMT is favorable for temozolomide treatment [180], which could also be shown for aggressive pituitary tumors [186]. It has therefore been used in other pituitary tumors as well yielding mixed results [187-191]. In a French multicentric trial of temozolomide treatment in 11 patients, response was seen early in the treatment and response after three cycles was predictive of further response [187]. Currently, experience with temozolomide in the treatment of aggressive somatotroph carcinomas is still limited [192,193]. Temozolomide may play a role in cases of acromegaly refractory to surgery, medical therapy and irradiation. 8.

Potential development issues

Heterodimerization of somatostatin receptors hints at complex interactions between somatostatin and its receptors [74,194]. Information about the not only common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis has been found by closely investigating the function of each SSTR [195,196]. Heterodimerization is believed to be one reason for resistance to SSA [197]. As such, the scope of biochemical control of acromegaly to be expected by SSA is limited. This limitation is further enhanced by the fact that somatotroph adenomas are histologically a heterogeneous group of adenomas [198,199] and express diverse patterns of


87

88

Lanreotide

Octreotide

Compound

Ipsen

Novartis

Company


HO

H 2N

HO

HO

O

O

NH

O

N H

O

HN

NH2

N H

NH

O

S

O

S

O

H N

S

H

S

O

HN

H N

HN

O

O

H2N

N H

OH

NH

NH 2

O

O

H N

Structure

O

O

NH 2

NH

O

NH

NH

OH

H N

Indication

Stage of development

Acromegaly, carcinoid Marketed tumors*, VIPomas*

Acromegaly, carcinoid Marketed tumors, VIPomas

Table 2. Competitive environment for drugs used in or developed for treatment of acromegaly.


Somatostatin analog binding to SSTR2 and SSTR5 (binding affinity SSTR2 > SSTR5)

Somatostatin analog binding to SSTR2 and SSTR5 (binding affinity SSTR2 > SSTR5)

Mechanism of action


O


Ambrilia

Aegis Therapeutics See octreotide Camurus See octreotide

Indevus Glide

C2L

Intravail octreotide CAM-2029

VP-003 Octreotide SDI

N

N H

O

O O

O O

O

H H N

NH

NH

NH2

NH

See octreotide See octreotide

See octreotide

Cyclic[(R)-bMeNphe-Phe-DTrp-Lys-Thr-Phe]

Aspireo

O

HN

Somatoprim

O

NH

See octreotide

H2N

Chiasma (licensed by Roche)

Novartis

Pasireotide

Structure

18-L-aspartic acid-21-L-asparagine-120-L-lysine-167-L-asparagine168-L-alanine-171-L-serine-172-L-arginine-174-L-serine-179-Lthreonine growth hormone

Octreolin

Pfizer

Company

Pegvisomant

Compound

Acromegaly Acromegaly, neuroendocrine tumors Acromegaly Acromegaly

Acromegaly, neuroendocrine tumors, portal hypertension Acromegaly, neuroendocrine tumors, Cushing’s disease, diabetic retinopathy Acromegaly

Cushing’s disease filing for acromegaly and neuroendocrine tumors to be expected soon

Acromegaly

Indication

Table 2. Competitive environment for drugs used in or developed for treatment of acromegaly (continued).

Phase III clinical trials Phase II clinical trials

Phase III clinical trials, stopped due to bankruptcy Preclinical Phase II clinical trials

Phase II clinical trials

Phase III clinical trials

Phase III clinical trials; approved for the treatment of ACTH-dependent pituitary adenoma

Marketed

Stage of development




See octreotide

Somatostatin analog binding to SSTR2, SSTR4 and SSTR5

See octreotide

Somatostatin analog binding to SSTR1, SSTR2, SSTR3 and SSTR5 (binding affinity SSTR5 > SSTR2)

GH receptor antagonist

Mechanism of action


89

90

Alkylating agent methylating DNA of target cells

Acromegaly, diabetic retinopathy, age-related wet macular degeneration Glioblastoma Marketed, patent multiforme, refractory expiration immanent anaplastic astrocytoma, off-label use in aggressive pituitary tumors

Chimeric somatostatin analog binding to SSTR2 and SSTR5 as well as dopamine agonist binding to D2 Inhibition of GH receptor expression by binding to mRNA Phase II clinical trials, abandoned due to insufficient inhibition of GH and IGF-I in vivo Phase II clinical trials

SSTR [148,200]. These facts potentially limit the efficacy of any new agent developed. The high cost of drug development is further limiting investments made, especially by smaller companies. Even though acromegaly is a recognized orphan disease, which allows for development as orphan drug, some new and promising agents are abandoned due to insufficient financial backing before gaining marketing approval. 9.

Conclusion

Acromegaly is a rare disease that results from an excess of GH. It seriously impacts the patient’s health and well-being and leads to an increased mortality if left untreated. Treatment has significantly progressed over the last decades and surgical cure is possible in about half of cases. For the remaining half of cases, medical treatment can lead to biochemical remission of the disease. However, in some patients currently available treatment options do not lead to biochemical control of disease activity. This highlights the need for the development of new drugs. In the past few years, there have been numerous advances into producing agents that aim for better biochemical disease control, yield less side effects and ideally are easy and safe to administer with high comfort for the patients treated. Nevertheless, most of new developments seem to reach only one of the aforementioned goals, so that the need for new developments will remain for the foreseeable future.

N N

N

CH3

Antisense Therapeutics

Merck Sharp Dohme

ATL-1103

Temozolomide

H2N

N

O

N

O

Ipsen

O-linked glycosylated hGH

10.

BIM-23A760

Dop2-DLys(Dop2)-c(Cys-Tyr-DTrp-Lys-Abu-Cys)-Thr-NH2

Acromegaly

Mechanism of action Stage of development Indication Structure Company Compound

Table 2. Competitive environment for drugs used in or developed for treatment of acromegaly (continued).



Expert opinion

The development pipeline of established and aspiring pharmaceutical companies alike has new drugs which show great potential, some of which are already in Phase II and III trials. However, it is often at later stages of clinical development that drawbacks of new drugs come to light and sometimes even lead to utter disillusionment. Underneath the excitement for advances in the therapeutic armamentarium it is therefore important to remain critical and take the theoretical superiority of a newly developed drug with a grain of salt. Currently, many developments aim at improving the ease of use and the convenience of application respectively of established active pharmaceutical agents. As outlined in the market review section, there is a growing market in this field that makes it interesting for new competitors to strive for a share of the market. How much these innovations will actually be beneficial to patients from a medical perspective remains to be seen. From an economic point of view this development can be seen as a driver of further innovation as established companies have to strategically advance drug development in terms of improving biochemical control to defend their market share. This puts acromegaly in a rather fortunate position in contrast to many other rare diseases: There is enough economic incentive for pharmaceutical




companies to invest in costly research and development of new treatment options. This comes at a high price for the public health systems that actually pay for the treatment. Understandably, companies have to monetize their products in order to pay for expenses related to research, development and marketing, as well as post-approval surveillance. But the rate of market growth cannot be sustained for long, so that eventually prices for the yet very costly medical treatment options in acromegaly will have to drop. Competition might also help mitigating cost development. Due to the complex processes and different mechanisms involved in pathogenesis of acromegaly, it seems unlikely that there ever will be a single agent that can help all patients. Furthermore, advances in molecular research unveil evermore complex underlying details and new pathogenetic subtypes are proposed. Even though this may yield even more new questions, it also advances the understanding of interaction at the molecular level and offers thus new targets for medical treatment. Hence, development of new and promising therapies is reasonable and desirable, especially for those patients where currently available treatment options fail and new regimens are desperately needed. On the other hand, if new treatment options should target different subgroups of acromegalic patients, there is an urgent Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation

Sylve`re St€ormann† & Jochen Schopohl † Author for correspondence Klinikum der Universita¨t Mu¨nchen, Medizinische Klinik und Poliklinik IV, Ziemssenstr. 1, 80336 Mu¨nchen, Germany Tel: +49 0 89 5160 2111; Fax: +49 0 89 5160 2194; E-mail: [email protected]

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