Perspectives on investigational drugs for acromegaly

1. Introduction

Acromegaly is a serious disease with several debilitating symptoms and comorbidities. It is most commonly a result of the oversecretion of growth hormone (GH) secondary to a benign adenoma of the pituitary gland. Acromegaly is rare affecting only 40–70 patients per million with an incidence of approximately 3–4 new cases per million per year. Clinical manifestations of acromegaly are occasionally confused with normal signs of aging or other unrelated diseases. Therefore, patients suffering from acromegaly may go undiagnosed and untreated for several years. Common observable pathognomonic clinical manifestations of acromegaly include coarse facial features and enlargement of the hands and feet. The disease name is derived from the Greek words akros [άκρος] ‘extremities’ and megálos [μέγαλος] ‘large’.

The initial symptoms of acromegaly are often nonspecific including headaches, fatigue, hyperhidrosis, and hypertension. Other unnoticed symptoms and comorbidities may develop including organomegaly with organ dysfunction, arthropathy, carpal tunnel syndrome, macroglossia, scleroderma, obstructive sleep apnea, insulin resistance, diabetes, goiter, psychiatric disorders, and others. Pituitary adenoma enlargement may also cause pituitary deficiencies such as hypogonadism. If large enough, a pituitary adenoma may also compress the optic chiasm creating visual field defects. Untreated acromegaly results in higher mortality rates with life expectancy approximately 10 years less than the general population. Proper diagnosis with adequate treatment is important and can result in normal life expectancy as compared to the normal population.[1]

Surgical and pharmacological treatment of acromegaly focuses on symptom control through tumor reduction and biochemical remission. The first-line approach is surgical removal of the underlying adenoma.[2] Unfortunately, many years may pass before proper diagnosis and the underlying adenoma may not be amenable to surgical resection (e.g. infiltration of the cavernous sinus or encasing the internal carotid artery). Successful surgical intervention when treating acromegaly also correlates directly with the surgeon’s experience.[3] Surgical removal of GH-secreting pituitary adenoma is successful in approximately 50% of cases.[4]

To normalize GH levels in patients where surgical intervention fails or is not feasible, several pharmaceutical treatment options are available. These options include dopamine agonists, somatostatin analogs (SAs), and GH receptor antagonists.[2]

SAs are often the first-line pharmacological treatment due to their efficacy and favorable safety profiles. SAs are ligands of somatostatin receptors with a longer half-life than somatostatin. Most GH-secreting pituitary adenomas express somatostatin subtype receptor (SSTR) 2 and 5. SAs activate somatostatin subtype receptors and suppress GH secretion. In approximately 30–60% of cases, SA therapy achieves appropriate biochemical control.[5–7] SA also induces tumor shrinkage in 60–75% of cases. Since their inception, SAs have revolutionized the treatment of acromegaly and have become the cornerstone of pharmacological treatment.[2,3] Currently, there are three commercially available SAs including octreotide, lanreotide, and pasireotide. These SAs differ by the extent they bind to specific SSTR.

Despite their leading role in pharmacotherapy, current SAs have some shortcomings.[5] Despite good response rates when treating acromegaly, SAs are not effective in every patient. Furthermore, some patients experience significant side effects including diarrhea, abdominal pain and cramping, nausea, and cholelithiasis. Another significant side effect is hyperglycemia due to inhibition of insulin secretion, more commonly associated with pasireotide therapy. All approved SAs are administered parenterally once every 4 weeks. In recent years combination therapies (SA + dopamine agonists; SA + GH receptor antagonists) have proven effective with significant treatment success.[4]

Utilization of SAs in the treatment of acromegaly has increased steadily reaching an estimated annual revenue of 2 billion U.S. dollars in 2014. Due to significant financial incentive, pharmaceutical companies have focused on developing new and improved SAs. Pharmaceutical companies are currently modifying existing and developing new SAs with improved efficacy, tolerability, and ease/comfort of administration.[4]

2. Needle-free route of administration

SA is a peptide and cannot effectively be administered orally. However, utilization of a newly developed Transient Permeability Enhancer (TPE) has proven effective when administering oral formulations of octreotide. TPE loosens intestinal tight junctions and allows paracellular transport of small octreotide molecules. Octreotide utilizing TPE was tested in a multicenter Phase III trial including 151 acromegaly patients previously controlled on prior SA treatment [8]; 62% of these patients maintained an appropriate response after full treatment with oral octreotide. Interestingly, doses of parenteral octreotide did not correlate well with the required oral dose of octreotide needed to achieve adequate biochemical control in the study. Of the 102 subjects completing the core treatment, 86% enrolled in a 6-month extension which will provide additional valuable data. Reported side effects were mild and mostly transient. However, one major drawback is the required twice daily administration in a fasting state, which could prove difficult among several patients.

Glide Technologies developed a needle-free delivery system called Solid Dose Injector (SDI). This needle-free system allows administration of solid drug formulations through the skin into the subcutaneous tissue. A preclinical study evaluating the pharmacokinetic profile of octreotide administered via SDI demonstrated no statistical difference between the SDI variant and standard-of-care subcutaneous octreotide (Glide Technologies, press release). A human bioequivalence study is currently planned.

3. New delivery systems

Camurus, a Swedish biotechnology company, developed a technology titled FluidCrystal, a liquid solution that transforms into a controlled release liquid crystal gel matrix in situ with minute quantities of aqueous fluid at the injection site (Camurus, press release). Octreotide utilizing this technology (CAM2029) utilizes small gauged relatively painless needles, is packaged in ready-to-inject syringes, and stable at room temperature. This is a significant improvement considering current transdermal octreotide administration requires painful intramuscular injections, is not pre-mixed, and must be stored in a refrigerator. A study evaluating the pharmacokinetics and pharmacodynamics in healthy volunteers observed increased octreotide bioavailability and a more rapid onset with comparable efficacy to current octreotide treatment.[9] A multicentric Phase III study is currently planned.

The Q-Sphera delivery system is based on bioresorbable, monodisperse microspheres with controllable burst release after injection. This controllable burst release technology also has near zero order release kinetics. According to a company presentation, the particle size can be selected based upon preferred route of administration for intramuscular, subcutaneous, or even intraocular application. One of the drugs to be developed using this technology is octreotide. A human bioequivalence study is planned for 2016 with expectations to launch this product by 2018 (press release).

4. Increased dosing intervals

During the past two decades new formulations of octreotide and lanreotide utilize longer dosing intervals. Currently, all three major SA formulations are administered once every 4 weeks. Lanreotide, utilizing the Autogel® formulation, is the only SA approved for longer dosing intervals (i.e. up to 8 weeks).[10] A new variant labeled Prolonged Release Formulation with even longer dosing intervals has been developed and currently being tested in a Phase IIa study (NCT02396953).

Pharmaceutical companies are also developing octreotide subcutaneous implants. These implants have been studied in several clinical trials, including Phase III trials. In a recent trial, patients receiving a stable monthly dose of octreotide LAR injections were randomly selected to receive an octreotide implant (for a period of 6 months) or continue octreotide LAR injections. After 24 weeks, 86% of implant patients remained biochemically in remission. Diarrhea and headache were common side effects reported by the implant group. Implant breakage also occurred in 32 of 122 explants, but was not associated with significant safety-related events or side effects.[11]

5. New somatostatin analogs

Somatoprim (DG3173, after acquisition by Cortendo AB also labeled COR-005) is a novel hexapeptide SA that binds to SSTR2, 4, and 5. As compared to other SAs, it leads to low insulin suppression as observed in Phase I and Phase II of performed clinical trials.[12,13] At least one multinational pivotal clinical trial for registration will be required with further planning to begin in 2016 (notice to shareholders, Cortendo AB).

The compound ITF2984 is another newly developed SA with high-affinity binding to SSTR1, 2, 3, and 5. The manufacturer completed Phase I clinical trials in 2013 and is performing a randomized, multicentric Phase II clinical trial to assess the effect of treatment on GH and IGF-1 levels (NCT02111044).

6. Other developments

Recently it has been debated whether estrogens and selective estrogen receptor modulators (SERMs) are effective when treating acromegaly, especially in men.[14] A recent publication from a small sample single-center study in Brazil provided promising data from 16 men with uncontrolled acromegaly and central hypogonadism. Data suggest the addition of the SERM clomiphene citrate improved IGF-1 and testosterone levels significantly.[15] Additional larger studies are needed to fully understand this debate.

ATL1103 (after acquisition by Cortendo AB also labeled COR-004) is a second-generation antisense oligonucleotide that blocks transcription of the GH receptor. A small multicentric Phase II clinical trial reported that biweekly administration induced a significant reduction of IGF-1 levels when administered over a period of 13 weeks. All patients received full treatment with no serious adverse events reported. Occasionally, observable side effects included injection site reactions, an increase of liver enzymes, and transient thrombocytopenia. There are goals to perform additional studies and move clinical development into Phase III trials.

7. Expert opinion

Many novel pharmacological treatments for acromegaly have been developed in the recent past. Clearly there is financial incentive for pharmaceutical companies to produce newer and more effective drugs, and we expect many more developments as a result of this incentive. These new developments are promising; however, there is little data published as these developments are in their early stages. It is difficult to predict which, if any, newly developed treatment options will be available for daily patient care. However, with more resources directed toward acromegaly drug research and development, we are hopeful more effective treatment will be available for patients suffering from acromegaly. We must also take into consideration, given the wide range of complex mechanisms involved in the pathogenesis of acromegaly, utilizing combination therapy targeting specific receptors is becoming increasingly important. Therefore, rather than finding a one-fits-all solution, future pharmacological intervention may target more specific receptors, and deliver optimal therapy to every patient through various drug combinations. Although the current developments may fail, we expect to see many new and promising drugs that will expand the therapeutic armamentarium in the next decades.

Declaration of interest

J Schopohl has received grants from Ipsen, Novartis, and Chiasma. He is a consultant for Novartis and Ipsen. S Störmann has received grants from Novartis and Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.