The Future of Somatostatin Receptor Ligands in Acromegaly.

Currently, the first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot, and nasal octreotide, may improve patients' adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788, and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.

Somatostatin receptor ligands (SRLs) have had a leading role in the medical treatment of acromegaly for more than 30 years (1). Worldwide, there are currently 3 drugs in use (octreotide, lanreotide, and pasireotide) that have an important place in the algorithm of acromegaly treatment (2-4). In this review, we will discuss the future of SRLs in acromegaly, including new formulations of currently available drugs and new SRLs and the use of precision medicine to better guide the use of SRLs in acromegaly treatment (Fig. 1).

Figure 1.

Possible future perspectives of somatostatin receptor ligands (SRLs) in acromegaly.

Current Role of Somatostatin Receptor Ligands in Acromegaly Treatment

Somatostatin is a widely distributed polypeptide hormone with a broad range of actions, including the inhibition of hormone release, cell growth, and differentiation (5). Somatostatin is initially synthesized as a large precursor molecule that, after tissue-specific enzymatic cleavage, generates the 2 biological forms somatostatin-14 and somatostatin-28 (6). Enzymatic degradation of somatostatin reduces its activity or inactivates it, a rapidly occurring process, such that somatostatin has a short half-life (< 3 minutes), making it not useful in clinical practice (5). Therefore, synthetic SRLs, with longer half-lives, have been developed (7, 8). The first produced SRL was octreotide, developed in the 1980s, a synthetic octapeptide that was fashioned from the most biologic active fragment of endogenous somatostatin, resulting in a compound that was 20 times more active than somatostatin and had a longer half-life (90-120 minutes), enabling a pharmacodynamic action lasting up to 8 to 12 hours (7, 8). Later, at the end of the 1990s, a long-acting formulation of octreotide (octreotide LAR [long-acting repeatable]) was developed, allowing administration every 4 weeks (8).

Somatostatin and SRL actions are mediated by a family of 7 transmembrane domain G-protein-coupled receptors that include 5 subtypes (somatostatin receptors 1 to 5 [SST1-5]), which are encoded by separate genes located on different chromosomes and are bound by somatostatin with nanomolar affinity (9).

First-generation somatostatin receptor ligands (fg-SRLs) are currently the mainstay of acromegaly treatment (3). Two long-acting fg-SRLs (octreotide LAR and lanreotide autogel) are considered the first-line medical therapy for patients not cured by surgery or for those cases where surgery is not the first-line treatment (high surgical risk, patients refusing surgery, or for tumors almost entirely located inside the cavernous sinus with very low chance of surgical resection) (3, 10). In addition to monotherapy, they can also be used in combination with the dopamine agonist cabergoline and the growth hormone (GH)-receptor antagonist pegvisomant (3).

Octreotide is highly selective for SST2 and to a lesser extent to SST5, and it has a 20- to 40-fold greater potency than native somatostatin (7, 8). Subcutaneous octreotide was shown to be effective in the treatment of acromegaly, with GH suppression < 5 mcg/L and normalization of IGF-I levels being achieved in up to 65% and 68% of patients, respectively (11, 12). First-generation long-acting SRLs also act by binding with the highest affinity to SST2 and with less affinity to SST5 and allow disease control, defined as random GH levels <1.0 μg/L and normal age-matched insulin-like growth factor I (IGF-I) levels, in approximately 40% of patients in prospective studies without patient preselection (13-15). In addition, tumor shrinkage above 20% is observed in 66% of patients with octreotide LAR (mean reduction of 51%) and in 63% of patients with lanreotide autogel (mean reduction of 27%) (16, 17). Treatment has been shown to improve patients’ symptoms and quality of life (QoL) (18). These drugs have a good safety profile, with the most frequent side effects being mild gastrointestinal complaints (nausea, vomiting, diarrhea, and abdominal pain), observed in approximately 50% of patients, but rarely leading to drug interruption (19-21). Also, occurrence of gallstones is expected in about 15% of patients (11, 21).

Although disease control with strict criteria is achieved in approximately 40% of patients, complete resistance (reduction of GH and IGF-I < 20%) is observed in only about 10% of patients (22). Thus, a large proportion of patients benefit from a partial response to the drug and in these patients, combination of fg-SRLs with the dopamine agonist cabergoline or with the GH-receptor antagonist pegvisomant is possible (3). Cabergoline add-on is especially useful in patients with mild disease under fg-SRLs treatment (IGF-I up to 2 × upper limit of normal [ULN]) and disease control can be achieved in approximately 30% of patients with this combination (3, 23-25). The combination with pegvisomant in patients with partial response to fg-SRLs allows disease control in a high proportion of patients (approximately 80%) (26, 27).

The second-generation SRL pasireotide long-acting release (LAR) differs from fg-SRLs due to its higher affinity to SST3 and SST5 (5 and 40 times more affinity than octreotide, respectively), with half the affinity of octreotide for SST2 (28). In a head-to-head prospective randomized study including 358 drug-naïve acromegaly patients, disease control (random GH < 2.5 μg/L and normal age-matched IGF-I levels) was observed in more patients treated with pasireotide LAR than with octreotide LAR (31.3% vs 19.2%, respectively; P = 0.007) (29). Additionally, in a prospective randomized trial that included patients not controlled with treatment with fg-SRLs at the maximal dose, treatment change to pasireotide LAR 60 mg achieved disease control (random GH < 2.5 μg/L and normal age-matched IGF-I levels) in 20% of resistant patients (30). Disease control with pasireotide LAR can be achieved in around 54% of patients resistant to fg-SRLs in real life scenarios (31).

Tumor shrinkage (≥ 20%) was observed in 80.8% of drug-naïve patients during treatment with pasireotide LAR and in 77.4% of patients treated with octreotide LAR (29). In addition, Coopmans et al (32) described that there was an increase in the signal intensity of adenomas in T2-weighted magnetic resonance imaging (MRI) sequences during pasireotide LAR treatment, which may indicate cystic degeneration, tumor apoptosis, or necrosis. There is also a description of 2 patients harboring mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene that were resistant to fg-SRL and presented an excellent response to pasireotide with important tumor reduction, leading to no tumor remnant after long-term treatment (33). Nevertheless, additional studies are needed to show whether pasireotide LAR treatment can lead to tumor involution and, consequently, to disease remission, which is not expected with fg-SRLs that are a life-long treatment (34, 35).

The safety profile of pasireotide is similar to that of fg-SRLs with the exception of the effect on glucose metabolism, with elevation of glucose levels and development of diabetes mellitus (DM) being more frequent with pasireotide (57% vs 21% with octreotide LAR in a randomized prospective study with drug-naïve patients) (29). The elevation of glucose levels is mild and manageable in the majority of patients and reversible after drug withdrawal (36, 37). Nevertheless, a great proportion of patients will need antidiabetic drugs; metformin is usually the first option of medical therapy, with addition of incretin-based therapy being suggested in patients not controlled with monotherapy with metformin, due to the inhibitory effect of pasireotide on incretin secretion (38).

Considering its efficacy and safety profile, pasireotide LAR is generally not prescribed as a first-line therapy and instead is used in patients not controlled with fg-SRLs, especially when there is a concern with the tumor mass and glucose metabolism is normal (2, 3).

Future Perspectives for Currently Available Injectable SRLs

As previously stated, fg-SRLs are a first-line medical treatment for patients with acromegaly, with control rates of approximately 40% in nonselected patients (14). Therefore, currently, acromegaly treatment is based on a trial-and-error approach in which all patients are treated equally, regardless of their own particularities (39). This means that all acromegaly patients are treated with fg-SRLs, and a different treatment is used only when these drugs fail. Currently, unlike 3 decades ago when octreotide started to be used in the treatment of acromegaly, diverse options have emerged and are now available for the treatment of these patients. Therefore, efforts have recently been made to move toward biomarker-based therapy (precision medicine) in which the drug is chosen based on the patient characteristics that make a particular drug more appropriate to a particular individual (39-45). In this scenario, fg-SRLs will be used in patients with a high probability of response, whereas other treatments (such as pasireotide, cabergoline, pegvisomant, or other drugs in development or to be developed in the future) will be used in patients in whom they seem appropriate. For example, pasireotide LAR could be a first-line medical therapy for young patients with large tumors, considering its higher efficacy compared with fg-SRLs, better effect on tumor volume, and lower probability of glucose abnormalities in younger patients (29, 30, 39). In the future, to better implement precision therapy in acromegaly, the analysis of biomarkers of response to SRLs is essential, and there are already data in the literature that can help guide the treatment, as discussed below (39, 46).

Biomarkers of response to SRLs have long been studied; and several factors, related to both patient and tumor characteristics, have been proposed as predictors of response to SRL. There have been some conflicting results, but no biomarker has achieved high accuracy (47). These characteristics include age, gender, GH and IGF-I levels, adenoma signal in MRI T2-weighted sequence, cytokeratin granulation pattern, gsp oncogene, SST and SST5 truncated isoforms, AIP, zinc-finger protein which regulates apoptosis and cell cycle arrest 1 (ZAC1), E-cadherin, beta-arrestins, and Ki-67 expression (48).

The most well-established predictor of response to fg-SRLs is SST2 expression in somatotropinomas. Our group has demonstrated that SST2 mRNA expression, evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction, was correlated with GH and IGF-I decreases after 3 and 6 months of treatment with octreotide LAR, as well as with tumor volume reduction (49, 50). We also demonstrated similar results at the protein level (51). In this study, SST2 protein expression was able to predict biochemical control with a 100% negative predictive value and 60% positive predictive value (51). These findings are similar to others in the literature (52-58).

Another important biomarker of response to fg-SRL is AIP expression in adenoma, a protein that seems to be involved in the mechanism of action of fg-SRLs (48). Mutations in the AIP gene are associated with familial isolated pituitary adenomas, especially familial somatotropinomas (59). AIP-mutated somatotropinomas seem to be larger, more hidden and invasive, and to respond poorly to treatment with fg-SRL (60). Mutations in the MEN1 gene are also associated with somatotropinomas, requiring neurosurgery more often and multimodal approaches (61). However, a series comparing patients with isolated acromegaly with acromegaly associated with MEN1 found similar IGF-I control (62). Other forms of hereditary acromegaly include Carney complex and McCune Albright syndrome (63).

AIP seems to be directly involved in SST signaling pathways. It has been shown, in vitro, that treatment with octreotide increases AIP expression (64, 65). Moreover, tumors from patients treated with SRL before surgery exhibited higher AIP expression (65). We demonstrated that out of 18 patients whose tumors exhibited low AIP expression, only 4 (22%) achieved disease control with octreotide therapy, in contrast to 11 (65%) of the 17 patients whose tumors presented high AIP expression (P = 0.013) (66). Another study did not find AIP mutations to be more frequent among patients with sporadic acromegaly that poorly responded to fg-SRL, but these patients exhibited lower AIP and SST2 immunoexpression than patients with good response (67). Furthermore, Iacovazzo et al (68) found, in a subset of patients resistant to fg-SRLs, that SST5 protein expression may predict biochemical response to pasireotide, which was not related to AIP expression. Also, Coopmans et al (69) showed that, among patients resistant to fg-SRL, those who had significant tumor shrinkage had lower SST2 expression and lower SST2/SST5 ratio.

Based on this, we proposed an algorithm for acromegaly management considering SST2, SST5, and AIP expression, IGF-I levels, and tumor remnants (40). In this algorithm, patients with high SST2 and AIP expression would be treated with fg-SRLs. Those with low expression of either SST2 or AIP would be treated with cabergoline if IGF-I levels were lower than 2 × ULN; with pasireotide if there was high SST5 expression; and pegvisomant if SST5 expression was low and IGF-I higher than 2 × ULN, without tumor remnant concern.

Other algorithms have been proposed in the literature, one of them focusing mainly on the acute octreotide test (AOT) and on adenoma signal intensity on MRI T2 weighted sequences, proposing that patients responding to AOT (GH nadir < 3.5 ng/mL) and with hypointense tumors should be initiated fg-SRL monotherapy. Those with an intermediate response on AOT (GH nadir > 3.5 ng/mL but < 9 ng/mL) and hyperintense tumors should be treated with a combination of fg-SRLs and pegvisomant. Finally, patients who do not respond to AOT (GH nadir > 9 ng/mL) and with hyperintense tumors would be treated with pegvisomant monotherapy (42). The value of AOT as a predictor of response to fg-SRL is matter of debate and is not supported by all studies (70, 71). On the other hand, T2 signal intensity in the adenoma is a reliable biomarker, as tumors with higher T2 signal seem to show lower SST2 expression and respond worst to fg-SRL, which has been demonstrated in several studies (72-75).

In another algorithm, SST2 expression, cytokeratin granulation pattern, and signal intensity on MRI T2 weighted sequences were used, but also concerns with respect to tumor remnants, IGF-I levels and the presence of DM were considered (44). In this algorithm, patients presenting densely granulated tumors with high SST2 expression and hypointense T2 signals should be treated with fg-SRLs. Otherwise, patients should be treated with cabergoline if they possess modestly elevated IGF-I levels or pegvisomant if they had DM and there was no tumor remnant concern.

Recently, researchers have been seeking to combine different biomarkers and develop models to predict the response to fg-SRLs. Cuevas-Ramos et al (76) performed cluster analysis of 338 acromegaly patients, from which 292 were classified into 3 acromegaly types. Clustering was based on cytokeratin granulation pattern, tumor size, and invasiveness. Type 1 patients were older and harboring densely granulated, noninvasive microadenomas and macroadenomas, with high SST2 expression and more favorable outcomes. Type 2 patients presented noninvasive densely or sparsely granulated macroadenomas and intermediate outcomes. Finally, type 3 patients were characterized by a young age, sparsely granulated invasive macroadenomas, and low SST2 expression with adverse outcomes (76).

Coopmans et al (77) developed a multivariable prediction model of biochemical response to fg-SRLs. In this study, with 8 European centers, biochemical response was categorized as follows: biochemical response (IGF-I ≤ 1.3 ULN), partial response (>20% relative IGF-I reduction without normalization) and nonresponse (≤ 20% relative IGF-I reduction). The variables that were included in the analysis were the following: age (at diagnosis and baseline), sex, body weight, height, GH and IGF-I (at diagnosis and baseline), tumor size (micro, macroadenoma, or nonvisible at diagnosis) and the presence of type 2 DM at the baseline and previous treatment modalities (surgery and medical therapy with a [partial] dopamine agonist). In a multivariable analysis, the determinants of biochemical response were baseline IGF-I and body weight. A lower IGF-I concentration at the baseline (OR 0.82; 95% CI, 0.72-0.95 IGF-I ULN; P = 0.0073) and a lower body weight (OR 0.99; 95% CI, 0.98-0.99 kg; P = 0.038) were associated with biochemical response. Combining IGF-I levels and body weight yields an ability to discriminate patients who would present biochemical responses with an area under the curve of 0.77 (95% CI, 0.72-0.81) (77).

Our group performed a multicenter study with 17 Brazilian centers including 153 patients in which we evaluated several biomarkers of response to fg-SRLs using machine learning (ML) techniques (46). The cohort comprises a very homogeneous population of patients with acromegaly not medically treated prior to surgery. We evaluated SST2 and SST5 expression and cytokeratin granulation patterns using immunohistochemistry, which was performed in the same laboratory and evaluated by 2 experienced researchers who were blinded to biochemical response data. Other features were age at diagnosis, sex, and GH and IGF-I levels at diagnosis and baseline. Six ML models were evaluated: the logistic regression, the k-nearest neighbor classifier, the support vector machine, the gradient-boosted classifier, the random forest, and the multilayer perceptron. The model that presented the best performance was the support vector machine including the features SST2 and SST5, cytokeratin granulation pattern, sex, age, and baseline GH and IGF-I levels. This model predicted biochemical control with fg-SRLs (GH < 1.0 ng/mL and normal age-adjusted IGF-I) with an accuracy of 86.3%. The sensitivity was 71.4%, and the specificity was 93.3%; furthermore, the positive predictive value was 83.3%, and the negative predictive value was 87.5%. This model is publicly available, and the results are expressed as the probability of the patient’s condition being controlled with the treatment (46).

With the increased availability of SRLs with different patterns of interaction with SST and even drugs from other classes, expansion of the knowledge and applicability of biomarkers of response is needed. Personalized acromegaly treatment has the potential to increase control rates, with the subsequent reduction in comorbidities associated with the disease and mortality. Likewise, it could decrease the already elevated treatment costs. However, there are still some challenges for the full implementation of this precision treatment. First, although appropriate antibodies against SST have been developed, the method of quantification of SST expression has yet to be standardized. There are some scores described, such as immunoreactivity score (52) or H-score (78), but a standard quantification method is essential for comparison among studies. Also, SST and AIP evaluation are not performed in many centers treating patients with acromegaly, which may hamper its use as predictors. However, it is possible to have referral centers performing these evaluations for other centers where it cannot be implemented. And for those treated primarily with fg-SRL, T2 signal intensity may be used to estimate response. Moreover, a clear definition of full, partial, and no response to medical therapy is also lacking, which is also crucial for comparing results. Finally, there is a need for prospective studies addressing the usefulness of these biomarkers.

Therefore, in the future, it may be possible to determine the probability of a patient being controlled with fg-SRLs and choose therapy based on that information. The model proposed by our group may permit this if our results are confirmed in other series. For example, if the clinician has the information that the patient has less than a 10% chance of being controlled with fg-SRLs, it may be more reasonable to choose a different treatment option.

New Formulations of Currently Used SRLs

Oral Octreotide Capsules

Oral octreotide capsules (OOC), enabling oral administration of octreotide, are enteric-coated capsules that enable the capsule to remain intact in the stomach; the capsules also contain a transient permeability enhancer (TPE) formulation that leads to transitory and reversible opening of the tight junctions between intestinal epithelial cells and paracellular absorption of the drug (79). Although small molecules, such as octreotide, are well absorbed, larger molecules are only minimally absorbed, limiting the risk of the internalization of immunoglobulins and intestinal pathogens (79).

In a phase I study with healthy volunteers (n = 75), OOC demonstrated a similar pharmacokinetic profile as the subcutaneous (SC) administration of octreotide (80). Plasma concentrations were similar between 20 mg OOC and 100 μg octreotide SC. After oral administration, octreotide levels peak after 2.7 hours with therapeutic levels maintained up to 8 hours, resulting in the need for 2 daily doses. The use of proton pump inhibitors or concomitant food intake significantly decreased the absorption of OOC (80). In the same study, it was observed that OOC was able to suppress the GH peak after GHRH-arginine administration and that the safety profile was similar to that of SC octreotide, with the exception of injection site reactions which were only observed with SC octreotide.

After the encouraging results of the phase I trial, 2 phase III trials were performed (81, 82). The first included 151 acromegaly patients who were completely or partially controlled (2-hour integrated GH levels < 2.5 ng/mL and IGF-I levels < 1.3 × ULN) under treatment with injectable fg-SRLs for more than 3 months (81). Treatment was switched to 40 mg/day OOC (administered in the morning and evening, ≥ 1 hour before a meal and ≥ 2 hours after a meal, respectively). During a 2- to 5-month period, the dose was escalated to 60 mg/day and up to 80 mg/day to maintain IGF-I control. This was followed by a fixed-dose period of 8 to 11 months to allow completion of at least 13 months of treatment. Patients whose condition was controlled at the end of the fixed-dose period were offered an extension of 6 months of treatment. The primary efficacy endpoint was the proportion of responders (IGF-I < 1.3 × ULN and 2-hour integrated GH < 2.5 ng/mL) at the end of the core treatment.

Despite the inclusion criteria, only 88.7% of patients were controlled or partially controlled at baseline, and disease control was maintained in 65% of patients after 7 months and 62% of patients after 13 months (81). At the end of the dose escalation phase, 46% were on 40 mg/day treatment, 23% were on 60 mg/day treatment, and 31% were on 80 mg/day treatment. The side effects were similar to those observed with injectable fg-SRLs and were observed in 89% of patients; and the most common side effects (occurring in >5%) were nausea, diarrhea, dyspepsia, abdominal pain, and flatulence, which occurred in general in the first 2 months with posterior resolution (81). Cholelithiasis was observed in 7.7% of patients. A single case of viral gastroenteritis and no cases of bacterial infection were reported.

A second phase III trial, the CHIASMA OPTIMAL trial, was more recently published (82). This was a prospective, multicenter, randomized, double-blind study that included patients previously controlled with injectable fg-SRLs (defined as average IGF-I levels < 1.0 × ULN for 2 assessments) treated for a minimum of 6 months with a stable dose for at least 3 months. Fifty-six patients were included and randomly assigned to OOC or placebo at a ratio of 1:1 for 36 weeks. The primary endpoint (mean IGF-I levels < 1.0 × ULN measured at weeks 34 and 36) was achieved by 58.2% of patients taking OOC and 19.4% in those treated with placebo (P = 0.008). Mean IGF-I levels at baseline and at the end of treatment were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, respectively. Growth hormone levels were considered controlled (< 2.5 ng/mL) in 77.7% of patients treated with OOC and in 30.4% of patients in the placebo group (P = 0.007). Safety profile was similar to that of the previous phase III study and consistent with that observed with injectable fg-SRLs.

The results of this second phase III trial led to drug approval by the US Food and Drug Administration (FDA) in 2020 for long-term maintenance treatment in acromegaly patients who responded to and tolerated treatment with injectable octreotide or lanreotide.

More recently, results of the MPOWERED study, a randomized, open-label, noninferiority study, were presented (83). In this trial, 92 acromegaly patients previously controlled with OOC were randomized to 9 months of continued treatment with OOC or with their previous injectable SRL. The primary endpoint was maintenance of disease control (defined as average IGF-I levels < 1.3 × ULN), and it was comparable between OOC and injectable SRLs (91% vs 100%, respectively). No new or unexpected adverse event was observed. In addition, higher overall treatment satisfaction was reported in patients under OOC treatment in comparison with injectable SRLs (92% vs 75%) (84).

CAM2029 (Octreotide SC Depot)

A new octreotide formulation named CAM2029 (octreotide SC depot) consists of the drug with FluidCrystal technology, which allows SC monthly injection (85). It is a liquid formulation based on naturally occurring lipids, permitting the use of thin needles. In a phase I study that included 122 healthy volunteers who were randomly assigned to receive 3 monthly doses of 10, 20, or 30 mg CAM2029 or 30 mg octreotide LAR, CAM2029 demonstrated a faster onset of action with a 4- to 5-fold greater bioavailability and a stronger suppression of IGF-I levels in comparison with octreotide LAR (85). Octreotide SC depot was well tolerated with a similar safety profile to octreotide LAR.

A phase II multicenter study evaluated the pharmacokinetics, efficacy, and safety profile in patients with acromegaly and functioning neuroendocrine tumors (NETs) (86). Patients treated for ≥ 2 months with octreotide LAR (10, 20, or 30 mg every 4 weeks) were randomized to receive 10 mg octreotide SC depot every 2 weeks or 20 mg every 4 weeks. The primary endpoint was to compare the pharmacokinetic profile of octreotide SC depot after each injection with that of octreotide LAR. Twelve patients were included: 4 in the 10 mg group (acromegaly n = 3 and NET n = 1) and 8 in the 20 mg group (acromegaly n = 4 and NET n = 4). Octreotide plasma concentrations were higher in both octreotide SC depot groups than in the octreotide LAR group. Three out of 5 (60%) acromegaly patients who had IGF-I levels < 1.0 × ULN at study entry maintained normal IGF-I levels on day 84. The safety profile was again similar to octreotide LAR, with the most common adverse event being diarrhea. Two patients reported injection site pain.

Two phase III trials are currently ongoing (ClinicalTrials.gov NCT0476462 and NCT04125836) in order to assess the long-term (12 months) safety and efficacy of CAM2029.

Future Perspectives With New Formulations of Currently Used SRLs

The efficacy and safety of the new formulations is expected to be similar to that of currently available SRLs, although long-term data are lacking and no data on tumor volume are available to date. Thus, the great contribution of these formulations for acromegaly treatment will probably be on treatment adherence.

The availability of oral drugs, as is the case with OOC, which has recently been approved in some countries, expands the possibilities for acromegaly treatment, with the advantage of an improvement in QoL for some patients who report injection site reactions and poorer QoL with injectable therapies (84, 87). In addition, oral drugs seem to have a similar safety profile, although the follow-up is short, and data for long-term use are needed.

The possible availability of octreotide SC depot will represent another alternative to patients in addition to the already available oral and intramuscular administration. That may potentially facilitate treatment because of the easiness of self or partner administration at home and possible less injection pain due to the thinner needle, which may improve adherence. Nevertheless, results of phase III trials are not yet available and need to confirm the efficacy of octreotide SC depot.

Another formulation of octreotide, nasal octreotide, was studied in the early 1990s (88, 89), but further studies were not performed, and no new clinical data is available from the last 30 years.

New Drugs

Paltusotine

Paltusotine (formerly CRN00808) is an oral nonpeptide small SST2 agonist with transcellular absorption (Table 1) (90). A phase I study (ClinicalTrials.gov NCT03276858) including a total of 20 healthy volunteers demonstrated a half-life of 42 to 50 hours following administration of 5- to 30-mg capsules, showing that once-daily administration is possible (91). Nevertheless, administration of a high-fat, high-calorie meal resulted in an 83% reduction in plasma concentrations. The side effects were consistent with those observed for other SRLs. More recently, a spray-dried dispersion (SDD) tablet, whose absorption is less affected by food, was developed (92).

Table 1.

New somatostatin receptor ligands under development

Drugw	Development stage	Route of administration
Paltusotine	Phase III (ongoing)	Oral
Somatropim	Phase II (completed)	Subcutaneous
ONO-5788	Phase I (ongoing)	Oral
ONO-ST-468	Phase I (ongoing)	Oral

After a phase I study, 2 phase II studies were performed: ACROBAT Edge (ClinicalTrials.gov NCT03789656) and ACROBAT Evolve (ClinicalTrials.gov NCT03792555) (90).

ACROBAT Edge was a single-arm study to evaluate the safety and efficacy of switching patients with acromegaly from injectable SRLs to paltusotine (93). The primary analysis population consisted of patients who had not achieved normal IGF-I levels (> 1.0 and ≤ 2.5 × ULN) during monotherapy with octreotide LAR or lanreotide autogel. Patients were treated with paltusotine in monotherapy for a 13-week treatment period (starting dose 10 mg/day with subsequent increases of 10 mg up to a maximum of 40 mg/day). The primary endpoint was the change in IGF-I from baseline to 13 weeks. Subsequently, a 4-week washout period was performed, and the rise in IGF-I levels after washout was also documented (93).

The primary endpoint was achieved as no significant rise in IGF-I levels was observed at week 13 (median IGF-I change of −0.034 [interquartile range, −0.107 to +0.107]; P > 0.6) (93). Of the 23 patients who completed the dosing period, 20 (87%) achieved IGF-I levels that were within 20% of the baseline or lower at the end of treatment. Of 22 patients, 18 (82%) showed a > 20% increase in IGF-I levels 4 weeks after drug withdrawal. The most common side effects were diarrhea (10.6%) and abdominal pain (8.5%), but no treatment discontinuation due to side effects occurred (93).

ACROBAT Evolve was a double-blind, placebo-controlled, randomized withdrawal study that included 13 patients controlled (IGF-I levels < 1.0 × ULN) with injectable fg-SRLs, but the sample size did not allow for meaningful statistical comparisons between groups in the randomized withdrawal period (94).

A phase III randomized, placebo-controlled study designed to evaluate the safety and efficacy of paltusotine in subjects with acromegaly previously treated with fg-SRLs with controlled disease (PATHFNDR 1) is planned to start in 2021 with an expected recruitment of 52 patients (ClinicalTrials.gov NCT04837040).

Somatropim

Somatropim, also known as DG3173 or COR-005, is an SRL with affinity to SST2, SST4, and SST5 (95). In an in vitro study, somatropim demonstrated a similar agonistic effect to octreotide in the human carcinoid-derived cell line BON-1 (95). In hormone secretion studies with rats, the drug was 1000-fold and more than 10 000-fold more potent at inhibiting GH release than glucagon and insulin release, respectively (95). In a study including 8 healthy male volunteers, somatropim demonstrated less pronounced inhibition of insulin and glucagon secretion and no effect on glucose levels in comparison with a more pronounced inhibition of insulin and glucagon secretion and elevation of glucose levels with octreotide (96).

An in vitro study compared the effect of somatropim and octreotide in primary cultures of GH-secreting adenomas and fetal pituitaries (97). Octreotide and somatropim had similar inhibitory effects on GH secretion in fetal human pituitaries. In cultures of 8 somatotropinomas, somatropim was more potent in inhibiting GH secretion in 3 tumors, octreotide was more potent in 2 tumors, and 3 tumors did not respond to either SRL.

Afterwards, a second study compared the efficacy of somatropim and octreotide in primary cultures of GH-secreting adenomas (98). Somatropim suppressed GH release (>80% decrease in comparison to the baseline) in more tumors than octreotide (10/21 vs 5/21, respectively); and interestingly, it was able to suppress GH secretion in 38% (6/16) of tumors that were unresponsive to octreotide.

A phase II study that included 20 untreated acromegaly patients showed that somatropim administered SC in 4 ascending doses (100, 300, 900, and 1800 μg) led to a similar reduction in GH levels in comparison to octreotide (300 μg). The results were not yet published but are available on ClinicalTrials.gov (NCT02235987) (Table 1).

ONO-5788 and ONO-ST-468

ONO-5788 is a novel oral SST2 selective agonist and has an active metabolite (ONO-ST1-641) that also signals through SST2 (99). In vitro, it showed a greater agonistic effect on SST2 than octreotide and pasireotide (99). In vivo studies in rats observed that orally administered ONO-5788 significantly inhibited GHRH-induced GH secretion and basal GH secretion at all doses (99). Interestingly, in this same study, ONO-5788 demonstrated no significant effect on insulin secretion in rats while octreotide and pasireotide significantly inhibited insulin secretion. The drug was also tested in primary cultures of 12 human somatotropinomas, showing similar reduction in GH secretion to octreotide (100).

Two trials in healthy adult volunteers to evaluate the safety, tolerability, and pharmacokinetics of ONO-5788 are registered as completed in ClinicalTrials.gov (NCT03849872 and NCT03571594), but no results are available yet.

Another SST2 selective agonist, ONO-ST-468, was evaluated in comparison with octreotide in 1 study with male cynomolgus monkeys, showing similar GH suppression (101). No trials in human subjects exist to date.

Future Perspectives With New Drugs

The development of new drugs of the SRL class has the potential to improve acromegaly treatment, facilitating treatment adherence and perhaps presenting an increased efficacy in comparison with fg-SRLs and even pasireotide. Also, some drugs may also have a better safety profile, with less deleterious effects on glucose metabolism.

Conclusion

In conclusion, fg-SRLs are currently the mainstay in the medical management of acromegaly and are indicated for the majority of patients as first-line medical therapy, despite presenting moderate efficacy. The development of biomarkers of response to treatment and the use of these biomarkers to guide clinical decision making will improve the management of patients with acromegaly, increase control rates, and reduce morbimortality and treatment costs. The development of different formulations of existing drugs has the potential to decrease the impact of therapy on patients’ QoL. Additionally, the availability of new drugs that can impact patients’ QoL, have higher efficacy, better safety profile and be useful in patients who do not respond to currently available treatments is essential to improve acromegaly care. Therefore, the future of this class of tumor-directed drugs is promising, and these drugs will probably continue to be the mainstay of acromegaly medical treatment.