Oral octreotide capsules for acromegaly treatment: application of clinical trial insights to real-world use

ABSTRACT

Introduction

Acromegaly is a rare endocrine disorder usually caused by a benign growth hormone‒secreting pituitary adenoma. Surgical adenoma resection is typically the first line of treatment, and medical therapy is used for patients with persistent disease following surgery, for adenoma recurrence, or for patients ineligible for, or declining, surgery. Approved somatostatin receptor ligands (SRLs) have been limited to injectable options, until recently. Oral octreotide capsules (OOC) are the first approved oral SRL for patients with acromegaly.

Areas covered

We review published reports and provide case study examples demonstrating practical considerations on the use of OOC. Using two hypothetical case scenarios, we discuss current treatment patterns, breakthrough symptoms and quality of life (QoL), efficacy of SRLs, OOC dose titration, evaluation of OOC treatment response, and incidence and management of adverse events.

Expert opinion

OOC are an option for patients with acromegaly including those who experience breakthrough symptoms, who have preference for oral therapies, or other reasons for declining injectable SRLs. OOC have been associated with improved patient-reported QoL measures compared with those reported for lanreotide and octreotide. Continued real-world experience will determine whether OOC, alone or in combination with other therapies, provides further advantages over current injectable acromegaly treatments.

KEYWORDS:

• Acromegaly
• case study
• dose titration
• HRQoL
• oral octreotide capsules
• OOC
• pituitary adenoma
• somatostatin receptor ligand

1. Introduction

Acromegaly is a rare endocrine disorder caused by excess circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-I) levels, typically resulting from a benign GH-secreting pituitary adenoma, but can also result from extremely rare ectopic GH or GH-releasing hormone (GHRH) excess due to neuroendocrine tumors, pheochromocytoma, and/or tumors of the hypothalamus or lung [1–6]. The excess IGF-I and GH can lead to somatic tissue growth and a disruption of the negative GH feedback loop [1,7]. A meta-analysis reported a pooled global acromegaly prevalence of 5.9 (95% CI, 4.4–7.9) per 100,000 people albeit with considerable between-study heterogeneity [8]. The disease is typically present in the fifth decade of life (ages 40.5–47.0 years) [9], affecting males and females equally [10], with males usually diagnosed at a younger age (median difference of 4.5 years) [11]. Acromegaly affects multiple systems with a slow, insidious onset of symptoms over a period of a decade or more before diagnosis [10,12]. Patients may present with characteristic changes in facial features, arthritis, headache, hypertension, carpal tunnel syndrome, sleep apnea, and diabetes mellitus [12–14]. Other complications include cardiovascular and respiratory diseases, increased risk of colon polyps, hypopituitarism, and vertebral fractures [15,16]. The classic clinical presentation includes enlargement of the hands and feet, facial modifications (including frontal bossing and enlargement of the nose), snoring, and headaches [17]. Visual field disturbances can also occur due to direct central compressive effects of an expanding pituitary mass [18]. Although mortality in acromegaly has decreased over time, mortality risk still remains higher than healthy controls [1,19]. For example, a recent nationwide study from South Korea found that patients with acromegaly had increased mortality risk compared with the control group (hazard ratio [HR] 1.74; 95% CI, 1.38–2.19; p < .001) [20].

When suspected, confirmation of a diagnosis of acromegaly is achieved with a measurement of serum IGF-I >1.3 times the upper limit of normal (× ULN) for age. For patients with unclear results, a GH measurement after an oral glucose tolerance test can also be useful. In general, measuring GH after fasting overnight could inform complications or prognosis but is not deemed necessary for diagnosis [21].

Normalization of IGF-I and reduction of GH levels to <1.0 ng/mL, the primary treatment goals, lead to improved mortality rates and decrease comorbidities [1,22]. Surgical adenoma resection is the first-line approach for most patients and can result in immediate remission or even cure especially for small well-circumscribed adenomas [1,12,23,24]. However, 10% to 25% of patients with microadenomas and 40% to 60% of patients with macroadenomas do not attain remission following resection [1,12,22,25–27]. Due to the heterogeneity of pituitary surgery reports, prediction of outcomes is challenging [28]. In patients with persistent GH hypersecretion following surgery, medical therapy is used [1]. Injectable somatostatin receptor ligands (iSRLs), long-acting lanreotide and octreotide, represent the most commonly used first-line pharmacotherapy per management guidelines and expert consensus [1,29,30]. Other therapies include the multiligand SRL, pasireotide, the GH receptor antagonist pegvisomant, and dopamine agonists bromocriptine or cabergoline [1,24,30]. Lanreotide and octreotide achieve biochemical control rates of approximately 55% for both mean GH levels and for IGF-I normalization [25,31]. However, despite optimal biochemical control while on treatment, these iSRL therapies may not be associated with improved quality of life (QoL) [32–34].

The use of iSRLs may be associated with a significant treatment burden [30,35,36] including treatment-related injection site pain, as well as anxiety and frustration due to the logistics of iSRL administration requiring a visit to a trained health-care provider. Travel to a clinic, health-care facility, or infusion center may be challenging and/or costly and entail missing work. They may feel loss of autonomy having to adhere to the injection schedule in timeslots available. Patient travel schedules may interrupt injection schedules, causing missed or delayed doses [29]. Furthermore, the inadequate symptom control reported for iSRL therapy, especially in the final days of an injection cycle, can contribute to poor patient-reported outcomes [37,38].

Oral octreotide capsules (OOC) are an oral formulation of octreotide that uses transient permeability enhancer (TPE®) technology to enable temporary and reversible paracellular tight junction passage of octreotide between small intestinal epithelial cells. This process is similar to the natural physiological process used for food and nutrient absorption [26,39,40]. Currently, OOC is approved for use as long-term maintenance treatment in patients with acromegaly who have responded to and tolerated treatment with iSRLs based on the findings from three phase 3 trials [26,30,36].

Here, we address clinical considerations for patients with acromegaly on oral therapy by presenting illustrative case studies from a cumulative review of OOC clinical trials and other published reports. All cases are hypothetical clinical scenarios included for educational purposes.

2. Example case study 1

A female aged 46 years has a history of a 15-mm diameter intrasellar pituitary macroadenoma without optic chiasm contact found 7 years before her visit to a Pituitary Center. During the initial diagnosis, her prolactin level was minimally elevated and considered caused by the stalk effect. She presented to the Pituitary Center with worsening frequency and severity of headaches, mild frontal bossing, and enlarged hands (ring size 9) and feet (shoe size 10, increased from 9 over 2 years). After evaluation, she underwent pituitary surgery. At 3 months post-transsphenoidal surgery, her IGF-I level decreased (from 3.1 × ULN to 1.5 × ULN) but did not normalize. At her 6-month postoperative follow-up visit, clinical features of GH excess were apparent, including worsening headaches, sweating, and joint pain. Magnetic resonance imaging (MRI) revealed a 4-mm residual mass, and her IGF-I was 1.7 × ULN. Based on these results, iSRL therapy with deep subcutaneous long-acting lanreotide 90 mg every 4 weeks was prescribed. After 18 months of therapy, her IGF-I level was 0.8 × ULN. Despite apparent biochemical control, she reported worsening of headaches, fatigue, and joint pain toward the end of each monthly injection interval. She agreed to switching to OOC, and treatment was initiated 4 weeks after her last lanreotide injection at a dose of 20 mg twice daily 2 hours before breakfast or only eating 1 hour after each dose. Two weeks after initiating OOC, her IGF-I was 1.3 × ULN. OOC were titrated to 60 mg (40 mg in am, 20 mg in pm). After another 2 weeks, her IGF-I was 1.1 × ULN, resulting in further uptitration of OOC to 80 mg (40 mg twice daily). During her 3-month follow-up, she reported no worsening symptoms and remained on OOC with an IGF-I of 0.8 × ULN.

2.1. Clinical case study 1 points and relevant literature

2.1.1. Current treatment patterns for patients with acromegaly

In this case study, the patient transitioned to OOC due to inadequate symptom control during the entire injection interval despite achieving controlled IGF-I level ≤1 × ULN. OOC 20 mg twice daily was initiated 4 weeks after the last lanreotide injection. Target IGF-I levels (≤1 × ULN) and symptoms were controlled by gradual OOC uptitration to a total daily dose of 80 mg. Other available options for the medical treatment of acromegaly are included in Table 1.

Table 1. Medical therapies for acromegaly [1].

Therapy	Dose	Mechanism of Action	Specific Conditions for Prescription (if applicable)
Cabergoline	up to 2.5–5 mg/week oral administration	Acts on dopamine-2 receptors	IGF-1 <1.5–2 × ULN (most experts suggest <1.5)
Octreotide Octreotide LAR Lanreotide	50 μg subcutaneous injection, three times daily 10–40 mg intramuscular injection every 4 weeks 60–120 mg deep subcutaneous injection every 4–8 weeks	Signal through SST receptors to suppress growth hormone secretion and control somatotroph proliferation	First-line postoperative medical therapy in most patients and primary medical therapy in patients who are not suitable candidates for surgery or not willing to have surgery
Oral octreotide capsules	40–80 mg/day		Patients controlled on injectable octreotide/lanreotide who have injection-related treatment burden
Pasireotide LAR	40–60 mg intramuscular injection every 4 weeks		Second-line or third-line medical therapy in most patients, but first-line in select patients with predicted resistance to octreotide/lanreotide, adenoma growth or headache not responsive to octreotide/lanreotide, or non-response or intolerance to pegvisomant or octreotide/lanreotide – pegvisomant combination
Pegvisomant	10–30 mg/day, up to 40 mg/day, subcutaneous injection	Competitively blocks GH receptor signaling	Second-line medical therapy in most patients and first-line medical therapy in select patients with predicted resistance to treatment with octreotide/lanreotide and no adenoma growth concern
SRL-pegvisomant			Treatment with combined octreotide/lanreotide – pegvisomant is favored if tumor volume is large, patient has headache, control on SRL is inadequate, or diabetes is inadequately controlled with SRL or pegvisomant monotherapy; treatment with combined pasireotide LAR – pegvisomant is often third-line medical therapy and is favored if symptoms are relieved with SRL but patient is inadequately controlled on octreotide/lanreotide – pegvisomant, if large adenoma volume is non-responsive to octreotide/lanreotide – pegvisomant, or if patient does not have diabetes
SRL-cabergoline			Mildly elevated IGF-1 concentrations (<2 × ULN) on SRL monotherapy
Cabergoline-pegvisomant			Rarely used, data are scarce [41]

LAR, long-acting release; SST, somatostatin; ULN, upper limit of normal.

2.1.2. Breakthrough symptoms and assessment of patient QoL

In patients whose acromegaly is biochemically controlled (IGF-I ≤1 × ULN), over half report experiencing ≥1 acromegaly symptom, and of these patients, symptoms worsened toward the end of an injection cycle in ≤48% [29]. Reducing breakthrough symptoms is important given that symptoms in general negatively impact health-related quality of life (HRQoL) [29,37]. Among patients achieving biochemical control (IGF-I <1.3 × ULN or GH <2.5 ng/mL), >80% reported that symptoms interfered with daily life, leisure, and work activities [29]. For patients experiencing breakthrough symptoms on long-acting iSRLs, possible interventions include supplemental short-acting octreotide [42], decreasing the interval between long-acting iSRL doses [43], or combination therapy [44]. Regardless, these interventions may increase medication-related costs, and transition to OOC could be considered as an additional option.

A real-world analysis in the USA showed that patients frequently change acromegaly treatments for various reasons, as illustrated in this case study, and assessing adherence and persistence to treatment is paramount for ensuring optimal outcomes and QoL [45]. Long-term pharmacological management of biochemical control does not adversely affect QoL, compared to other modalities such as surgery and/or radiation, regardless of the monotherapy used [46].

In the global, phase 3, randomized, open-label, active-controlled MPOWERED trial (Maintenance of acromegaly Patients with Octreotide capsules compared With injections – Evaluation of REsponse Durability; NCT02685709), there was a numerically lower incidence of breakthrough symptoms in patients receiving OOC versus iSRLs based on descriptive statistics [30]. Similar outcomes were seen in this group of patients upon transition to OOC during the preceding run-in phase of the study. Of the patients who responded to OOC and subsequently entered the randomized controlled treatment (RCT) phase, 25% reported breakthrough symptoms at study entry compared with 7% at the end of the run-in phase. Significant improvements were also seen in the proportion of patients experiencing swelling of extremities (p = 0.01) and fatigue (p = 0.03) during this study phase [30]. Additionally, the HRQoL domains of Emotional Reaction, Treatment Satisfaction, and Treatment Convenience domains improved numerically in this group as measured using the validated Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) tool [30].

2.1.3. Response to OOC therapy

In this case, the patient transitioned to OOC therapy and maintained biochemical control with appropriate dose titration. The first phase 3, multicenter, open-label, dose-titration, baseline-controlled trial of OOC (CH-ACM-01; NCT01412424; N = 155) found that 65% of evaluable subjects who had ≥1 post‒first-dose efficacy assessment (95% CI, 58.4–74.2) were responders (defined as IGF-I <1.3 × ULN) for ≤7 months, and 62% (95% CI, 54.9–71.7) were responders for ≤13 months [26]. The phase 3, randomized, placebo-controlled, double-blind OPTIMAL trial (Octreotide capsules versus Placebo Treatment In MultinationAL centers; NCT03252353) assessed the efficacy and safety of OOC vs placebo across a 36-week treatment period [36]. Sixteen of 28 participants in the OOC group (58.2%) met the primary endpoint of achieving biochemical response (IGF-I ≤1 × ULN) compared with 5/28 (adjusted proportion, 19.4%) in the placebo group (p = 0.008; odds ratio [OR], 5.77; 95% CI, 1.44–28.21) at the end of 36 weeks. Patients who did not respond to OOC regained biochemical control upon reverting to their prior iSRL dose within one treatment cycle [36].

The subsequent phase 3 MPOWERED trial demonstrated noninferiority of OOC compared with injectable lanreotide or octreotide in patients who responded to both therapies. The adjusted difference in proportions between participants who demonstrated biochemical response on OOC (n = 50/55) vs iSRLs (n = 37/37) achieved the prespecified noninferiority criterion of the lower bound of the 2-sided 95% CI of −20% (95% CI, −19.9–0.5). MPOWERED also included a combined substudy of OOC and cabergoline for patients who failed to maintain biochemical response on OOC alone. IGF-I levels improved in most patients receiving the combination treatment [30,47].

Durability of the OOC response has been demonstrated across open-label extensions (OLEs) of the OPTIMAL and MPOWERED trials. In the MPOWERED OLE, >80% of patients maintained response at the end of the 3-year follow-up [47]. The OPTIMAL OLE demonstrated similar results; the overall responder rate at week 48 was 92.6%, and 13 of the 14 patients who completed the trial on OOC also completed the first year of the OLE as responders. Of note, neither OLE (MPOWERED nor OPTIMAL) demonstrated new safety signals [47,48].

2.1.4. OOC initiation and dose titration

The patient in case study 1 initiated OOC 4 weeks after the last lanreotide injection and underwent dose titration (20 mg to 80 mg) over a period of 4 weeks to achieve disease control. The timing of OOC initiation can take place at the physician’s discretion [49]. Each of the three clinical trials employed different OOC initiation protocols. During the CH-ACM-01 study, the first dose of OOC was given ≥4 weeks after the last iSRL dose [26]. The OPTIMAL study had patients initiate OOC on the day they would have received their next iSRL dose ±3 days [36]. In the MPOWERED study, OOC could be initiated at any time within the dosing interval, provided the interval between the last iSRL dose and the first OOC dose did not exceed the routine dosing interval by >3 days [30]. Post-hoc analyses of the data from the MPOWERED study did not find any significant increases in reported treatment-emergent adverse events (TEAEs) for participants who initiated OOC <3 weeks since their last iSRL injection (n = 26/40; 65%) compared with those who initiated ≥3 weeks since their last injection (n = 79/105; 75%) [50]. Per the current labeling, treatment may be initiated at any time following the last SRL injection and before the next injection would have been administered [49,51]; OOC dose is initiated at 40 mg/day, titrated in increments of 20 mg based on IGF-I levels and acromegaly signs and symptoms, with a maximum dose of 80 mg/day [49,51]. Conversely, the Pituitary Society update to treatment guidelines discusses that initiating OOC at the off-label dose of 60 mg/day could be considered in some patients based on safety results from the OPTIMAL OLE [11]. These results showed that patients receiving placebo during the OPTIMAL randomized phase and started on OOC 60 mg did not have increased adverse events (AEs) despite being OOC treatment-naïve and starting on a higher dose [11,48]. OOC can be titrated every 2 to 4 weeks based on IGF-I levels and clinical symptoms, which is more rapid than iSRLs (often titrated every 3 months) [11]. Timely titration may help reduce symptom burden and support biochemical control [11,49,51]. For most OOC-treated patients completing the OPTIMAL study, the final dose was above the starting dose of 40 mg/day (60 mg/day, n = 2/21; 80 mg/day; n = 13/21) [36].

2.1.5. Evaluation of treatment response

Adherence with meal timelines should be evaluated when the IGF-I response is not complete, especially after uptitration. Results of a single-dose, crossover pharmacokinetics study in healthy subjects demonstrated that administration of OOC 20 mg with food led to an approximate 90% decrease in the rate (C_max) and extent of absorption (AUC_0-t) [49,52]. Patients with acromegaly usually take many concomitant medications [53]. Coadministration of acid-reducing medications or other medications that alter the pH of the upper gastrointestinal (GI) tract may also alter the absorption and decrease OOC bioavailability [49,52]. Coadministration of OOC with antacids may require increased OOC doses [49,52].

Post hoc analysis revealed a relationship between prior effective iSRL (octreotide or lanreotide) dose and OOC dose needed to normalize IGF-I and control symptoms [54]. Of OOC responders who previously received a high dose of iSRLs, 45% completed the core trial on the lowest tested dose of OOC (40 mg) and 69% on low-mid doses (40–60 mg) in the CH-ACM-01 study [54]. In the OPTIMAL study, patients who previously received both low- and mid-to-high doses of iSRLs responded to OOC treatment, and the OR for both groups were similar and in favor of OOC versus placebo (OR [95% CI]: low dose 5.41 [0.26–165.99]; mid to high dose 5.86 [1.13–41.15]) [36]. Secondary analysis of the MPOWERED data demonstrated that baseline IGF-I levels are the solely significant factor predictive of OOC response, while other baseline characteristics are not predictive [55].

In patients with incomplete responses to OOC, consideration may be given to reversion to prior therapy, addition of a second agent, or an entirely new treatment regimen [30]. During the OPTIMAL trial, seven patients (25%) who were receiving OOC reverted to previous iSRL treatment, and patients requiring reversion reestablished their baseline biochemical response within a median of 4 weeks, the same duration as an iSRL administration cycle [36].

In the MPOWERED trial, the efficacy of OOC was assessed with coadministration of cabergoline for 14 participants who had moderately elevated IGF-I (defined as IGF-1 ≥1.3 to <2 × ULN) and mean integrated GH ≥2.5 ng/mL after treatment with OOC alone [56]. OOC (80 mg/day) with cabergoline (≤3.5 mg/week) administered for a mean duration of 25.4 weeks (standard deviation [SD], 14.1) [56] showed IGF-I levels had improved in most participants (n = 12, 85.7%). Of the 9 participants who began the substudy with IGF-I levels ≥1.3 × ULN, 5 (55.6%; 95% CI, 21.2–86.3) demonstrated a decrease in IGF-I to a predefined responder rate of <1.3 × ULN [56]. Six participants (42.9%) reduced their overall number of active acromegaly symptoms at the end of the combination therapy treatment phase compared with baseline, and all 14 (100%) participants maintained or reduced their overall number of acromegaly symptoms (95% CI, 16.9–68.8) [57].

3. Example case study 2

A male aged 57 years presented with long-term acromegaly, most likely for 10 years or more. He had originally sought treatment for headaches, and an MRI conducted 4 years before revealed a pituitary macroadenoma (1.6 × 1.5 × 1.1 cm) with no optic chiasm compression. Biochemical testing showed an IGF-I level of 2.7 × ULN and a GH level of 64 ng/mL. He underwent transsphenoidal surgical resection, and histologic evaluation confirmed a densely granulated GH adenoma. After surgery, his IGF-I returned to normal (0.6 × ULN), and after 3 months, the MRI showed no adenoma tissue remnant. However, 2 years later, he reported increased headaches, and MRI revealed a 5-mm lesion, possibly representing a recurrent adenoma, with slightly elevated (1.2 × ULN) IGF-I levels. The patient declined surgical intervention and was treated with cabergoline 0.5 mg twice weekly (off-label) for several months, but discontinued treatment because of persistent nausea and dizziness. He then presented to the Pituitary Center with fatigue, sweating, headache, sleep apnea, and worsening jaw protrusion. He was initiated on 20 mg twice daily OOC as injection treatments did not fit his lifestyle (e.g., traveling to receive treatment conflicted with his unpredictable work schedule and sense of independence). After 3 weeks, he reported nausea and abdominal pain, along with loose stools. He discontinued OOC and subsequently initiated self-injectable subcutaneous injections of pegvisomant.

3.1. Clinical case study 2 points and relevant literature

3.1.1. OOC indications and impact on adenoma

OOC are not currently approved for patients who have not received prior iSRLs, and published results are limited to individual case reports describing three patients who demonstrated a biochemical response to de novo OOC either alone or combined with cabergoline [58,59]. It is not yet known whether OOC are a viable option as primary treatment for patients naïve to medical treatment and further investigation is needed.

The patient in example case study 2 was successfully treated with transsphenoidal surgery for his pituitary adenoma but became a candidate for medical therapy when he presented with clinical and biochemical evidence of recurrent GH excess. Effects of iSRLs on adenoma shrinkage are influenced by both the timing of SRL therapy (primary vs adjuvant) and the size of the adenoma [60].

3.1.2. Incidence of GI AEs

Compared with injectable SRLs, no new or unexpected safety signals were detected with OOC or associated with the TPE delivery technology in any of the phase 3 studies [26,30,36]. Discontinuations due to TEAEs occurred during the phase 3 trials but rates were similar to the placebo and iSRL groups and the safety profile was similar to that of injectable octreotide [26,30,36].

In example case 2, this patient ultimately decided to discontinue OOC due to GI AEs. GI symptoms are a known effect associated with the SRLs (Table 2) [26,30,35,36,61]. Current results suggest that the incidence of AEs, including GI, is not dose related, and this may support decisions to uptitrate OOC doses. Results from the MPOWERED OLE phase demonstrated no reported safety issues for participants randomized to octreotide or lanreotide during the RCT phase and restarted on OOC >40 mg/day for the OLE [47]. The incidence of TEAEs during the OPTIMAL OLE was similar between patients who started on placebo and transitioned to 60 mg/day OOC during the OLE and patients who initiated OOC at the lowest dose of 40 mg/day at trial onset [48]. Interestingly, a phase 1 crossover study in patients with neuroendocrine tumors also found that higher doses of ≤80 mg OOC daily had a favorable safety profile, consistent with octreotide and lanreotide [62].

Table 2. Common gastrointestinal adverse events associated with acromegaly and currently approved somatostatin receptor ligands for acromegaly.

Therapy Type	Clinical Trial	Diarrhea	Abdominal pain or discomfort	Nausea	Flatulence	Constipation	Vomiting	Dyspepsia
Placebo [36]	OPTIMAL NCT03252353 N = 28^a	6 (21.4)	3 (10.7)	3 (10.7)	–	–	0	1 (3.6)
iSRLs [30]	MPOWERED NCT02685709 N = 37^b	5 (14)	2 (5)	1 (3)	6 (16)	3 (8)	^–	–
Octreotide (LAR) [35]	NCT00600886 N = 182^c	81 (45.0)	40 (22.2)	39 (21.7)	–	–	^–	–
Pasireotide (LAR) [35]	NCT00600886 N = 176^c	70 (39.3)	32 (18.0)	24 (13.5)	–	–	–	–
Octreotide capsules [30,36]	OPTIMAL NCT03252353 N = 28^a	8 (28.6)	4 (14.3)	6 (21.4)	–	–	4 (14.3)	3 (10.7)
	MPOWERED NCT02685709 N = 55^b	4 (7)	3 (6)	9 (16)	10 (18)	1 (2)	–	–

Data are n (%). AE, adverse event; iSRL, injectable somatostatin receptor ligand; LAR, long-acting release; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.

^aTEAEs were defined as all AEs that occurred after random assignment (i.e., date of onset was on or after the date of random assignment) and on or before the end of treatment (last dose of blinded study drug) in the double-blind, placebo-controlled period. A patient could be counted only once within each category. AEs were coded using MedDRA v18.1.

^bTEAEs were defined as AEs with an onset on or after study drug initiation and before the end of treatment in the randomized treatment phase. AEs were coded using MedDRA v18.1.

^cTwo patients randomized to the octreotide LAR treatment arm received pasireotide LAR in error. These two patients are included in the pasireotide LAR treatment arm for the purposes of the safety analysis.

3.1.3. Management of GI AEs

In phase 3 OOC clinical trials, mild or moderate GI disorders, such as nausea and flatulence, were the most frequently reported TEAE but were transient in nature in most cases. Cholelithiasis was also commonly reported [26,30,36]. In the OPTIMAL trial, the median time to GI AE onset was 68 days, and most resolved with a median duration of 8 days while subjects remained on treatment [36].

There are no formally studied approaches to the management of GI AEs. Patients with acromegaly may use antisecretory protein pump inhibitor/histamine H2 receptor agonists, antacids, and laxatives at significantly higher frequency than healthy individuals [63]. As noted above, patients using such medications may require higher OOC doses.

Specific guidelines for managing GI effects have not been established. It is unknown whether predictors may identify patients prone to GI side effects. The patient in case study 2 discontinued OOC due to GI AEs, consistent with results of the OPTIMAL study [36]. Thus, understanding susceptibility to these events may enhance treatment adherence. Further investigation is needed to determine how to both prevent and manage GI events to avoid treatment discontinuation and improve HRQoL.

4. Conclusions

OOC represent a viable well-tolerated long-term therapeutic alternative to iSRLs with similar efficacy in patients responsive to both OOC and iSRLs [30]. OOC may also improve patient QoL through symptom management and route of administration. Indeed, based on the Acro-TSQ scores, numerically improved patient-reported treatment convenience and satisfaction with OOC vs iSRLs may lead to increased treatment adherence in some patients [30].

Timely uptitration of OOC to therapeutic dose can optimize patient outcomes [11]. However, this shift to a more rapid uptitration compared with slower timelines for long-acting injectable therapies requires more frequent monitoring of IGF-I and acromegaly signs and symptoms during dose titrations. Adherence to fasting restrictions may not suit all patients and could potentially affect the transition to OOC [26,30,36,49].

Based on clinical trial and associated OLE results, OOC have transient AEs, mostly GI related, similar to other SRLs [36,61]. Although these events tend to resolve within the first 2 weeks after onset [36], physicians should counsel patients if they transition to oral therapy.

Limitations of OOC include a lack of trials in patients with no prior medical therapy for acromegaly. No predictors of OOC responses are specific to the oral route of administration that may preclude its use in populations where injectable forms of SRLs have shown clinical improvement. However, acromegaly is rare, which limits the number of eligible participants for clinical trials [9,32], thus presenting a research challenge for this disorder.

In summary, OOC broadens the currently available therapeutic options for treating acromegaly by providing clinical noninferiority and a comparable safety profile to conventional iSRLs for patients treated with both OOC and iSRLs [47]. Patient-reported improved HRQoL measures while on OOC further underscore the potential benefits of oral therapies. Improved QoL and symptom management have also been observed with off-label clinical use and could lead to an individualized treatment pathway. Differentiation from other investigational drugs in development, including the oral somatostatin receptor type 2 (SST2) receptor agonist, paltusotine, taken once a day, and new injectable subcutaneous formulations of octreotide once a month), is yet to be determined [59,64,65].

5. Expert opinion

Patients with acromegaly have historically been reliant on injectable medications as adjuvant therapy after surgery, while awaiting beneficial effects of radiation or, in some cases, as primary medical therapy [1,22]. Oral octreotide capsules (OOC) are approved for patients who have responded to and tolerated injectable somatostatin receptor ligands (iSRLs) [26,30,36]. Unlike injectable therapies, OOC allow the physician to rapidly titrate up the dose as early as every 2 weeks, based on insulin-like growth factor I levels and acromegaly symptoms [11,49]. OOC may be a particularly valuable treatment option for patients who experience breakthrough symptoms during the end phase of the injection cycle, as these may be less common with OOC compared with iSRLs. Patients may also have a preference for oral therapies, or other reasons for declining iSRLs. At the time of writing this article, there were reports of a shortage of certain doses of injectable octreotide, which may also prompt patients to choose to switch to OOC [66]. OOC were noninferior to iSRLs in MPOWERED, a randomized phase 3 trial that included patients responsive to both oral and injectable SRLs [30]. Results from the MPOWERED trial also suggested that OOC treatment may be associated with improved patient-reported quality of life measures, including Treatment Satisfaction and Treatment Convenience [30]. Open-label extension studies of both the MPOWERED (NCT02685709) and OPTIMAL (NCT03252353) phase 3 clinical trials, which followed patients for up to 3 years while receiving OOC, further showed that the effects of OOC on acromegaly disease control are durable [47,48].

We consider that the currently approved indication of OOC precludes prescription in clinical practice as first-line treatment after surgery in patients who have predictive factors of response to SRL (e.g., densely granulated GH adenomas). A clinical study in SRL-naïve patients is needed. Such a study could also establish the use of OOC in potential responder patients naïve to medical therapy [67].

In selected patients, OOC are a well-tolerated alternative, making it a viable treatment option [47,48]. Thus, future studies might explore the efficacy of higher doses of OOC in patients with acromegaly and potentially other patient populations, broadening the utility of OOC. Future directions may also include assessment of decreased calorie intake on bioavailability of OOC to decrease administration restrictions, protocol-driven dose titrations to optimize outcomes, use of OOC in combination regimens, and optimizing management of gastrointestinal adverse events.

Looking ahead, patients diagnosed earlier could have higher postsurgical remission rates (especially for smaller adenomas) as well as fewer complications due to less tissue exposure to excess growth hormone. Furthermore, surgical techniques, including medial cavernous wall resection, would likely lead to an improvement such that a greater proportion of patients could achieve surgical cure even for macroadenomas [23]. As knowledge of adenoma biology improves [68], personalized medical treatment based on adenoma histology and biomarkers will gain momentum in the field of acromegaly research. Oral therapies, including other oral molecules currently in clinical trials, have the potential to further enhance treatment options either as monotherapy or as part of a combination therapy. Health-related quality-of-life and patient-reported outcome measures should also be prioritized in a more holistic and individualized treatment approach to become a mainstay in practice [69].

Article highlights

• Acromegaly is a rare endocrine disorder with multiple therapeutic options. Until recently, all approved therapies were injectable, including injectable somatostatin receptor ligands (iSRLs) and pegvisomant.

• Oral octreotide capsules (OOC) are the only approved oral SRL option currently indicated for the treatment of acromegaly.

• In clinical trials, OOC were shown to be noninferior to iSRLs in patients previously controlled on either OOC or iSRLs, with improvements in symptom management and patient-reported quality of life measures versus iSRLs.

• The clinical program for OOC showed that they are well tolerated with no dose-related safety issues detected.

• The short half-life allows for rapid titration to an effective dose within weeks of initiating therapy

Declaration of interest

MF has received grants to their institution from Amryt/Chiesi, Crinetics, Ionis, and Recordati; has received occasional consulting fees from Camurus, Crinetics, Chiesi, Ipsen, Recordati.

LBN has received a consulting fee from Amryt/Chiesi, Ipsen, Recordati, and Pfizer, and is a grant recipient from Ipsen.

SLS is an advisory board member for and research investigator for Amryt/Chiesi.

SM is an advisory board member for Ionis, Crinetics, has received consulting fees from Ipsen, and is a grant recipient from Pfizer.

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

MF designed the study and wrote the initial outline, all authors performed a literature review, contributed to the outline and manuscript editing and all approved final versions of the manuscript.

Acknowledgments

Editorial support was provided by Gloria Bravante and Rebecca Myers of PRECISIONscientia, funded by Chiesi, under direction of the authors who performed the literature review, developed the manuscript outline, and participated in drafting the manuscript. All authors edited subsequent versions and approved the final version.

Additional information

Funding

This manuscript was developed with medical writing assistance from PRECISIONscientia, funded by Chiesi.