Acromegaly is a chronic, systemic disease characterized by high levels of growth hormone (GH) and insulin-like growth factor I (IGF-I) that is nearly always caused by a somatotroph pituitary adenoma (or somatotropinoma) [1], [2]. Persistent exposure to elevated levels of GH and IGF-I is associated with many comorbidities, including osteoarthropathy, respiratory disease, and metabolic complications related to hyperglycemia, insulin resistance, and lipid disturbance [3]. The clinical presentation of acromegaly is insidious, and 10-year delays in diagnosis are common. The physical findings for this disease include facial changes with acral enlargement, headaches, paresthesia, and chronic joint pain [4]. Cardiovascular disease and respiratory and cerebrovascular disorders are common causes of mortality in acromegaly. More recent studies also point to cancer as an important cause of death in these patients [2].

Surgical resection of the somatotropinoma is the treatment of choice for most patients [5]. However, even in reference centers for treatment of pituitary diseases, biochemical remission is only achieved in approximately 50% of patients [6], [7]. So, roughly half of the patients with acromegaly will need adjuvant therapy, which is mainly medical therapy [5].

Somatostatin receptor ligands (SRLs), dopamine agonists (DA), and GH receptor antagonists are the drug classes of current acromegaly treatment [5]. The first-generation SRLs (fg-SRLs) octreotide LAR and lanreotide autogel are the cornerstone of the medical management of acromegaly [8]. They act mainly via interaction with somatostatin receptor subtype 2 (SST2) and subtype 5 (SST5), but with lower affinity for the latter (Table 1) [9]. Fg-SRLs induce IGF-I normalization, the current biochemical remission criterion, in up to 50% of patients [10], [11]. These drugs have been used for several years, and they have known and acceptable safety profiles. On the other hand, they are injectable drugs intended for lifelong treatment, and patients may experience injection-associated pain or technical problems with injection (such as clogging and difficulty in completing dose administration) [12]. In a study with 105 patients with acromegaly, 83% of patients reported pain during injection, while 68% reported pain for hours and 49% for days after injection [13]. Moreover, gluteal nodules have been detected on computed tomography in 67% of patients being treated with injectable SRLs [14]. Approximately half of patients receive their injections in a doctor´s office, outpatient hospital, or clinic, with the inconvenience of travel to these facilities [13].

In addition, it has been demonstrated that IGF-I levels vary in the period between SRL injections [15]. In this study, IGF-I levels in patients controlled with fg-SRLs were lower one week after injection and higher just before the next injection [15]. Furthermore, despite receiving a stable dose of long-acting SRL to treat acromegaly, a subgroup of patients with normalized IGF-I reported worsening of acromegaly symptoms at the end of the cycle between injections [13]. These symptoms included swelling of soft tissues, headache, joint pain, and carpal tunnel syndrome [13].

Octreotide may also be administered orally, twice daily [9]. In a phase 3 trial including 151 patients with IGF-I levels < 1.3 x ULN on fg-SRL treatment, 62% of patients maintained response (defined as IGF-I < 1.3 x ULN and integrated 2 hours GH < 2.5 ng/mL) at the end of treatment (up to 13 months) [16]. More recently, in a double-blind, placebo controlled trial, IGF-I levels remained normal in 58.2% of patients in the treatment arm and 19.4% of patients in the placebo arm [17]. Predictors of oral octreotide responsiveness include good IGF-I control (IGF-I ≤1 x ULN) and/or GH control (GH < 2.5 ng/mL) with low or mid doses of fg-SRLs [16], [17]. In the MPOWERED trial, 92 patients responsive to oral octreotide (IGF-I < 1.3 x ULN) were randomly assigned to oral octreotide (n=55) or injectable SRL (n=37) [18]. After 36 weeks, 91% of patients in the oral octreotide arm and 100% of patients in the injectable SRL arm maintained IGF-I < 1.3 x ULN, showing non-inferiority when compared to injectable fg-SRL [18]. In both studies, adverse effects were mostly mild and comparable to fg-SRL, and no new or unexpected safety signals were observed [17], [18].

CAM2029 represents a novel formulation of octreotide subcutaneous depot that was developed to allow SC monthly injection [19]. It is a formulation based on lipids that enables the use of a prefilled, single-dose pen injector with 20 mg per dose for self-administration, which makes it more convenient [19]. In a phase 2 study that evaluated CAM2029 in patients with acromegaly and well differentiated neuroendocrine tumors with carcinoid symptoms, biochemical control of acromegaly and symptom control of carcinoid syndrome was maintained [20]. It was evaluated in a phase 3 placebo controlled study including 72 patients (48 in CAM2029 arm and 24 in placebo arm) with normalized IGF-I levels under octreotide LAR or lanreotide autogel treatment [21]. CAM2029 was superior to placebo in maintaining mean IGF-I ≤ULN at week 22 and week 24 (72.2% vs 37.5%, p = 0.0018). Median time to loss of response (IGF-I >ULN) was 8.4 weeks in the placebo arm and not reached in the CAM2029 arm. CAM2029 was also superior with respect to quality of life, treatment convenience, and patient satisfaction. Similar to oral octreotide, CAM2029 was well tolerated, and its safety profile was not different from that of currently approved injectable SRL formulations.

Paltusotine is a novel, oral, highly selective SST2 agonist that is in development [22]. In this review we will describe the pharmacokinetics, pharmacodynamics, clinical data, safety, and the possible role of paltusotine in the management of acromegaly.

Paltusotine is a small, nonpeptide, highly selective SST2 agonist (Fig. 1) [23]. It intrinsically permeates the intestinal epithelium without the need for absorption enhancers, which allows oral administration, with an oral solution bioavailability of 70% [22]. It presents affinity for SST2 similar to that of currently available fg-SRLs, and a > 4000-fold selectivity for this receptor subtype over the others (Table 1) [22], [24].

A phase 1, first-in-human, randomized, double-blind, placebo-controlled study was conducted in healthy volunteers to assess pharmacodynamics, pharmacokinetics, safety, and tolerability [22]. The single-dose cohorts included 55 individuals who were randomized 6:2 to ascending doses of paltusotine (1.25, 2.5, 5, 10, 20, 40, and 60 mg) or placebo. Pharmacodynamics were assessed in the single-dose cohorts using GHRH-analog stimulated GH levels to evaluate the ability of paltusotine to inhibit GHRH-stimulated GH secretion [22]. Multiple-dose cohorts enrolled a total of 36 individuals and randomized 6:3 to once-daily oral paltusotine capsules or placebo at doses of 5 mg for 7 days, and 10, 20, and 30 mg daily for 10 days. Pharmacodynamics were assessed in the multiple-dose cohorts using IGF-I measurements.

A 3-way, single-dose crossover cohort was used to evaluate food effect (30 min after a high-fat, high-calorie breakfast) and relative bioavailability of the capsule formulation compared to the oral solution [22]. Paltusotine was rapidly absorbed in the single-dose cohort, with a median peak concentration being reached at 1.3 to 2.2 hours after drug administration and a half-life of 22 to 29 hours under fasting conditions [22]. Peak concentration increased in a dose-dependent manner from 1.25 mg to 20 mg, but from 40 to 60 mg there was no increase. When administered with a standard high-fat, high-calorie meal, the plasma peak concentration was lower and the time to reach peak concentration was higher (3.0 h), with a similar half-life. GHRH-stimulated GH secretion showed dose-dependent suppression with paltusotine as the dose increased from 1.25 mg to 20 mg [22].

In the multiple-dose cohorts, paltusotine presented a dose-proportional increase in the peak concentration for doses from 5 mg to 20 mg, whereas from 20 mg to 30 mg, the increase was not dose-proportional [22]. Paltusotine steady state was reached after 3 to 5 days of daily administration, and the mean half-life was 42 to 50 hours for doses from 10 mg to 30 mg. In this cohort, IGF-I concentrations were reduced, reaching near-maximum suppression after 7 days, which was supported for 4 days after the 10-day period of paltusotine administration. After that, IGF-I concentrations began to rise, reaching pre-treatment levels on day 20. Doses of 10 mg, 20 mg, and 30 mg induced IGF-I decreases of 37%, 37%, and 30%, respectively, after 10 days of treatment, while in the placebo group, a 2.4% increase was seen.

In the food effect cohort, it was shown that capsules taken with a high-fat, high-calorie meal demonstrated significantly lower maximal concentrations and area under the drug concentration curves compared to when taken in the fasting state. For this reason, paltusotine capsules used in the phase 2 trials were administered in the morning after an overnight fast, followed by a 2-hour post-dose fast. The phase 1 investigators concluded paltusotine suppresses GH and IGF-I in a dose-dependent fashion, with a safety profile similar to those of approved SRLs [22]. The food effect observed with the capsule formulation of paltusotine was addressed by the development of a second-generation tablet formulation for use in phase 3 trials (see Section Phase 3 Formulation Development below).

Paltusotine is mainly excreted in feces (89.9%), with minimal excretion in urine (3.9%) [25]. Also, plasma peak concentrations, time to reach peak concentrations, and half-life were similar among controls and patients with mild, moderate, or severe hepatic impairment, indicating that there is no need for dose adjustment [26]. Side effects were mostly gastrointestinal, affecting about 30% of patients, and mild elevation of pancreatic enzymes affected around 10% of participants. These findings were similar and consistent with those observed for other SRLs [26].

Two phase 2 trials were conducted to evaluate the efficacy, safety, and pharmacokinetics of paltusotine in patients with acromegaly: ACROBAT Evolve and ACROBAT Edge.

ACROBAT Evolve was a phase 2 double-blind, placebo-controlled, randomized withdrawal study designed to evaluate safety, pharmacokinetics, and efficacy of paltusotine in patients with acromegaly treated with fg-SRLs who had normal IGF-I concentrations. It included 13 patients, and enrollment was stopped due to positive results of ACROBAT Edge [27].

This phase 2 study evaluated the safety, efficacy, and pharmacokinetics of paltusotine in patients with acromegaly who were treated with fg-SRLs alone or in combination with cabergoline or pegvisomant. It was an open-label, multicenter, multinational, single-arm exploratory, prospective, nonrandomized trial in which uptitration of paltusotine dose was conducted in a double-blinded manner [28].

The study comprised a 4- to 6-week screening period, a 13-week treatment period with paltusotine, and a 4-week washout period. IGF-I was measured at visits 1b and 2 during the screening period to analyze eligibility (ie, patients presenting either complete or partial response to standard treatment [depot SRL alone or in combination with cabergoline or pegvisomant]). Current standard treatment was interrupted at 4 weeks (visit 1b) and cabergoline or pegvisomant at 2 weeks (visit 2), respectively, before paltusotine was initiated. Patients received paltusotine 10 mg at visit 3. The dose of paltusotine could be increased in 10-mg increments up to 40 mg at weeks 4, 7, and 10, according to IGF-I concentrations, which were measured at weeks 2, 5, and 8. Uptitration occurred during the 13-week paltusotine treatment period if the patient tolerated the drug and when IGF-I was > 0.9 x ULN measured at week 2 and 5 or > 1.0 x ULN measured at week 8.

A total of 47 patients were enrolled and allocated in 5 groups according to prior SRL regimen (monotherapy or combination with another drug) and IGF-I status [28]. Group 1 consisted of patients on fg-SRL monotherapy, with elevated IGF-I concentrations (1.0 < IGF-I x ULN < 2.5) and was used for primary analysis. The primary endpoint was the change in IGF-I measurements at week 13 (or the end of paltusotine treatment for those who did not complete treatment) in patients in group 1 (28).

Groups 2-5 formed an exploratory cohort. Patients using a combination of an fg-SRL with a dopamine agonist (cabergoline) were included in groups 2 and 3 if they had elevated or normal IGF-I levels, respectively. Groups 4 and 5 included patients with normal IGF-I measurements under treatment with pasireotide LAR or fg-SRL plus pegvisomant, respectively.

Group 1 included 25 patients with baseline IGF-I levels of 1.34 x ULN (IQR: 1.08, 1.47 x ULN) [28]. After 13 weeks of treatment, IGF-I levels remained stable, with a median change of –0.03x ULN (IQR: −0.11 to 0.11 × ULN; P =.6285). Two patients discontinued paltusotine during the treatment period and 23 completed this period, from which 20 (87%) presented IGF-I levels within 20% of baseline or lower at the end of the 13 weeks. After this period, paltusotine was withdrawn and IGF-I concentrations were reevaluated after 4 weeks, showing a 39.0% (IQR: 28.8% to 63.3%; p <.0001) increase. A similar pattern was observed with GH concentrations. The final paltusotine dose was 40 mg in 18 patients, 30 mg in two, 20 mg in two, and 10 mg in the remaining patient.

Groups 2 and 3 consisted of 15 patients using fg-SRLs combined with cabergoline, which presented a median IGF-I of 1.21 x ULN (IQR: 0.93-1.50 x ULN) at baseline. In these groups, cabergoline was withdrawn and the fg-SRL was changed to paltusotine. An IGF-I increase of 0.28 x ULN (IQR: 0.15-0.99 x ULN; p =.0020) was observed at week 13 (cabergoline contribution). A further IGF-I increase of 22.1% (IQR: 3.7%-36.7%; p=.0067) was observed after the washout period (paltusotine contribution). The dose of paltusotine was uptitrated to 40 mg/day in most patients. Group 4 was composed of complete responders to a stable dose of pasireotide LAR (n=4), and group 5 included complete responders to a stable dose of octreotide LAR or lanreotide depot plus pegvisomant (n=3). Both groups were too small to reach conclusions about paltusotine efficacy; however, these participants contributed with information on safety and tolerability [28].

Plasma levels of octreotide and lanreotide were measured at baseline and at week 13 to investigate whether maintenance of IGF-I levels was due to residual effects of long acting fg-SRLs [28]. By week 7, octreotide concentrations were below the lower limit of detection, and by week 13 (17 weeks after last dose of fg-SRL) lanreotide had decreased by 77.3%. Nevertheless, no difference was found in median IGF-I change from baseline to week 13 between patients previously treated with octreotide or lanreotide. Also, IGF-I increase after paltusotine withdrawal was also similar between them.

Clinical parameters were evaluated using the Acromegaly Symptoms Diary (ASD), which was developed by Crinetics Pharmaceuticals, Inc (San Diego, CA) in accordance with US Food and Drug Administration patient-reported outcomes guidance. The ASD consists of a 7-item patient reported outcome measurement for assessment of symptoms associated with acromegaly (headache, joint pain, sweating, fatigue, leg weakness, swelling, numbness/tingling) [29]. The symptoms experienced in the last 24 h were rated on an 11-point numeric scale ranging from 0 (no symptoms) to 10 (worst symptoms). Total scores ranged from 0 to 70 (worst state). Sleep difficulties and short-term memory impairment were also evaluated but not included in the total score [29]. The median ASD score was low in ACROBAT Edge, (12.00 [IQR: 4.21-23.93] n=20) and showed no significant change from baseline to week 13 nor after paltusotine was withdrawn [28]. The Patient Global Impression of Improvement (PGI-I) scale was completed at week 13 [28]. Compared to baseline, 11 (23.4%) patients considered “very much improved” or “much improved”, while 26 (55.3%) patients had “minimally improved” or reported “no change”. No degree of worsening was reported.

Paltusotine was well tolerated; the most frequently reported adverse events (AE) were related to acromegaly symptoms: headache, arthralgia, fatigue, hyperhidrosis, paresthesia, and peripheral swelling [28]. Diarrhea was also commonly mentioned. Two serious AEs were reported, but neither of them was considered related to paltusotine. No patients discontinued treatment due to AEs and no rescue treatment was necessary [28].

Although ACROBAT Edge showed promising results, the short-term treatment period and the absence of medical treatment–naïve patients with active acromegaly resulted in the need for further investigation. To that end, patients included in both ACROBAT Edge and Evolve could be included in the extension study, ACROBAT Advance. Also, the phase 3 PATHFNDR-2 study is designed to address the utility of paltusotine in medically untreated patients.

ACROBAT Advance is an ongoing single-arm, open-label extension study designed to evaluate long-term paltusotine safety and efficacy [27], [30]. Eligibility criteria include completion of the parent paltusotine studies (ACROBAT Evolve or ACROBAT Edge). After the four-week withdrawal period in ACROBAT Edge and Evolve, paltusotine was re-initiated at a 10-mg dose of the capsule formulation, with the possibility of 10-mg dose increases according to patients’ IGF-I concentrations. If IGF-I levels were not normalized after paltusotine dose stabilization, participants could receive additional treatment with cabergoline or pegvisomant.

Forty-three patients were enrolled in ACROBAT Advance (32 from Edge and 11 from Evolve, representing 88% of eligible patients) [30]. Year 2 interim analysis demonstrated that IGF-I concentrations remained stable throughout the study: median (IQR) at baseline (on fg-SRL) was 1.15 x ULN (0.84, 1.46; n=43); 1.08 x ULN (0.87, 1.26; n=37) at week 51, 1.01 x ULN (0.85, 1.28; n=27) at week 77, and 1.10 x ULN (0.96, 1.45; n=10) at week 103. Growth hormone levels also remained stable over time. More data are being collected in the ongoing study.

Median ASD scores were 8.6 (IQR: 3.57, 20.14; n=21) at baseline and 8.0 (5.0, 18.0; n=14) at week 77. At 52 weeks in the study (or at the last visit for those who dropped out from the study), patients were asked to choose their preferred treatment option: the current treatment (paltusotine) or the previous treatment (SRL depot injections) [30]. Among 36 patients who responded, 32 (89%) preferred once-daily oral paltusotine, 2 (5.5%) preferred their previous injections, and 2 (5.5%) had no preference.

The paltusotine safety profile was very similar to what was described for ACROBAT Edge [30]. The most common AEs were headache (30.2%), arthralgia (25.6%), and fatigue (18.6%). No serious drug-related AEs were reported.

Limitations of the capsule formulation include the food effect and the lack of dose-proportional increases in drug exposure above the 40-mg dose. In addition, the capsule formulation requires acidic gastric pH for optimal absorption. For these reasons, a second-generation, spray-dried dispersion (SDD) tablet formulation, with improved solubility characteristics, was developed for use in the phase 3 trials. The tablet was first compared to the capsule in a relative bioavailability study in healthy volunteers. A clinically significant reduction in systemic exposure was observed when SDD tablets were co-administered with high-fat, high-calorie meals, but only when post-dose fasting periods were shorter than 1 hour. Proton pump inhibitors reduced absorption of paltusotine for both formulations; however, the extent of this reduction is unlikely to be clinically significant for the tablet formulation [31]. Results from this study confirmed that a 1-hour post-dose fast period is appropriate for use of the tablets in phase 3 trials.

PATHFNDR-1 is a phase 3, randomized, placebo-controlled, multicenter study to evaluate the safety and efficacy of paltusotine in patients with acromegaly treated with long-acting SRL monotherapy [32]. The study included patients with acromegaly treated with a stable dose of fg-SRL and normal IGF-I concentrations (≤ 1.0 x ULN). The primary endpoint was the proportion of patients who maintained IGF-I ≤1.0 × ULN at the end of the randomized controlled phase. Secondary endpoints were IGF-I and ASD change from baseline and proportion of patients who maintained GH < 1.0 ng/mL at week 34. Tumor volume was centrally assessed by magnetic resonance imaging. After the core phase, patients could opt for continuing in an open-label extension.

Patients were randomized 1:1 to receive paltusotine or placebo for 36 weeks. During the first 24 weeks, paltusotine could be titrated based on IGF-I levels and tolerability [32]. Dosing was started at 20 mg, with an automatic increase to 40 mg after two weeks based on tolerability. If patients’ IGF-I measurements increased to > 0.9 x ULN while taking paltusotine 40 mg, the dose was further uptitrated to 60 mg.

Patients on paltusotine 60 mg who presented with IGF-I ≥ 1.3 x ULN in two consecutive laboratory tests and exacerbation of acromegaly signs and symptoms received rescue with the pre-trial therapy [32]. Eligible patients could participate in an open-label extension after completing the randomized controlled phase.

Fifty-eight patients were enrolled in this trial—30 to paltusotine and 28 to placebo. Among patients in the paltusotine group, 5/30 (83%) maintained normal IGF-I values after 34 to 36 weeks, versus only 1/28 (4%) in the placebo group (p < 0.001), thus meeting the primary endpoint [32]. All three secondary endpoints were also met. IGF-I change from baseline was significantly lower in the paltusotine group in comparison to the control group (+0.04 vs +0.83 x ULN, p < 0.001). More patients in the paltusotine arm maintained GH < 1.0 ng/mL than in the placebo group (87% vs 28%, p = 0.0003). The ASD results demonstrated that acromegaly signs and symptoms were stable for the paltusotine group but worsened for the placebo group (-0.6 vs +4.6; p = 0.02). Out of 30 patients in the paltusotine group, only two received rescue medication, and one was discontinued due to AE. In the placebo group, 17 out of 28 patients received rescue medication [32]. Paltusotine was well tolerated, with the most common AEs being consistent with either SRL therapy or acromegaly [32]. As expected, diarrhea, abdominal pain, and nausea occurred more often in the paltusotine group. One serious AE (SAE) occurred in the placebo group. There were no discontinuations due to AEs or deaths in the study.

PATHFNDR-2 is a phase 3 randomized, controlled, multicenter study to evaluate the safety and efficacy of paltusotine in patients with non–pharmacologically-treated acromegaly (naïve, drug interrupted for at least 4 months prior to study entry, or washout). Patients included in the washout group agreed to stop their current medication (SRL depot) for a period of 3-4 months, and an IGF-I increase of at least 30% was necessary for inclusion. This study enrolled 111 patients from 79 centers around the world and is still ongoing.

Quality of life has been given increasing importance in the management of acromegaly [1]. It is well known that that quality of life may remain impaired, despite long-term biochemical control [33], [34], [35]. Geraedts and colleagues [33] describe that, although medical management would reasonably improve quality of life, convincing results of this association are still missing.

As previously mentioned, injectable SRLs are associated with injection site reactions and pain, which may have an impact on patients’ quality of life. Moreover, treatment with these drugs is associated with IGF-I variability, with a nadir seven days after injection and a progressive increase afterward [15]. This may be responsible for the worsening of clinical symptoms experienced by some patients at the end of the injection cycle [13].

In this context, an oral drug administered once a day, such as paltusotine, may be of important benefit for some patients who may have quality of life impaired by injections or variability of clinical symptoms. Also, due to the shorter half-life of paltusotine, in case of adverse effects, it can be stopped with rapid elimination from circulation. Finally, it allows faster titration, possibly reaching biochemical control more rapidly.

Another interesting point is to evaluate whether there might be any predictors of paltusotine response, which would identify the best candidates for treatment with the drug. In this context, it should be assessed if known and robust predictors of response to fg-SRLs (such as SST2 expression, cytokeratin granulation pattern, AIP mutation or expression) are also associated with response to paltusotine [9]. Since paltusotine is highly selective for SST2, it would be reasonable to think that expression of this receptor is associated with response to the drug. Prediction models of response to fg-SRL can applied to evaluation of paltusotine [36]. This would allow for paltusotine treatment to be based on a precision medicine model, rather than a model of trial and error.