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Les Essentiels 2024 : New treatments for acromegaly, is the revolution underway ?

Justine Cristante1, Frederic Castinetti2

1Université Grenoble Alpes, CHU Grenoble Alpes, INSERM, CEA, IRIG Biosanté, 38000 Grenoble, France

2Aix Marseille Univ, INSERM, MMG, Department of endocrinology, La Conception Hospital, Assistance Publique Hopitaux de Marseille, Marseille, France

Corresponding author : Frederic Castinetti

La Conception Hospital – 147 Boulevard Baille – 13385 Marseille Cedex 05 – France

Email: Frederic.castinetti@ap-hm.fr

Phone: +33491383479

ORCID: 0000-0002-1808-8800

Keywords : Acromegaly, octreotide, lanreotide, paltusotine, transsphenoidal surgery

Disclosure : JC has nothing to disclose. FC has received research grants from Ipsen, Pfizer, Recordati rare diseases, and consultancy fees from Ipsen and Recordati rare diseases.

Funding: This article, part of the French Endocrine Society “Les essentiels”, is produced with the institutional support of Merck, Rhythm and Pfizer.

 

ABSTRACT

The first-line treatment for acromegaly is transsphenoidal surgery. Somatostatin receptor ligands are usually given if surgery fails, or in some patients as a pre-surgical medical treatment. The efficacy and tolerability of first-generation somatostatin
receptor ligands are well established, but they have unmet medical needs due to their mode of administration or side effects. We report here the results of new compounds that may be used in the near future as alternatives to the first-generation somatostatin
receptor ligands currently in use, as well as current data on their efficacy and tolerability: oral octreotide, paltusotine and long-acting subcutaneous octreotide are reviewed in detail, together with potential new compounds under investigation.
We also discuss their potential role in the therapeutic armamentarium of acromegaly.

 

INTRODUCTION

Acromegaly is a rare disease caused by a GH-producing pituitary adenoma. Symptoms include enlargement of the hands and feet, facial modifications, headaches, sweating, and joint pain1. A poorly controlled disease can lead to cardiac comorbidities,
colonic polyposis, and thyroid nodules. Patients with uncontrolled disease have increased mortality. The first-line treatment is pituitary surgery, but about 20% of patients with microadenoma and 40% of patients with macroadenoma are not cured and
require long-term medical treatment1–3.

To date, 4 treatments are available: Somatostatin Receptor Ligands (SRLs), either first-generation (Octreotide and Lanreotide, SRLgen1) or second-generation (Pasireotide, SRLgen2), dopamine agonists (Cabergoline, DA), and GH receptor antagonists (Pegvisomant).
The SRL treatments are administered as monthly intramuscular or deep subcutaneous injections and are associated with digestive adverse effects (AEs). Pegvisomant is administered as daily subcutaneous injections, while Cabergoline is taken orally.

The first treatments developed targeted the somatostatin receptor. Somatostatin inhibits the secretion of growth hormone (GH) via five somatostatin receptors (SST1 to SST5), which belong to the G protein-coupled receptor family and are differentially
expressed across various tissues. The pituitary mainly expresses SST2, SST5, and SST1 receptors4. Somatotroph adenomas often express higher levels of somatostatin receptors, particularly SST2 and SST55.

While Octreotide and Lanreotide selectively bind to SST2 (and to a lesser extent to SST5), Pasireotide binds to SST2, SST3, and SST5, with its binding to the latter receptor explaining the occurrence of hyperglycemia. All of these drugs are peptides.
Their mechanism of action leads to the activation of Gi signaling, thus inhibiting cAMP production and resulting in an antisecretory effect: in the pituitary, somatostatin inhibits the secretion of GH mainly by binding to SST2 and SST5. However, it
also promotes receptor internalization through phosphorylation, leading to desensitization, which may explain why some patients do not achieve normal IGF-1 levels.

Despite medical treatment and biochemical control, patients often experience persistent alterations in their quality of life and socioeconomic impact6,7. In uncontrolled patients, refusal to escalate therapy, variable IGF-1 levels, and non-compliance
with treatment are the major reasons for poor disease control8.

Thus, the development of new treatments with better efficacy, tolerance, and delivery mechanisms could help improve patient adherence and alleviate their burden.

This review will particularly focus on three drugs that have recently been approved or are in the process of approval by health authorities, or are in phase 3 trials. Treatments currently in phase 1 or 2 will be briefly mentioned at the end of this review.

 

MOST STUDIED NEW SOMATOSTATIN RECEPTOR LIGANDS

Oral Octreotide Capsules (MycapssaTM)

Oral octreotide is a modified octreotide acetate, prepared in an oily suspension called Transient Permeability Enhancer (TPE®), which allows the transient opening of intestinal tight junctions, thereby increasing drug absorption9.
In brief, octreotide is solubilized, lyophilized, and dispersed in a lipophilic medium before being packed in capsules with an enteric coating to prevent degradation by gastric enzymes (Oral Octreotide Capsules, OOCs). A phase 1 study showed that
the maximum concentration and half-life of OOC is similar to subcutaneous octreotide. Food intake decreased the absorption of OOCs by 90%10. Three phase 3 studies on OOCs have been published.

The first one, CH-ACM-01, an open-label study11, included 151 patients over 13 months. OOCs were started with 40 mg and could be increased to 80 mg between months 2 and 5. When IGF-1 remained normal on at least two successive visits, patients
entered the « Fixed Dose Period » for 2-5 months (maximum duration of « Dose Escalation Period » + « Fixed Dose Period » = 7 months) and could then participate in a 6-month extension period, for a total treatment duration of 13 months. In the modified intention-to-treat
(ITT) analysis, 65% of patients who switched from SC SRLgen1 to OOCs remained controlled up to 13 months (IGF-1 < 1.3 x the Upper Limit of Normal (ULN) and GH < 2.5 ng/mL). In the 6-month extension period, which enrolled 88 patients, 62% of
patients remained controlled. Side effects were experienced by 89% of patients, consistent with those already known with octreotide acetate.

The second phase 3 trial is the CHIASMA OPTIMAL trial12, a double-blind, multicentric study that aimed at evaluating the efficacy and safety of OOCs in patients controlled by SRLgen1. Fifty-six patients were randomized 1:1 to receive either
OOCs (starting dose 40 mg, then titrated depending on IGF-1 results) or placebo for 36 weeks. The primary endpoint was the maintenance of biological control defined as IGF-1 < 1.0 ULN. Thirty patients completed the study (n=21/28 in the OOCs group
vs. 9/28 in the placebo group). In the OOCs group, most patients (13/21) had the maximum dose of 80 mg. Among the patients who did not complete the study, 5/7 in the OOCs group stopped due to treatment failure vs. 18/19 in the placebo group. Other
patients stopped the study due to AEs. At the end of the study, in the ITT analysis, 58.2% (16/28 patients) of the OOCs group reached the primary endpoint versus 19.4% for placebo (p = 0.008, OR 5.77, 95% CI 1.44 – 28.21). Fifty-five patients (98.2%)
experienced at least one AE, including 27 patients (96.4%) in the placebo group. The most common AEs were digestive.

Patients who completed the OPTIMAL trial were eligible to enroll in the open-label extension (OLE) phase for 48 weeks. The objective is to assess long-term biochemical response and safety13. The published results are from an interim analysis:
no new safety signals emerged.

The last phase 3 study is the MPOWERED study14, an open-label, multicentric, randomized study that aimed at evaluating the non-inferiority of OOCs compared to SRLgen1, in a larger cohort of patients previously controlled by SRL. The primary
evaluation criterion was the proportion of patients with IGF-1 < 1.3 ULN at the end of the treatment phase, with non-inferiority defined as a difference between groups < 20%. The study lasted 62 weeks, with a run-in period of 26 weeks, during
which OOCs were tested and dosage escalated to reach biochemical control, defined as IGF-1 < 1.3 ULN and GH < 2.5 ng/mL. Biological responders were then randomly assigned (3:2) to either continue OOCs or return to their injectable SRL. The run-in
phase included 146 patients, and 116 patients completed this phase. Finally, 92 patients were randomized in the treatment phase, 55 in the OOCs group and 37 in the SRL group, and 89 patients completed the study. At the end of the treatment period,
91% of patients maintained biochemical control in the OOCs group vs. 100% in the SRL group, and the non-inferiority criterion was achieved. In line with previous data, 71 of the participants experienced at least one AE, most of them gastrointestinal.
When considering the whole cohort of 146 patients, 94 patients (64%) were biochemical responders.

The open-label extension phase of MPOWERED was also recently published15. Sixty patients accepted to enrol in the OLE phase (35 from the previous OOCs group, 19 from the SRL group, and 6 from a combination substudy). The OLE phase could last
up to 5 years, and the study presents the response depending on the duration of follow-up in the OLE phase. Forty-five patients (75%) completed the OLE study, defined as switching to a commercial drug or expanded access program, or patients who were
receiving OOCs at the time of study termination. Fifteen patients stopped the OLE. The presentation of results is somewhat complex to understand, but to summarize, depending on the year, between 87.5% and 93.5% of patients maintained biochemical control.
No new safety signals were detected.

Since 2021, OOCs have been considered a reasonable treatment option by the Pituitary Society16 for patients with controlled acromegaly under SRLgen1, except for patients whose tumor characteristics are associated with SRL resistance (MRI T2
hyperintensity or sparsely granulated tumors).

OOCs is the only medication to date approved by the European Medicines Agency17 and the Food and Drug Administration18, under the commercial name Mycapssa™ (Chiesi Farmaceutici). However, it is still not available in Europe. The
FDA approved its use in patients who have demonstrated a complete or partial response to SRLgen1 treatment but not for treatment-naïve patients.

 

Paltusotine

Paltusotine (Crinetics Pharmaceuticals) was discovered through a medicinal chemistry approach to select an oral non-peptidic molecule that promotes Gi signaling over internalization. The compound was designed and selected to be a potent and selective
agonist of SST2 without stimulating SST5, with efficient digestive absorption to allow oral delivery. It should also be stable at room temperature and have a pharmacokinetic profile permitting once-daily dosing19.

A Phase-1 study20 showed that the maximal concentration is reached between 1.3 and 2.2 hours with a half-life of elimination between 22 and 34h. The minimum serum IgF1 concentration was reached after 7 days of administration. IgF1 suppression
is dose-dependent between 5 and 30mg. For unknown reason, increasing the dose to 40mg have no additional effect on IgF1 suppression. Additionally, Paltusotine absorption is limited when taken with food, resulting in a 7-fold decrease in maximal serum
concentration.

Two Phase 2 studies have evaluated the efficacy and safety of Paltusotine capsules in patients with acromegaly: ACROBAT Edge21 and ACROBAT Evolve22. ACROBAT Edge is a single-arm, open-label, multicentric, blinded-dose study aimed
at evaluating the efficacy of Paltusotine monotherapy in maintaining normal IGF-1 levels in patients previously on SRLgen1. The main objective was to assess efficacy in patients who were partial responders to SRLgen1 monotherapy. The study included
adult patients with a stable dose of acromegaly medication and either a partial (IGF-1 > 1.0ULN but ≤ 2.5 ULN) or complete (IGF-1 ≤ 1 ULN) response to treatment. Patients were divided into five groups based on their usual treatment: Group 1 (SRLgen1,
partial responders); Group 2 (SRLgen1 in combination with DA, partial responders); Group 3 (SRLgen1 in combination with DA, complete responders); Group 4 (Pasireotide monotherapy, complete responders); and Group 5 (SRLgen1 in combination with pegvisomant,
complete responders). To avoid residual effects, SRLs were stopped 4 weeks before the first administration of Paltusotine, while other acromegaly medications were stopped 2 weeks prior. Paltusotine was administered once daily. Forty-seven patients
were enrolled in the study (Group 1: n = 25; Group 2: n = 10; Group 3: n = 5; Group 4: n = 4; Group 5: n = 3). Paltusotine was started at a 10 mg dose and gradually increased to 40 mg based on IGF-1 measurements. After 13 weeks of Paltusotine monotherapy,
no difference in IGF-1 levels was observed in Group 1. However, 70% of patients achieved periods under the maximal dose of 40 mg of Paltusotine. In the exploratory Groups 2 and 3 (i.e., with SRL+DA), IGF-1 significantly increased from 1.21ULN at baseline
to 1.44ULN at week 13 (p = 0.002), consistent with the effect of DA. Due to the low number of patients, no efficacy analysis was performed for Groups 4 and 5, but data were included in the safety analysis. Overall, Paltusotine was well tolerated,
with the most frequent AEs being headache, arthralgia, and asthenia.

The ACROBAT Evolve study was a Phase 2, double-blind, placebo-controlled, randomized study to evaluate the safety and efficacy of Paltusotine. The design was similar to ACROBAT Edge, but patients were randomized at week 8 to continue Paltusotine or receive
a placebo if IGF-1 was ≤ 1 ULN. The study was stopped after positive results from ACROBAT Edge. At the time of discontinuation, 13 patients had been included. Previously enrolled patients continued the study and were included in the safety analysis.

One limitation of these studies was their short duration. The ACROBAT Advance extension study (NCT04261712) is currently ongoing: voluntary patients from the ACROBAT Edge and ACROBAT Evolve studies will be followed up to 4 years to assess the safety (main
objective) and efficacy of long-term use of Paltusotine.

Recently, results from the PATHFNDR-1 trial, a Phase 3, randomized, double-blind, placebo-controlled trial, were published. Its primary objective was to assess the efficacy and safety of Paltusotine23. Patients controlled with SRLgen1 monotherapy
(IgF1 ≤ 1.0 ULN) were included. Patients were randomized to receive either Paltusotine or a placebo instead of their usual treatment (1:1), with stratification based on IGF-1 level and prior treatment. Treatment was to be taken after an overnight
fast of at least 6 hours, and patients were required to wait 1 hour after taking the treatment before eating. The primary endpoint was the proportion of patients with IGF-1 ≤ 1.0ULN between weeks 34 and 36. Fifty-eight patients were randomized: 30
in the Paltusotine group and 28 in the placebo group. In the Paltusotine group, 25/30 patients (83.3%) reached the primary endpoint compared to 1/28 patients (3.6%) in the placebo group (Odds Ratio (OR): 126.53; 95% Confidence Interval (95CI): 13.73
– >999.99; p < 0.0001). IGF-1 remained stable in the Paltusotine group (from 0.83 to 0.89ULN) while it increased from 0.82 to 1.68ULN in the placebo group.

At least one AE occurred in both groups (80% of patients in the Paltusotine group and 100% of patients in the control group), including arthralgia, headache, and gastrointestinal symptoms. This safety profile is consistent with the mechanism of action
of the drug. However, only 30.0% of these AEs were classified by the investigator as related to acromegaly in the treatment group, compared to 85.7% in the control group, likely due to poorer disease control. No change in tumor size compared to baseline
was observed in either group.

In treatment-naïve patients, who had never had any pharmacological treatment for acromegaly, results from PATHFNDR-2 (NCT05192382), a Phase 3, randomized, double-blind, and placebo-controlled study, were announced at ENDO 202424: 42.5% of patients
achieved normal IGF-1 levels after 24 weeks of treatment compared to 2.4% in the control group (p < 0.0001).

Moreover, at ENDO 2024, primary results of ACROBAT Advance (NCT04261712), evaluating the long-term safety and efficacy of Paltusotine in patients from ACROBAT Edge and Evolve, showed a sustained response to Paltusotine with median IGF-1 levels of 1.14,
1.06, and 1.08ULN at months 12, 24, and 4225.

 

CAM2029: octreotide subcutaneous depot

The FluidCrystal® technology26,27 enables the subcutaneous delivery of Octreotide. In this technology, a lipid-based liquid containing the active principle is injected and transforms into a crystalline gel upon contact with interstitial
fluid. This newly formed gel encapsulates and then traps the active compound, which is subsequently released as the crystalline gel matrix degrades in the subcutaneous tissue.

A Phase I study included 122 patients who first received a single dose of 200 µg subcutaneous Octreotide28. After a 7-day washout period, patients were randomized to receive octreotide SC (Camurus) at different dosage or Octreotide LAR. IGF-1
suppression appeared to be more effective with octreotide SC in a dose-dependent manner compared to LAR. Overall, the bioavailability of Octreotide SC was four to five times higher than Octreotide LAR, and the Cmax was also greater for Octreotide
SC compared to LAR.

The ACROINNOVA studies are the two Phase 3 trials involving CAM2029. ACROINNOVA 1 (NCT04076462) is a 24-week, double-blind, placebo-controlled study aimed at assessing the efficacy and safety of CAM2029 in patients already treated and controlled with
a stable dose of somatostatin analogues. While results are not yet published, Camurus Company announced the first results in June 202329 via a press release. The trial enrolled 72 patients, randomized 2:1 to receive either CAM2029 or placebo.
At week 24, 72.2% of patients receiving CAM2029 had an IGF-1 ≤ ULN compared to 37.5% of patients in the placebo group (p = 0.0018, 95% CI 11.3-57.9). Moreover, IGF-1 remained stable throughout the study period. The Treatment Satisfaction Questionnaire
for Medication score was higher for CAM2029 than for placebo. However, the fact that 37.5% of patients remained controlled for IGF-1 while receiving a placebo is questionable.

ACROINNOVA 2 (NCT04125836) is an open-label Phase 3 extension trial to assess the long-term safety and efficacy (52 weeks) of CAM2029. The trial enrolled 135 patients, and results were presented at ECE 2024, with separated presentation for the 81 new
patients enrolled30 and the 54 patients previously included in ACROINNOVA 1 (36 patients who received CAM2029 and 18 patients who received placebo)31. The primary endpoint was safety. When pooling the data together, among the
103 patients for whom results are available, 100 patients (74.1%) experienced an AE, with 73 (54.1%) related to CAM2029. The most frequent AE reported were injection site reactions (about 40% of patients), though the proportion of patients with this
AE decreased with each injection. We calculated that 58.3% of patients achieved biochemical control (60/103). However, control in patients previously enrolled in ACROINNOVA 1 was significantly better, with between 89.3% and 100% of patients achieving
IgF1 ≤ ULN, whereas in patients directly enrolled in ACROINNOVA 2, 33.3% of patients (20/60) achieved IgF1 ≤ 1ULN at weeks 50-52. Interestingly, only 12 patients (12/81, 14.8%) achieved this goal at inclusion, indicating that CAM2029 improves acromegaly
control in previously uncontrolled patients. At the time of analysis, 25 patients (18.5%) were still ongoing, while 7 patients (5.2%) had withdrawn from the trial.

 

OTHER DRUGS CURRENTLY ON DEVELOPMENT

Drugs targeting known therapeutic targets: other SRL or GH receptors antagonists

Somatropim (Aspireo Pharmaceuticals Limited), formerly known as PTR-3173, DG3173, or COR-005, binds to SST2, SST5, and SST4 receptors and has a similar effect on GH secretion without altering insulin secretion32. Compared to
Octreotide or Lanreotide, which have a high affinity for SST2 and mild affinity for other receptors, Somatropim exhibits mild affinity for SST2, SST4, and SST5 receptors, and no affinity for SST1 and SST3 receptors33. In a Phase 1 study,
Somatropim appeared to have similar efficacy in suppressing GH secretion in humans34. Gastrointestinal AEs also seem to be less frequent with Somatropim. It has entered Phase 2, and while results are not yet published, preliminary results
are available on ClinicalTrials.gov (NCT02217800 and NCT02235987).

Sit1-binding Helix (S1H) is a 16-residue peptide that mimics the site 1 mini-helix of GH, a region involved in the interaction between GH and its receptor. S1H is predicted to inhibit the interaction of GH with its receptor through competitive
inhibition
35. In vitro, S1H attenuates GH receptor and prolactin receptor activation and limits STAT5 phosphorylation (a signaling molecule activated when GH normally binds to its receptor).

AZP-3813 (Amolyt Pharma) is a 16-amino acid bicyclic peptide that directly antagonizes GH receptors. In vivo studies in rats showed a potential to suppress IGF-1 secretion36,37. In dogs, repeated subcutaneous injections
over 7 days resulted in a dose-dependent decrease in IGF-1 levels of between 69% and 75%38. Additionally, AZP-3813 can enhance the reduction of IGF-1 when used in combination with Octreotide and could be a candidate for add-on therapy39.
Results of the Phase I study were announced at the ECE 2024 congress. A randomized, double-blind, placebo-controlled study with single (SAD) and multiple ascending dose (MAD) designs was conducted in 13 healthy subjects (SAD n = 5, MAD n = 8)40.
AZP-3813 decreased IGF-1 in a dose-dependent manner by 44% to 50%. AZP-3813 data support further testing in patients with acromegaly.

AP-102 (Amryt Pharma) is a disulfide-bridge octapeptide that binds to SST2 and SST5 but not to SST1 and SST341,42. In vivo, AP-102 significantly decreases GH secretion without increasing blood glucose levels43. To
our knowledge, no clinical studies are currently ongoing.

GT-02037 (GlyTech, Inc) is a glycosylated somatostatin. The glycosylation technology provided by GlyTech Inc ensures high blood stability and allows GT-02037 to have affinity for all SST receptors. According to the company’s website,
GT-02037 has demonstrated GH-suppressing effects in animals, and a Phase I clinical trial confirmed the safety and tolerability of the product44.

 

New formulations of SRL

Lanreotide Prolonged Release Formulation (LanPRF, Ipsen Pharma) has been developed to provide a higher dose of Lanreotide compared to the Autogel formulation. The development of this product is based on two observations: first, some patients
have been able to extend the interval between injections of Lanreotide Autogel 120 mg from 4 weeks to 8 weeks, and second, the efficacy of Lanreotide is primarily driven by its concentration rather than its exposure. Thus, it is theoretically feasible
to increase the dosage to extend the interval between injections, although this could result in higher peak plasma levels and potentially more AEs. LanPRF was developed to safely increase the dosage of Lanreotide, allowing injections every 12 weeks.
This new formulation includes a co-solvent with lubricating properties that facilitates the injection of a larger total dose, limits the peak concentration, and results in a longer half-life.

Results from the Phase I/II study were published in 202145. This open-label, dose-ascending study included patients with stable disease control (IGF-1 < 1.3 ULN) who had been on SRLgen1 for at least 3 months. Patients were assigned to one
of three ascending dose cohorts (180 mg, 270 mg, and 360 mg) to receive one subcutaneous injection. The study had two primary endpoints: a safety endpoint to determine the maximum tolerated dose and a pharmacological endpoint to assess the pharmacokinetic
properties of LanPRF. Nine patients were enrolled in cohorts 1 and 2, and ten patients were in cohort 3, with a follow-up period of 24 weeks. Eighteen patients completed the study. Seven patients (25%) were excluded due to an increase in their IGF-1
levels. The published results indicate that the maximum tolerated dose of LanPRF was not reached, as no dose-limiting toxicities were observed during the study. Peak serum concentrations were reached 6h after injection, with mean Cmax values similar
across all cohorts (mean ± SD = 19.0 ± 15.7, 14.0 ± 10.3, and 20.5 ± 5.86 for cohorts 1, 2, and 3, respectively). The half-life did not seem to depend on the dose (mean ± SD = 54.2 ± 17.0, 61.7 ± 13.9, and 63.1 ± 13.3 days for cohorts 1, 2, and 3,
respectively). Safety analysis included all 28 patients, with a total of 69 AEs reported (cohort 1 n = 17, cohort 2 n = 25, and cohort 3 n = 27). The most frequent AE was diarrhea, cholelithiasis, asthenia, and headache, consistent with the known
AEs of Lanreotide. GH and IGF-1 levels appeared to remain stable over 13 weeks, but a larger cohort is needed to confirm these results. Additionally, patients were included in a cohort regardless of their previous dosage, a factor that should be considered
in future studies.

MTD201 (Q-Sphera™) is an octreotide acetate formulation encapsulated using Q-Sphera technology, which employs 3-D printing to encapsulate the drug in bioresorbable polymer microspheres. This method allows for easy injection and gradual
release of Octreotide. The microspheres facilitate easier reconstitution compared to existing SRLgen1 formulations and enable injection with a smaller needle. Results from Phase I were announced at ENDO 2019, showing pharmacological parameters similar
to Octreotide LAR but with fewer injection site reactions46. Additionally, MTD201 can be administered via the subcutaneous route.

 

New mechanism of action: antisense oligonucleotides

Antisense oligonucleotides (ASOs) are single-stranded synthetic oligonucleotides of approximately 20 nucleotides. They bind to pre-mRNA and/or mRNA to induce their degradation, thereby inhibiting protein synthesis. Currently, in the context of acromegaly,
ASOs in development target the mRNA that encodes the GH receptor.

ATL1103 (Percheron therapeutics) has completed phase 2, results were published in 201847. The study included 26 patients with uncontrolled acromegaly, who were randomized to receive 200 mg either once (group 1) or twice (group
2) weekly for 13 weeks. No change in IGF-1 levels was observed in group 1, whereas IGF-1 levels decreased by 27.8% in group 2 (p = 0.0002). AEs included injection site reactions (85% of patients), headache (26.9%), fatigue, gastrointestinal AEs. Since
then, no new results for ATL1103 have been published.

 

DISCUSSION

Several new treatments are now available or should be available in the following years. Their main caveat is however that they have all been compared to SRLgen1, meaning that their potential new role will be an alternate to this first line treatment.
The development of an oral form of octreotide (especially with a once daily intake) represents a safe alternative to traditional injections and allows patients to choose their preferred treatment. CAM2029 offers patients the option to self-administer
their injections via a monthly subcutaneous route, which may also enhance adherence and increase patient autonomy. Numerous other drugs are currently in development. Among them, Lanreotide PRF provided every 3 months could also reduce the burden of
monthly intramuscular injections (and we could even hope for an extended interval in a similar approach of the one currently used for lanreotide, which can be delivered every 6 or 8 weeks). While most drugs in development target SSTR or GHR directly,
only one belongs to a new therapeutic class: antisense oligonucleotides. As the mechanism of action is different from SRLgen1, its potential role, should current phase 2 shows its efficacy, will have to be defined in the global therapeutic amantarium
of acromegaly.

While the development of new formulations and the use of innovative technologies (such as FluidCrystalTM, Transient Permeability Enhancer®, or Q-SpheraTM technologies, as well as advancements in medicinal chemistry) are
exciting and might have a safe profile, it is important to remember that phase 3 studies published to date have primarily included patients who were already controlled. No studies have yet been published on treatment-naive patients, and initial efficacy
results should be confirmed through long-term real-world studies48. Moreover, the design of studies based on previously controlled patients on SRLgen1, which also means patients with a good tolerance, might overestimate the efficacy or
the tolerance of these new compounds. For the oral form, the requirement for a one-hour fasting period after drug administration should be evaluated in real-world settings to ensure that, outside the controlled environment of clinical trials, patients
will continue to adhere to these administration guidelines.

Finally, as discrepancies between IGF-1 control and quality of life have been observed in about one-third of published studies49, it is essential to evaluate patients’ quality of life (AcroQol) and Treatment Satisfaction Questionnaire for Medication
scores when initiating or switching to these new treatments. Moreover, while quality of life tends to improve with disease control in patients with acromegaly, it remains lower than that of the general population and persists in the long term50,51.
The oral form will need to prove its benefits in real life, as a recent study suggested that patients might prefer subcutaneous injections at home over oral capsules taken twice a day52, even though patients were not offered the choice
between intramuscular injections at the hospital or home and oral capsules.

To conclude, after decades of targeting anti-secretory efficacy, improving the life of patients with acromegaly is another major aim for treatments. In this setting, new methods for drug delivery could be of major help in patients with failed surgery,
requiring a prolonged medical treatment. It adds several possibilities in an individualized therapeutic approach at least in first line of medical treatment after failed surgery. These advancements will expand the range of treatment options available
to patients and enhance patient choice, thereby likely improving treatment adherence.

 

Name of drug Type/way of action Way of delivery Timing Half life Dosage Phase Percentage of control
Paltusotine Non peptidic molecule, binding to SST2 Oral Once a day, after overnight fasting and at least 1h before a meal 22-34h 20 to 60mg Phase 3 terminated, in preparation for submission to FDA 83.3%23 (W34-36) 42.5%

24  (W24, naïve patients)
CAM2029 (OclaizTM) Octreotide Acetate: binding to SST2 Subcutaneous Montlhy 151-226h 10 to 30mg Submission to FDA 72.2%29 (W24) 58.3%

30,31 (W52)
OOCs (MycapssaTM) Octreotide Acetate Oral Daily, twice a day, 1h before meal or 2h after 6-8h 40 to 80mg Approved (FDA and EMA) 62-7411 (M13) 58.2%

12 64%

14 (MPOWERED)
Octreotide LAR53 Binding to SST2 (and SST5) Deep subcutaneous / IM Once a month Plateau at 14-21d 10 to 30mg Approved About 40%
Lanreotide Autogel53 Binding to SST2 (and SST5) Deep subcutaneous / IM Once a month 23-30d 30 to 120mg Approved
Pasireotide53 Pasireotide Once a month 17-11h 10 to 60mg Approved About 30%
Pegvisomant53 Antagonist GHR Subcutaneous Once a day 74-172h 10 to 30mg Approved About 79%
Cabergoline53 Cabergoline Oral Once a week to once a day 63-109h 0.5mg Approved 34% (alone) 52% in combination54

Table 1: Comparison of available compounds and compounds in late-stage development for the treatment of acromegaly

 

 

Name Molecule Route Development
New SRL or antagonist of GH receptors
Somatropim SRL, binds SST2, 5 and 4 Subcutaneous Phase II
ONO-578855 SRL, binds selectively SST2 Oral, daily Phase I / discontinued
S1H Competitive inhibitor of GH receptor NA Preclinical
AZP-3813 GH receptor antagonist Subcutaneous Phase I
AP-102 SRL, binds SST2 and 5 Subcutaneous Preclinical
GT-02037 SRL, all SST NA Phase I
New formulation of SRL
Lanreotide PRF Lanreotide Deep subcutaneous / IM, every 12 weeks Phase I/II
DP103856 Octreotide Acetate Nasal, daily Phase I / no communication since 2017
MTD201 Octreotide Acetate Subcutaneous or IM Phase I
New class: antisense oligonucleotide against GH receptor mRNA
ATL1103 Against GH receptor mRNA Subcutaneous, once or twice a week Phase III
ISIS76672057 Against GH receptor mRNA, liver specificity Subcutaneous, once a month Phase II / discontinued

Table 2: New compounds in early-stage of development for the treatment of acromegaly

 

REFERENCES

  1. Melmed S, Bronstein MD, Chanson P, et al. A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14(9):552-561. doi:10.1038/s41574-018-0058-5
  2. Brue T, Rahabi H, Barry A, et al. Position statement on the diagnosis and management of acromegaly: The French National Diagnosis and Treatment Protocol (NDTP). Ann Endocrinol. 2023;84(6):697-710. doi:10.1016/j.ando.2023.08.003
  3. Buchfelder M, Schlaffer SM. The surgical treatment of acromegaly. Pituitary. 2017;20(1):76-83. doi:10.1007/s11102-016-0765-7
  4. Raulf F, Pérez J, Hoyer D, Bruns C. Differential Expression of Five Somatostatin Receptor Subtypes, SSTR1-5, in the CNS and Peripheral Tissue. Digestion. 2009;55(Suppl. 3):46-53. doi:10.1159/000201201
  5. Colao A, Auriemma RS, Lombardi G, Pivonello R. Resistance to Somatostatin Analogs in Acromegaly. Endocr Rev. 2011;32(2):247-271. doi:10.1210/er.2010-0002
  6. Störmann S, Cuny T. The socioeconomic burden of acromegaly. Eur J Endocrinol. 2023;189(2):R1-R10. doi:10.1093/ejendo/lvad097
  7. Kimball A, Dichtel LE, Yuen KCJ, et al. Quality of Life after Long-Term Biochemical Control of Acromegaly. Pituitary. 2022;25(3):531-539. doi:10.1007/s11102-022-01224-0
  8. Schöfl C, Grussendorf M, Honegger J, et al. Failure to achieve disease control in acromegaly: cause analysis by a registry-based survey. Eur J Endocrinol. 2015;172(4):351-356. doi:10.1530/EJE-14-0844
  9. Tuvia S, Pelled D, Marom K, et al. A Novel Suspension Formulation Enhances Intestinal Absorption of Macromolecules Via Transient and Reversible Transport Mechanisms. Pharm Res. 2014;31(8):2010-2021. doi:10.1007/s11095-014-1303-9
  10. Tuvia S, Atsmon J, Teichman SL, et al. Oral Octreotide Absorption in Human Subjects: Comparable Pharmacokinetics to Parenteral Octreotide and Effective Growth Hormone Suppression. J Clin Endocrinol Metab. 2012;97(7):2362-2369. doi:10.1210/jc.2012-1179
  11. Melmed S, Popovic V, Bidlingmaier M, et al. Safety and Efficacy of Oral Octreotide in Acromegaly: Results of a Multicenter Phase III Trial. J Clin Endocrinol Metab. 2015;100(4):1699-1708. doi:10.1210/jc.2014-4113
  12. Samson SL, Nachtigall LB, Fleseriu M, et al. Maintenance of Acromegaly Control in Patients Switching From Injectable Somatostatin Receptor Ligands to Oral Octreotide. J Clin Endocrinol Metab. 2020;105(10):e3785-e3797. doi:10.1210/clinem/dgaa526
  13. Samson SL, Nachtigall LB, Fleseriu M, et al. Durable biochemical response and safety with oral octreotide capsules in acromegaly. Eur J Endocrinol. 2022;187(6):733-741. doi:10.1530/EJE-22-0220
  14. Fleseriu M, Dreval A, Bondar I, et al. Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly: a phase 3, multicentre, randomised controlled trial. Lancet Diabetes Endocrinol.
    2022;10(2):102-111. doi:10.1016/S2213-8587(21)00296-5
  15. Fleseriu M, Molitch M, Dreval A, et al. MPOWERED Trial Open-Label Extension: Long-term Efficacy and Safety Data for Oral Octreotide Capsules in Acromegaly. J Clin Endocrinol Metab. 2023;108(12):3214-3222. doi:10.1210/clinem/dgad365
  16. Fleseriu M, Biller BMK, Freda PU, et al. A Pituitary Society update to acromegaly management guidelines. Pituitary. 2021;24(1):1-13. doi:10.1007/s11102-020-01091-7
  17. Mycapssa | European Medicines Agency (EMA). December 22, 2022. Accessed September 29, 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/mycapssa
  18. MyCapssa FDA Approval. Accessed September 29, 2024. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=309310
  19. Zhao J, Wang S, Markison S, et al. Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist. ACS Med Chem Lett. 2023;14(1):66-74. doi:10.1021/acsmedchemlett.2c00431
  20. Madan A, Markison S, Betz SF, et al. Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers. Pituitary. 2022;25(2):328-339. doi:10.1007/s11102-021-01201-z
  21. Gadelha MR, Gordon MB, Doknic M, et al. ACROBAT Edge: Safety and Efficacy of Switching Injected SRLs to Oral Paltusotine in Patients With Acromegaly. J Clin Endocrinol Metab. 2023;108(5):e148-e159. doi:10.1210/clinem/dgac643
  22. ACROBAT Edge Study Of Paltusotine In Acromegaly Met Endpoint. October 26, 2020. Accessed September 29, 2024. https://crinetics.com/acrobat-edge-study-of-paltusotine-in-acromegaly-met-endpoint/
  23. Gadelha MR, Casagrande A, Strasburger CJ, et al. Acromegaly Disease Control Maintained After Switching From Injected Somatostatin Receptor Ligands to Oral Paltusotine. J Clin Endocrinol Metab. Published online June 3, 2024:dgae385. doi:10.1210/clinem/dgae385
  24. Biller BMK. MON-694. Efficacy And Safety Of Once-daily Oral Paltusotine In Medically Untreated Patients With Acromegaly: Results From The Phase 3, Randomized, Placebo-controlled Pathfndr-2 Study. In: ; 2024. Accessed September 29, 2024. https://www.abstractsonline.com/pp8/#!/11016/presentation/10007
  25. Gadelha M. MON-695. Long-term Safety And Efficacy Of Once-daily Oral Paltusotine In The Treatment Of Patients With Acromegaly: Update From Acrobat Advance. In: ; 2024. Accessed September 29, 2024. https://www.abstractsonline.com/pp8/#!/11016/presentation/10006
  26. Tiberg F, Johnsson M. Drug delivery applications of non-lamellar liquid crystalline phases and nanoparticles. J Drug Deliv Sci Technol. 2011;21(1):101-109. doi:10.1016/S1773-2247(11)50009-7
  27. Tiberg F, Johnsson M, Jankunec M, Barauskas J. Phase Behavior, Functions, and Medical Applications of Soy Phosphatidylcholine and Diglyceride Lipid Compositions. Chem Lett. 2012;41(10):1090-1092. doi:10.1246/cl.2012.1090
  28. Tiberg F, Roberts J, Cervin C, et al. Octreotide s.c. depot provides sustained octreotide bioavailability and similar IGF-1 suppression to octreotide LAR in healthy volunteers. Br J Clin Pharmacol. 2015;80(3):460-472. doi:10.1111/bcp.12698
  29. Camurus’ octreotide SC depot (CAM2029) achieves superior treatment response compared to placebo in Phase 3 acromegaly trial – Camurus. June 20, 2023. Accessed August 13, 2024. https://www.camurus.com/media/press-releases/2023/camurus-octreotide-sc-depot-cam2029-achieves-superior-treatment-response-compared-to-placebo-in-phase-3-acromegaly-trial/
  30. Ferone D, L SSJ, Fidan YG, et al. EP320. An open-label long-term Phase 3 study of CAM2029 in patients with acromegaly (ACROINNOVA 2): interim analysis of the subgroup of patients. In: Endocrine Abstracts. Vol 99. Bioscientifica; 2024. doi:10.1530/endoabs.99.EP320
  31. Ferone D, Silverstein J, Freda P, et al. EP321. An open-label long-term Phase 3 study of CAM2029, an octreotide subcutaneous depot, in patients with acromegaly (ACROINNOVA 2): interim analysis of the ACROINNOVA 1 roll-over patients subgroup. In: Endocrine Abstracts.
    Vol 99. Bioscientifica; 2024. doi:10.1530/endoabs.99.EP321
  32. Afargan M, Janson ET, Gelerman G, et al. Novel Long-Acting Somatostatin Analog with Endocrine Selectivity: Potent Suppression of Growth Hormone But Not of Insulin. Endocrinology. 2001;142(1):477-486. doi:10.1210/endo.142.1.7880
  33. Shimon I, Rubinek T, Hadani M, Alhadef N. PTR-3173 (SomatoprimTM), a novel somatostatin analog with affinity for somatostatin receptors 2, 4 and 5 is a potent inhibitor of human GH secretion. J Endocrinol Invest. 2004;27(8):721-727.
    doi:10.1007/BF03347512
  34. Kutz K, Haschke M, Beglinger C, Dehning C, Cohen F. GP123. A placebo-controlled study to assess the dose-effect of COR-005, a novel somatostatin analogue on plasma glucose regulation compared to octreotide in healthy male subjects. In: Endocrine Abstracts.
    Vol 41. ; 2016. doi:10.1530/endoabs.41.GP123
  35. Basu R, Nahar K, Kulkarni P, et al. A novel peptide antagonist of the human growth hormone receptor. J Biol Chem. 2021;296:100588. doi:10.1016/j.jbc.2021.100588
  36. Culler M, Milano S, Kurasaki H, et al. ODP353 Sustained Suppression of IGF1 with AZP-3813, a Bicyclic 16-Amino Acid Peptide Antagonist of the Human Growth Hormone Receptor and a Potential New Treatment for Acromegaly. J Endocr Soc. 2022;6(Supplement_1):A511.
    doi:10.1210/jendso/bvac150.1062
  37. Milano S, Kurasaki H, Tomiyama T, Reid P, Jan V der LA, Culler MD. AZP-3813, a bicyclic 16-amino acid peptide antagonist of the human growth hormone receptor as a potential new treatment for acromegaly. In: Endocrine Abstracts. Vol 81. Bioscientifica;
    2022. doi:10.1530/endoabs.81.P148
  38. Ravel G, Chalmey C, Berardet C, et al. THU046 Repeated Treatment With AZP-3813, A Bicyclic, 16-Amino Acid Peptide Antagonist Of The Human Growth Hormone Receptor, Induces Enhanced Suppression Of IGF1 In Beagle Dogs. J Endocr Soc. 2023;7(Supplement_1):bvad114.1126.
    doi:10.1210/jendso/bvad114.1126
  39. Ravel G, Berardet C, Chalmey C, et al. Additive effect of combined treatment with the small peptide GH receptor antagonist, AZP-3813, and the somatostatin analog, octreotide, in decreasing IGF1 levels in the rat. In: Endocrine Abstracts.
    Vol 99. Bioscientifica; 2024. doi:10.1530/endoabs.99.P333
  40. Allas S, Ravel G, Farrell C, et al. A phase 1 clinical study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of AZP-3813, a novel, small peptide growth hormone receptor antagonist, in healthy subjects. In: Endocrine Abstracts.
    Vol 99. Bioscientifica; 2024. doi:10.1530/endoabs.99.RC5.4
  41. Moore SB, van der Hoek J, de Capua A, et al. Discovery of Iodinated Somatostatin Analogues Selective for hsst2 and hsst5 with Excellent Inhibition of Growth Hormone and Prolactin Release from Rat Pituitary Cells. J Med Chem. 2005;48(21):6643-6652.
    doi:10.1021/jm050376t
  42. Streuli J, Harris AG, Cottiny C, et al. Cellular effects of AP102, a somatostatin analog with balanced affinities for the hSSTR2 and hSSTR5 receptors. Neuropeptides. 2018;68:84-89. doi:10.1016/j.npep.2018.02.005
  43. Tarasco E, Seebeck P, Pfundstein S, et al. Effect of AP102, a subtype 2 and 5 specific somatostatin analog, on glucose metabolism in rats. Endocrine. 2017;58(1):124-133. doi:10.1007/s12020-017-1386-2
  44. Glyco-Somatostatin | GlyTech, Inc. Accessed August 25, 2024. https://www.glytech-inc.com/pipeline/gt-02037/
  45. Neggers S, Badiu C, Biagetti B, et al. Pharmacological and safety profile of a prolonged-release lanreotide formulation in acromegaly. Expert Rev Clin Pharmacol. 2021;14(12):1551-1560. doi:10.1080/17512433.2021.1986004
  46. Seaman P, Damment S, Bamsey K, Dryja A, Cook C. SAT-432 MTD201 Has a Favourable 28-Day Sustained Release Profile Compared to Sandostatin LAR in Healthy Subjects. J Endocr Soc. 2019;3(Supplement_1):SAT-432. doi:10.1210/js.2019-SAT-432
  47. Trainer PJ, Newell-Price JDC, Ayuk J, et al. A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly. Eur J Endocrinol. 2018;179(2):97-108. doi:10.1530/EJE-18-0138
  48. Castinetti F, Brue T. Paltusotine: A Step Toward Precision Medicine in Acromegaly. J Clin Endocrinol Metab. Published online July 15, 2024:dgae489. doi:10.1210/clinem/dgae489
  49. van der Meulen M, Zamanipoor Najafabadi AH, Broersen LHA, et al. State of the Art of Patient-reported Outcomes in Acromegaly or GH Deficiency: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2022;107(5):1225-1238. doi:10.1210/clinem/dgab874
  50. Wolters TLC, Roerink SHPP, Sterenborg RBTM, et al. The effect of treatment on quality of life in patients with acromegaly: a prospective study. Eur J Endocrinol. 2020;182(3):319-331. doi:10.1530/EJE-19-0732
  51. Kyriakakis N, Lynch J, Gilbey SG, Webb SM, Murray RD. Impaired quality of life in patients with treated acromegaly despite long-term biochemically stable disease: Results from a 5-years prospective study. Clin Endocrinol (Oxf). 2017;86(6):806-815.
    doi:10.1111/cen.13331
  52. Sisco J, Furumalm M, Yssing C, Okkels A, Zavisic S. Preferences for different treatment options among people living with acromegaly in the US. Curr Med Res Opin. 2024;40(4):657-664. doi:10.1080/03007995.2024.2314244
  53. Grasso LFS, Auriemma RS, Pivonello R, Colao A. Somatostatin analogs, cabergoline and pegvisomant: comparing the efficacy of medical treatment for acromegaly. Expert Rev Endocrinol Metab. 2017;12(1):73-85. doi:10.1080/17446651.2016.1222899
  54. Sandret L, Maison P, Chanson P. Place of Cabergoline in Acromegaly: A Meta-Analysis. J Clin Endocrinol Metab. 2011;96(5):1327-1335. doi:10.1210/jc.2010-2443
  55. Komagata T, Tanaka H, Ishida A, et al. MON-464 Non-Clinical Profiling of ONO-5788, a Novel Oral Small Molecule Somatostatin Receptor Type-2 (SST2) Agonist, to Support Studies in Humans. J Endocr Soc. 2019;3(Supplement_1):MON-464. doi:10.1210/js.2019-MON-464
  56. Levisetti M. C12. Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of DP1038, an Intranasal Formulation of Octreotide Acetate, in Healthy Volunteers. Accessed August 25, 2024. https://nanets.net/abstract-posters/posters-2017/819-c12-poster-4/file
  57. Bhanot S, Fleseriu M, Geary R, et al. OR27-4 Placebo-Controlled and Open-Label Extension Study of a Novel Hepatic-Targeted Antisense Cimdelirsen (IONIS-GHR-LRx) Under Investigation in Acromegaly Patients. J Endocr Soc. 2022;6(Supplement_1):A526.
    doi:10.1210/jendso/bvac150.1095