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The 24th European Conference on Endocrinology (ECE) in 2022 has been held recently, and well-known experts in the field of international acromegaly (hereinafter referred to as "limb enlargement") have shared the latest achievements and experiences in the treatment of many limb large drugs, let's take a look at what new progress has been made in pevesolem and oral octreotide capsules? What new drugs with great potential have emerged?
Expert introduction
Professor Zeng Tianshu
Doctor of Medicine Chief Physician Doctoral Supervisor
Director of the Department of Endocrinology, Union Hospital Affiliated to Huazhong University of Science and Technology
Standing Committee Member of Endocrinology and Metabolism Physician Branch of Chinese Medical Doctor Association
Member of the Endocrinology Branch of the Chinese Medical Association and Deputy Leader of the Basic Science Group;
Vice Chairman of diabetes prevention and rehabilitation professional committee of Chinese Rehabilitation Medicine Association
Vice President of Clinical Rare Metabolic Diseases Branch of Chinese Biophysical Society
He is a standing committee member of the Geriatrics Branch of the Chinese Society of Gerontology and Geriatrics, and the chairman of the Metabolic Diseases Committee
Member of the Scientific Research Ethics Group of the Medical Ethics Branch of the Chinese Medical Association
·Chairman-designate of Diabetes Branch of Hubei Medical Association
· Current Medical Science, Journal of Clinical Internal Medicine, Editorial Board Member of Journal of Clinical Cardiovascular Disease; Corresponding editorial board member of Chinese Journal of Endocrinology and Metabolism
Member of the Medical Ethics Committee of Huazhong University of Science and Technology, Vice Chairman of the Medical Ethics Committee of Union Hospital
Efficacy, safety and metabolic effects of long-term reception of pevisomon in the treatment of large limbs: results from 10 years of single-center experience
Introduction and Purpose: Pevisomon (PEG) is effective in treating large limbs and has a positive effect on human glucose metabolism. Although the effect of PEG on lipid metabolism is less well understood, there have been reports of an overall mild increase in triglycerides and high-density lipoprotein cholesterol (HDL-c) after PEG treatment. Data on long-term treatment of PEGs are still limited, so this study aims to investigate the effects of PEG in disease control, pituitary adenoma size, and metabolic profile in PEG treatment of somatostatin analogues (SRLs)-resistant patients with macaly of limbs over a 10-year period.
Methods: A total of 22 patients (9 males, 13 females, age range 45.54±12.83 years) who had been treated with PEG for 10 years were included in this study from 2002 to 2022, including patients treated with PEG monotherapy or combined with SRLs. Over 20 years, the study evaluated anthropometric [body mass index (BMI), systolic and diastolic blood pressure], hormone [growth hormone (GH), insulin-like growth factor-1 (IGF-1)], biochemical indicators (fasting blood glucose and insulin, lipid profile), and maximum tumor diameter. In the current study, data before and after PEG treatment were evaluated.
Results: After 10 years of PEG treatment, 91% of the patients maintained IGF-I levels within the normal range (P<0.0001), and the dose of PEG or SRLs did not change significantly. The maximum tumor diameter of the patient was slightly reduced across the cohort. Fasting blood glucose (FG) levels were significantly increased (P=0.035), while the prevalence of glycosylated hemoglobin (HbA1c) and diabetes remained stable, fasting insulin (FI) and insulin resistance index decreased, islet β cell function index decreased significantly (P=0.013), and insulin sensitivity index increased. Total cholesterol (P=0.03) and low-density lipoprotein cholesterol (LDL-c) (P=0.05) levels were significantly reduced, and triglyceride levels were slightly elevated. Baseline IGF-I was significantly correlated with the percentage change (Δ) after 10 years of FI (r=-0.354, P=0.015) and high-density lipoprotein (HDL) (r=0.045, P=0.045) (Figure 1). The course of the disease before PEG treatment was inversely proportional to the insulin resistance index (r=-0.563, P=0.029), HDL (r=-0.424, P=0.049), ΔFG (r=-0.462, P=0.03), ΔFI (r=-0.546, P=0.05), and Δtriglycerides (TG) (r=-0.445, P=0.034) after 10 years (Figure 2). Transaminasase levels were stable after 10 years of PEG treatment compared to baseline. No cases of fatty hypertrophy in site injections were recorded.
Figure 1. A study of the correlation between baseline IGF-I and (A) fasting insulin and (B) percentage change in HDL (Δ).
Figure 2. A study of the correlation between the course of disease before PEG treatment and the percentage change (Δ) of (A) FG and (B) FI and (C) HDL
Discussion: After 10 years of continuous treatment, PEG monotherapy or combination therapy can effectively control the disease and has a high safety profile. The beneficial effects of long-term PEG therapy on insulin and lipid metabolism persist. Patients resistant to SRLs should start PEG therapy as soon as possible, as the degree of metabolic improvement is inversely correlated with the course of the disease before PEG therapy.
Expert reviews
This study shows that PEG has good efficacy and safety in both monotherapy and combination therapy, and clinicians may choose to receive PEG treatment for long-term treatment as early as possible in patients who are resistant to SRLs.
Long-term efficacy and safety data for oral octreotide capsules (OOCs) in the treatment of large limbs: MPOWERED Trial Open Label Extension (OLE) Phase
Background: OOC is a treatment option for patients with large limbs in the United States. The MPOWERED trial (NCT02685709) showed that for patients who have responded, the OOC maintains biochemical control no less than injectable somatostatin receptor ligands (iSRLs; octreotide or lanreotide), and demonstrated improvement in patients treated with OOC.
Objective: To report long-term safety and efficacy results from OOC in MPOWERED OLE.
Methods: Patients were required to voluntarily join the OLE phase study, and the MPOWERED core treatment period (6 months of introduction period plus 9 months of randomized controlled therapy [RCT] period, and the addition of cabergoline combination therapy subgroups that did not respond to OOC at the introduction period or end) and were evaluated by the investigators to achieve biochemical control. Maintenance of remission is assessed annually in patients in OLE middle-aged and early remission [Definition: IGF-I< 1.3× Normal Level On-Line (ULN)]. In the core study, additional analyses were performed on patients in OLE who switched from iSRLs to OOC treatment.
Results: A total of 60 patients were enrolled in OLE (35 patients received OOC in the RCT phase, 19 patients received iSRLs, and 6 patients from the joint subgroup study). In OLE, the median and maximum OOC exposure time were 2.2 years and 3.5 years, respectively. At the end of 1, 2, and 3 years of OLE, 94%, 90%, and 93% of patients receiving OOC monotherapy maintained biochemical remission (estimated using the final observations) (Figure 3). Of the patients who switched from iSRLs to OOC during the OLE period, 79 percent showed very good or excellent symptom control at the end of the OLE (47 percent) or excellent (32 percent), compared to 47 percent of patients who received iSRLs showed very good symptom control (42 percent) or excellent (5 percent) at the end of the RCT phase. Patients who switched from iSRLs to OOC also had significant improvements in treatment convenience and satisfaction with the Acromegaly Satisfaction Questionnaire (both P<0.05). The median OOC compliance rate during OLE was 99%, OOC safety was consistent with what was observed during the core study, and no new safety signals were observed during long-term exposure.
Figure 3. Proportion of patients who achieved remission after 1, 2, and 3 years of treatment
Conclusion: The OLE results of MPOWERED showed that the proportion of patients receiving OOC monotherapy to maintain biochemical response was higher (≥90%) and had a good long-term safety profile (Table 1). Patients who switched from iSRLs to OOC improved in terms of symptom control, ease of treatment, and satisfaction with treatment.
Table 1. Treatment-related adverse events (TRAE) occurring in OLE ≥5%
Expert reviews
The long-term (3-year) efficacy and safety of OOC monotherapy have been fully validated. For iSRLs-resistant patients, clinically or consider continuing long-term OOC treatment may improve symptom control, convenience, and satisfaction with treatment. However, the longer-term efficacy and safety have yet to be further clarified.
AZP-3813, a 16-amino acid bicyclic peptide antagonist of human growth hormone receptors, as a potential new therapy for the treatment of large limbs
Introduction: Treatment of large limbs is based on inhibiting the secretion of GH or inhibiting elevated IGF-1 levels by preventing it from binding to the receptor. AZP-3813 is a growth hormone receptor (GHR) bicyclic peptide antagonist consisting of 16 amino acids screened from a cell-free in vitro transcription-translation system, which increases the affinity, solubility and half-life of binding to the receptor by rational design optimization. To determine whether strong GHR antagonism translates into efficacy in vivo in vitro experiments, the study examined the ability of AZP-3813 to inhibit IGF-1 levels in normal juvenile rats.
Methods and results: AZP-3813 had a KD of 1.9 nM for human GHR and 18.5 nM for rat GHR. AZP-3813 has a circulatory half-life of 11.2 h in rats. To study the ability of AZP-3813 to antagonize GH and its receptor interactions in vivo to reduce IGF-1 levels, the researchers injected AZP-3813 subcutaneously into 5-week-old (~150g) normal male SD rats at a dose of 0.3, 1, 3, and 10 mg/kg twice daily or 10/30 mg/kg once daily n=8/group). Blood samples were collected before and 24, 48, and 72 h after AZP-3813 injection, and the total amount of IGF-1 was determined by radioimmunoassay. IgF-1 level inhibition was associated with the injected dose 24 hours after injection, and when AZP-3813 was 30 mg/kg, either once daily (QD) or twice daily (BID) injections achieved maximum inhibition (38.4 + 3.8% and 39.2 + 3.7%, respectively, compared to controls) (Figure 4).
Figure 4. Inhibition of IGF-1 levels of AZP-3813 dose-related QD vs BID
After 48 h of injection, IGF-1 levels returned to the levels of rats in the control group treated with drugs. In subsequent experiments, AZP-3813 is administered daily subcutaneously at a dose of 30 mg / kg, QD or BID for 4 consecutive days. As a control, the marketed GH antagonist pevesomon is also administered subcutaneously at 100 mg/kg once daily for 4 days. Blood samples were taken before injection and 24, 48, and 72 h after the last injection to detect IGF-1. Within 24 h after the first injection, AZP-3813 had the strongest inhibitory effect on IGF-1 (a decrease of 47.2 + 2.6% compared to the control group), and after continuing treatment, this inhibition lasted 24 h after the last injection. In contrast, Pevesomone gradually inhibited IGF-1 and reached a maximum inhibition 24 h after the third injection: 32.5 + 3.6%.
Conclusions: The current findings suggest that AZP-3813 exhibits a strong GHR antagonist activity that translates into an effective in vivo inhibition of IGF-1 levels, potential treatment for acromegaly.
ACROBAT Advance: Oral Paltusotine once a day can maintain IGF-1 for a long time at the levels previously achieved with long-acting somatostatin receptor ligand (LA SRL).
Paltusotine is an oral non-peptide somatostatin receptor type 2 (SST2) specific agonist (once daily) for the treatment of large limb and neuroendocrine tumors under study.
This study studies the interim results of ACROBAT Advance (NCT04261712), an ongoing, multicenter, open-label, long-term extended study of patients with acromegaly who had previously completed ACROBAT Edge (NCT03789656) or Evolve (NCT03792555) Phase 2 studies (Table 2).
ACROBAT Edge included 47 participants with elevated (n=35) or normal (n=12) IGF-1 who received LA-SRL monotherapy or combination therapy at baseline. ACROBAT Evolve enrolled 13 normal IGF-1 subjects who received octreotide long-acting extended-release or lanreotide monotherapy. Both ACROBAT Edge and Evolve include a 13-week treatment with Paltusotine and a followed 1-month drug-elutation period.
In ACROBAT Advance, depending on IGF-1 and tolerability, the patient resumes treatment with Paltusotine at a starting dose of 10 mg / day and titrated to 40 mg / day. Adjuvant therapy is allowed in subjects who do not achieve normal IGF-1 values on monotherapy with Paltusotine 40 mg/day. Of the 49 eligible subjects, 41 (84%) [median age 52 years (IQR 46-62 years, 56.1% females] were enrolled at the time of the interim analysis, 23 were treated for 51 weeks, and 4 were withdrawn from the study. At week 51, the dose of Paltusotine was titrated to 40 mg / day for most subjects (73%). The proportion of assisted treatment with cabergoline during the trial period was the same as before the trial (24%). Median IGF-1 levels were maintained for 51 weeks at the time of previous intravenous LA-SRL treatment (Table 2).
The most common adverse events during treatment were headache [12 (29.3%)], arthralgia [9 (22%)], and fatigue [6 (14.6%)]. Most adverse events were transient and mild to moderate. Three non-treatment-related serious adverse events occurred in two studies. Discontinuation of the drug was in 4 cases (1 due to headache and 3 for causes unrelated to the drug under study).
Median HbA1c levels remained stable [baseline 6.0% (5.7-6.2), 5.9% (5.7-6.1) at week 23, 5.8% (5.6-6.4) at week 51]. The patient's once-daily oral Paltusotine was well tolerated, and IGF-1 levels were maintained for up to 51 weeks at levels comparable to previous LA-SRL treatments.
These results were broadly consistent across all subgroups of patients who had previously received various treatment regimens and a range of baseline disease control modalities.
Table 2. Patient profiles included in this study
*Median IGF-1 and unixF0B4; Upper Normal (IQR)
Expert reviews
In this conference, two new drugs in different stages of development showed therapeutic potential, among which AZP-3813 showed strong GHR antagonist activity in rats, which can effectively inhibit the level of IGF-1 in vivo; But there is still a long way to go from preclinical research to clinical research. Paltusotine's Phase 2 study showed similar IGF-1 control effects to LA-SRL monotherapy or combination therapy and was well-safe. The drug is closer to actual clinical use, and more research results are expected.
brief summary
This year's ECE shared the latest data on the long-term efficacy and safety of PEG and OOC in the treatment of large limbs. PEG for 10 years on a single or combination therapy not only has good efficacy and safety, but also has a persistent beneficial effect on insulin and lipid metabolism, it is worth noting that patients resistant to SRLs should be started as soon as possible PEG therapy, because the degree of metabolic improvement is inversely related to the course of disease before PEG therapy. After receiving OOC monotherapy for 3 years, 90% of patients with ≥ maintain biochemical remission sustainably, have good safety, and can improve symptom control, treatment convenience and treatment satisfaction. In addition, two new drugs, AZP-3813 and Paltusotine, have good development potential.
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Bibliography:
1.RosaPirchio, et al. Presented at 2022 ECE. P679
2.Maria Fleseriu, et al. Presented at 2022 ECE. OC4.3
3.Stéphane Milano, et al. Presented at 2022 ECE. P148
4.Mônica R Gadelha, et al. Presented at 2022 ECE. OC4.6
Approval number: SOM-CN-001281
Validity: June 29, 2023