Acromegaly Patients Research Articles

Variable anatomical features of acromegaly in the nasal cavity and paranasal sinuses: implications for endoscopic endonasal transsphenoidal surgery.

Growth hormone (GH)-secreting pituitary neuroendocrine tumors (PitNETs) are the most common cause of acromegaly. The endoscopic endonasal transsphenoidal approach (EEA) is commonly employed to remove them. Although morphological differences in the nasal cavity exist between acromegaly patients and those with other types of PitNET, few quantitative studies have been performed. This study aimed to evaluate the anatomical features of the nasal cavity and paranasal sinuses in patients with acromegaly. Preoperative computed tomography images of the nasal cavity and paranasal sinuses were compared between 20 patients with a GH-secreting PitNET (acromegaly group) and 22 with a non-functioning PitNET (control group). In the acromegaly group, the relationships between preoperative GH and/or insulin-like growth factor 1 (IGF-1) levels and anatomical characteristics were assessed. In the acromegaly group, the distance between the nostril and dorsum sellae was significantly longer and the distance between the parasellar internal carotid arteries was significantly shorter (p = 0.0022 and 0.0092, respectively). Pneumatization volume in the nasal cavity did not differ between the groups. Nasal mucosa and bony hypertrophy were observed in the acromegaly group. Preoperative GH level was correlated with the width of the piriform aperture (p = 0.0171). The nasal and paranasal changes associated with acromegaly can make EEA challenging to perform. Widening the surgical corridor anterior to the sphenoid sinus is important in these patients.

Echocardiographic and Impedance Cardiography Analysis of Left Ventricular Diastolic Function in Acromegaly Patients

Echocardiographic and Impedance Cardiography Analysis of Left Ventricular Diastolic Function in Acromegaly Patients

The association between change in temporal muscle mass and treatment of acromegaly

PurposeWe aimed to evaluate the relationship between temporal muscle thickness and GH/IGF-1 elevation and the effect of acromegaly treatment on temporal muscle thickness. MethodsPatients with acromegaly and healthy controls were included in the study. While laboratory parameters, clinical findings and temporal muscle thickness of acromegaly patients at the time of diagnosis and one year after treatment were evaluated, laboratory parameters and temporal muscle thickness of healthy controls were evaluated only during the period when they were included in the study. Temporal muscle thickness was measured using pituitary MRI. Temporal muscle thickness of patients with acromegaly was compared with healthy controls. We also evaluated how temporal muscle thickness changes with treatment in patients with acromegaly and the association between laboratory parameters and temporal muscle thickness. ResultsIn patients with acromegaly, measurements of left, right, and mean temporal muscle thickness at the time of diagnosis were found to be significantly higher than those of healthy controls' measurements at the time of their inclusion in the study (p = 0.007, p = 0.014 and p = 0.018, respectively). However, no significant difference was found when comparing the temporal muscle thickness of the 1st year of acromegaly treatment with the temporal muscle thickness of healthy controls at the time of their inclusion in the study (p = 0.155, p = 0.189, p = 0.198, respectively). In addition, a significant decrease was detected in the left, right and mean temporal muscle thicknesses of patients with acromegaly before and after treatment. While the temporal muscle thickness at the time of diagnosis was thicker in patients with acromegaly receiving surgical + medical treatment than in patients receiving exclusively surgical treatment, statistical significance was only found in the left temporal muscle thickness (p = 0.042). ConclusionTemporal muscle thickness was found to be associated with treatment modalities in patients with acromegaly.

8068 Beneficial Effects of a Personalized Exercise Program for Patients with Cushing's Disease and Acromegaly After Biochemical Control

Abstract Disclosure: E. Valassi: None. L. Martel-Duguech: None. H. Bascuñana: None. V. Priego-Corredor: None. J. Viñals-Ribé: None. O. González-Viñuela: None. T. Caparrós-Pons: None. S.M. Webb: None. Background: Patients with Cushing’s disease (CD) in remission and controlled acromegaly (ACRO) present with residual metabolic derangements, muscle dysfunction, and poor quality of life (QoL). Although exercise is known to exert positive effects on psychophysical health in several conditions, evidence demonstrating its potential benefits in pituitary diseases is scanty. Main hypothesis: A personalized program of combined (aerobic and resistance training) exercise lasting 12 weeks improves cardiometabolic parameters, body composition, physical performance and QoL in patients with CD in remission and controlled ACRO. Methodology: Ten female patients with CD in remission [mean (±SD) age, 59±4 years, mean (±SD) BMI, 35±2 Kg/m2, median (IQR) duration of remission, 5(4) years] and 10 male patients with controlled ACRO [mean (±SD) age, 53±9 years, mean (±SD) BMI, 27±4 Kg/m2, median (IQR) duration of control, 6(3) years] underwent a 12-week, structured, personalized program of combined aerobic and resistance exercise, under the supervision of professional trainers. We evaluated the following parameters at baseline and within 72 hours after the completion of the exercise program: blood pressure (BP), BMI, waist and neck circumferences; physical performance (gait speed, hand grip strength, 30-Second Chair Stand; Timed “Up and Go”); lumbar and femoral bone mineral density (BMD) and body composition, using dual x-ray absorptiometry (DXA); muscle thickness (cm) at the middle and distal third of rectus femoris (RF) and vastus intermedius (VI) on both sides, using muscle ultrasound scans in the transverse plane (Philips Affiniti 70; The Netherlands); quality of life (QoL), using the questionnaires CushingQoL in CD patients and AcroQoL in ACRO patients. Major results: After completion of the exercise program, CD patients had lower diastolic BP and waist circumference as compared with baseline (p<0.05). Physical performance globally improved (p<0.01 for all function tests). Femoral BMD was higher, percentage of lean mass increased while trunk fat decreased (p<0.01). RF and VI muscle thickness was greater at both the middle and distal third on the right side (p<0.01), and at the distal third on the left as compared with baseline (p<0.05). ACRO patients had a lower systolic BP as compared with baseline. Gait speed and hand grip strength increased while performance on the 30-Second Chair Stand improved (p<0.05). Muscle thickness at the middle third of the right RF was greater as compared with baseline (p<0.05). QoL was unchanged in both CS and ACRO patients at the end of the program. Conclusions: A customized exercise program promotes beneficial cardiometabolic and muscle changes in patients with CD and ACRO and, therefore, should be offered in a specialized pituitary clinic, within an integrated multidisciplinary team approach. Study financed by ISCIII research project number FIS PI21/01223 Presentation: 6/1/2024

12571 Ultrasonography Is A Potential Cost-effective Tool To Evaluate Muscle Impairment In Patients With Controlled Cushing’S Disease And Acromegaly

Abstract Disclosure: L. Martel-Duguech: None. H. Bascuñana: None. S. Webb: None. E. Valassi: None. Myopathy is a frequent feature in patients with Cushing’s syndrome (CS) and in patients with acromegaly (ACRO) long-term after biochemical control is achieved. Although ultrasonography (US) is an easy and cost-effective tool to evaluate muscle impairment in the clinical setting, its usefulness in patients with “controlled” ACRO end CS patients has not been established The aim of our study was to evaluate muscle structure using US and assess the correlation between US parameters, muscle function and quality of life (QoL). We included 36 female patients with CS [mean (±SD) age, 50±12 years; mean (±SD) BMI, 26.7±3.8] and 36 age- and BMI-matched healthy women. Mean (±SD) duration of remission was 132±87 months. We also included 36 patients with ACRO [20 females and 16 males, mean (±SD) age, 53±9 years, BMI 27±4 Kg/m2 and duration of control 92±58 months], and 36 age, gender and BMI-matched controls. We obtained transverse ultrasound images of the rectus femoris and assessed muscle intensity at both the midpoint (QmitR) and the distal third (QtercR), between the anterior inferior iliac spine and the proximal end of the patella. We scored muscle intensity using the Heckmatt’s rating scale and classified our findings as follows: 1-normal, 2-mildy increased muscle echoes with normal bone reflection, 3-moderately increased muscle echoes with reduced bone, 4-severely increased muscle echoes with absent bone reflection. We found that mean US intensity score was increased in patients with CS (QmitR p<0.001) and in patients with ACRO (QmitR p<0.05; QtercR p<0.001) vs. the controls, suggesting more impaired muscle architecture in the former, likely due to fibrosis/fatty infiltration. We also measured muscle function using the following tests: gait speed velocity (GS), timed up and go (TUG) and 30-second chair stand. QoL was assessed using both generic (SF-36) and disease-specific (CushingQoL and AcroQoL) questionnaires. US parameters, QoL and muscle function were correlated; in CS patients, higher QtercR was associated with slower GS (r=-0.421, p=0.041) and lower scores in social dimensions on CushingQoL ( friends/family , r=-0.510, p=0.013; and work/study, r=-0.523, p=0.010) . In ACRO patients, higher QmedR was associated with slower GS (r=-0.382, p=0.031) and decreased TUG (r=-0.497, p=0.004) and 30-second chair stand (r=-0.444, p=0.011) in all patients. Higher QmedR was also associated with lower score in physical function (ρ=-0.734, p=0.024), vitality (ρ=-0.728, p=0.026), and AcroQoL total score (ρ=-0.725, p=0.027), in male patients only. Conclusion: muscle US architectural parameters are impaired in “controlled” CS and ACRO patients, and are correlated with muscle function and QoL in both groups of patients. US may be a useful technique to identify, in a clinical setting, those CS and ACRO patients showing residual myopathy. This work was supported by PI17/00749 and PI21/01223 and FEDER funds Presentation: 6/3/2024

8406 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

Abstract Disclosure: S. Allas: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. G. Ravel: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. C. Farrell: Employee; Self; ICON plc. S. Fillon: Employee; Self; Amolyt Pharma. O. Taha: Employee; Self; Amolyt Pharma. M.D. Culler: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. M. Ovize: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. M. Sumeray: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. A.J. Van der Lely: Consulting Fee; Self; Amolyt Pharma. Acromegaly is a rare disease typically caused by a benign growth hormone (GH)-secreting pituitary adenoma that stimulates over-production of insulin-like growth factor-1 (IGF1) from the liver. Treatment with somatostatin analog (SSA) monotherapy does not provide optimal control of circulating IGF-1 levels in the majority of patients. AZP-3813, a 16-amino acid, bicyclic GH receptor antagonist (GHRA) binds to the GH receptor and prevents endogenous GH from stimulating the production of IGF-1. The compound is being developed as an add-on therapy for the treatment of acromegaly in patients insufficiently controlled with SSAs. In normal animals, AZP-3813 potently decreases circulating levels of IGF-1 and further suppressive effects are observed when combined with the SSA, octreotide. Randomized double-blind placebo-controlled single and multiple ascending dose studies (SAD and MAD, respectively) are being conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZP-3813 in healthy subjects. Here we report data from all SAD cohorts and the first 3 MAD cohorts. In the SAD study, 5 subjects received a single subcutaneous administration of 3 mg AZP-3813 or placebo (3:2) and 8 subjects received 10, 20, 40, 60, 90, 120 mgAZP-3813 or placebo (6:2). In the MAD study, 8 subjects received 10, 20, 40 mg AZP-3813 or placebo (6/2) QD for 14 consecutive days. In both SAD and MAD studies, treatment was well tolerated in all subjects with no safety concerns. Cmax and AUC increased in a dose-proportional manner. The half-life of AZP-3813 was estimated to be 18-22 hours. In the SAD study, AZP-3813 induced a dose-related decrease in circulating IGF-1 levels at doses of 10 mg and above with a more prolonged reduction up to 72 hours at higher doses. In the MAD study, AZP-3813 induced a gradual and sustained dose-related decrease in circulating IGF-1 levels at 20 and 40 mg/day, with a larger effect after 2 weeks of dosing as compared to single administration at the same dose, consistent with a cumulative effect of repeated administration. Mean placebo-adjusted % change from baseline for the 20 and 40 mg cohorts were 19% and 44%, respectively. This study is ongoing, and updates on additional MAD cohorts will be reported at the meeting. These data clearly demonstrate that AZP-3813, the novel GHRA, substantially decreases circulating IGF-1 levels in healthy individuals, thereby supporting further testing in patients with acromegaly. Presentation: 6/1/2024

7377 CAM2029, Octreotide Subcutaneous Depot, Improves Patient-Reported Outcomes From Standard-of-Care Baseline in Patients With Acromegaly: Interim Results From a Phase 3 Study (ACROINNOVA 2)

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Grant Recipient; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Research Investigator; Self; Camurus AB. P. Maffei: Research Investigator; Self; Camurus AB. J. Silverstein: Consulting Fee; Self; Xeris Pharmaceuticals. Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. A. Gilis-Januszewska: None. M. Doknic: Speaker; Self; Pfizer, Inc., Novo Nordisk, Merck, Sandoz. P. Kadioglu: None. P. Freda: Research Investigator; Self; Camurus AB. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. G. Fidan Yaylali: None. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Introduction: Standard-of-care (SoC) therapies for acromegaly typically require healthcare provider administration and can pose a significant treatment burden. CAM2029 is a novel subcutaneous octreotide depot designed for convenient once-monthly self-administration as a ready-to-use syringe or injection pen. In a 24-week Phase 3 trial (ACROINNOVA 1), CAM2029 achieved superior insulin-like growth factor 1 (IGF-1) response vs placebo in acromegaly patients (pts) previously controlled with SoC (octreotide LAR/lanreotide Autogel). We report patient-reported outcome (PRO) data from an interim analysis of a Phase 3, open-label trial of CAM2029 (ACROINNOVA 2; NCT04125836). Methods: ACROINNOVA 2 enrolled pts with acromegaly who completed ACROINNOVA 1 (prior CAM2029 or placebo groups) and new pts with IGF-1 ≤2x upper limit of normal during stable SoC. Pts received once-monthly CAM2029 20 mg for up to 52 weeks (28 weeks for prior placebo pts [week 24−52]). Primary endpoint was adverse events. PROs were assessed using Acromegaly Index of Severity (AIS, 0−18; sum of 6 scores [0−3; none−severe] for headache, sweating, fatigue, joint pain, paresthesia, soft tissue swelling) for symptoms; Acromegaly Quality of Life Questionnaire (AcroQoL, 0−100) for QoL; Treatment Satisfaction Questionnaire for Medication (TSQM, 0−100) and patient satisfaction scale (0−5) for treatment satisfaction; and Self-Injection Assessment Questionnaire (SIAQ v2.0, 0−10) for satisfaction with self-administration. Higher scores signify improvements, except for AIS. Data are shown for the overall population. Results: At data cutoff (May 23, 2023), 54 roll-over pts (prior CAM2029 n=36; prior placebo n=18) and 81 new pts were enrolled; mean CAM2029 exposure was 56.3 weeks. CAM2029 was well tolerated with no unexpected side effects. Mean AIS score improved from baseline SoC to week 52 (−1.2; 95% CI: −1.8, −0.7); estimated proportion of pts with any acromegaly symptoms reduced by 15.1% (95% CI: −23.9, −6.3). At week 52 vs baseline: mean total AcroQoL increased by 3.5 (95% CI: 1.3, 5.7); mean TSQM increased for ‘convenience’ by 15.6 (95% CI: 11.8, 19.3), ‘effectiveness’ by 6.3 (95% CI: 2.8, 9.8), ‘satisfaction’ by 4.7 (95% CI: 1.1, 8.4), and for ‘side effects’ by 2.4 (95% CI: −2.0, 6.8). Mean patient satisfaction score at week 52 was 4.1 (95% CI: 3.9, 4.3); 32.6% and 19.3% of pts reported a ‘much better’ or ‘slightly better’ experience, respectively, with CAM2029 vs prior SoC. Mean SIAQ increased at week 48 vs pre-treatment, ‘satisfaction with way of taking medication’ by 1.6 (95% CI: 0.9, 2.2) and ‘feelings about injections’ by 0.8 (95% CI: 0.3, 1.3). Conclusion: CAM2029 improved symptom burden, QoL, treatment convenience, and patient satisfaction vs baseline SoC, including in pts with stable or controlled disease at baseline, supporting the clinical benefit of CAM2029 and its potential to address unmet needs for pts with acromegaly. Presentation: 6/2/2024

9191 Real-world Biochemical And Symptoms Outcomes With Oral Octreotide: Management Of Acromegaly (MACRO) Registry Experience

Abstract Disclosure: K.C. Yuen: Consulting Fee; Self; Novo Nordisk, Neurocrine, Crinetics, Recordati, Ascendis, Chiesi. Grant Recipient; Self; Ascendis, Corcept Therapeutics, Chiesi, Sparrow. Speaker; Self; Recordati, Novo Nordisk. W. Huang: Advisory Board Member; Self; Chiesi, Novo Nordisk, Neurocrine, Crinetics, Recordati. Speaker; Self; Chiesi, Recordati. M. Fleseriu: Consulting Fee; Self; Camurus, Crinetics, Recordati. Grant Recipient; Self; Crinetics (via institution). E.B. Geer: Advisory Board Member; Self; Chiesi, Crinetics. Consulting Fee; Self; Crinetics. T. Araki: Advisory Board Member; Self; Chiesi. A. Labadzhyan: None. P.U. Freda: None. A.G. Ioachimescu: Consulting Fee; Self; Crinetics, Camurus, Xeris. E.A. Christofides: Advisory Board Member; Self; Chiesi. Speaker; Self; Chiesi. J. Sisco: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Pfizer, Inc.. N.R. Biermasz: None. J.A. Crompton: Employee; Self; Chiesi. M.E. Molitch: Consulting Fee; Self; Chiesi, Takeda, Sention, Jansen Pharmaceuticals. Background: MACRO is a non-interventional, prospective, disease-based cohort registry that collects data on patients with active acromegaly. We report data of real-world experience with oral octreotide capsules (OOC) using paired data from acromegaly patients and their physicians. Methods: Patients (pts) and physicians completed questionnaires at enrollment and every 3 mos (up to 3 yrs) on demographic, disease activity, treatment information, ratings of symptom and biochemical control (“well”, “partially”, “not”, “unsure”), and patient-reported outcomes. Descriptive statistics were analyzed. Results: Out of 230 pts, 32 (14%) received OOC at baseline [30 monotherapy; 1 combination w/pegvisomant (PEG), 1 w/cabergoline (CBG)] and 26 (11%) initiated post-baseline [20 monotherapy; 6 combination (3 w/CBG; 1 w/PEG; 1 w/PEG&CBG; 1 w/bromocriptine)]. Reasons for initiating OOC included patient preference (13, 50%) and lack of symptom control (10, 38%) or biochemical control (7, 27%). Starting dose was unknown, 40, 60, or 80mg/day in 1 (4%), 20 (77%), 2 (8%), and 3 (12%) of newly-initiated pts. Mean (±SD) time on OOC was 19.7±18.1 mos with 42 (72%) receiving for ≥ 6 mos. Last recorded daily dose (n, %) for pts remaining on OOC monotherapy (n=31) was 20 (1, 3%), 40 (16, 52%), 60 (5, 16%), and 80mg (9, 29%). In pts with available IGF-I levels at last follow-up, 81% (39/48) overall and 100% (33/33) on monotherapy were ≤ 1x ULN (mean ± SD = 0.8 ± 0.4 for overall group). Among all pts, 19 (33%) discontinued OOC [5 (9%), 3 (5%), and 9 (16%) for lack of biochemical control, symptom control or adverse events, respectively]. Median (range) time on OOC prior to discontinuation was 5 (2-72) mos. In monotherapy pts discontinued solely for lack of biochemical and/or symptom control, 3/4 (75%) were receiving < 80mg/day. Of 39 pts remaining on OOC-based therapy (31 monotherapy, 8 in combination), 34 (87%) were biochemically well-controlled at last follow-up and 24/34 (71%) were also symptomatically well-controlled per patient report. In the 16 pts initiated on OOC post-baseline and remaining on therapy (8 monotherapy; 8 in combination), 12 (75%) were biochemically well-controlled. Patient-reported symptom control was maintained or improved in newly-initiated pts in 11/16 (69%). Last patient reported symptom control in newly-initiated OOC pts (n, %) was well (8, 50%), partially (4, 25%), not controlled (1, 6%) or unsure/not reported (3, 19%). Conclusions: Most patients were on OOC as monotherapy at 40mg/day and maintained or achieved biochemical control. Discontinuation reasons were consistent with clinical trial experience. In over half of patients discontinuing OOC due to inadequate biochemical or symptom control, dose titration up to 80mg/day was not implemented. Approximately half of patients receiving OOC reported well-controlled symptoms. Presentation: 6/2/2024

12200 Impact Of Strict IGF-1 Control (I-Con) On Quality Of Life Scores In Patients With Acromegaly

Abstract Disclosure: C. Gandhi: None. C.L. Chik: Advisory Board Member; Self; Ipsen, Novo Nordisk, Novartis Pharmaceuticals. Grant Recipient; Self; Pfizer, Inc.. J.A. Rivera: None. M. Denis: None. S. Van Uum: Advisory Board Member; Self; Ipsen, Pfizer, Inc., Novo Nordisk, Spruce. D.T. Holmes: Other; Self; Roche Diagnostics. S.Z. Ezzat: Advisory Board Member; Self; Bayer, Inc., Eli Lilly & Company, Ipsen, Novartis Pharmaceuticals, Merck, Eisai. Objective: Examine, in a real world setting, whether strict normalization of modestly elevated IGF-1 can result in clinical and health-related quality of life benefits in patients with acromegaly in a prospective 6-month multicenter interventional study. Methods: Strict IGF-1 control was achieved by the addition or dose optimization of pegvisomant (PEGV) in acromegaly patients with modest elevation of IGF-1 levels (>100% and <150% of upper limit of normal [%ULN]). IGF-1 measurements were completed in a designated central laboratory, initially using the IDS-iSYS and after the first four patients with the Roche Elecsys® method. The transition did not impact study results. Clinical and biochemical parameters were assessed at baseline, 1 and 3 months for dose titration of PEGV and at 6 months. The Patient-Assessed Acromegaly Symptom Questionnaire (PASQ), the Acromegaly Quality of Life questionnaire (AcroQoL) and the Acromegaly Disease Activity Tool (ACRODAT®) were completed at baseline and at 6 months. Results: Ten patients (8 males, mean age at screening 50.7 ± 11.3 years) from four centers across Canada participated in the study. Age at diagnosis was 43.9 ± 12.1 years and all patients had macrotumors. Nine patients had prior transsphenoidal surgeries including one with adjunct radiation therapy. All 10 patients had trials of somatostatin analogs (SSA) and SSA was switched to PEGV in two patients because of lack of efficacy. At the time of screening, six patients were on SSA, two on PEGV, and two on SSA and PEGV. At six months, the mean daily dose of PEGV increased from 7.5 ± 12.3 mg (range 0 to 30 mg daily) to 17.6 ± 13.7 mg (range 5 to 40 mg daily). After six months of dose escalation or the addition of PEGV, IGF-1 decreased from 258.5 ± 59.2 µg/L (121.8 ± 14.4 %ULN) to 184.1 ± 41.1 µg/L (86.6 ± 20.0 %ULN) (p=0.001). The summation of PASQ1 to PASQ6 score decreased from 14.6 ± 10.7 to 11.1 ± 8.9 (p=0.02); however there was no statistically significant difference in the AcroQoL score (63.8 ± 24.0 vs 66.5 ± 22.6, p=0.11). The ACRODAT® overall status decreased from 84.3 ± 27.6 to 33.8 ± 17.1 (p=0.001) and there was a decline in the summation of the tumor status, comorbidities, symptoms and health-related qualify of life impairment score (7.1 ± 1.8 vs 6.4 ± 1.8, p=0.02). Hemoglobin A1c, fasting lipids, liver enzymes and renal function were not significantly affected. Repeat MRI of the sella at 6 months showed no change. Conclusions: In spite of the small number of patients participating in this study, strict control in patients with a modest IGF-1 elevation was accompanied by clinical improvements detected by the PASQ and ACRODAT®. Our results support the notion that strict IGF-1 control can be accompanied by improvement in clinical symptoms with lower PASQ scores. These findings need to be confirmed in a larger scale clinical trial. Presentation: 6/2/2024

12208 Impact Of Transition From The IDS-iSYS To The Roche Elecsys® Immunoassays On A Clinical Study Assessing Strict IGF-1 Control (I-Con) In Patients With Acromegaly

Abstract Disclosure: C.L. Chik: Advisory Board Member; Self; Ipsen, Novo Nordisk, Novartis Pharmaceuticals. Grant Recipient; Self; Pfizer, Inc.. C. Gandhi: None. J.A. Rivera: None. M. Denis: None. S. Van Uum: Advisory Board Member; Self; Ipsen, Pfizer, Inc., Novo Nordisk, Spruce. S.Z. Ezzat: Advisory Board Member; Self; Bayer, Inc., Eli Lilly & Company, Ipsen, Novartis Pharmaceuticals, Merck, Eisai. D.T. Holmes: Other; Self; Roche Diagnostics. Objective: IGF-1 measurements were transitioned from the IDS-iSYS to the Roche Elecsys® immunoassays by the central laboratory during our clinical study that assessed strict IGF-1 control (I-Con) and quality-of-life scores in patients with acromegaly. Given the known variabilities of the IGF-1 measurements and the critical nature of IGF-1 results to the validity of the study, a retrospective analysis of the stored samples was completed using both methods. Methods: IGF-1 was measured in available stored samples (n=38) using IDS-iSYS at one of the hospital laboratories and the Roche Elecsys® at the central laboratory. In addition, the end-of-study (EOS) IGF-1 results were compared with IGF-1 measurements during the study (DTS) at the central and the local laboratory of the two sites with more than 10 stored samples, with one site using IDS-iSYS and the second site using IGF-1-RIACT. Bland-Altman plot, regression analysis and intra-class correlation were used to assess the reliability of the IGF-1 measurements. Results: Ten acromegaly patients from four sites in Canada participated in the clinical study. After six months of addition of pegvisomant to a somatostatin analog (n=6) or dose escalation of pegvisomant (n=4), IGF-1 decreased from 258.5 ± 59.2 µg/L [121.8 ± 14.4 % upper limit of normal (%ULN)] to 184.1 ± 41.1 µg/L (86.7 ± 20.0 %ULN) (p=0.001). Two to five stored samples were available from the 10 patients (n=38) and the mean difference of IGF-1 between the IDS-iSYS and Roche Elecsys® was 10.8 µg/L or 4.6% when expressed as %ULN, with a trend to a higher value at the central laboratory. Linear regression of the difference between IGF-1 measurements against their average showed a slope of 0.1 (p<0.001) or 0.15 (p=0.01) when expressed as %ULN. Intra-class correlations between the central laboratory DTS and EOS measurements were compared with those by the local laboratory. In the site that used IDS-iSYS for IGF-1 measurements, the intra-class correlations with the Roche Elecsys® was 0.99 (n=11) for DTS measurements and 0.98 (n=13) for EOS measurements. In the second site that used IGF-1-RIACT, the intra-class correlations with the IDS-iSYS was 0.38 (n=13) for DTS results, and with the Roche Elecsys® was 0.64 (n=15) for EOS results. Conclusion: Although there were variabilities between the IDS-iSYS and the Roche Elecsys® IGF-1 measurements, the small difference between the two IGF-1 assays confirmed that the transition from the IDS-iSYS to the Roche Elecsys® by the central laboratory had little impact on the IGF-1 results of our study. Using intra-class correlations to assess reliability of the IGF-1 measurements, the reliability of the IGF-1 results appeared dependent on the IGF-1 method used in the individual site. Presentation: 6/2/2024

7373 CAM2029, Octreotide Subcutaneous Depot, Provides Sustained Biochemical Control of Acromegaly: Interim Results From a Phase 3 Study (ACROINNOVA 2)

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Grant Recipient; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Research Investigator; Self; Camurus AB. J. Silverstein: Consulting Fee; Self; Xeris Pharmaceuticals. Research Investigator; Self; Camurus AB. P. Freda: Research Investigator; Self; Camurus AB. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. F. Gatto: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. P. Kadioglu: None. P. Maffei: Research Investigator; Self; Camurus AB. J. Seufert: Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. E. Isaeva: None. A. Dreval: None. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is characterized by excess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) production. A key treatment goal is long-term biochemical control to minimize adverse effects of prolonged excess GH. CAM2029 is a novel, subcutaneous, octreotide depot, designed for convenient monthly self-administration using a pre-filled injection/pen. In a 24-week Phase 3 trial (ACROINNOVA 1, NCT04076462), CAM2029 achieved superior IGF-1 control vs placebo (IGF-1 ≤ upper limit of normal [ULN]: 72.2 vs 37.5%; P=0.0018) in acromegaly patients previously controlled with standard-of-care (SoC; octreotide long-acting repeatable/lanreotide Autogel). On trial completion, patients could roll over to a Phase 3, 52-week, open-label, long-term safety trial (ACROINNOVA 2, NCT04125836). Here, we report data from an interim analysis of roll-over patients in ACROINNOVA 2. Methods: Roll-over patients received monthly CAM2029 20 mg for 28 weeks in ACROINNOVA 2. Primary endpoint: occurrence of adverse events (AEs). Key secondary endpoints: proportion of patients with available assessments who had (i) IGF-1 ≤1x ULN (mean of weeks 50/52 measurements) and (ii) both IGF-1 ≤1x ULN (weeks 50/52 mean) and mean GH <2.5 µg/L (week 52). Data are reported according to prior treatment in ACROINNOVA 1. Safety data from the whole trial period are reported. Results: Fifty-four of the 64 patients completing ACROINNOVA 1 (prior CAM2029 n=36; prior placebo n=18) entered ACROINNOVA 2. At data cut-off (May 23, 2023) 28 and 15 patients in the prior CAM2029 and prior placebo groups, respectively, had completed treatment week 52; 7 and 3 were ongoing; 1 and 0 had discontinued. The medication was well tolerated with a safety profile comparable to SoC treatment; no new safety signals were observed. One treatment-related serious AE (cholelithiasis, moderate severity, resolved) occurred in the prior placebo group. Injection site treatment-emergent AEs (Grade ≤2) occurred in 50% of patients in the prior CAM2029 (18/36) and prior placebo (9/18) groups. Of evaluable patients in the prior CAM2029 and prior placebo groups, 89.3% (25/28) and 100% (15/15) had IGF ≤1x ULN at weeks 50/52; 88.5% (23/26) and 100% (14/14) had both IGF ≤1x ULN (week 50/52) and GH <2.5 µg/L (week 52). Mean IGF-1 levels remained <ULN throughout the 52-week study period for the prior CAM2029 group; in the prior placebo group, mean IGF-1 increased above 1x ULN during placebo treatment, returning to <ULN after switching to CAM2029 for 28 weeks. All patients previously treated with placebo regained IGF-I control upon switching to CAM2029. Conclusions: The safety profile of CAM2029 was consistent with SoC, with no new or unexpected safety signals during extended treatment. CAM2029 provided persistent control of IGF-1 and GH during 52 weeks of treatment. All patients in the prior placebo group regained biochemical control of acromegaly after switching to CAM2029. Presentation: 6/1/2024

Assessment of hearing and balance functions in patients with acromegaly by the use of an audiovestibular test battery: a cross-sectional study.

Patients with acromegaly may have abnormalities in their hearing and balance as a result of modifications in body composition and involvement of the temporal bone. The objective of this study is to examine if there are any changes in the auditory and vestibular systems in individuals with acromegaly by using audiogram and vestibular function tests. This prospective study included 33 healthy controls and 33 acromegaly patients who were matched for age and gender distribution. A pure-tone audiometry test was conducted, including frequencies ranging from 250Hz to 8000Hz. Videonystagmography (VNG) was employed to assess nystagmus, an essential parameter used for assessing vestibular functions. The Video Head Impulse Test (v-HIT) was used to assess the vestibulo-ocular reflex (VOR). The Dizziness Handicap Inventory (DHI) was applied to evaluate the subjective complaints of the participants. The acromegaly patients had significantly elevated hearing thresholds at all frequencies (250, 500, 1000, 2000, 4000, and 6000Hz) compared to the control group (p < 0.005). The VNG tests, including gaze horizontal, gaze vertical, saccade, spontaneous nystagmus, optokinetic, smooth pursuit, and positioning tests, did not show any statistically significant difference between the two groups (p values > 0.05). The patient group demonstrated reduced VOR gains compared to the control group in the anterior and posterior channels (p < 0.005). There was no statistically significant difference between the two groups for the occurrence of aberrant eye movements (p values > 0.05). The patient group had a total DHI score of 6.6 ± 3.2, while the control group had a score of 3.2 ± 2.6 (independent samples t-test; p < 0.001). Therefore, The patient group exhibited significantly greater subjective vestibular symptoms. Patients with acromegaly experience impaired auditory function. The central vestibular system remains unaffected, while the gains of the vestibulo-ocular reflex (VOR) in the posterior and anterior semicircular canals are decreased. Additionally, these patients report experiencing subjective dizziness. Screening for hearing and balance in patients with acromegaly may improve the quality of life of patients and prevent problems related to balance disorders at an early stage.

Electrocardiographic ventricular arrhythmia parameters during diagnosis and after the treatment of acromegaly: A case-control study

BackgroundThe risk of death is increased in acromegaly patients compared to the general population, and cardiovascular system-related complications are among the risk factors decreasing life expectancy. The Tp-e interval, which is the distance between the point where the T-wave peaks and ends on electrocardiography (ECG), shows ventricular rapolarization and, together with the Tp-e/QT and Tp-e/QTc ratios, these are relatively new tools that predict ventricular arrhythmia. We aimed to evaluate the ECG of acromegaly patients at the time of diagnosis and compare the results with current ECG findings. Material and methodsThe study included 103 acromegaly patients and 81 control subjects. Of the 103 patients, 41 patients had only baseline ECG, 23 patients had only current ECG and 39 patients had both baseline and current ECGs. Heart rate, QT interval and corrected QT (QTc) interval, Tp-e, Tp-e/QT, Tp-e/QTc values on the ECGs were measured by a cardiologist. ResultsIn the acromegaly patients with both baseline and current ECGs, heart rate, QRS duration, Tp-e, and Tp-e/QTc ratio were decreased. The decrease in these arrhythmia parameters was similar in active and remission patients. Compared to the control group, in acromegaly patients with only baseline ECG, heart rate, QTc interval, Tp-e, Tp-e/QT, and Tp-e/QTc were decreased. ConclusionVentricular arrhythmia parameters improve with treatment in patients with acromegaly. The decrease in ventricular arrhythmia parameters was similar in active and remission patients, which can be explained by the significant decrease in IGF-1 levels compared to the time of diagnosis, even in patients with active disease.

Every Third Male Patient with Acromegaly Recovers from Hypogonadism after Neurosurgical Treatment.

Background: Acromegaly is a rare endocrine condition caused by excessive growth hormone (GH) production. Hypogonadotropic hypogonadism (HH) affects 30%-50% of acromegaly patients. Objectives: This study examined the frequency of HH in men with acromegaly and the effects of neurosurgical treatment during the follow-up period. Materials and Methods: A retrospective analysis of medical records from January 2015 to December 2022 was conducted. Data included clinical history, laboratory results, and pituitary MRI findings. Statistical analysis was performed using Statistica 13.3. Results: Patients were divided into two groups: a cross-sectional sample (preoperative n = 62; postoperative n = 60) and a longitudinal sample (n = 53). In the longitudinal sample, preoperative HH was diagnosed in 41 males (77.36%). Post-surgery, HH prevalence decreased to 58.49% (n = 31), with a significant increase in postoperative testosterone levels (9.1 vs. 12.1 nmol/L; p < 0.001), particularly in patients with preoperative HH (7.2 vs. 10.2 nmol/L; p < 0.001). Among 41 patients with HH, 12 (29.27%) showed recovery. Testosterone levels were lower in patients with macroadenomas (7.2 nmol/L vs. 11.05 nmol/L; p < 0.001). Patients with HH had higher baseline levels of GH and insulin-like growth factor 1 (IGF-1) (GH: 3.37 ng/mL; IGF-1: 551 ng/mL vs. GH: 1.36 ng/mL; IGF-1: 355 ng/mL). Luteinizing hormone (LH) levels above 3.3 mIU/mL and follicle-stimulating hormone (FSH) levels above 4.4 mIU/mL predicted hypogonadism remission (Area under the curve (AUC): 0.838 and 0.792, respectively). Conclusions: Younger patients with macroadenoma and hyperprolactinemia are more likely to have preoperative hypogonadism. Neurosurgical treatment can normalize LH, FSH, and total testosterone in approximately 30% of these patients.

Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort.

Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.

Outcome of endoscopic transsphenoidal surgery for acromegaly: Comparison of using and not using the floor standing pneumatic powered endoscope-holder system

IntroductionEndoscopic transsphenoidal surgery can be performed by two surgeons, including an endoscopist (PE/2S), and by a single surgeon with an endoscope-holder system (PE/1S + H). We analyzed the surgical outcome, and outcome predictors in acromegaly patients in endoscopic transsphenoidal surgery using floor standing pneumatic endoscope-holder system. MethodsEndoscopic transsphenoidal surgery was performed with PE/1S+H (n = 51) and PE/2S (n = 20). Postoperative remission was evaluated by the 2010 consensus criteria for acromegaly. We compared the surgical results of PE/2S style and PE/1S+H style, and investigated the factors associated with favorable surgical outcomes. ResultsThere was no difference in clinical background between the PE/2S and the PE/1S + H groups. The remission rates for PE/2S and PE/1S+H were 65.0% and 82.4%, respectively, with no significant difference (p = 0.128). In consecutive 71 cases, statistically useful predictors of remission were low preoperative growth hormone (GH) level (<12 ng/mL), low Knosp grade (0–2), and low revised Knosp grade (0–3A). In the conventional Knosp grade 0–2 and 3/4, the sensitivity was 0.76 and the specificity was 0.81. In the revised Knosp grade 0–3A and 3B/4, the sensitivity was 0.96 and the specificity was 0.44. ConclusionThe outcome of GH-producing pituitary neuroendocrine tumors surgically removed by PE/1S+H could be almost equivalent to that by PE/2S. Preoperative low GH level and Knosp grades, including revised Knosp grades, are useful preoperative predictors for surgical remission of acromegaly.

Evaluation of the foot health with baropodometric analysis of acromegaly patients followed after pituitary surgery

Evaluation of the foot health with baropodometric analysis of acromegaly patients followed after pituitary surgery

Impact of medical therapy for hormone-secreting Pituitary tumors on bone.

Bone health is often impaired in patients with hormone-secreting pituitary tumors. Since medical therapy is central to their care, understanding how its use impacts on this is highly important. This review summarizes a systemmatic review of the literature on the effects of medical therapies for hormone-secreting pituitary tumors on bone. In acromegaly, medical therapy lowers bone turnover marker (BTM) levels, consistent with correction of the high bone turnover of active disease, and overall, areal bone mineral density (aBMD) does not change or increases. Somatostatin-receptor ligand (SRL) and pegvisomant-treated acromegaly patients have persistently reduced volumetric BMD and microarchitectural abnormalities of the peripheral skeleton, deficits that are similar to those in surgically-treated patients. Fracture risk remains elevated in medically-treated acromegaly patients but in conjunction with biochemical control the risk is lessened. Treatment of prolactin-secreting tumors with dopamine agonists is associated with improvements in aBMD, but this does not always fully normalize despite effective medical treatment of the prolactinoma. In one cross-sectional study, prolactinoma patients had lower total volumetric BMD and impaired microarchitecture suggesting that bone microstructure does not fully normalize despite dopamine agonist therapy. Cross-sectional studies show a high rate of VF in patients with prolactin-secreting tumors that is lowered on cabergoline therapy, but still the fracture rate of men and postmenopausal women is higher than that of controls in some studies. Studies on the effects of modern-day medical therapy for Cushing's disease on bone are lacking. More research is needed on the effectsof medical therapies for hormone secreting pituitary tumors on bone health.

Temporal and masseter muscle evaluation by MRI provides information on muscle mass and quality in acromegaly patients

PurposeThe impact of GH/IGF-1 levels on skeletal muscle in acromegaly is still controversial. Temporal (TMT) and masseter muscle (MMT) thickness has been recently demonstrated as a reliable measure of muscle mass. We aimed to investigate the relationship between TMT, MMT and clinical/biochemical characteristics in patients with acromegaly.MethodsSingle center retrospective longitudinal study including 69 patients with at least one available brain/sella turcica MRI and matched clinical data. TMT, MMT, and muscle fatty infiltration (modified Goutallier score) were evaluated in all patients at baseline (first available MRI) and over time (182 MRIs analyzed).ResultsAt baseline, both TMT and MMT were higher in males than females (p = 0.001 and p = 0.016, respectively). TMT and MMT were positively associated (β 0.508, p < 0.001), and they were positively correlated with IGF-1 xULN (TMT, p = 0.047; MMT, p = 0.001). MMT had a positive correlation with patients’ weight (p = 0.015) and height (p = 0.006). No correlation was found between TMT, MMT and the presence of hypogonadism. Considering all available MRIs, sex and IGF-1 xULN were significant determinants of TMT and MMT at multivariable analysis (female sex: β -0.345/-0.426, p < 0.001; IGF-1 xULN: β 0.257/0.328, p < 0.001). At longitudinal evaluation, uncontrolled patients at baseline showed a significant reduction of MMT over time (p = 0.044). Remarkable fatty infiltration was observed in 34–37% of MRIs; age was the main determinant (temporal muscle: OR 1.665; p = 0.013; masseter muscle: OR 1.793; p = 0.009).ConclusionMale patients with higher IGF-1 values have thicker temporal and masseter muscles, suggesting that sex and IGF-1 have a significant impact on muscle mass in acromegaly.

Three-Dimensional Speckle-Tracking Echocardiography-Derived Tricuspid Annular Properties in Acromegaly-Results from the MAGYAR-Path Study.

Acromegaly is an endocrine pathology characterized by the overproduction of human growth hormone. The present study aimed to analyze three-dimensional speckle-tracking echocardiography (3DSTE)-derived tricuspid annular (TA) properties in detail in patients with acromegaly and to compare the findings to those of matched healthy controls. The present study consisted of 29 patients with acromegaly (mean age: 55.9 ± 14.5 years, 21 males), of which 13 had an active disease. The control population comprised 57 healthy subjects (mean age: 53.2 ± 8.4 years, 38 males). In the presence of acromegaly, left atrial and end-diastolic left ventricular (LV) sizes were dilated, and LV ejection fraction was increased, which was accompanied by thickened interventricular septum and LV posterior wall as compared with matched healthy controls. The presence of grade 1 mitral (MR) and tricuspid (TR) regurgitations were more frequent in acromegaly than in controls, regardless of disease activity. Higher than grade 1 MR/TR was uncommon in acromegaly. The 3DSTE-derived all end-diastolic (2.47 ± 0.27 cm vs. 2.23 ± 0.27 cm; 8.73 ± 1.77 cm2 vs. 6.67 ± 1.40 cm2; 11.56 ± 1.34 cm vs. 10.20 ± 1.10 cm, p < 0.001 for all) and end-systolic (1.97 ± 0.27 cm vs. 1.77 ± 0.28 cm; 6.24 ± 1.61 cm2 vs. 5.01 ± 1.42 cm2; 9.80 ± 1.35 cm vs. 8.72 ± 1.10 cm, p < 0.001 for all) TA diameters, areas, and perimeters proved to be dilated, while TA functional parameters including TA fractional area change (28.77 ± 9.80% vs. 27.64 ± 15.34%, p = 0.720) and fractional shortening (20.60 ± 9.08% vs. 20.51 ± 8.81%, p = 0.822) were normal in acromegaly regardless of whether acromegaly was active or not. RA volumes respecting the cardiac cycle were dilated in acromegaly as compared with those of healthy controls regardless of disease activity and were associated with respective changes in TA dimensions. In the presented acromegaly patients, significant TA dilation with preserved function could be detected regardless of disease activity. RA volumes and TA dimensions are correlated in acromegaly.