Maria Fleseriu, MD, FACEProfessor of Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition,

Professor of Neurological Surgery, School of Medicine

Director of Pituitary Center

Oregon Health & Science University

Portland, Oregon, USA

Acromegaly Highlights from ENDO 2021

Learning Objective

Describe the latest research being presented to better manage acromegaly and its clinical relevance

ENDO 2021• Annual meeting focused on endocrine disorders and cancers• Usually, a 4-day live event in March• 2021 – virtual• In the last few decades, a considerable body of evidence supports

the concept that patients with pituitary tumors would receive the best care from units of excellence. Multidisciplinary care in acromegaly requires a team approach (endocrinologists, neurosurgeons, general practitioners, radiation-oncologists, neuroradiologists, neuro ophthalmologists, oncologists, etc.)

• Here, the goal is to keep updated all health care professionals involved in acromegaly with the latest ENDO 2021 information

Casanueva FF, Barkan AL, Buchfelder M; Pituitary Society, Expert Group on Pituitary Tumors. Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement. Pituitary. 2017 Oct;20(5):489-498.

Acromegaly

• A chronic, progressive, and potentially lethal disease if not treated

• Due to growth hormone (GH)-secreting adenoma

• Affects multiple organs/systems but often takes years to be diagnosed

• Numerous comorbidities, including type 2 diabetes, hypertension, heart disease, sleep apnea, arthritis, carpal tunnel syndrome, bone pain

• Main treatment goals• Normalize GH and IGF-1• Reduce tumor size• Manage symptoms/comorbidities• Improve quality of life• Reduce morbidity and mortality

• Surgery, medical therapy, radiation or multiple adjuvant treatment

Giustina A, Barkhoudarian G, Beckers A, et al. Rev Endocr Metab Disord 2020; 21: 667-678. Zahr R, Fleseriu M. Eur Endocrinol. 2018: 14: 57-61. Image couresey of wikmedia.

Surgical vs Surgical + Medical TreatmentQuaLAT Study• Quality of life after acromegaly treatment (QuaLAT)

• Patients who had surgical and disease remission vs patient who had surgery who did not achieve remission and required medical therapy

• Similar quality of life in both groups. All scores lower compared to scores from healthy controls

Arshad MF, Ogunleye O. J Endo Soc. 2021: 5(suppl 1): A522.

Surgery alone Surgery + Treatment

Years with acromegaly 9.8 ± 6.9 yrs 9.7± 6.9 yrs

Acromegaly quality of life (ACROQOL) score 54.4 ± 24.8 54.4 ± 26.1

Short Form Survey (SF32) – physical score 40.1 ± 11.1 45.6 ± 12.0

SF32 – mental score 41.7 ± 13.0 43.1 ± 16.4

Fatigue Severity Scale (FSS) 4.4 ± 2.2 4.5 ± 2.0

Acromegaly – Medical Treatment OptionsMedical Therapy Route Dose schedule Efficacy Possible side effects

Octreotide Subcutaneous 1-4 times/day 30-60% Nausea, vomiting, diarrhoea, constipation, abdominal pain, cholelithiasis/biliary sludge, bloating, bradycardia, fatigue, headache, alopecia, dysglycemia

Octreotide LAR Intramuscular Monthly 30-60% Nausea, vomiting, diarrhoea, constipation, abdominal pain, cholelithiasis/biliary sludge, bloating, bradycardia, fatigue, headache, alopecia, dysglycemia

Octreotide oral Oral Daily 65% Nausea, vomiting, diarrhoea, dyspepsia, cholelithiasis, headaches, dizziness, dysglycemia

Lanreotide DeepSubcutaneous

Monthly (4-6 weeks)

30-60% Nausea, vomiting, diarrhoea, constipation, abdominal pain, cholelithiasis/biliary sludge, bloating, bradycardia, fatigue, headache, alopecia, hyperglycemia

Pasireotide LAR Intramuscular Monthly 40% Nausea, vomiting, diarrhoea, constipation, abdominal pain, cholelithiasis/biliary sludge, bloating, bradycardia, fatigue, headache, alopecia, dysglycemia

Pegvisomant Subcutaneous Daily 60-90% Transaminases elevation, lipodystrophy, arthralgias

Cabergoline (off label) Oral Daily to biweekly

30-40% (mild)

Nausea, dizziness, orthostatic hypotension

Adapted from Zahr R, Fleseriu M. Eur Endocrinol. 2018: 14: 57-61; Fleseriu M, Biller BMK, Freda PU, et al. A Pituitary Society update to acromegalymanagement guidelines. Pituitary. 2021;24(1):1-13. doi:10.1007/s11102-020-01091-7.

New Data on Pharmaceutical Treatment OptionsOral Octreotide Capsules• Numerous abstracts presented from the phase 3 MPOWERED trial

• Patients with acromegaly previously treated with injectable octreotide or lanreotide• Insulin growth factor 1 (IGF-1) < 1.3 times upper limit of normal• Mean growth hormone (GH) < 2.5 ng/ml• 26 week run in phase to find effective dose of oral octreotide• 36 week randomized controlled phase

• Oral octreotide capsules (n=55)• Injectable octreotide or lanreotide (n=37)

Biermasz N, Fleseriu M, Dreval AV, et al. J Endo Soc. 2021: 5(suppl 1): A522-3. Freda P, Fleseriu M, Dreval AV, et al. J Endo Soc. 2021: 5(suppl 1): A527-8. Gordon MB, Fleseriu M, Dreval AV, et al. J Endo Soc. 2021: 5(suppl 1): A520-1. Fleseriu M, Dreval AV, Pokramovich Y, et al. J Endo Soc. 2021: 5(suppl 1): A5217. Samson SL, Nachtigall LB, Fleseriu M. J Endo Soc. 2021: 5(suppl 1): A515-6. Fleseriu M, Dreval AV, Yulia Pokramovich Y, et al. J Endo Soc. 2021: 5(suppl 1): A5218-9.

Oral OctreotideOpen label extension of OPTIMAL study (Samson et al, 2021)

• 40 patients from study entered open-label extension (20 from oral group, 20 from injectable group)• Results from 48 weeks• IGF-1 levels remained stable. No additional safety concerns

Maintenance of response, MPOWERED study (Fleseriu et al, 2021)• Study met noninferiority to maintaining biochemical response• Oral: 91% maintained response• Injectable: 100% maintained response

Addition of cabergoline, MPOWERED study (Fleseriu et al, 2021b)• 14 patients in run-in phase who did not meet criteria to enter RCT (due to failure to response to oral SSA or

inadequate biochemical control) entered a sub-study given all oral therapy (oral SSA plus cabergoline)• Of 9 with IGF-1 > 1.3 times upper limit, 5 showed a response

Samson SL, Nachtigall LB, Fleseriu M. J Endo Soc. 2021: 5(suppl 1): A515-6. Fleseriu M, Dreval AV, Pokramovich Y, et al. J Endo Soc. 2021: 5(suppl 1): A5217. Fleseriu M, Dreval AV, Yulia Pokramovich Y, et al. J Endo Soc. 2021: 5(suppl 1): A5218-9.

Efficacy, MPOWERED study (Biermasz et al, 2021)• 26 week run in phase: significant reduction in extremity swelling, fatigue• 36-week randomized phase:

• Oral SSA: 73% maintained or reduced AIS score; 75% maintained or reduced active symptoms• injectable SSA: 68% maintained or reduced AIS score; 70% maintained or reduced active symptoms

AIS Scores, MPOWERED study (Freda et al, 2021)• Oral octreotide: 73% maintained or reduced AIS score; 75% maintained or reduced active symptoms• injectable SSA: 68% maintained or reduced AIS score; 70% maintained or reduced active symptoms

Patient satisfaction, MPOWERED study (Gordon et al, 2021)• 26 week run in phase: 3 of 5 domains improved (emotional reaction, treatment convenience, and

treatment satisfaction) • 36-week randomized phase:

• Oral SSA: no change in satisfaction• injectable SSA: reduced satisfaction (more anxiety and frustration)

Biermasz N, Fleseriu M, Dreval AV, et al. J Endo Soc. 2021: 5(suppl 1): A522-3. Freda P, Fleseriu M, Dreval AV, et al. J Endo Soc. 2021: 5(suppl 1): A527-8. Gordon MB, Fleseriu M, Dreval AV, et al. J Endo Soc. 2021: 5(suppl 1): A520-1.

Oral Octreotide

Oral Paltusotine• Paltusotine is a SSTR2 receptor agonist• ACROBAT Edge Phase 2 study• Single arm, 13-week switch study (n=25)• Patients taking long acting SSA (monthly injections) were switched to once

daily oral paltusotine • Results: no change in IGF-1 over 13 weeks (i.e., new treatment could be

similar to injectables, but further studies are needed)• Treatment-emergent adverse events include headache, arthralgia, fatigue,

peripheral swelling, paresthesia and hyperhidrosis• Next steps – phase 3 clinical trials starting 2021

Gadelha MR, Gordon MB, Doknic M, et al. J Endo Soc. 2021: 5(suppl 1): A526-7.

Pegvisomant• Pegvisomant is a GH receptor antagonist• Used as monotherapy or in combination with SSAs or dopamine agonists patients not

responding to standard SSA therapies• Retrospective large study looked at efficacy of above options over 6-month treatment

period

• Minor changes in blood pressure also observed in monotherapy group. No changes observed in ALT, AST, or A1C measurements

Hordejuk D, Laws ER, Kaiser UB. J Endo Soc. 2021; 5(suppl 1): A523-4.

Pegvisomant monotherapy (n=8)

Pegvisomant + SSA (n=8)

Pegvisomant + cabergoline (n=5)

Pegvisomant + SSA + DA agonist (n=2)

IGF-1 levels 40% decrease 53% decrease 36% decrease 47% decrease

Comorbidities and polypharmacy

• MarketScan database used to examine medical claims January 2010 – January 2020

Fleseriu M, Barkan A, del Pilar Schneider M, et al. J Endo Soc. 2021; 5(suppl 1): A649-50.

Comorbidities Acromegaly patients (n=1175)

Matched cohort(n=5875)

Cardiovascular disorders 68% 48%

Hypopituitarism/hypothalamic disorders 26% 0%

Sleep apnea 25% 8%

Malignant neoplasms 23% 9%

Arthritis, musculoskeletal disorders 20% 13%

• MarketScan database used to examine medical claims January 2010 – January 2020

• Similar trends observed in post-hoc analysis by Petersenn et al (2021) of the PRIMARYS and LEAD studies showing most patients with acromegaly require concomitant oral medications for their comorbidities

Fleseriu M, Barkan A, del Pilar Schneider M, et al. J Endo Soc. 2021; 5(suppl 1): A649-50. Petersenn S, Houchard A, del Pilar Schneider M, et al. J Endo Soc. 2021; 5(suppl 1): A528-9.

Medications Acromegaly patients (n=1175)

Matched cohort(n=5875)

Thyroid medication 35% 9%

Lipid modifying agents 34% 26%

renin-angiotensin agents 34% 25%

Taking > 3 oral medications 79% 58%

Number of oral meds taken 12.01 + 10.49 7.21 + 7.21

Comorbidities and polypharmacy

Glucose metabolism (Khan et al)• Study of 89 patients• Major risk factors for dysglycemia include age, male sex, obesity, and macroademona• Glycemic control improves after surgery and medical therapy

Carpal tunnel syndrome (Vinueza et al)• Study of 68 patients• 97.8% showed signs of carpal tunnel syndrome

• 9% mild; 63% moderate; 25% severe

Anemia (Firlatan et al)• Study of 381 patient data from one hospital, 1980 - 2018• 57% diagnosed with anemia• Anemia may be related to characteristics of tumor, hormonal status, type of treatment, and presence of

cancer

Khan SA, Ram N, Masood MQ. J Endo Soc. 2021; 5(suppl 1): A647-8. Vinueza DFP MD1, del Socorro G-P, Solis-Pazmino AP. J Endo Soc. 2021; 5(suppl 1): A648. Firlatan B, Sendur SN, MD, Oguz SH et al. J Endo Soc. 2021; 5(suppl 1): A650.

Other Comorbidities

• No data specifically about Covid-19 and acromegaly presented at ENDO 2021, but…

• Comorbidities make this patient population more fragile towards the SARS-CoV-2 infection• Cardiovascular disease• Glycemic control• Drug-drug interactions?• Vertebral fractures?

• Metformin as a protective agent?

• How to maintain multidisciplinary management virtually?

Mercuri V, D’Amico T, Gargiulo P. J Endocrinol Invest. 2021; 44:637-8. Fleseriu M. Front endocrinology. 2021; 12: 656025.

Covid-19

§ Individualized approach

§ Medical treatment

.

Somatostatin receptor ligands (SRLs)Octreotide 100-200 mcg tds sc *Lanreotide 120 mg deep sc every 6-8 wks *Octreotide LAR 30 mg im every 6-8 wks

* self-injected

Addition of cabergoline, if no response, depending on regulatory approval

Consider pegvisomant sc * with gradual dose titration in small tumours and normal liver function depending on country availability and regulatory approval

* self-injected

Training of patients or family members on administration of injections by

online visits or by video

im, intramuscular; sc, subcutaneous; tds, three times a day.

Fleseriu M, et al. Eur J Endocrinol 2020;183:G17–G23

Acromegaly during the Covid-19 pandemic

• Survey of 84 health care professionals (HCPs)

Giustina A, Legg E, Cesana BM, et al. Endocrine. 2021; 71: 273-80.

Patient management Percentage of HCPs reported anegative impact

The acromegaly diagnostic pathway 44.7%

Patients presenting with worsening symptoms 25.0%

HCP’s capacity to assess patients 54.8%

Lab’s capacity to process samples/conduct tests 39.3%

Radiologists’ capacity for imaging diagnostics 45.2%

None of the above 21.4%

HCP Survey

• Survey of 182 acromegaly patients (June 23 – July 13, 2020)

Giustina A, Cesana BM, Marks M et al. Endocrine. 2020; 70: AEP1074.

Patients reported an impact

Appt with specialist cancelled/postponed 55.5%

Unable to access hospital for blood tests 28.6%

Unable to access holistic care/other support of care 22.0%

Surgery cancelled/postponed 9.3%

Limit set on amount of medicines collect/order (vs pre-Covid-19) 8.8%

Nurse unable to visit home to administer injections 7.7%

Could not access hospital pharmacy for medicine 7.7%

Endocrine ward was transformed to Covid-10 ward 3.3%

Other 29.1%

Patient Survey

• New data show therapies are effective and can improve symptoms• Comorbidities and polypharmacy• Covid and patient care; physicians’ and patients’ perspective• Covid and comorbidities• Multidisciplinary approach – ENDO 2021 data adds to the knowledge

needed by all specialists to be an effective team

Clinical Pearls