Signifor LAR

Understanding a rare endocrine disease

RECOGNIZING AND ADDRESSING ACROMEGALY

The Unmet Need

In the treatment of acromegaly today, unmet needs continue to exist.

Excess GH and IGF-1 lead to a biochemical imbalance and the clinical manifestations of acromegaly, usually due to a benign somatotrophic pituitary adenoma.1-3

GH, growth hormone; IGF, insulin-like growth factor.

Diagnosis may be delayed and surgery is not always successful4,5

  • Average time from symptom onset to diagnosis of acromegaly is 8 to 10 years.5
  • Transsphenoidal surgery is recommended by clinical guidelines as the primary treatment in most patients.5,6
75 – 85%

of somatotroph pituitary tumors at the time of diagnosis are macroadenomas (>10 mm).7

40 – 50%

of patients with a macroadenoma fail to achieve remission post surgery.8

The Acromegaly Consensus Group recognizes the following
treatment goals for acromegaly5:

  • Maintain Biochemical Control
  • Reduce Tumor Size
  • Manage Symptoms and Comorbidities to Improve QOL

Response to first-generation somatostatin receptor
ligands varies among patients9,10

First-generation somatostatin receptor ligands (SRLs) target the source of acromegaly, but results may vary among patients.9‑11

  • Initial medical therapy for patients for whom surgery fails has typically been a first-generation SRL.12
  • SRLs are designed to target the biochemical imbalance induced by excess GH and IGF-1 when surgery fails or is not feasible.1,6,9,10,12
≈30% – 50%

of patients do not achieve biochemical control with first-generation SRLs.13,14

  • Failure defined as inability to achieve biochemical control; octreotide LAR and lanreotide LAR studies defined biochemical control as mean growth hormone levels of <2.5 ng/mL and normal IGF-1 levels.9,10
  • The clinical trials of octreotide LAR were performed in patients who had been receiving lanreotide LAR injection for a period of weeks to as long as 10 years. In the clinical trials of lanreotide LAR, half of the patients had never been treated with an SRL or dopamine agonist.9,10
  • A systematic review that included 9 prospective studies of medically naïve patients reported a mean efficacy rate of 31% (range, 20-54%) for patients who obtained biochemical control with first-generation SRL.15

Consider alternative treatment options for patients uncontrolled on
first-generation SRLs18

In a pivotal clinical trial, inadequate control was defined as the following biochemical measurements19:

mGH ≥2.5 μg/L

(from a 5-point profile over a 2-hour period)

IGF-1 >1.3 x the age

– and sex-adjusted ULN

mGH, mean growth hormone; IGF, insulin-like growth factor; ULN, upper limit of normal.

Persistent symptoms of acromegaly

Even when biochemical control is achieved, many patients will continue to experience severe, disruptive
signs and symptoms.16

In a clinical study of 118 patients, all in biochemical remission from acromegaly, findings revealed the following symptoms:17

Joint stiffness
61%
Respiratory impairment
64%
Paresthesia
40%
Impaired memory
36%
Perspiration
30%
Limited concentration
25%
  • In the same study, 46% of patients reported cardiovascular disease.17

What is Acromegaly?

Often referred to as somatotroph adenoma or growth hormone excess, acromegaly is a chronic metabolic disorder caused by the presence of too much growth hormone.20

About 25,000 patients in the U.S.21
3,000 new cases per year21
Affects men
and women1
Becomes more common with increasing age1

Risk factors

Underlying conditions include certain genetic syndromes that predispose individuals to growth hormone (GH)‑secreting pituitary tumors. Several germline and somatic mutations can predispose people to acromegaly.22

  • Individuals with multiple endocrine neoplasia type 1 (MEN1, formerly called Wermer syndrome) are at increased risk for acromegaly.22 MEN1 is a rare endocrine tumor syndrome caused by mutations in the tumor suppressor gene MEN1. Pituitary adenomas occur in approximately 40% of patients. Prolactin-secreting tumors are the most common, while GH-secreting tumors (leading to acromegaly) represent the second most frequent subtype.23
  • A GH-producing tumor may also develop in individuals with multiple endocrine neoplasia type 4 (MEN4), caused by mutations in gene CDKN1B.24
Patient portrayal

Comorbidities associated with untreated acromegaly

Joint pain and arthritis

The overgrowth of bone and cartilage can lead to osteoarthritis, particularly in weightbearing joints.25

The overgrowth of bone and cartilage can lead to osteoarthritis, particularly in weightbearing joints.25

Sleep apnea

Increased soft tissue in the upper airways and facial bones can contribute to obstructive sleep apnea, reported in up to 60% of acromegaly patients.25

Increased soft tissue in the upper airways and facial bones can contribute to obstructive sleep apnea, reported in up to 60% of acromegaly patients.25

Hypertension and cardiovascular disease26,27

Acromegaly is associated with increased risk for cardiovascular complications, including left ventricular hypertrophy and heart failure. GH directly impacts myocardial function.

Acromegaly is associated with increased risk for cardiovascular complications, including left ventricular hypertrophy and heart failure. GH directly impacts myocardial function.

Diabetes and glucose intolerance28,29

GH interferes with insulin signaling, causing hyperinsulinemia and increased risk of developing diabetes mellitus.

GH interferes with insulin signaling, causing hyperinsulinemia and increased risk of developing diabetes mellitus.

Identifying Symptoms

Identification of acromegaly begins with its clinical signs and symptoms7

Consider acral enlargement and orofacial changes, especially if these occur with unexplained systemic manifestations, such as sleep apnea or ventricular hypertrophy. These may be indicative of acromegaly.7,30

Common acromegaly symptoms31

Screening & Diagnosis

Consensus guidelines specify IGF-1 as the primary biomarker for monitoring disease activity and treatment efficacy. This is because GH levels are more directly reflective of the disease state and are crucial for determining the success of therapeutic interventions.30 Screening evaluations may include:

1

IGF-1 measurement.

In a patient with typical acromegaly features, a serum level of IGF-1 greater than 1.3 times the upper limit of normal for age confirms the diagnosis.30

2

Growth hormone suppression test.

GH measured after overnight fasting may inform prognosis, but is not required for diagnosis.30

3

Imaging.

Recommendation to perform imaging study post-biochemical diagnosis to assess tumor size and presence.

Diagnostic algorithm for acromegaly30

Note: Random GH measured after overnight fasting may be useful for informing prognosis, but not necessary for diagnosis.
Modified from: Giustina et al, 2024.30

IGF, insulin-like growth factor; GH, growth hormone; OGTT, oral glucose tolerance test.

Treatment goal for acromegaly

Once diagnosed, the goal of treatment is to restore the pituitary gland to normal function, producing normal levels of growth hormone.

Surgical removal of the pituitary tumor

is the treatment recommended for most patients with acromegaly. While surgery is successful in many patients, some will see their levels of GH and IGF-1 remain too high even after surgery.31

Non-surgical treatment

may include radiation therapy and injection of growth hormone blocking medications.31

LEARN HOW SIGNIFOR LAR WORKS

INDICATIONS AND USAGE

SIGNIFOR LAR® (pasireotide) is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

IMPORTANT SAFETY INFORMATION

Hyperglycemia, Diabetes, and Ketoacidosis: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Monitor glucose levels as clinically appropriate during therapy. There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with or without history of diabetes. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic treatment or adjustment in their current anti-diabetic treatment. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled despite medical management, reduce the dose or discontinue SIGNIFOR LAR. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history. If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient.

Bradycardia and QT Prolongation: Bradycardia has been reported with the use of SIGNIFOR LAR. Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high grade heart block, or concomitant use of drugs associated with bradycardia, should be monitored. Adjustments in the dose of drugs known to slow the heart rate (e.g., beta-blockers, calcium channel blockers) and correction of electrolyte disturbances may be necessary when initiating or during the course of SIGNIFOR LAR treatment. In cardiac electrophysiology studies with pasireotide via subcutaneous route, QT prolongation occurred at therapeutic and supra-therapeutic doses. Use with caution in patients at significant risk; evaluate ECG and electrolytes prior to dosing and periodically while on treatment. Hypokalemia or hypomagnesemia must be corrected prior to initiating SIGNIFOR LAR and should be monitored periodically during therapy.

Liver Test Elevations: Increases in liver enzymes have been observed with SIGNIFOR LAR. Evaluate liver enzyme tests prior to and during treatment.

Cholelithiasis and Complications of Cholelithiasis: There have been reports of cholelithiasis resulting in complications including cholecystitis or cholangitis and requiring cholecystectomy in patients taking SIGNIFOR LAR. Monitor periodically. Discontinue SIGNIFOR LAR if complications of cholelithiasis are suspected and treat appropriately.

Pituitary Hormone Deficiency(ies): Suppression of anterior pituitary hormones may occur on SIGNIFOR LAR. Monitor for occurrence periodically and treat if clinically indicated.

Steatorrhea and Malabsorption of Dietary Fats: New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency.

The most common adverse reactions occurring in ≥ 20% of patients with acromegaly were diarrhea, hyperglycemia, cholelithiasis, and diabetes mellitus.

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions

  • Drugs that Prolong QT: Co-administration of drugs that prolong the QT interval with SIGNIFOR LAR may have additive effects on the prolongation of the QT interval. Monitoring effects on the QT interval at 21 days is recommended.
  • Cyclosporine: Concomitant administration of cyclosporine with SIGNIFOR LAR may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary.
  • Bromocriptine: Co-administration of SIGNIFOR LAR with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.

Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy.

SIGNIFOR LAR® (pasireotide) for injectable suspension, for intramuscular use, is available as 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg powder in a vial to be reconstituted with the provided 2 mL diluent.

Please see full Prescribing Information and Patient Information.

References: 1. Christofides EA. Clinical importance of achieving biochemical control with medical therapy in adult patients with acromegaly. Patient Prefer Adherence. 2016 Jul 13;10:1217-25. doi: 10.2147/PPA.S102302 2. Carmichael JD, Bonert VS, Nu.o M, Ly D, Melmed S. Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. J Clin Endocrinol Metab. 2014;99(5):1825-1833. doi: 10.1210/jc.2013-3757 3. Carroll PV, Jenkins PJ. Acromegaly. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext [Internet]. South Dartmouth, MA: MDText.com, Inc.; 2016. 4. Gatto F, Barbieri F, Arvigo M, et al. Biological and biochemical basis of the differential efficacy of first and second generation somatostatin receptor ligands in neuroendocrine neoplasms. Int J Mol Sci. 2019;20(16):3940. doi: 10.3390/ijms20163940 5. Giustina A, Barkhoudarian G, Beckers A, et al. Multidisciplinary management of acromegaly: A consensus. Rev Endocr Metab Disord. 2020;21(4):667-678. doi: 10.1007/s11154-020-09588-z 6. Katznelson L, Laws ER Jr, Melmed S, et al. Endocrine Society Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951. doi: 10.1210/jc.2014-2700 7. AlDallal S. Acromegaly: a challenging condition to diagnose. Int J Gen Med. 2018;11:337-343. doi:10.2147/IJGM.S169611 8. Ershadinia N, Tritos NA. Diagnosis and treatment of acromegaly: an update. Mayo Clin Proc. 2022;97(2):333- 346. doi:10.1016/j.mayocp.2021.11.007x 9. SOMATULINE® DEPOT (lanreotide) injection, for subcutaneous use [prescribing information]. Cambridge, MA: Ipsen Biopharmaceuticals, Inc.; 2019 10. SANDOSTATIN® LAR DEPOT (octreotide acetate) for injectable suspension, for gluteal intramuscular use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021. 11. Poullot A-G, Chevalier N. New options in the treatment of Cushing’s disease: a focus on pasireotide. Res Rep Endocr Disord. 2013;3:31-38. 12. Coopmans EC, Muhammad A, van der Lely AD, et al. How to position pasireotide LAR treatment in acromegaly. J Clin Endocrinol Metab. 2019;104(6):1978-1988. doi: 10.1210/jc.2018-01979 13. Silverstein JM. Need for improved monitoring in patients with acromegaly. Endocr Connect. 2015;4(4):R59-R67. doi:10.1530/EC-15-0064 14. Mercado M, Borges F, Bouterfa H, et al; SMS995B2401 Study Group. A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol (Oxf). 2007;66(6):859-868. doi:10.1111/j.1365-2265.2007.02825.x 15. Shanik MH, Cao PD, Ludlam WH. Historical response rates of somatostatin analogues in the treatment of acromegaly: a systematic review. Endocr Pract. 2016;22(3):350-356. doi: 10.4158/EP15913.RA 16. Fleseriu M, Molitch M, Dreval A, et al. Disease and treatment-related burden in patients with acromegaly who are biochemically controlled on injectable somatostatin receptor ligands. Front Endocrinol (Lausanne). 2021;12:627711. doi:10.3389/fendo.2021.627711 17. Biermasz NR, Pereira AM, Smit JWA, Romijn JA, Roelfsema F. Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life. J Clin Endocrinol Metab. 2005;90(5):2731-2739. doi:10.1210/jc.2004-2297 18. Gadelha M, Bex M, Colao A, et al. Evaluation of the efficacy and safety of switching to pasireotide in patients with acromegaly inadequately controlled with first-generation somatostatin analogs. Front Endocrinol (Lausanne). 2020;10:931. doi:10.3389/fendo.2019.00931 19. Signifor LAR. Package insert. Recordati Rare Diseases Inc; 2024. 20. Acromegaly. UCLA Health System. https://www.uclahealth.org/medical-services/surgery/endocrine-surgery/patient-resources/patient-education/endocrine-surgery-encyclopedia/acromegaly. Accessed August 23, 2022. 21. Broder MS, Chang E, Cherepanov D, Neary MP, Ludlam WH. Incidence and prevalence of acromegaly in the United States: a claims-based analysis. Endocr Pract. 2016 Nov;22(11):1327-1335. doi: 10.4158/EP161397.OR 22. Bogusławska A, Korbonits M. Genetics of Acromegaly and Gigantism. J Clin Med. 2021;10(7):1377. doi: 10.3390/jcm10071377 23. Singh G, Mulji NJ, Jialal I. Multiple Endocrine Neoplasia Type 1. 2023 Jul 10. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan. PMID: 30725665. 24. Ahmed FW, Majeed MS, Kirresh O. Multiple Endocrine Neoplasias Type 4. 2023 Oct 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan. PMID: 33760487. 25. Adigun OO, Nguyen M, Fox TJ, et al. Acromegaly. [Updated 2023 Feb 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431086/. 26. Fukuda I, Hizuka N, Muraoka T, et al. Clinical features and therapeutic outcomes of acromegaly during the recent 10 years in a single institution in Japan. Pituitary. 2014 Feb;17(1):90-5. doi: 10.1007/s11102-013-0472-6 27. Berg C, Petersenn S, Lahner H, et al. Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J Clin Endocrinol Metab. 2010 Aug;95(8):3648-56. doi: 10.1210/ jc.2009-2570 28. Hannon AM, Thompson CJ, Sherlock M. Diabetes in Patients With Acromegaly. Curr Diab Rep. 2017 Feb;17(2):8. doi: 10.1007/s11892-017-0838-7 29. Ferraù F, Albani A, Ciresi A, Giordano C, Cannavò S. Diabetes Secondary to Acromegaly: Physiopathology, Clinical Features and Effects of Treatment. Front Endocrinol (Lausanne). 2018 Jul 6;9:358. doi: 10.3389/fendo.2018.00358 30. Giustina A, Biermasz N, Casanueva FF, et al. Acromegaly Consensus Group. Consensus on criteria for acromegaly diagnosis and remission. Pituitary. 2024 Feb;27(1):7-22. doi: 10.1007/s11102-023-01360-1
31. Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK; AACE Acromegaly Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly–2011 update: executive summary. Endocr Pract. 2011 Jul-Aug;17(4):636-46. doi: 10.4158/ep.17.4.636