SIGNIFOR LAR (pasireotide) for injectable suspension Signifor

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SIGNIFOR® LAR is 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.1


SIGNIFOR LAR mechanism of action

SIGNIFOR LAR binds with high affinity to SST receptors 5 and 2, which are expressed on pituitary adenoma cells1

Signs and symptoms of acromegaly stem from an imbalance in the normal regulatory mechanism2-5:

  1. A pituitary adenoma secretes excessive amounts of GH over a prolonged period of time.
  2. Secretion of GH by the pituitary gland into the bloodstream stimulates the liver to overproduce IGF-1.
  3. High levels of IGF-1, in turn, signal the pituitary gland to reduce GH production.
  4. This disruption of hormonal balance can lead to signs and symptoms of acromegaly such as bone overgrowth and organ enlargement.
Methanism of action diagram

SIGNIFOR LAR binds with high affinity to SST receptors 5 and 2, which are expressed on pituitary adenoma cells1

Binding Affinity chart
  • SIGNIFOR LAR has the highest affinity for SST5 and SST2 and lower affinity for the other SST receptors1
  • This effect has been shown to lower GH and IGF-1 levels in patients with acromegaly in vivo1

SST receptors are also expressed on pancreatic cells; their activation decreases insulin secretion6-10

  • In vitro studies of human pancreatic cells have shown that when pancreatic SST receptors are activated insulin secretion is suppressed7,8
  • In clinical studies of healthy volunteers, treatment with the SST analog SIGNIFOR LAR decreased total plasma insulin levels9,10

GH=growth hormone; IC50=concentration that inhibits 50%; IGF-1=insulin-like growth factor 1; SEM=standard error of mean; SST=somatostatin.

SIGNIFOR LAR efficacy in acromegaly

In previously untreated patients
SIGNIFOR LAR restore balance at the source


Results from clinical studies

Drug-naive patients treated with SIGNIFOR LAR were more likely to achieve biochemical normalization than those who received another SSA active comparator1


CLINICAL TRIAL: EFFICACY IN DRUG-NAIVE PATIENTS1,11

PRIMARY ENDPOINT
IN DRUG-NAIVE PATIENTS

Percentage of patients who achieved biochemical normalization1

(GH level <2.5 mcg/L and normalized IGF-1 at month 12)

Chart

*The maximum dose approved for use in the US was not used in this trial, but the majority of patients were receiving the dose most commonly used in the US to treat acromegaly.


STUDY DESIGN: DRUG-NAIVE PATIENTS WITH ACROMEGALY1

A multicenter, randomized, double-blind study was conducted to assess the safety and efficacy of SIGNIFOR LAR in patients with active acromegaly. A total of 358 patients naive to drugs used to treat acromegaly were randomized in a 1:1 ratio to SIGNIFOR LAR or another SSA active comparator. Randomization was stratified based on previous pituitary surgical status (eg, at least 1 prior pituitary surgery versus no prior pituitary surgery).

In patients who were inadequately controlled on a first-generation SSA11

Patients who were inadequately controlled on a first-generation SSA who switched to SIGNIFOR LAR experienced incremental benefits

Patients inadequately controlled on another SSA who switched to SIGNIFOR LAR treatment were more likely to experience biochemical control than those who remained on their previous SSA1

CLINICAL TRIAL: EFFICACY IN PATIENTS INADEQUATELY CONTROLLED†‡ AFTER 6 MONTHS TAKING A FIRST-GENERATION SSA1,11

PRIMARY ENDPOINT IN INADEQUATELY CONTROLLED PATIENTS

Percentage of patients who achieved biochemical normalization1
(GH level <2.5 mcg/L and normalized IGF-1 at month 6§)

Chart

For one active comparator, the maximum approved US dose was not used, but most patients received the most common US dose for acromegaly.

Inadequate control defined as GH concentration of >2.5 mcg/L (ie, mean of 5 samples over 2 hours) and sex- and age-adjusted IGF-1 level >1.3 times upper limit of normal (ULN).

§Primary endpoint (patients with IGF-1 < lower limit of normal [LLN] were not considered as "responders").


STUDY DESIGN: PATIENTS WITH ACROMEGALY INADEQUATELY CONTROLLED ON A FIRST-GENERATION SSA1,11

A multicenter, randomized, 3-arm study was conducted in patients with acromegaly inadequately controlled on SSAs. Patients were randomized to double-blind SIGNIFOR LAR 40 mg (n=65) or SIGNIFOR LAR 60 mg (n=65) or to continued open-label pretrial SSA therapies at maximal or near maximal doses (n=68). A total of 181 patients completed the 6-month trial.

Percentage of patients with acromegaly that was inadequately controlled with a first generation SSA in whom tumor volume decreased or did not change1*

Table
  • The median change from baseline in tumor volume was -10.4% (range: -74.5% to 19.4%) for SIGNIFOR LAR 40 mg and -6.3% (range: -66.7% to 14.5%) for SIGNIFOR LAR 60 mg

*Tumor volume changes from baseline as assessed by MRI at month 6.

MRI=magnetic resonance imaging.


Percentage of drug naive patients with acromegaly in whom tumor volume decreased or did not change1†

Table
  • The median change in tumor volume with SIGNIFOR LAR was -40% (range: -97.6% to 16.9%)

Tumor volume changes from baseline as assessed by MRI at month 12.

Impact on tumor volume in patients previously inadequately controlled on other first-generation SSAs11,12

PERCENTAGES OF PATIENTS WHO ACHIEVED TUMOR REDUCTION OF ≥25%12

Table

Adverse reactions in acromegaly

Documented in a clinical trial in drug-naive patients with acromegaly1

Adverse reactions occurring in patients exposed to SIGNIFOR LAR who were previously naive to drug therapy (n=178)

Table

*Diabetes mellitus includes the terms diabetes mellitus and type 2 diabetes mellitus.

SEE SECTION 6.1 IN FULL PRESCRIBING INFORMATION FOR COMPLETE ADVERSE REACTION TABLE.


Documented in a clinical trial in patients with acromegaly who were previously inadequately controlled on other SSAs1

Adverse reactions occurring in patients exposed to SIGNIFOR LAR who were previously treated with a first-generation SSA11 (n=125)

Table

*Diabetes mellitus includes the terms diabetes mellitus and type 2 diabetes mellitus.

SEE SECTION 6.1 IN FULL PRESCRIBING INFORMATION FOR COMPLETE ADVERSE REACTION TABLE.

Dosing and administration for acromegaly

SIGNIFOR LAR is an intramuscular injection in the left or right gluteal muscle, and is administered by a physician or nurse, providing the opportunity to encourage ongoing adherence and to support patients throughout the course of treatment.1

1 INJECTION EVERY 4 WEEKS (28 DAYS)1

Table

Intramuscular SIGNIFOR LAR dosing and titration1

  • The long-acting formulation of intramuscular SIGNIFOR LAR provides 4 weeks (28 days) of medication release with a single injection1
  • The clinical benefits of SIGNIFOR LAR should be evaluated after the first 3 months of treatment and periodically thereafter1
  • Management of suspected adverse reactions or over-response to treatment (age- and sex-adjusted IGF-1 less than the lower limit of normal) may require dose reduction, interruption, or discontinuation of treatment with SIGNIFOR LAR1

References: 1. SIGNIFOR LAR (pasireotide) for injectable suspension, for intramuscular use [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020. 2. Christofides EA. Clinical importance of achieving biochemical control with medical therapy in adult patients with acromegaly. Patient Prefer Adherence. 2016;10:1217-1225. 3. Carmichael JD, Bonert VS, Nuño 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. 4. Carroll PV, Jenkins PJ. Acromegaly. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext [Internet]. South Dartmouth, MA: MDText.com, Inc.; 2016. 5. National Institutes of Health. US National Library of Medicine. Acromegaly.https://www.niddk.nih.gov/-/media/Files/Endocrine-Diseases/Acromegaly_508.pdf?la=en&hash=496113F1BCD2A416D4FED99108A2E854. Updated May 2008. Accessed February 13, 2020. 6. Silverstein JM. Hyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly. Pituitary. 2016;19(5):536-543. 7. Zambre Y, Ling Z, Chen MC, et al. Inhibition of human pancreatic islet insulin release by receptor-selective somatostatin analogs directed to somatostatin receptor subtype 5. Biochem Pharmacol. 1999;57(10):1159-1164. 8. Singh V, Brendel MD, Zacharias S, et al. Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab. 2007;92(2):673-680. 9. Breitschaft A, Hu K, Hermosillo Reséndiz K, Darstein C, Golor G. Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. Diabetes Res Clin Pract. 2014;103(3):458-465. 10. Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013;98(8):3446-3453. 11. Melmed S, Bronstein MD, Chanson P, et al. A consensus statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14(9):552-561. 12. Gadelha MR, Bronstein MD, Brue T, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(11):875-884.

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.

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

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 the accompanying full Prescribing Information and Patient Information.

References: 1. 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. 2. 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. 3. SIGNIFOR LAR (pasireotide) for injectable suspension, for intramuscular use [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020. 4. 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. 5. Broder MS, Chang E, Cherepanov D, Neary MP, Ludlam WH. Incidence and Prevalence of Acromegaly in the United States: A Claims-Based Analysis. AACE Endocrine Practice. https://www.endocrinepractice.org/article/S1530-891X(20)35591-9/pdf. Published November 1, 2016. Accessed August 23, 2022. 6. Christofides EA. Clinical importance of achieving biochemical control with medical therapy in adult patients with acromegaly. Patient Prefer Adherence. 2016;10:1217-1225. 7. Acromegaly. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/endocrine-diseases/acromegaly. Accessed August 23, 2022. 8. 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. 9. Carroll PV, Jenkins PJ. Acromegaly. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext [Internet]. South Dartmouth, MA: MDText.com, Inc.; 2016 10. Giustina A, Barkhoudarian G, Beckers A, et al. Multidisciplinary management of acromegaly: A consensus. Rev Endocr Metab Disord. 2020;21(4):667-678. 11. 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. 12. Lavrentaki A, Paluzzi A, Wass JA, Karavitaki N. Epidemiology of acromegaly: review of population studies. Pituitary. 2017;20(1):4-9. 13. SOMATULINE® DEPOT (lanreotide) injection, for subcutaneous use [prescribing information]. Cambridge, MA: Ipsen Biopharmaceuticals, Inc.; 2019 14. SANDOSTATIN LAR DEPOT (octreotide acetate) for injectable suspension, for gluteal intramuscular use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021. 15. 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. 16. 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. 17. Casar-Borota O, Heck A, Schulz S, et al. Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide. J Clin Endocrinol Metab. 2013;98(11):E1730-E1739. 18. Silverstein JM. Hyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly. Pituitary. 2016;19:536-543. 19. Zambre Y, Ling Z, Chen MC, et al. Inhibition of human pancreatic islet insulin release by receptor-selective somatostatin analogs directed to somatostatin receptor subtype 5. Biochem Pharmacol. 1999;57(10):1159-1164. 20. Singh V, Brendel MD, Zacharias S, et al. Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab. 2007;92(2):673-680. 21. Breitschaft A, Hu K, Hermosillo Res.ndiz K, Darstein C, Golor G. Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. Diabetes Res Clin Pract. 2014;103(3):458-465. 22. Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013;98(8):3446-3453. 23. Gadelha MR, Bronstein MD, Brue T, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(11):875-884. 24. Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014;99(3):791-799. 25. Gadelha MR, Gu F, Bronstein MD, et al. Risk factors and management of pasireotide-associated hyperglycemia in acromegaly. Endocr Connect. 2020;9(12):1178-1190. 26. American Diabetes Association. Standards of Medical Care in Diabetes-2020 Abridged for Primary Care Providers. Clin Diabetes. 2020;38(1):10-38. doi:10.2337/cd20-as01. 27. Samson SL, Gu F, Feldt-Rasmussen U, Zhang S, Yu Y, et al. Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study. Pituitary. 2021;24(6):887-903.