Signifor LAR

Understanding a rare endocrine disease

RECOGNIZING AND ADDRESSING ACROMEGALY

In clinical trials, SIGNIFOR LAR was shown to achieve biochemical control in medically naïve patients and patients inadequately controlled on first-generation somatostatin receptor ligands (SRLs).1,2

Efficacy in Medically Naïve Patients

31.3% of patients receiving SIGNIFOR LAR (n=176) achieved biochemical control compared with 19.2% of those on octreotide LAR (n=182) overall.

  • Patients who received SIGNIFOR LAR were 63% more likely to achieve biochemical controla than patients who received octreotide LAR.2

Study design

A multicenter, randomized, double-blind study was conducted over 12 months to assess the safety and efficacy of SIGNIFOR LAR in drug-naive patients with active acromegaly, defined by elevated GH and IGF-1 levels.2,b

The primary endpoint was biochemical control, defined as a GH level less than 2.5 ug/L and an IGF-1 level that was normal for the patient’s sex and age at month 12.2

A total of 358 patients naive to drugs used to treat acromegaly were randomized in a 1:1 ratio to SIGNIFOR LAR 40 mg q28d (a dose increase to 60 mg q28d was permitted at month 3 or 7) or octreotide LAR 20 mg q28d (a dose increase to 30 mg q28d was permitted at month 3 or 7).2 Randomization was stratified based on previous pituitary surgical status (eg, at least 1 prior pituitary surgery vs no prior pituitary surgery).2,c,d

a
Biochemical control defined as achieving GH <2.5 μg/L and normal IGF-1 for age and sex at month 12.2
b
As confirmed by a 2-hour five-point mean GH level >5 μg/L or lack of suppression of GH nadir to <1 μg/L after an OGTT and elevated IGF-1 for age and sex-matched controls.2
c
De novo patients with a pituitary adenoma visible on MRI but who refused pituitary surgery or for whom surgery was contraindicated were also eligible.2
d
Stratified into two groups: 1) after pituitary surgery or 2) de novo. A dose increase to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, at month 3 or 7 based on biochemical response (mean GH ≥2.5 g/L and/or IGF-1 above the ULN).2
GH, growth hormone; IGF-1, insulin-like growth factor 1; OGTT, oral glucose tolerance test; q28d, every 28 days; ULN, upper limit of normal.

Primary endpoint:
Percent of patients achieving GH <2.5 μg/L and normal IGF-1 for age and sex at month 122

  • The study was not powered to detect treatment differences in subgroups.2
CI, confidence interval.

Observed adverse reactions

Adverse reactions occurring in ≥10% of patients exposed to SIGNIFOR LAR
who were previously medically naïve (n=178)3

ADVERSE REACTIONS
(FREQUENCY ≥10%)
SIGNIFOR LAR
40-60 mg
OVERALL, % (n=178)
ACTIVE
COMPARATOR

OVERALL, % (n=180)
Diarrhea
39
45
Hyperglycemia
29
8
Diabetes mellitusa
26
4
Cholelithiasis
26
36
Headache
19
26
Abdominal pain
18
22
Alopecia
18
19
Nasopharyngitis
16
16
Nausea
14
22
Blood creatine phosphokinase increased
13
12
Abdominal distension
12
12
Arthralgia
10
12
Dizziness
10
11
Fatigue
10
10
Sinus bradycardiab
10
7
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a
Diabetes mellitus includes the terms diabetes mellitus and type 2 diabetes mellitus.3
b
Sinus bradycardia includes the terms bradycardia and sinus bradycardia.3

Efficacy in Inadequately Controlled Patients

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

SIGNIFOR LAR was directly compared with octreotide LAR and lanreotide autogel, in a prospective, multicenter, randomized, parallel-group, phase 3 study in patients who were inadequately controlled with first-generation SRLs.1

Study Design

A multicenter, randomized, 3-arm study conducted in patients with acromegaly inadequately controlled on a first-generation SRL.4 Patients were randomized to double-blind SIGNIFOR LAR 40 mg q28d (n=65) or SIGNIFOR LAR 60 mg q28d (n=65) or to continued open-label pretrial SRL therapies at maximal or high doses (n=68); (30 mg octreotide LAR or 120 mg lanreotide autogel).1

a
Inadequately controlled acromegaly defined as GH >2.5 μg/L; IGF-1 >1.3 ULN.
GH, growth hormone; IGF-1, insulin-like growth factor 1; q28d, every 28 days; ULN, upper limit of normal.

Primary endpoint:
Inadequately controlled patients previously on a first-generation SRL who were randomized to SIGNIFOR LAR and achieved mean GH <2.5 μg/L and normalized IGF-1 at week 241

a
Primary endpoint: proportion of patients with a mean GH level less than 2.5 μg/L and normal IGF-1 levels at week 24.1
b
For one active comparator, the maximum approved US dose was not used, but most patients received the most common US dose for acromegaly.3
GH, growth hormone; IGF-1, insulin-like growth factor 1; q28d, every 28 days; ULN, upper limit of normal.

Key secondary endpoint: SIGNIFOR LAR demonstrated reductions in IGF-11,a; IGF-1 normalization was achieved by 16 (25%) patients receiving SIGNIFOR LAR 40 mg and 17 (26%) receiving 60 mg at 24 weeks; no patients receiving active control achieved normal IGF-1 concentrations1,b

Secondary endpoint: Mean changes (%) in IGF-1 values from baseline to week 241,c

CI, confidence interval.

Secondary endpoint: Mean changes (%) in GH concentrations from baseline to week 241,c

a
In a 24-week, prospective, multicenter, randomized, parallel-group, phase 3 study in patients who were inadequately controlled with and changed from a first-generation SRL. Patients were randomly assigned to 40 mg SIGNIFOR LAR, 60 mg SIGNIFOR LAR, or continued treatment on their SRL.1
b
SIGNIFOR LAR 40 mg group absolute difference 24.6%, 95% CI,14.8-36.9, P=.0006.
SIGNIFOR LAR 60 mg group absolute difference 26.2%, 95% CI,16.0-38.5, P<.0001.
c
No multiplicity adjustment was made to test this endpoint. Confidence intervals are provided for descriptive purposes only.
CI, confidence interval.

Tumor reductions observed in patients taking SIGNIFOR LAR1,a

Secondary endpoint: 81% and 70% of patients treated with SIGNIFOR LAR 40 mg and 60 mg, respectively, had either a reduction or no change in tumor volume from baseline assessed by MRI at Month 6. The median (range) change in tumor volume was a reduction of -10.4% (-74.5% to 19.4%) and -6.3% (-66.7% to 14.5%) from baseline for SIGNIFOR LAR 40 mg and 60 mg, respectively.3

Secondary endpoint: The proportion of patients with >25% reduction in tumor volume was assessed
at 24 weeks (N=198)1

Tumor volume outcomes were descriptive in nature; the study was not powered to assess statistical significance for tumor volume changes.

a
Percent change in tumor volume assessed by pituitary MRI at 24 weeks compared between treatment groups.1,4
b
SIGNIFOR LAR 40 mg group absolute difference 24.6%, 95% CI, 14.8-36.9, P=.0006. SIGNIFOR LAR 60 mg group absolute difference 26.2%, 95% CI, 16.0-38.5, P<.0001.1

Patients taking SIGNIFOR LAR reported overall improvements in
health‑related QOL4,5

Secondary endpoint: Improvements in AcroQoL at 24 weeks4,a,b
At week 24, AcroQoL scores improved by4,5:

SIGNIFOR LAR 40 mg group

2.6 points
(95% CI: –2.0, 7.2)
 SIGNIFOR LAR 60 mg group

5.2 points
(95% CI: 0.5, 9.9)
SIGNIFOR LAR active control groups
1.6 points
(95% CI: –1.4, 4.6)
  • The study was not powered to assess statistical significance in these parameters; therefore, no definitive conclusions can be drawn.

SIGNIFOR LAR patients saw a reduction in the frequency and degree of diminished QOL from acromegaly4,5,b:

Physical
Psychological
Interpersonal
  • Patients reported feeling less rejected, tired, and self-conscious of their appearance due to acromegaly.4,5

At week 24, patients also experienced symptom reductions in4,5,b:

Headache
Fatigue
Perspiration
Osteoarthralgia
Paresthesia
a
Change of severity from baseline at week 24 in health-related QOL assessed every 4 weeks using the AcroQoL questionnaire.1,4 AcroQoL was measured using a 22-item instrument with scores ranging from 0 (worst health-related QOL) to 100 (best health-related QOL), divided into 2 scales: 1 physical
(8 items) and 1 psychological (14 items). The second (psychological) scale was also divided into 2 subscales: 1 physical appearance and 1 impact of the disease on personal relationships of the patient (7 items each).4,5
b
Change of severity from baseline at week 24 in five symptoms of acromegaly (headache, fatigue, perspiration, paresthesia, and osteoarthralgia) were evaluated every 4 weeks on a five-point scale from 0 (no symptom) to 4 (very severe).1,4
AcroQoL, Acromegaly Quality of Life; Questionnaire QOL, quality of life.

Adverse reactions

Adverse reactions occurring in ≥5% of patients exposed to SIGNIFOR LAR who were previously treated with a first-generation SLR (n=125)3

ADVERSE REACTIONS (FREQUENCY ≥10%)
SIGNIFOR LAR
40 mg
OVERALL % (n=63)
SIGNIFOR LAR
60 mg
OVERALL % (n=62)
ACTIVE
COMPARATOR
OVERALL % (n=66)
Hyperglycemia Related Adverse Reactions
Hyperglycemia
33
30
14
Diabetes mellitusa
21
31
9
Blood glucose increased
5
7
0
Hypoglycemia
3
7
0
Gastrointestinal Related Adverse Reactions
Diarrhea
16
19
5
Diarrhea
8
8
3
Nausea
3
7
3
Hepatobiliary Related Adverse Reactions
Cholelithiasis
10
13
14
Cardiac Related Adverse Reactions
Atrioventricular block first degree
6
0
0
Nervous System Related Adverse Reactions
Headache
14
3
5
Dizziness
8
2
3
Skin and Subcutaneous Tissue Related Adverse Reactions
Alopecia
2
7
0
Infections Related Adverse Reactions
Nasopharyngitis
6
11
3
Blood Related Adverse Reactions
Anemia
6
3
3
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a
Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus.3

Managing Hyperglycemia

Hyperglycemia is a natural consequence of acromegaly and its treatment6

SSTRs 2 and 5 are expressed on pancreatic cells—their activation results in decreased insulin and glucagon secretion, which may lead to hyperglycemia.7

Importantly, in patients with poorly controlled diabetes mellitus, optimize anti-diabetic treatment before starting SIGNIFOR LAR3

The Acromegaly Consensus Group highlights hyperglycemia as a known metabolic consideration in the treatment of acromegaly, particularly with pasireotide, and emphasizes the importance of monitoring glucose metabolism.

SIGNIFOR LAR-related hyperglycemia was manageable in a clinical trial8

The first prospective, multicenter, randomized, open-label phase 4 study to investigate the management of pasireotide-associated hyperglycemia studied 249 patients.9

Response to antihyperglycemic medications in the first 16 weeks8,a

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Future Rare Diseases. 2024; 4(1). Originally published by, adapted and used with permission from Taylor & Francis.

Study Design: A multicenter, randomized, open-label, phase 4 study comprising a core phase (a ≤16-week prerandomization period, followed by a 16-week randomized treatment period) and an optional extension phase.8 249 patients were enrolled and treated with pasireotide IM (n=190 with acromegaly) or pasireotide SC (n=59 with Cushing’s disease) between May 2014 and March 2018.8 The primary objective was to assess the difference in change in HbA1c, from randomization to the end of the core study (16 weeks after randomization), between the incretin-based therapy and insulin arms.8

SIGNIFOR® (pasireotide) SC is indicated for treatment of adults with Cushing’s disease in whom pituitary surgery is not an option or has not been curative.3

a
Patients with acromegaly or Cushing’s disease (n=190 and n=59, respectively) were initiated on SIGNIFOR LAR 40 mg IM once every 28 days (acromegaly) or SIGNIFOR SC 600 μg twice daily (Cushing’s disease).8
HbA1c, glycated hemoglobin; IM, intramuscular; SC, subcutaneous.

A large proportion (≈60%) of patients taking pasireotide responded to metformin or did not develop hyperglycemia8,a

49.7%

of the acromegaly group did not develop hyperglycemia that required antidiabetic treatment through 16 weeks.8

Patients with acromegaly who were either on no antihyperglycemic or
who were on oral metformin maintained HbA1c <6.5% and FPG <126 mg/dL while on SIGNIFOR LAR.8

  • SIGNIFOR LAR decreases secretion of incretin hormones, suggesting the potential for increased benefit with incretin-based diabetes medications.7,10,11
  • There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with history of diabetes and in patients without history of diabetes. Assess patients who present with signs and symptoms consistent with ketoacidosis during SIGNIFOR LAR treatment.3
a
Patients on SIGNIFOR LAR who did not require antidiabetic medications based on normal glucose tolerance were classified based on FPG <100 mg/dL and/or HbA1c <5.7%; those who did not require antidiabetic medications but were classified as prediabetic had FPG ≥100 mg/dL and/or HbA1c from 5.7% to <6.5%.8 Patients on SIGNIFOR LAR who required antidiabetic medications (metformin, other OADs, insulin) were classified as diabetic based on FPG ≥126 mg/dL at 2 different visits and/or HbA1c ≥6.5%, prior history of diabetes, or previous treatment with antidiabetic medications.8
FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; OAD, oral antidiabetic drug.
EXPLORE DOSING, TESTING & MONITORING

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. Gadelha MR, Bronstein MD, Brue T, et al; Pasireotide C2402 Study Group. 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. doi:10.1016/S2213-8587(14)70169-X 2. Colao A, Bronstein MD, Freda P, et al; Pasireotide C2305 Study Group. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014;99(3):791-799. doi:10.1210/jc.2013-2480 3. Signifor LAR. Package insert. Recordati Rare Diseases Inc; 2024. 4. Gadelha MR, Bronstein MD, Brue T, et al; Pasireotide C2402 Study Group. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Supplementary appendix. Lancet Diabetes Endocrinol. 2014;2(11):875-884. doi:10.1016/S2213-8587(14)70169-X 5. Badia X, Webb SM, Prieto L, Lara N. Acromegaly Quality of Life Questionnaire (AcroQoL). Health Qual Life Outcomes. 2004;2:13. doi:10.1186/1477-7525-2-13 6. Moustaki M, Paschou SA, Xekouki P, et al. Secondary diabetes mellitus in acromegaly. Endocrine. 2023;81(1):1-15. doi:10.1007/s12020-023-03339-1 7. Störmann S, Meyhöfer SM, Groener JB, et al. Management of pasireotide-induced hyperglycemia in patients with acromegaly: an experts’ consensus statement. Front Endocrinol (Lausanne). 2024;15:1348990. doi:10.3389/fendo.2024.1348990 8. Samson SL, Gu F, Feldt-Rasmussen U, et al. Managing pasireotide-associated hyperglycemia: a randomized, open-label, phase IV study. Pituitary. 2021;24(6):887-903. doi:10.1007/s11102-021-01161-4 9. 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. doi: 10.1530/EC-20-0361 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. doi:10.1210/jc.2013-1771 11. Breitschaft A, Hu K, Reséndiz KH, Darstein C, Golor G. Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. Diabetes Res Clin Pract. 2014;103(3):458-465. doi:10.1016/j.diabres.2013.12.011