Signifor LAR (pasireotide) for Cushing’s disease
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What is Signifor LAR for Cushing’s disease?
Signifor LAR (pasireotide) is an injectable medication approved for people with Cushing’s disease for whom pituitary surgery is not an option or has been ineffective.
Administered via into-the-muscle, or intramuscular, injections, Signifor LAR is designed to lower cortisol levels and ease disease symptoms. The LAR in its name indicates it is a long-acting release formulation.
The therapy originally was developed by Novartis. Recordati acquired its worldwide rights in 2019 and its subsidiary, Recordati Rare Diseases, now markets Signifor LAR.
The medication also is approved for certain patients with acromegaly, a hormonal disorder that arises when the pituitary gland produces excessive amounts of growth hormone.
Therapy Snapshot
| Brand Name: | Signifor LAR |
| Chemical Name: | Pasireotide |
| Usage: | Used to treat Cushing’s patients for whom surgery was ineffective or is not an option; can lower cortisol levels and ease disease symptoms |
| Administration: | Intramuscular injection |
How does Signifor LAR work?
In Cushing’s disease, tumors called adenomas in the pituitary gland, located at the base of the brain, result in the excessive release of a pituitary hormone called adrenocorticotropic hormone, or ACTH.
This hormone normally stimulates the adrenal glands, sitting atop the kidneys, to produce another hormone called cortisol. But its excess release in people with Cushing’s disease lead to cortisol overproduction, which drives disease symptoms.
Signifor LAR is a long-acting release (LAR) formulation of pasireotide, a second-generation somatostatin analogue, or SSA. As the name implies, the molecule mimics the actions of somatostatin, a naturally-occurring hormone that regulates the release of other hormones, including ACTH, when it binds to somatostatin receptors (SSTRs).
By binding to SSTRs on adenomas in the pituitary gland, Signifor LAR is expected to reduce ACTH production and subsequent cortisol release in Cushing’s disease patients. Compared with first-generation SSAs, pasireotide has a particular affinity for a somatostatin receptor subtype, called SSTR5, which is found at high levels in Cushing’s-associated adenomas.
A shorter-acting formulation of pasireotide, marketed as Signifor and given via under-the-skin or subcutaneous injections, also is approved to treat Cushing’s. But while that formulation is administered twice-daily, Signifor LAR is given once monthly.
Who with Cushing’s can take Signifor LAR?
Signifor LAR was approved by the U.S. Food and Drug Administration (FDA) in 2018 for people with Cushing’s disease who are not eligible for surgery to remove their pituitary tumor or for whom surgery did not completely resolve symptoms.
The medication is the first and only clinically proven pituitary-directed long-acting treatment shown to help lower cortisol levels and ease Cushing’s symptoms.
It also is approved for a similar indication in Europe and in several countries, including Canada and Japan.
Who should not take Signifor LAR?
The prescribing information for Signifor LAR lists no contraindications. However, the therapy should be avoided in patients with severe liver problems.
Caution is advised when prescribing the medication for people with risk factors for QT prolongation — an extension of the interval between the heart contracting and relaxing. The medication has been associated with heart rhythm abnormalities in patients with QT prolongation risk factors.
How is Signifor LAR administered in Cushing’s?
Signifor LAR must be given by a trained healthcare provider, and is administered via monthly intramuscular injections into the buttocks. It comes as a slightly yellow to yellow powder, and is available in five dosage strengths: 10, 20, 30, 40, and 60 mg.
Before giving the therapy, a healthcare provider will dilute the powder into a liquid suspension at the appropriate dose.
For Cushing’s disease patients, the recommended starting dose is 10 mg, delivered once every four weeks, specifically every 28 days. If urinary cortisol levels are not normalized after four months, the dose can be increased up to a maximum of 40 mg every four weeks, as tolerated. The dosing will be determined by a healthcare provider.
For patients with moderate liver function impairments, the recommended starting dose is 10 mg every four weeks, with a maximum dose of 20 mg every four weeks.
Before starting treatment with Signifor LAR, patients should undergo blood tests to measure fasting blood sugar levels, as well as potassium and magnesium levels. Tests to assess liver and heart function also should be conducted before treatment begins. Patients with poorly controlled diabetes should have their anti-diabetic treatment regimen optimized before starting on Signifor LAR.
If a planned dose is missed and a patient visits a healthcare provider before the next scheduled dose, a dose of Signifor LAR may be given up to, but no later than, 14 days before the next dose is due.
Signifor LAR in clinical trials
The approval of Signifor LAR for the treatment of Cushing’s disease was backed by data from a global Phase 3 trial (NCT01374906). That trial tested the therapy’s safety and efficacy in 150 patients with the disorder, all with elevated urinary cortisol levels.
The participants were randomly assigned to receive monthly intramuscular injections of Signifior LAR at a dose of 10 mg or 30 mg for about a year. Some dose adjustments were allowed over the course of the study based on efficacy and tolerability.
The study’s main goal was to assess the proportion of so-called treatment responders at each dose level after seven months, regardless of dose adjustments. Patients were considered responders if their urinary cortisol levels were within normal limits.
After the seven months, 41.9% of the patients in the 10 mg group and 40.8% of those in the 30 mg group were considered responders, meeting the study’s main goal. Partial disease control, defined as levels still above the normal range but 50% lower than at the study’s start, was achieved by 5% of patients in the lower dose group and 13% of those given the 30 mg dose.
The therapy’s safety profile was found to be similar to that of Signifor.
After a year of treatment, other clinical improvements also were observed with Signifor LAR, including reductions in blood pressure, weight loss, and improvements in life quality.
After completing the main trial, about half of the patients (54%) then opted to continue treatment in an open-label extension phase. In that extension, Signifor LAR was associated with sustained normalizations in cortisol levels and clinical improvements, with no new emerging safety signals.
Common side effects of Signifor LAR
The most common side effects associated with Signifor LAR in Cushing’s disease clinical trials include:
- diarrhea
- gallstones (cholelithiasis)
- high blood sugar (hyperglycemia)
- diabetes.
Hyperglycemia and diabetes
Signifor LAR may cause significant increases in blood sugar (glucose) levels, a hallmark of diabetes also referred to as hyperglycemia. This can lead to ketoacidosis, a serious complication of diabetes that develops when the body is not able to use glucose as an energy source in the way that it should.
Patients should tell their healthcare providers if they experience symptoms like excessive thirst, frequent urination, nausea, vomiting, abdominal pain, tiredness, fruity-scented breath, breathing difficulties, confusion, or increased appetite with weight loss.
Glucose levels should be monitored before and during treatment, and all patients with diabetes should have their anti-diabetic treatment regimen optimized prior to starting on Signifor LAR. Blood sugar increases may require anti-diabetic treatment or Signifor LAR dose adjustments. If ketoacidosis is suspected, Signifor LAR should be discontinued and supportive treatment should be considered.
Heart rhythm abnormalities
Signifor LAR may cause a slow heartbeat, known as bradycardia, or QT prolongation, which is an abnormality in the heart’s electrical rhythm. Symptoms may include weakness, dizziness, or fainting spells.
Heart function and electrolyte levels — of potassium and magnesium — should be monitored prior to dosing and periodically during treatment, particularly in patients with heart disease or with risk factors for cardiac problems. Dose adjustments for medications that can slow heart rate also may be required.
If detected, abnormally low potassium or magnesium levels should be corrected before patients start treatment with Signifor LAR, as low levels of these electrolytes have been associated with heartbeat irregularities.
Liver abnormalities
The levels of certain liver enzymes may become elevated during Signifor LAR treatment, potentially indicating the presence of liver damage.
Assessment of liver function is recommended prior to starting Signifor LAR and periodically thereafter, as clinically indicated.
Treatment should be discontinued if signs of clinically significant liver disease develop and should not be resumed if abnormalities in liver function are suspected to be related to treatment.
Gallstones
Gallstones, hardened deposits of bile that form in the gallbladder, are a serious but common side effect of Signifor LAR. These deposits can cause gallbladder inflammation and infections. Symptoms may include sudden pain in the upper right abdomen, sudden pain in the right shoulder or between shoulder blades, yellowing of the skin and whites of the eyes, fever with chills, and nausea.
An ultrasound should be performed to look at the gallbladder before and during Signifor LAR treatment, and the medication should be stopped if gallstones are identified.
Pituitary hormone deficiency
Suppression of hormones normally released from the pituitary gland may occur during treatment with Signifor LAR due to the therapy’s mechanism of action. Patients should be monitored periodically, and are advised to tell their doctor if they experience symptoms like nausea and vomiting, tiredness, dizziness, diarrhea, low blood sugar, appetite loss, or weight loss.
Use in pregnancy and breastfeeding
It is not known whether Signifor LAR has adverse effects on a developing fetus or if it passes into human breastmilk. However, in animal studies where the therapy’s active ingredient was administered subcutaneously to rats and rabbits, it was found to cause harm to the developing fetus and to be able to pass into breastmilk.
Patients who are pregnant or nursing, or who wish to become pregnant or breastfeed, should discuss the topic with their doctor.
Cortisol normalizations in women with Cushing’s disease may lead to increased fertility. Patients should discuss the possibility of unintended pregnancy and birth control options with their healthcare providers.
Cushing’s Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Signifor LAR
The U.S. Food and Drug Administration (FDA) approved Signifor LAR in June 2018 for the treatment of people with Cushing’s disease who had an inadequate response to pituitary surgery or who were ineligible for surgery. The decision marked the first approval by the FDA of a pituitary-directed long-acting treatment shown to help lower cortisol levels and ease Cushing’s symptoms. The LAR in its name indicates that it’s a long-acting release formulation.
There is no known interaction between Signifor LAR and alcohol. However, because excessive alcohol consumption can damage the liver and increases in the levels of liver enzymes have been observed in patients on Signifor LAR, those wishing to drink while taking the medication should discuss the issue with a healthcare professional.
In a clinical trial that supported the approval of Signifor LAR, reductions in urinary cortisol levels in Cushing’s disease patients were observed as early as within one month following treatment. However, every patient’s case is unique and responses to any therapy may vary. Patients should talk with their doctors about how Signifor LAR may help in their particular case.
The most common side effects associated with Signifor LAR in Cushing’s disease patients include high blood sugar, diabetes, gallstones, and diarrhea. Other adverse events commonly reported with the medication include pain in the stomach region, hair loss, cold-like symptoms, low blood sugar, back pain, nausea, loss of appetite, and high blood pressure. Before starting treatment, patients should ask their doctors about the side effects that may be expected with the medication’s use.
Weight gain is not a known side effect of Signifor LAR. Rather, a large proportion of patients experienced reductions in weight after starting on the medication. However, weight gain can be a symptom of uncontrolled Cushing’s disease, so patients who experience unexpected weight gain or other unanticipated side effects should let their healthcare team know.
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