Isturisa (osilodrostat) for Cushing’s disease
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What is Isturisa for Cushing’s disease?
Isturisa (osilodrostat), formerly known as LCI699, is an oral medication approved in the U.S. to treat adults with Cushing’s disease for whom pituitary surgery is not an option or did not completely resolve disease symptoms.
In Europe, Isturisa is approved for people with endogenous Cushing’s syndrome, of which Cushing’s disease is the most common type.
Isturisa initially was developed by Novartis, and global rights to the therapy were acquired by Recordati in 2019.
Therapy snapshot
| Brand name: | Isturisa |
| Chemical name: | Osilodrostat |
| Usage: | Treatment of adults with Cushing’s disease for whom surgery is not an option or has been ineffective |
| Administration: | Oral tablets |
How does Isturisa work?
In Cushing’s disease, a tumor in the brain’s pituitary gland leads to the excessive release of adrenocorticotropic hormone (ACTH), stimulating the adrenal glands, which sit atop the kidneys, to produce too much cortisol. The resulting hypercortisolism is the cause of Cushing’s hallmark symptoms.
Surgery to remove the pituitary tumor is the disease treatment of first choice, but some patients are ineligible for the procedure, while for others the disease can recur. In such cases, medications to reduce cortisol levels can help alleviate symptoms.
Isturisa works to inhibit cortisol production in the adrenal glands by blocking 11-beta-hydroxylase, which is involved in cortisol synthesis. By preventing excessive cortisol, Isturisa is expected to help ease Cushing’s disease symptoms.
Who can take Isturisa?
Isturisa was approved by the U.S. Food and Drug Administration (FDA) in 2020 to treat adults with Cushing’s disease for whom pituitary surgery is not possible or was not curative.
That same year, the therapy was approved by the European Commission for people with endogenous Cushing’s syndrome, including Cushing’s disease. It also is approved in Japan for people with endogenous Cushing’s for whom surgery was ineffective or is not an option.
Who should not take Isturisa?
There currently are no contraindications for Isturisa’s use, according to the therapy’s FDA prescribing information.
However, the therapy can lead to hypocortisolism (very low levels of cortisol) and the possibility of life-threatening adrenal insufficiency, and patients should be carefully monitored. Reducing Isturisa’s dose or interrupting its dosing may be necessary in some cases.
Isturisa should be used with caution by people with risk factors for QTc prolongation — that is, an extended interval between the heart contracting and relaxing — as the treatment has been associated with cardiac arrhythmias.
How is Isturisa administered?
Isturisa is taken in the form of oral tablets. Tablets are unscored, round, and biconvex with a beveled edge. They come in three different strengths:
- 1 mg pale yellow tablets, debossed “Y1” on one side
- 5 mg yellow tablets, debossed “Y2” on one side
- 10 mg pale orange to brown tablets, debossed “Y3” on one side.
The starting dose of Isturisa is 2 mg, taken twice daily, with or without food. This dose can be increased gradually based on a person’s cortisol levels, tolerability, and clinical improvements up to a maximum recommended dose of 30 mg twice daily.
Once the optimal maintenance dose is reached, cortisol levels should be reassessed every one to two months, or as needed, to determine if dose adjustments are necessary.
Starting doses might need to be adjusted based on a person’s medical condition. Specifically, in those with moderate hepatic (liver) impairment, the recommended starting dose is 1 mg twice daily; for those with severe hepatic impairment, the recommended starting dose is 1 mg once every evening.
Isturisa in clinical trials
Isturisa’s approvals mainly were supported by data from the Phase 3 LINC-3 trial (NCT02180217), which involved a total of 137 patients with Cushing’s disease.
LINC-3 trial
LINC-3 evaluated the safety and efficacy of Isturisa in 137 Cushing’s disease patients with persistent or recurrent disease despite surgery, in those who refused surgery, or in those for whom the procedure was not indicated.
Participants received Isturisa, at a dose of 2 to 30 mg twice daily for 26 weeks, or about six months.
Then, 71 patients with normal urinary cortisol levels, who required no dose adjustments since week 12 and tolerated the therapy well, were randomly assigned to either continue with Isturisa or switch to a placebo for an additional eight weeks. Patients who did not meet these criteria moved directly into an open-label extension, where all continued with Isturisa for another 12 weeks; they were joined by patients in the trial’s placebo-controlled phase after its eight weeks.
In the placebo-controlled period, 86% of those on continuous Isturisa treatment maintained normal urinary cortisol levels at week 34, as compared with 29% of those who switched to a placebo.
By the end of the trial’s 48-week core period, results indicated that 66% of all patients maintained normal urine cortisol levels. Additionally, nearly all patients (96%) saw their cortisol levels normalize at least once during the study.
Of its 137 participants, 106 LINC-3 trial patients entered an extension study, continuing with Isturisa for up to 72 weeks of treatment, about 1.5 years. Results showed that 81% maintained normal cortisol levels at week 72. Improvements in cardiovascular function, physical features of Cushing’s disease, and quality of life also were observed.
LINC-4 trial
The Phase 3 LINC-4 trial (NCT02697734) confirmed the safety and efficacy of Isturisa in 73 Cushing’s disease patients, who were randomly assigned to receive Isturisa or a placebo for 12 weeks. After that, all participants were treated with Isturisa through week 48 (for about a year).
Top-line trial results indicated that 77% of Isturisa-treated patients saw their urinary cortisol levels normalize after the first 12 weeks, compared with 8% of those on placebo. This was sustained for 81% of patients at week 36, during the trial’s open-label phase.
Data presented at a scientific conference indicated that among evaluable patients continuing on treatment, 61.5% had normal urinary cortisol levels after 1.5 years.
Ongoing trials
A Phase 2 roll-over study (NCT03606408) is continuing to evaluate Isturisa in patients who successfully completed any of its previous trials. These people are continuing treatment at the dose given in the initial trial.
Another Phase 2 trial (NCT03708900) is evaluating the safety and pharmacological effects of Isturisa in 12 children and adolescents, ages 6-17, with Cushing’s disease.
Other ongoing Recordati-sponsored trials include LINC-6 (NCT05382156), which is monitoring the real-world safety and efficacy of Isturisa, and LINC-7 (NCT05633953), a retrospective study to explore Isturisa in people with forms of Cushing’s syndrome other than Cushing’s disease.
Common side effects of Isturisa
The most common side effects associated with Isturisa include:
- very low cortisol levels (adrenal insufficiency)
- fatigue
- nausea
- headache
- swelling of the legs and ankles, or other signs of fluid retention.
Hypocortisolism
For some patients taking Isturisa, cortisol levels may drop too low, a condition known as hypocortisolism. Patients can develop adrenal insufficiency when these levels become critically low, and this condition may be life threatening.
Symptoms of low cortisol levels include nausea, vomiting, fatigue, abdominal pain, loss of appetite, or dizziness. Significantly low cortisol also may be accompanied by low blood pressure, abnormal electrolyte levels, and low blood sugar (hypoglycemia).
Patients should be continuously monitored to make sure their cortisol levels stay within a normal range when taking Isturisa. Should hypocortisolism occur, a dose reduction or treatment pause may be necessary.
Heart function abnormalities
Some patients taking Isturisa may experience QTc prolongation, an electrical disturbance where the heart muscle takes longer to recharge in between heartbeats. This can cause an irregular heartbeat (arrhythmia).
Heart function should be monitored in all patients taking the medication, particularly in individuals with known risk factors for arrhythmia, such as existing heart problems, electrolyte imbalances, or using certain medications known to cause QTc prolongation. Treatment may need to be discontinued in patients experiencing significant QTc prolongation.
Hormonal changes
Isturisa has been associated with elevations in other hormones or hormone precursors released from the adrenal glands. Dose reductions or treatment discontinuation may be required if certain hormonal changes occur.
Patients should be monitored for clinical signs of hormonal changes, including potassium deficiency, worsening high blood pressure, or swelling. Female patients also may experience abnormal hair growth (hirsutism) or acne due to changes in certain sex hormones.
Use in pregnancy and breastfeeding
No information on the use of Isturisa during pregnancy in humans currently exists, but active Cushing’s syndrome is associated with maternal and fetal risks. The treatment’s U.S. label notes the lack of available data for such risks, and the European Union label notes a potential for fetal harm. Patients using Isturisa who are pregnant or wish to become pregnant should talk with their healthcare providers.
No harmful effects on fetal development have been observed in animal studies in pregnant rats and rabbits exposed to Isturisa’s active ingredient.
No data exist on the presence of Isturisa in human breastmilk, or for its effects on a breastfed infant or on milk production. However, due to a potential risk of serious adverse events to a breastfed infant, such as adrenal insufficiency, breastfeeding is not recommended during treatment with Isturisa and for at least a week after a final dose of the medication.
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 Isturisa
Isturisa was approved by the U.S. Food and Drug Administration (FDA) in 2020 for adults with Cushing’s disease who are not eligible for pituitary surgery or for whom the procedure was not effective.
There are no known interactions between Isturisa and alcoholic beverages. However, using alcohol while taking some medications can reduce their effectiveness or cause side effects. Patients wishing to drink while using Isturisa should discuss such preferences with their healthcare providers.
In the LINC-3 clinical trial that supported Isturisa’s approval, the median time to first complete response was reported to be 41 days, meaning that some patients may see their cortisol levels drop within a few months after starting with Isturisa. However, every patient is different and the time it takes for a treatment response can vary. Patients are advised to talk with their doctors about how Isturisa can help in their individual case.
The most common side effects of Isturisa include low cortisol levels, fatigue, nausea, headache, and swelling. If patients experience these side effects, or new or worsening side effects, they should talk with their doctor. A healthcare provider may recommend dose adjustments, or stopping or pausing treatment.
Weight gain is not a known side effect of Isturisa, but it is among the known symptoms of Cushing’s disease. Some evidence from clinical trials indicate that Isturisa is associated with reductions in body weight. Patients who gain weight while using Isturisa or experience other unexpected side effects should discuss them with their healthcare team.
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