Long-acting Signifor Has Similar Safety Profiles as Twice-daily Treatment in Cushing’s Patients, Trial Showed

A long-acting, once-a-month treatment of Signifor (pasireotide) normalized cortisol levels in 40% of patients with Cushing’s disease whose disease had recurred after surgery, or who were not candidates for surgery, according to new data from a Phase 3 trial.

The safety profiles of the once-monthly regimen proved to be similar to standard twice-daily Signifor treatments, researchers found.

The study, “Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial,” was published in the journal The Lancet Diabetes & Endocrinology.

Novartis‘ Signifor in its twice-daily injection formulation has already been approved for treating Cushing’s in the U.S. and elsewhere.

The 12-month, Phase 3 trial (NCT01374906) was conducted at 57 sites in 19 countries. The study included 150 patients with Cushing’s whose cortisol levels had risen or not dropped at all after surgery, or who were unable to undergo surgery.

Between Dec. 28, 2011, and Dec. 9, 2014, participants were randomized to receive either 10 mg or 30 mg of Signifor every four weeks, via an injection to the muscle. If, after four months of therapy, cortisol urinary levels (mUFC) were 50% greater than the upper normal limit, the dose could be increased from 10 mg to 30 mg, or from 30 mg to 40 mg. It could also be increased after seven, nine, or 12 months if the mUFC concentration was greater than normal.

The goal was to normalize average concentrations of free cortisol in the urine to less than or equal to the upper normal limit at month seven. It was met by 31 of the 74 patients in the 10 mg group (41.9%) and 31 of the 76 patients in the 30 mg group (40.8%).

The most common adverse events were hyperglycemia (high concentration of blood sugar), diarrhea, cholelithiasis (gall stones), diabetes, and nausea.

The researchers consider this treatment to be a good option for patients whose disease has returned after surgery, or who cannot undergo surgery. The long-lasting treatment schedule of one injection per month is more convenient for patients than the twice-daily subcutaneous injection, making it more likely that they would not discontinue treatment.

“Surgical resection of the causative pituitary adenoma is the first-line treatment of choice for most patients with Cushing’s disease, which leads to remission in greater than 75% of patients if done by an expert pituitary surgeon,” wrote Dr. Andre Lacroix, MD, a professor in the Department of Medicine at the University of Montreal teaching hospital, and colleagues.

“However, surgery is not always successful, and disease recurrence can occur several years after initial remission, while some patients refuse or are not candidates for surgery. As a result, many patients require additional treatment options.”

“Long-acting pasireotide normalized mUFC concentration in about 40% of patients with Cushing’s disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide,” the team wrote in the study.

“Long-acting pasireotide is an efficacious treatment option for some patients with Cushing’s disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule,” researchers concluded.

From https://cushingsdiseasenews.com/2017/10/31/long-acting-signifor-for-cushings-disease-has-similar-efficacy-and-safety-as-twice-daily-treatment/

Osilodrostat maintained cortisol control in Cushing’s syndrome

Osilodrostat, a drug that normalized cortisol in 89% of patients with Cushing’s syndrome who took it during a phase II study, continued to exert a sustained benefit during a 31-month extension phase.

In an intent-to-treat analysis, all of the 16 patients who entered the LINC-2 extension study responded well to the medication, with no lapse in cortisol control, Rosario Pivonello, MD, said at the annual meeting of the Endocrine Society.

“We also saw significant improvements in systolic and diastolic blood pressure and decreases in fasting plasma glucose,” said Dr. Pivonello of the University of Naples Federico II, Italy. “Surprisingly, after 31 months, we also observed declines in body mass index and weight.”

Osilodrostat, made by Novartis, is an oral inhibitor of 11 beta–hydroxylase. The enzyme catalyzes the last step of cortisol synthesis in the adrenal cortex. The drug was granted orphan status in 2014 by the European Medicines Agency.

In the LINC-2 study, 19 patients took osilodrostat at an initial dose of either 4 mg/day or 10 mg/day, if baseline urinary-free cortisol exceeded three times the upper normal limit. The dose was escalated every 2 weeks to up to 60 mg/day, until cortisol levels were at or below the upper limit of normal. In this study, the main efficacy endpoint was normalization of cortisol, or at least a 50% decrease from baseline at weeks 10 and 22.

Overall response was 89%. Osilodrostat treatment reduced urinary-free cortisol in all patients, and 79% had normal cortisol levels at week 22. The most common adverse events were asthenia, adrenal insufficiency, diarrhea, fatigue, headache, nausea, and acne. New or worsening hirsutism and/or acne were reported among four female patients, all of whom had increased testosterone levels.

The LINC-2 extension study enrolled 16 patients from the phase II cohort, all of whom had responded to the medication. They were allowed to continue on their existing effective dose through the 31-month period.

Dr. Pivonello presented response curves that tracked cortisol levels from treatment initiation in the LINC-2 study. The median baseline cortisol level was about 1,500 nmol per 24 hours. By the fourth week of treatment, this had normalized in all of the patients who entered the extension phase. The response curve showed continued, stable cortisol suppression throughout the entire 31-month period.

Four patients dropped out during the course of the study. Dr. Pivonello didn’t discuss the reasons for these dropouts. He did break down the results by response, imputing the missing data from these four patients. In this analysis, the majority (87.5%) were fully controlled, with urinary-free cortisol in the normal range. The remainder were partially controlled, experiencing at least a 50% decrease in cortisol from their baseline levels. These responses were stable, with no patient experiencing loss of control over the follow-up period.

The 12 remaining patients are still taking the medication, and they experienced other clinical improvements as well. Systolic blood pressure decreased by a mean of 2.2% (from 130 mm Hg to 127 mm Hg). Diastolic blood pressure also improved, by 6% (from 85 mm Hg to 80 mm Hg).

Fasting plasma glucose dropped from a mean of 89 mg/dL to 82 mg/dL. Weight decreased from a mean of 84 kg to 74 kg, with a corresponding decrease in body mass index, from 29.6 kg/m2 to 26.2 kg/m2.

Serum aldosterone decreased along with cortisol, dropping from a mean of 168 pmol/L to just 19 pmol/L. Adrenocorticotropic hormone increased, as did 11-deoxycortisol, 11-deoxycorticosterone, and testosterone.

Pituitary tumor size was measured in six patients. It increased in three and decreased in three. Dr. Pivonello didn’t discuss why this might have occurred.

The most common adverse events were asthenia, adrenal insufficiency, diarrhea, fatigue, headache, nausea, and acne. These moderated over time in both number and severity.

However, there were eight serious adverse events among three patients, including prolonged Q-T interval on electrocardiogram, food poisoning, gastroenteritis, headache, noncardiac chest pain, symptoms related to pituitary tumor (two patients), and uncontrolled Cushing’s syndrome.

Two patients experienced hypokalemia. Six experienced mild events related to hypocortisolism.

Novartis is pursuing the drug with two placebo-controlled phase III studies (LINC-3 and LINC-4), Dr. Pivonello said. An additional phase II study is being conducted in Japan.

Dr. Pivonello has received consulting fees and honoraria from Novartis, which sponsored the study.

Global Cushing’s Syndrome Market Size 2015

Cushing’s as money makers for drug companies 😦

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Steroidogenesis inhibitors were responsible for approximately 28% of total drug sales in the 6MM in 2013, equating to around $50m. As a consequence of this trend, GlobalData expects overall revenues generated by this drug class to increase by approximately 390% to reach around $247m, encompassing 49% of total drug sales in the 6MM in 2018.

The expansion in this segment of the CS market is fuelled by the introduction of premium-priced pharmacological agents such as Novartis’ LCI699 and Cortendo AB’s NormoCort (COR-003) in the US, as well as the arrival of HRA Pharma’s Ketoconazole HRA (ketoconazole) to the European CS stage. One of the greatest unmet needs in this indication is a lack of effective drugs directed against the underlying cause of Cushing’s disease (the pituitary tumor).

Despite this demand, pharmaceutical companies are continuing to adopt a strategy that simply targets the adrenal glands. As a result, there is a vast amount of room for new or existing players to penetrate the market and capture considerable patient share.

Highlights

Key Questions Answered

Although the current standard of care (ketoconazole) is cheap and reasonably effective in most CS patients, it possesses worrying safety profiles, inconvenient dosing schedules, is difficult to obtain and can display waning efficacy over time. Newer medical treatments, for example, Novartis’ Signifor (pasireotide) and Corcept Therapeutics’ Korlym (mifepristone) address only some of these issues; yet, present their own limitations. The CS market is still marked by the existence of a multitude of unmet needs. What are the main unmet needs in this market? Will the drugs under development fulfil the unmet needs of the CS market?

The late-stage CS pipeline is sparsely populated; however, those drugs in development will be a strong driver of CS market growth. Which of these drugs will attain high sales revenues during 2013-2018? Which of these drugs will have the highest peak sales at the highest CAGR, and why?

Key Findings

One of the main drivers influencing growth in the Cushing’s syndrome market will be the introduction of second-generation steroidogenesis inhibitors, LCI699 and NormoCort (COR-003), in the US, which will rival existing standard of care medical treatments.

Another strong driver will be the arrival of Corcept Therapeutics’ Korlym (mifepristone) and HRA Pharma’s Ketoconazole HRA (ketoconazole) to the European CS market. Both drugs will stimulate significant growth here.

The launch of Novartis’ Signifor LAR (pasireotide) in the 6MM will equip physicians with a less frequently administered formulation of Signifor.

Reasons for inadequate CS treatment include poor physician awareness of the condition, delayed diagnosis, a lack of efficacious drugs for individuals suffering from severe hypersecretion, and a shortage of effective medicines targeting the source of Cushing’s disease.

Scope

Overview of Cushing’s syndrome, including epidemiology, etiology, pathophysiology, symptoms, diagnosis, and treatment guidelines.

Annualized Cushing’s syndrome therapeutics market revenues, annual cost of therapies and treatment usage pattern data from 2013 and forecast for five years to 2018.

Key topics covered include strategic competitor assessment, market characterization, unmet needs, clinical trial mapping and implications for the Cushing’s syndrome therapeutics market.

Pipeline analysis: comprehensive data split across different phases, emerging novel trends under development, and detailed analysis of late-stage pipeline drugs.

Analysis of the current and future market competition in the global Cushing’s syndrome therapeutics market. Insightful review of the key industry drivers, restraints and challenges. Each trend is independently researched to provide qualitative analysis of its implications.

Reasons to buy

Develop and design your in-licensing and out-licensing strategies through a review of pipeline products and technologies, and by identifying the companies with the most robust pipeline. Additionally a list of acquisition targets included in the pipeline product company list.

Develop business strategies by understanding the trends shaping and driving the Cushing’s syndrome therapeutics market.

Drive revenues by understanding the key trends, innovative products and technologies, market segments, and companies likely to impact the Cushing’s syndrome therapeutics market in the future.

Formulate effective sales and marketing strategies by understanding the competitive landscape and by analysing the performance of various competitors.

Identify emerging players with potentially strong product portfolios and create effective counter-strategies to gain a competitive advantage.

Track drug sales in the 6MM Cushing’s syndrome therapeutics market from 2013-2018.

Organize your sales and marketing efforts by identifying the market categories and segments that present maximum opportunities for consolidations, investments and strategic partnerships.

From http://www.medgadget.com/2015/10/global-cushings-syndrome-market-size-2015-share-trend-analysis-price-research-report-forecast.html

Pituitary Tumor Roundtable – Part One: A Focus on Diagnosis

Novartis is committed to supporting the pituitary community and continues to address the evolving needs of patients and caregivers.

In this video, a multidisciplinary panel discusses the diagnosis of acromegaly and Cushing’s disease.

For more information, visit: http://www.AboutAcromegaly.com and http://www.AboutCushings.com.

 

The Voices of Cushing’s Disease

The perspectives of individuals living with Cushing’s disease, their caregivers and advocates.

In creating this series, Novartis hoped to shine a spotlight on key factors involved in living with Cushing’s disease, including diagnosis, disease management and the importance of a strong support network.

The video series has been posted on the Novartis YouTube channel and can be viewed via the following links:

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