Novartis presented results from a pivotal phase III trial of investigational therapy Signifor LAR (pasireotide LAR; SOM230) in patients with acromegaly for whom current standard of care provides inadequate disease control. The study findings showed that patients taking pasireotide long-acting release (LAR) achieved greater disease control when compared to continued treatment with the standard somatostatin analogue therapies, octreotide LAR or lanreotide Autogel. These data were presented at the 16th European Congress of Endocrinology (ESE).

Acromegaly is caused by a benign (non-cancerous) tumor within the pituitary gland that secretes excess growth hormone (GH), leading to elevated levels of insulin-like growth factor-1 (IGF-1). This combined effect of elevated GH and IGF-1 levels causes the enlargement of body parts, including the hands, feet and facial features, along with serious morbidities such as cardiovascular, metabolic and respiratory diseases. If exposed to long-term elevated levels of GH and IGF-1, acromegaly patients face a two- to three-fold increased risk of death. Biochemical control of the disease, as measured by both GH and IGF-1 levels, is the primary goal of treatment. Other disease management objectives include tumor shrinkage and improvement in clinical signs and symptoms.

"Historically, we have evaluated somatostatin analogues for the treatment of acromegaly by the decrease in either growth hormone or insulin-like growth factor levels. With more sensitive assays and more stringent evaluation criteria, a recent meta-analysis indicates that up to 45% of patients can have either GH or IGF-I still elevated," said Dr. Monica Gadelha, professor, Federal University of Rio de Janeiro and study author. "As the health risks associated with acromegaly may persist until both GH and IGF-1 levels are normalized, this study further supports the importance of monitoring for and achieving full biochemical control."

This study evaluated pasireotide LAR 40 mg and 60 mg against continued therapy with octreotide LAR or lanreotide Autogel in patients who did not achieve GH and IGF-1 biochemical control despite receiving the maximum approved doses of these currently available somatostatin analogues (SSAs). In the trial, significantly more patients achieved biochemical control with each dose of pasireotide LAR compared to the octreotide LAR and lanreotide Autogel control arm. Specifically, 15.4% and 20.0% of those with inadequately controlled acromegaly taking pasireotide LAR 40 mg and 60 mg, respectively (95% confidence interval [CI], 7.6-26.5; P=0.0006; 95% CI, 11.1-31.8; P<0.0001), achieved biochemical control versus 0% achieving biochemical control on continued treatment with octreotide LAR or lanreotide Autogel (95% CI, 0-5.3). The incidence and severity of adverse events (AEs) was similar across all treatment groups, except for a higher frequency and degree of hyperglycemia in the pasireotide LAR arm.

"These results strengthen our understanding of this rare endocrine disorder and suggest pasireotide LAR may offer benefit for acromegaly patients whose disease is not fully controlled on their current therapy," said Alessandro Riva, president, Novartis Oncology ad interim and Global Head, Oncology Development and Medical Affairs. "As part of our long-standing commitment to transforming the care of rare pituitary diseases, we are working to bring this potentially meaningful solution to the acromegaly community."

Worldwide regulatory filings for pasireotide LAR in acromegaly are currently underway based on these results and separate previously published robust Phase III data.

The multicenter phase III study was a randomized, double-blind trial examining pasireotide LAR 40 mg or pasireotide LAR 60 mg versus continued open-label treatment with octreotide LAR 30 mg or lanreotide Autogel 120 mg (the control group) for 24 weeks. The trial included 198 patients with inadequately controlled acromegaly on maximum approved doses of octreotide LAR or lanreotide Autogel for at least 6 months, regardless of prior surgical status. The primary endpoint of this study was the proportion of patients achieving biochemical control as measured by the mean GH levels of <2.5Mu g/L and normalized IGF-1 at 24 weeks.

The key secondary endpoint was the percentage of patients achieving normalized IGF-1; other secondary endpoints included the percentage of patients achieving normalized GH levels, tumor reduction and safety. Notably, in this study, IGF-1 normalization was achieved by 24.6% and 26.2% of patients taking pasireotide LAR 40 mg and 60 mg, respectively (95% CI, 14.8-36.9; P<0.001; 95% CI, 16.0-38.5; P<0.001) and was not achieved by any patients in the control arm (95% CI, 0-5.3). Additionally, 35.4% and 43.1% of patients in the pasireotide LAR 40 mg and 60 mg arms, respectively (95% CI, 23.9-48.2; 95% CI, 30.8-56.0) had mean GH levels of <2.5Mu g/L compared to 13.2% in the control arm (95% CI, 6.2-23.6).

Tumor size was also evaluated and the study found a greater proportion of patients receiving pasireotide LAR 40 mg and 60 mg achieved a greater than 25% decrease compared with those receiving octreotide LAR and lanreotide Autogel (18.5% [95% CI, 9.9-30.0] and 10.8% [95% CI, 4.4-20.9] versus 1.5% [95% CI, 0-7.9], respectively).

The most common AEs associated with pasireotide LAR 40 mg, 60 mg and the control arm were hyperglycemia (33.3%, 30.6% and 13.6%), diabetes mellitus (20.6%, 25.8% and 7.6%) and diarrhea (15.9%, 19.4% and 4.5%), respectively.

Worldwide, the estimated prevalence of acromegaly is between 115 and 295 people per million and the estimated incidence is three to four people per million. Acromegaly most commonly presents in middle-aged men and women. This debilitating disease can be difficult to detect because it can develop gradually and/or individual symptoms may be mistaken for another medical condition. In fact, the average delay from disease onset to diagnosis has been estimated to be 6 to 10 years. Acromegaly is also associated with serious health risks including heart disease, hypertension, diabetes, arthritis and an increased risk of colon cancer. Heart disease is responsible for approximately 60% of deaths among people with acromegaly.

Pasireotide is approved as Signifor in the US for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative and in the EU for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed.

For the treatment of Cushing's disease, Signifor has been studied as a twice-daily subcutaneous (sc) injection and is currently being evaluated as a long-acting release (LAR), once-monthly intramuscular (IM) injection as part of a global phase III programme in Cushing's disease and acromegaly. Signifor is a multireceptor targeting somatostatin analog (SSA) that binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and 5). There is no guarantee that Signifor LAR will become commercially available anywhere in the world for Cushing's disease or any other indication.

Pasireotide LAR (SOM230) is an investigational multireceptor targeting SSA that binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and 5). As an investigational agent, the safety and efficacy profile of pasireotide LAR has not been established in acromegaly or any other indication. The formulation and dosage of pasireotide LAR when used for studying the acromegaly patient population are different from that of pasireotide sc in the approved Cushing's disease indication. Pasireotide LAR is available for patients with acromegaly through carefully controlled and monitored clinical trials which are designed to better understand the potential benefits and risks of the compound. For various reasons, including the uncertainty of clinical trials, there is no guarantee that pasireotide LAR will become commercially available for acromegaly anywhere in the world.

Octreotide LAR, a long-acting, injectable depot formulation of octreotide acetate, is approved in the United States (US) as Sandostatin® LAR® Depot for long-term maintenance therapy in patients with acromegaly who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option in patients in whom initial treatment with immediate release Sandostatin (octreotide acetate) Injection has been shown to be effective and tolerated. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal. Outside the US, octreotide LAR is available as Sandostatin LAR for the treatment of patients with acromegaly who are adequately controlled on subcutaneous treatment with Sandostatin or in whom surgery or radiotherapy is inappropriate or ineffective; in the interim period until radiotherapy becomes fully effective. Acromegaly indications vary by country.

Octreotide LAR is available from Novartis for different uses and not all indications are available in every country.