The US Food and Drug Administration (US FDA) has approved Novartis' Signifor long-acting release (LAR) (pasireotide) for injectable suspension, for intramuscular use, for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.
The approval of Signifor LAR, a next-generation somatostatin analog (SSA), helps address a critical unmet need among the acromegaly patient population. Signifor LAR has been studied and found effective in both medically naïve patients with acromegaly who have had prior surgery or for whom surgery was not an option, as well as patients whose disease is not fully controlled on first generation SSAs.
Acromegaly is a rare, debilitating endocrine disorder caused by the excess production of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). In the majority of cases, the disease is caused by a non-cancerous tumor on the pituitary gland. Prolonged exposure to GH and IGF-1 may cause patients to experience extreme physical changes including the enlargement of hands, feet and facial features. Acromegaly is also associated with two- to three-fold increased mortality rates and serious health complications, including heart disease, hypertension, diabetes, arthritis and colon cancer. In fact, heart disease is responsible for approximately 60 per cent of deaths among people with acromegaly.
"Treating acromegaly can be extremely challenging and the consequences of inadequate normalization of hormone levels can be serious for patients," said Dr. Monica Gadelha, Professor, Federal University of Rio de Janeiro and pivotal trial study author. "With the approval of Signifor LAR, physicians now have a new acromegaly therapy that provides an enhanced mechanism to address elevated hormone levels. This is a significant achievement and much welcomed news for patients with acromegaly."
Worldwide, the prevalence of acromegaly is estimated to be 60 cases per million, with an annual incidence of 3 to 4 new cases per million. However, recent studies suggest that pituitary adenomas may be more prevalent than previously thought, and that the prevalence of acromegaly may be between 115 and 295 cases per million. On average, patients experience a delayed diagnosis of 6 to 10 years from disease onset. Once diagnosed, the primary objective when treating acromegaly is to achieve biochemical control of the disease, as measured by both the reduction of GH levels and normalisation of IGF-1 levels. Notably, a recent meta-analysis using more sensitive assays and more stringent evaluation criteria showed that 45 per cent of patients with acromegaly fail to achieve recommended levels of GH or normalised levels of IGF-1. Reduction of tumour volume and minimisation of clinical manifestations are other important treatment goals.
This FDA approval was based on two multicenter phase III studies, C2305 and C2402, which respectively examined medically naïve patients who have had prior surgery or for whom surgery was not an option and patients with acromegaly inadequately controlled on first generation SSAs. In both studies, higher rates of full biochemical control (defined as mean GH level <2.5mcg/L and normal IGF-1 levels) were achieved with Signifor LAR compared to a first generation SSA.
"The FDA approval of Signifor LAR for acromegaly marks an important day for physicians and patients living with difficult-to-treat pituitary conditions and underscores our continued commitment to helping patients manage rare diseases," said Bruno Strigini, President, Novartis Oncology. "We are pleased that a new treatment option is now available to help address the serious impact of uncontrolled acromegaly, and are optimistic about providing this much needed treatment to other patients worldwide in the near future."
Signifor LAR is an SSA administered intramuscularly once-monthly that exerts its pharmacological activity via binding to somatostatin receptors (SSTRs). Signifor LAR has the potential to stimulate both SSTR2 and SSTR5 subtype receptors, which are relevant for inhibition of GH and IGF-1 secretion, making Signifor LAR a more effective treatment for acromegaly compared to other SSAs currently used to treat this disease.
In the US, Signifor LAR has orphan drug designation for acromegaly. Orphan drug designation is granted for products that treat a condition that affects fewer than 200,000 people in the US. In November 2014, the European Medicines Agency (EMA) approved Signifor to treat adult patients with acromegaly for whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with a first-generation SSA. Novartis has also submitted additional regulatory applications for Signifor LAR worldwide.
The C2305 study was a multicentre, randomised, double-blind study in patients with active acromegaly who were not previously treated with medication (medically naïve), and had persistent disease despite prior surgery or were ineligible for surgery. Patients were randomised to receive either Signifor LAR (starting dose of 40 mg with possibility to up-titrate to 60 mg) or the active comparator.
The efficacy endpoint of proportion of patients achieving full GH and IGF-1 biochemical control at month 12 was met. Specifically, the percentage of patients achieving biochemical control was 31.3 per cent for Signifor LAR and 19.2 per cent for the active comparator (P<.01 for treatment difference). Biochemical control was achieved early in the study (i.e., month 3) by 30.1 per cent of patients in the Signifor LAR arm.
Ninety-eight percent of patients treated with Signifor LAR had either a reduction or no change in tumor volume from baseline as assessed by MRI at month 12. Additionally, ring size and acromegaly symptoms score (i.e., headache, fatigue, perspiration, paresthesia or tingling sensation in limbs, and osteoarthralgia or joint pain) were followed. At month 12, reductions in ring size and in symptom severity scores in both treatment groups compared to baseline were noted.
The most common adverse events (AEs) with Signifor LAR versus the active comparator were diarrhea (39 per cent vs. 45 per cent ), cholelithiasis (26 per cent vs. 36 per cent ), hyperglycemia (29 per cent vs. 8 per cent ) and diabetes mellitus (26 per cent vs. 4 per cent ).
The C2402 study was a randomized study evaluating the efficacy and safety of double-blind Signifor LAR (40 mg and 60 mg) versus continued open-label pre-trial SSA therapies at maximal or near maximal doses in 198 patients with inadequately controlled acromegaly. Inadequate control was defined as mean GH level >2.5 mcg/L and IGF-1 >1.3 times the sex- and age-adjusted upper normal limit.
The efficacy endpoint of the proportion of patients achieving biochemical control, as defined by GH and IGF-1 levels, at 6 months with Signifor LAR 40 mg or 60 mg versus continued pre-trial SSA therapy, was met for both Signifor LAR doses. Specifically, 15.4 per cent and 20.0 per cent of patients treated with Signifor LAR 40 mg and 60 mg, respectively, achieved full GH and IGF-1 biochemical control at 6 months compared with 0 per cent in the pre-trial therapy SSA control arm. Biochemical control was achieved by month 3 in 15.4 per cent and 18.5 per cent of patients in the Signifor LAR 40 mg and 60 mg arms, respectively.
Eighty-one per cent and 70 per cent of patients treated with Signifor LAR 40 mg and 60 mg, respectively, had either a reduction or no change in tumor volume from baseline as assessed by MRI at month 6.The most common AEs associated with Signifor LAR 40 mg, 60 mg and pre-trial SSA therapies were hyperglycemia (33 per cent , 30 per cent , 14 per cent ) and diabetes mellitus (21 per cent , 31 per cent , 9 per cent ).
Signifor long-acting release (LAR) (pasireotide) for injectable suspension, for intramuscular use, is now approved by the US Food and Drug Administration (US FDA) for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.
The safety and efficacy profile of Signifor LAR has not yet been established in countries outside the US or the EU in patients with acromegaly. For various reasons, including the uncertainty of clinical trials, there is no guarantee that Signifor LAR will become commercially available for acromegaly anywhere else in the world.