We know them for their striking appearance. Ted Cassidy, better known as “Lurch” in television’s The Addams Family; Richard Kiel, the 7’ 2” tall actor best remembered as the metal-toothed villain “Jaws” of the James Bond movies; and André René Roussimoff, who went by the stage name Andre the Giant, and whose reputed 7’ 4” height and 520 lb weight made him a World Wide Wrestling Federation superstar during the 1970s. All three men suffered from acromegaly, a rare endocrine disorder characterized by excessive growth, which brought them fame and fortune, and also led to their untimely deaths at ages 46, 74, and 46, respectively.
Acromegaly is caused by excessive production of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), which is typically due to a noncancerous tumor of the pituitary gland. Excessive exposure to GH and IGF-1 can produce dramatic changes in physical characteristics, such as enlarged hands, feet, and facial features, or a deepened, coarse voice. Acromegaly is also associated with mortality rates that are 2 to 3 times higher than normal and with serious comorbidities, including heart disease, hypertension, diabetes, arthritis, and colon cancer. Heart disease is in fact responsible for approximately 60% of deaths among people with acromegaly. The prevalence of acromegaly is estimated to be about 60 cases per million persons, with an annual incidence of about 3 to 4 new cases per million; however, recent evidence has shown that pituitary tumors may be more prevalent than previously believed, raising the possibility that the true prevalence of acromegaly may actually be closer to 115 to 295 cases per million people—or, approximately 2 to 5 times greater than previously thought.
After disease onset, patients typically experience a 6- to 10-year delay in diagnosis. Diagnosis remains difficult due to the slow, insidious onset of the disease and the variability between GH and IGF-1 biological assays, reference ranges, and conversion factors. Once the patient has received a diagnosis, the primary treatment goal is biochemical control over the aberrant hormonal secretions through reduction of GH and normalization of IGF-1 levels. Nevertheless, 45% of patients fail to achieve normalized assays of either hormone. Tumor removal, significant reduction of tumor size or stabilization of tumor size, and minimizing the clinical manifestations of the disease are also important treatment goals.
Treatment options for acromegaly include surgery, radiotherapy, and pharmacologic therapy. In registry studies, patients treated with either radiotherapy alone or with radiotherapy and surgery or medical therapy were the most likely to achieve disease control; however, disease control was achieved by fewer than 50% of patients. Radiotherapy also has risks and disadvantages, including a greater than 6-year lag time to response (during which time symptoms continue) as well as possible development of hypopituitarism (occurring in half of patients), stroke, and secondary brain tumors.
Recently, Novartis announced FDA approval for Signifor® LAR (pasireotide) to treat patients with acromegaly. Pasireotide is a next-generation intramuscular injectable somatostatin analog that is administered once every 28 days. The drug exerts its effects by binding to and stimulating somatostatin receptors, of which there are 5 human subtypes. Pasireotide stimulates both the SSTR2 and SSTR5 subtype receptors, which are relevant in suppressing GH and IGH-1 secretion, an enhanced mechanism of action that provides an advantage over earlier somatastatin analogs. Pasireotide has demonstrated effectiveness in two phase 3 clinical trials: (C2305) a study examining medically naïve patients or those ineligible for surgery or with persistent disease despite prior surgery, and (C2402), which evaluated patients with uncontrolled disease. In trial C2305, the percentage (31.3%) of patients taking pasireotide and achieving biochemical control was statistically significantly greater than the percentage (19.2%) of patients taking an active comparator. In trial C2402, the efficacy endpoint of the percentage of patients achieving biochemical control at 6 months with pasireotide was met for both strengths (40 mg and 60 mg) tested.
There is no guarantee that Signifor LAR will become available anywhere in the world other than the United States, because its safety and efficacy have not been established outside the United States or the EU. It is FDA approved for the treatment of patients with acromegaly, and has been granted orphan drug status.
For further information regarding the activities of the Rare Disease Center of Excellence at Connexion Healthcare, contact:
Susan Stein, MPH, President/CEO