Somatostatin

Acromegaly is a rare condition where patients develop a benign tumor in the pituitary gland that secretes excess growth hormone, which in turn leads the liver to overproduce the hormone IGF-1. For patients that cannot have surgery, the standard of care for acromegaly is a monthly injection of peptide analogs of somatostatin to reduce the production of growth hormone. These treatments, which consist of depots of octreotide, lanreotide or pasireotide, are injected with a large needle and can be a burdensome therapy for patients. Crinetics’ trial, named PATHFNDR-1 enrolled patients with acromegaly to test the potential of the company’s small molecule drug paltusotine, a once-per-day oral alternative to hormone injections. The patients were originally receiving depot somatostatin analog injections and were switched to either paltusotine or a placebo during the trial. According to the results, 83% of patients given paltusotine were able to keep their IGF-1 levels from going too high, compared to just 4% in the placebo group, meeting the trial’s primary goal. The trial also met all secondary goals, such as symptom severity and change from baseline in IGF-1 level, and paltusotine was well tolerated. “We designed paltusotine to be the preferred therapeutic option for people living with acromegaly,” said Scott Struthers, founder and chief executive officer of Crinetics, in a public statement. “We could not be more excited by the results from PATHFNDR-1, which further reinforce our conviction that, if approved, paltusotine could address patients’ unmet need for a simple, oral, once-daily therapy.” googletag.cmd.push(function () { googletag.display('text-ad1'); }); He added that the company expects to apply for market approval of paltusotine when it completes its second phase 3 trial in acromegaly next year. In parallel, Crinetics is testing paltusotine in a phase 2 trial in patients with carcinoid syndrome. Another clinical-stage candidate in Crinetics’ pipeline is in phase 1/2 testing to evaluate it for the treatment of the conditions Cushing’s disease and congenital adrenal hyperplasia. A twice-daily oral form of octreotide called Mycapssa was approved by the FDA in 2020, making it the first oral somatostatin analog for the treatment of acromegaly. Nonetheless, if paltusotine is approved, its once-per-day dosing could help the small molecule drug to stand out in the market.

Pictured: Test-tube containing a patient's sample for an IGF-1 test/iStock, jarun011 Crinetics Pharmaceuticals’ oral investigational drug paltusotine met its primary endpoint and all secondary endpoints in the Phase III PATHFINDR-1 study of acromegaly patients, the California pharma company announced Sunday. Among the paltusotine-treated patients, 83% were able to keep their insulin-like growth factor 1 (IGF-1) levels within the upper limit of normal, as compared to only 4% of placebo comparators. This effect was strongly statistically significant, with a p-value less than 0.0001, according to the company’s announcement. Paltusotine also met all its key secondary endpoints, including change in IGF-1 levels, improvements in acromegaly symptoms and the proportion of participants who maintained growth hormone (GH) levels below 1.0 ng/mL. These data from PATHFINDR-1 demonstrate that paltusotine could induce reliable and durable disease control in patients with acromegaly who switch from the injectable standard of care, Crinetics CEO Scott Struthers said in a statement. “If approved, paltusotine could address patients’ unmet need for a simple, oral, once-daily therapy,” Struthers said. It would also be Crinetics’ first product to reach the market. Acromegaly is a rare disease and serious hormonal disorder that often arises due the presence of pituitary adenoma, a benign tumor in the pituitary gland. This results in the excess production of GH, which in turn triggers the surplus secretion of IGF-1 from the liver. Persistently high concentrations of IGF-1 and GH give rise to the symptoms of acromegaly, including headaches, joint pains, severe sweating, overgrowth of bone and cartilage and enlargement of the heart, liver and other organs. When left unchecked, acromegaly can have debilitating effects on patients’ functioning and quality of life and can lead to death. The standard initial treatment for acromegaly is surgical removal of pituitary adenoma. However, approximately 50% of patients are not eligible for surgery and must settle for monthly injections of depot somatostatin, which often cause pain and injection site reactions. Paltusotine, a selectively targeted somatostatin receptor type 2 (SST2) agonist, offers an oral and once-daily alternative to the injectable treatment. By activating SST2 in pituitary tumors, the drug candidate dampens the secretion of GH and IGF-1, according to a video from Crinetics. To verify its therapeutic effects, Crinetics is running the PATHFINDR clinical development program, which includes PATHFINDR-1. Full analysis of this study is currently ongoing and will be presented at upcoming medical meetings. A second study, dubbed PATHFINDR-2, will test paltusotine in treatment-naïve acromegaly patients who are not currently undergoing any medical therapy. PATHFINDR-2 is fully enrolled with topline data expected in the first quarter of 2024. “We intend to seek regulatory approval as quickly as possible once we complete the PATHFNDR-2 study early next year,” Struthers said. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.