Written By: Divyanjali Godage BPharm
Reviewed By: Pharmacally Editorial Team
The U.S. Food and Drug Administration (FDA) has approved Palsonify (paltusotine), developed and marketed by Crinetics Pharmaceuticals, Inc., for the treatment of adults with acromegaly who have not achieved adequate disease control with surgery or for whom surgery is not appropriate. Unlike currently available injectable therapies such as octreotide or lanreotide, Palsonify is a first-in-class, oral small-molecule somatostatin receptor agonist (SST2-selective). Its approval marks a significant milestone as the first once-daily oral option designed specifically for this rare endocrine disorder.
About Palsonify
Palsonify (paltusotine) is a first-in-class, orally active small-molecule somatostatin receptor agonist. It has been designed with high selectivity for somatostatin receptor subtype 2 (SST2), the main receptor responsible for regulating excess growth hormone (GH) secretion in acromegaly. By binding selectively to SST2, Palsonify suppresses GH release from the pituitary tumor, leading to a reduction in circulating insulin-like growth factor 1 (IGF-1) the biochemical hallmark of disease activity in acromegaly.
Paltusotine was developed using structure-based drug design to mimic the natural activity of somatostatin but with the added advantage of oral bioavailability. Because it avoids the need for injections, it reduces the burden of clinic visits and eliminates injection-related side effects. Moreover, its receptor subtype selectivity (SST2 over other somatostatin receptors) may provide effective biochemical control while minimizing off-target actions that can contribute to unwanted side effects.
Palsonify is taken 40 mg orally once daily on an empty stomach (at least 6 hours after a meal and at least 1 hour before the next meal). The dose can be temporarily reduced to 20 mg at initiation for tolerability and later titrated to 60 mg after 2 to 4 weeks based on IGF-1 levels.
About Acromegaly
Acromegaly is a rare, chronic endocrine disorder most often caused by a growth hormone (GH)-secreting pituitary adenoma. Excess GH leads to overproduction of insulin-like growth factor 1 (IGF-1), which drives abnormal tissue growth and metabolic changes. The disease typically develops gradually over years, with characteristic physical features such as enlarged hands, feet, jaw, and facial bones, along with soft tissue swelling.
Beyond physical appearance, untreated or poorly controlled acromegaly is associated with serious health risks, including cardiovascular complications, metabolic disorders, respiratory issues, musculoskeletal problems, neurological and tumor-related effects.
Clinical Evidence Supporting FDA Approval
The approval of Palsonify (paltusotine) is based on results from two pivotal Phase 3, randomized, double-blind, placebo-controlled trials, which together evaluated the drug in different patient populations: those who were inadequately controlled on prior therapy or untreated, and those already stable on injectable somatostatin analogs (SSAs). Both studies demonstrated robust efficacy and consistent safety, providing the foundation for FDA’s decision.
Study 1 (PATHFNDR-1): Treatment of Active Acromegaly
Adults with active acromegaly, defined by elevated IGF-1 levels above the age-adjusted upper limit of normal (ULN), were randomized to once-daily oral Palsonify or placebo for 24 weeks. Many participants had previously tried surgery or other therapies without full biochemical control. Primary endpoint includes Proportion of patients achieving biochemical control at week 24, defined as IGF-1 ≤1.0× ULN.
In the pivotal trial of patients with active acromegaly, 56% of those treated with Palsonify achieved biochemical control by week 24, compared with 5% on placebo. Most responders normalized IGF-1 within the first 12 weeks, and the drug also improved growth hormone levels and patient-reported symptoms such as headache, fatigue, sweating, joint pain, and swelling. These results demonstrate that Palsonify is an effective oral therapy for patients with uncontrolled disease, providing efficacy comparable to injectable somatostatin analogs.
Study 2 (PATHFNDR-2): Maintenance of Control after Switching from Injectables
In the second pivotal trial, adults with acromegaly who were already biochemically controlled on monthly depot injections of octreotide or lanreotide were switched to once-daily oral Palsonify or placebo for 36 weeks. The primary goal was to determine whether patients could maintain IGF-1 control after transitioning from injectables. Results showed that 83% of patients on Palsonify successfully maintained biochemical control compared with only 4% on placebo. Hormone levels remained stable throughout the study, and patients reported continued symptom management, including relief from headache, fatigue, joint pain, and excessive sweating. The safety profile was consistent with prior studies, with no unexpected adverse events, indicating that Palsonify can serve as a reliable oral alternative for patients wishing to switch from long-acting injections while sustaining disease control.
Overall Safety Profile
Across both pivotal Phase 3 trials, Palsonify demonstrated a safety profile consistent with other somatostatin receptor agonists, but with some specific considerations due to its oral formulation and mechanism of action.
The most common adverse events (occurring in 5% or more of patients) included gastrointestinal symptoms such as diarrhea, abdominal pain, nausea, and decreased appetite, reflecting the expected effects of somatostatin receptor activation on gut motility and hormone secretion. Cardiovascular effects such as bradycardia were observed in a subset of patients, while metabolic disturbances including hyperglycemia were reported, underscoring the need for glucose monitoring during treatment. Some patients also experienced gastroenteritis, likely related to changes in gastrointestinal function.
The warning and precautions includes gallbladder issues, glucose disturbances, thyroid hormone changes, bradycardia or conduction abnormalities, and fat malabsorption with potential vitamin B12 deficiencies. Patients should be monitored for abdominal pain, blood glucose levels, thyroid function, heart rate/rhythm, and nutritional status during therapy.
Prescribing Instructions for Physicians
Before initiating Palsonify (paltusotine), physicians should:
Dosing and administration: Start at 40 mg orally once daily on an empty stomach (at least 6 hours after a meal and 1 hour before the next). For patients who experience tolerability issues, consider a temporary reduction to 20 mg and titrate up to 60 mg after 2–4 weeks based on IGF-1 levels. Monitor IGF-1 and GH per standard endocrinology practice.
Baseline and ongoing monitoring: Assess thyroid function, blood glucose, and gallbladder health (symptoms or imaging) before and periodically during treatment. Monitor nutritional markers if patients develop signs of fat malabsorption or steatorrhea.
Drug interactions: Be aware that strong or moderate CYP3A4 inducers and proton pump inhibitors can alter Palsonify exposure. Adjust the dose according to the prescribing information if such medications are co-administered.
Key Opinions
Crinetics Pharmaceuticals announced the FDA approval of Palsonify (paltusotine) as the first once-daily oral treatment for acromegaly. CEO Dr. Scott Struthers expressed, “With the FDA approval of our lead therapy Palsonify, today marks a new era for those living with acromegaly and also for Crinetics as a company.” He highlighted that this approval is the first from their pipeline of first-in-class, small-molecule drugs, emphasizing the company’s commitment to transforming patient lives
Dr. Shlomo Melmed, Executive Vice President of Medicine and Health Sciences and Dean of the Medical Faculty at Cedars-Sinai, commented, “The PATHFNDR clinical development program set a new standard for acromegaly treatment by demonstrating the ability of Palsonify to drive both biochemical and symptom control, regardless of the degree of underlying disease severity.”
Jill Sisco, President of the Acromegaly Community, added, “For people living with acromegaly, treatment once meant burdensome injections, breakthrough symptoms, and lifestyle sacrifices just to stay on track.”
Palsonify will be available in October, offering the convenience of an oral, once-daily therapy with trial data showing significant biochemical control both in treatment-naïve and previously treated patients and in patients switching from injectables. The drug has a safety profile consistent with somatostatin receptor agonism, with specific warnings clinicians must monitor. Real world experience, cost, and payer access will determine how rapidly it becomes a routine alternative to injectable somatostatin analogs.
References
Crinetics Announces FDA Approval of PALSONIFY™ (paltusotine) for the Treatment of Acromegaly in Adults, Crinetics Pharmaceutics, 25 September 2025, https://crinetics.com/crinetics-announces-fda-approval-of-palsonify-paltusotine-for-the-treatment-of-acromegaly-in-adults/
Highlights of prescribing information, PALSONIFY (paltusotine) tablets, for oral use, https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219070s000lbl.pdf
FDA approves new treatment for acromegaly, a rare endocrine disorder, USFDA, 26 Sept 2025, https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-acromegaly-rare-endocrine-disorder
A Study to Evaluate the Safety and Efficacy of Paltusotine for the Treatment of Acromegaly (PATHFNDR-1), ClinicalTrials.gov ID NCT04837040, https://clinicaltrials.gov/study/NCT04837040
A Study to Evaluate the Safety and Efficacy of Paltusotine for the Treatment of Acromegaly (PATHFNDR-2) (PATHFNDR-2), ClinicalTrials.gov ID NCT05192382, https://www.clinicaltrials.gov/study/NCT05192382
Biller BM, Casagrande A, Elenkova A, et al,12535 Efficacy And Safety Of Once-daily Oral Paltusotine In Medically Untreated Patients With Acromegaly: Results From The Phase 3, Randomized, Placebo-controlled Pathfndr-2 Study. J Endocr Soc. 2024 Oct 5;8(Suppl 1):bvae163.1201. Doi: 10.1210/jendso/bvae163.1201. PMCID: PMC11453628