Acromegaly, a serious and rare disease caused by a pituitary adenoma, affects thousands of individuals worldwide. The excess secretion of growth hormone (GH) leads to the production of insulin-like growth factor 1 (IGF-1), resulting in systemic complications and debilitating symptoms. While surgical removal of pituitary adenomas is the preferred initial treatment, pharmacotherapy is necessary for patients who are not candidates for surgery or do not achieve treatment goals through surgery alone.
In the quest for an effective and convenient treatment option, Crinetics Pharmaceuticals has developed paltusotine, an oral, once-daily investigational compound. The recently concluded Phase 3 PATHFNDR-1 study has yielded positive results, demonstrating the potential of paltusotine as a game-changer in the management of acromegaly.
PATHFNDR-1 Study: Meeting Primary and Secondary Endpoints
The PATHFNDR-1 study, a randomized, double-blind, placebo-controlled trial, aimed to evaluate the efficacy of paltusotine in participants with acromegaly who were biochemically controlled on octreotide or lanreotide depot monotherapy. The primary endpoint of the study was the proportion of participants maintaining an IGF-1 level ≤ 1.0 times the upper limit of normal (xULN). The study also assessed several secondary endpoints, including changes in IGF-1 level, Acromegaly Symptoms Diary (ASD) total score, and growth hormone (GH) level.
The results of the PATHFNDR-1 study were highly promising. Paltusotine achieved statistical significance (p<0.0001) on the primary endpoint, with 83% of participants maintaining an IGF-1 level ≤ 1.0 xULN, compared to only 4% in the placebo group. All secondary endpoints, including changes in IGF-1 level, ASD total score, and GH level, also met statistical significance.
Benefits and Tolerability of Paltusotine
One of the key advantages of paltusotine is its oral administration, providing a convenient alternative to the standard-of-care injected depot somatostatin analogs. The transition from monthly injections to once-daily oral paltusotine was seamless, as demonstrated in the PATHFNDR-1 study. Participants experienced both symptom control and biochemical control, highlighting the potential of paltusotine as a reliable and effective treatment option.
Furthermore, paltusotine was well-tolerated in the study, with no reports of serious or severe adverse events. The frequency of treatment emergent adverse events (TEAEs) was comparable between the paltusotine and placebo groups. Commonly reported TEAEs in the paltusotine group included arthralgia, headache, diarrhea, abdominal pain, and nausea. Importantly, the frequency of adverse events related to acromegaly was significantly lower in the paltusotine-treated participants compared to the placebo group.
The Potential of Paltusotine: Addressing Unmet Needs
Crinetics Pharmaceuticals designed paltusotine with the goal of providing an optimal therapeutic option for individuals living with acromegaly. The positive results from the PATHFNDR-1 study reaffirm the company’s conviction that paltusotine, if approved, could address the unmet need for a simple, oral, once-daily therapy.
With plans to complete the PATHFNDR-2 study in the coming year, Crinetics aims to seek regulatory approval for paltusotine in 2024. This approval would encompass all acromegaly patients requiring pharmacotherapy, including both newly diagnosed patients and those switching from other therapies. The potential approval of paltusotine represents a significant step forward in the management of acromegaly.
Expanding Horizons: Beyond Acromegaly
Crinetics Pharmaceuticals is not only focused on acromegaly but also exploring the utility of paltusotine in the treatment of carcinoid syndrome. An open-label Phase 2 study is currently underway to evaluate the efficacy of paltusotine in patients with carcinoid syndrome. Preliminary results are expected later this year, offering promising insights into the potential of paltusotine for a broader range of endocrine-related tumors.
The Strength of Crinetics’ Platform
The success of paltusotine in the PATHFNDR-1 study underscores the strength of Crinetics Pharmaceuticals’ core platform for developing high-quality, small molecule, oral drugs. Crinetics is dedicated to creating innovative investigational compounds for individuals living with various endocrine diseases, including congenital adrenal hyperplasia, Cushing’s disease, hyperparathyroidism, Graves’ disease, hyperinsulinism, diabetes, and obesity. Paltusotine serves as a flagship program, paving the way for further advancements and breakthroughs.
The Road Ahead: Further Analysis and Future Prospects
While a full analysis of the PATHFNDR-1 results is still underway, Crinetics Pharmaceuticals plans to present the findings at upcoming scientific conferences. Additionally, the ongoing PATHFNDR-2 study, enrolling treatment-naïve acromegaly patients or those not currently receiving medical therapy, is expected to release topline data in the first quarter of 2024. The successful outcome of the PATHFNDR-2 study will enable Crinetics to submit a new drug application to the U.S. Food and Drug Administration, bringing paltusotine one step closer to regulatory approval.
The positive results from the PATHFNDR-1 study highlight the potential of paltusotine as a groundbreaking treatment option for individuals living with acromegaly. Crinetics Pharmaceuticals’ commitment to developing innovative and convenient therapies has paved the way for the introduction of paltusotine, an oral, once-daily compound that offers reliable symptom and biochemical control. With ongoing studies and future prospects, Crinetics Pharmaceuticals is poised to revolutionize the management of acromegaly and expand its impact in the field of endocrine diseases.