Oral Paltusotine Demonstrates Efficacy in Phase 3 Acromegaly Trial, Offering Alternative to Injectable Treatments
Key Insights
Paltusotine, a once-daily oral SST2 receptor (search) agonist, met its primary endpoint in the PATHFNDR-2 phase 3 trial with 55.6% of patients achieving normal IGF-I (search) levels compared to 5.3% on placebo.
The drug showed rapid onset of action with IGF-I (search) reduction observed in 92.6% of patients by treatment end, with most effects seen within 2-4 weeks of treatment initiation.
Long-term data from the ACROBAT Advance extension study demonstrates sustained biochemical and symptom control over up to 4 years of treatment with a manageable safety profile.
Crinetics Pharmaceuticals' investigational oral drug paltusotine has demonstrated significant efficacy in treating acromegaly (search) patients, meeting all primary and secondary endpoints in the phase 3 PATHFNDR-2 trial while showing sustained long-term benefits in an ongoing extension study.
Phase 3 Trial Results Show Strong Efficacy
The PATHFNDR-2 trial, a randomized, placebo-controlled study, enrolled 111 medically untreated patients with active acromegaly (search) across two strata: medication-naïve patients or those previously treated but off medications for at least 4 months (n=82), and patients previously controlled on injectable treatments who underwent washout (n=29).
Patients received either paltusotine (n=54) or placebo (n=57) for 24 weeks, with dosing starting at 20 mg once-daily and titrating up to 60 mg based on IGF-I (search) levels and tolerability. The primary endpoint was achieved with 55.6% of paltusotine-treated patients reaching normal IGF-I levels (≤1.0 ×ULN) at weeks 22 and 24, compared to only 5.3% in the placebo group (OR: 42.81; 95% CI: 8.44, 455.8; P<0.0001).
The efficacy was consistent across both patient populations in pre-specified sensitivity analyses. In stratum 1 (medication-naïve or previously treated), 42.5% of paltusotine patients achieved the primary endpoint versus 2.4% on placebo (P<0.0001). In stratum 2 (washout patients), the response rate was even higher at 92.9% versus 13.3% on placebo (P<0.0001).
Comprehensive Secondary Endpoint Success
All secondary endpoints were met, demonstrating paltusotine's broad therapeutic impact. Mean IGF-I (search) change from baseline was -0.82±0.08 ×ULN with paltusotine versus 0.09±0.08 ×ULN with placebo (P<0.0001). Additionally, 66.7% of paltusotine patients achieved IGF-I levels <1.3 ×ULN compared to 14.0% on placebo (OR: 18.32; 95% CI: 5.64, 79.16; P<0.0001).
Patient-reported symptoms also improved significantly, with the Acromegaly (search) Symptom Diary score decreasing by -2.7±1.4 points in the paltusotine group while worsening by +2.8±1.4 points in the placebo group (P=0.004). Growth hormone control was achieved in 57.4% of paltusotine patients versus 17.5% on placebo, with 5-sample mean GH <1.0 ng/mL (OR: 7.59; 95% CI: 2.78, 23.48; P<0.0001).
Rapid Onset and Sustained Long-term Benefits
The drug demonstrated rapid onset of action, with IGF-I (search) reduction observed in 92.6% of patients at treatment end, with the majority of effects seen by weeks 2 to 4. Long-term data from the ongoing ACROBAT Advance extension study, which has followed 43 patients for up to 4 years, shows sustained biochemical and symptom control.
In the extension study, median IGF-I (search) levels remained stable: 1.15× ULN at parent study baseline, 1.14× ULN at month 12, 1.06× ULN at month 24, and 1.08× ULN at month 42. Acromegaly (search) symptoms also remained well-controlled, with median Acromegaly Symptom Diary scores of 8.6 at baseline, 10.5 at month 12, 10.0 at month 24, and 13.5 at month 42.
Safety Profile Consistent with Drug Class
The safety profile was consistent with somatostatin receptor (search) ligands and acromegaly (search) symptoms. In the phase 3 trial, no serious adverse events were reported in the paltusotine group, and no new safety signals were observed. In the long-term extension study, the most common adverse events through month 42 were arthralgia (37.2%), headache (30.2%), and fatigue (23.3%). Only one serious drug-related adverse event (cholelithiasis) was reported, and of the 8 patients who discontinued, only 2 were due to adverse events (mild or moderate). Glycemic control remained stable throughout treatment as measured by HbA1c.
Potential to Transform Acromegaly Treatment
Paltusotine is a non-peptide, highly selective SST2 receptor (search) agonist being developed as a once-daily oral treatment for patients with acromegaly (search) or carcinoid syndrome (search). The drug represents a potential paradigm shift from current injectable somatostatin receptor (search) ligands that require monthly or bi-monthly injections.
The PATHFNDR-2 results, combined with findings from the earlier PATHFNDR-1 trial that demonstrated maintenance of biochemical and symptom control in patients converted from injectable treatments, indicate that paltusotine could offer a convenient oral alternative for patients requiring medical therapy for acromegaly (search).