PALSONIFY Film-coated tablet Ref.[116552] Active ingredients: Paltusotine

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues
ATC code: H01CB06

Mechanism of action

Similar to the natural hormone somatostatin (SST), paltusotine demonstrates potent suppression of GH and IGF-1 secretion. Paltusotine exerts its pharmacological activity via highly selective binding (>4 000-fold) to somatostatin receptor 2 (SST2) and exhibits little or no affinity for other SST receptor subtypes. Paltusotine inhibits cyclic adenosine monophosphate (cAMP) accumulation via human SST2 activation with an average drug (agonist) concentration that results in half-maximal response (EC₅₀) of 0.25 nM.

Pharmacodynamic effects

Paltusotine substantially reduces, and in many cases, normalises IGF-1 and GH levels in patients with acromegaly.

Cardiac electrophysiology

At 4.6 times the exposure of the paltusotine 60 mg therapeutic dose, clinically significant QTc interval prolongation was not observed.

Clinical efficacy and safety

The efficacy and safety of paltusotine for the medical treatment of adults with acromegaly was established in two phase 3 randomised, double-blind, parallel group, placebo-controlled clinical studies (PATHFNDR-2 and PATHFNDR-1).

Study PATHFNDR-2

This 24-week study (PATHFNDR-2) enrolled 111 adult patients with acromegaly who were not receiving medical treatment and were biochemically uncontrolled at randomisation. Patients were either not previously medically treated or had no treatment within the previous 4 months prior to screening (not medically treated) or were receiving, and washed out of, somatostatin receptor ligand monotherapy with octreotide or lanreotide during screening (washout). IGF-1 levels were required to be ≥1.3×ULN for those not medically treated and ≥1.1×ULN with at least a 30% rise in IGF-1 during the screening period for the washout patients. Patients were randomised to receive either paltusotine (N=54) or placebo (N=57) for the 24-week treatment period. The starting dose was 20 mg/day during 2 weeks and the dose could be increased to 40 mg/day at the week 2 visit after confirming tolerability. At week 6, the dose could be increased to 60 mg once daily, if the 40 mg dose was acceptably tolerated and based on biochemical control and the week 4 IGF-1 was >0.9×ULN. Dose down-titration was allowed at any time during the randomised control phase of the study if the dose was not tolerated. After week 12, the dose was maintained until the end of the randomised controlled period of the study (week 24).

Fifty-three per cent (53%) of patients were female; 52% were White, 31% Asian, 3% Black or African American, 9% Other and 5% Unknown race. The mean age at time of enrolment was 47 years (9% were ≥65 years). The mean duration since diagnosis of acromegaly was 87 months with 89% of patients receiving pituitary surgery within a mean duration of 75 months prior to study participation. The overall baseline mean IGF-1 was 2.3×ULN in the not medically treated patients and 1.5×ULN in the washout patients.

The primary endpoint was met, with 55.6% of paltusotine patients achieving biochemical control (IGF-1 level ≤1.0×ULN) at week 24 compared to 5.3% of placebo-treated patients (p-value <0.0001).

In addition to achieving the primary endpoint, paltusotine produced statistically significant (p-value <0.0001) reductions of IGF-1 to normal levels in both not medically treated (42.5%) and washout (92.9%) patients compared to placebo-treated patients regardless of prior treatment history (Table 2).

An analysis of change from baseline in IGF-1 to week 24 showed that, while baseline mean IGF- 1×ULN levels was consistent between the paltusotine and placebo groups (2.0 and 2.2, respectively), paltusotine resulted in a statistically significant difference (p-value <0.0001) compared to placebo-treated patients among all patients as well as in both the not medically treated and washout groups (Table 2).

Table 2. Study PATHFNDR-2 overall efficacy results based on IGF-1 levels:

Previously treated, LS mean
(SE) |<> -0.964 (0.1151) |<>0.108 (0.1151) |<> <0.0001 |
|Washout, LS mean (SE) |<> -0.600 (0.1044) |<>0.152 (0.1008) |<> <0.0001|

IGF-1 at week 24 is based on the average of the last 2 measurements of IGF-1 collected at weeks 22 and 24. When one of the two last IGF-1 measurements was missing a single value was used. Week 24 is the end of the randomised controlled portion of the study; if a patient received rescue therapy, the last assessment prior to rescue is used.
IGF-1=insulin-like growth factor-1, LS=least squares, SE=standard error, ULN=upper limit of normal.

Treatment with paltusotine resulted in an approximately 37% reduction in IGF-1 by 4 weeks following initiation of treatment and was sustained through the end of the treatment period (Figure 1).

Figure 1. Study PATHFNDR-2 LS mean (±SE) IGF-1 (×ULN) change from baseline by visit for all patients:

The population includes all randomised patients based on multiple imputation methods.
IGF-1=insulin-like growth factor-1, LS=least squares, SE=standard error, ULN=upper limit of normal.

An analysis of time to response from randomisation demonstrated 59% of paltusotine-treated patients achieved IGF-1 normalisation compared to 9% in the placebo-treated group during the study. The majority of IGF-1 normalisation events occurred during the first 4 weeks of treatment. These results are consistent with the primary endpoint analysis which demonstrated continued response in a majority of paltusotine-treated patients through the end of week 24.

Table 3. Study PATHFNDR-2 proportion of patients with IGF-1 <1.3×ULN:

IGF-1 at week 24 is based on the average of the last 2 measurements of IGF-1 collected at weeks 22 and 24. When one of the two last IGF-1 measurements was missing a single value was used. Week 24 is the end of the randomised controlled portion of the study; if a patient received rescue therapy, the last assessment prior to rescue is used.
IGF-1=insulin-like growth factor-1, ULN=upper limit of normal.

Consistent with the paltusotine mechanism of action, target GH levels of <1.0 ng/mL were achieved in 57% in the paltusotine-treated patients compared with 17.5% in the placebo-treated patients (p-value <0.0001) at week 24 (Table 4).

Table 4. Study PATHFNDR-2 proportion of patients with GH <1.0×ULN:

GH=growth hormone, ULN=upper limit of normal.

Study PATHFNDR-2 measured clinical symptom severity for 7 items associated with acromegaly (headache pain, joint pain, sweating, fatigue, weakness in legs, swelling, and numbness or tingling) using the acromegaly symptoms diary (ASD), with each item score ranging from 0 (no symptoms) to 10 (worst symptoms). A preliminary threshold range to characterise meaningful within patient change for the ASD total is a -4 to -6 point change for improvement or worsening out of a total score of 70. At baseline, patients presented with mild to moderate symptoms. The change from baseline to week 24 in total ASD score shows a statistically significant improvement of -2.669 for the paltusotine-treated patients compared to a worsening of 2.754 for placebo-treated patients (p-value=0.0039). In not medically treated or previously treated patients who received paltusotine, the ASD score showed an improvement of -4.187 compared to a worsening of 0.163 in placebo-treated patients. In washout patients, those receiving paltusotine exhibited an improvement of -1.610 compared to worsening of 5.777 in those receiving placebo (Table 5).

Table 5. Change from baseline to week 24 in total ASD score in study PATHFNDR-2:

Week 24 is the end of the randomised controlled portion of the study; if a patient received rescue therapy, the last assessment prior to rescue is used. Baseline total ASD is the sum of the weekly average on or prior to day 1, and post-baseline total ASD is the sum of the weekly average on or prior to the scheduled visit date, inclusive of the date of visit, for 7 items (headache, joint pain, sweating, fatigue, weakness in legs, swelling, and numbness or tingling).At baseline, mean total ASD score was 17.48 in the paltusotine group, and 15.54 in the placebo group.
ASD=Acromegaly symptoms diary, CI=confidence interval, LS=least squares, SE=standard error.

Results by ASD individual item score change from baseline to week 24 for all patients showed for all 7 items a trend in favour of paltusotine, 5 of which were statistically significant (headache pain, sweating, fatigue, weakness in legs, swelling; p<0.05).

The LS means (±SE) change from baseline to end of treatment in most bothersome symptoms were -0.553 (±0.4219) in the paltusotine group and 0.357 (±0.3770) in the placebo group, with a treatment difference of -0.910 (95% CI: -1.976, 0.157) in favour of paltusotine (nominal p=0.0935).

The observed safety and tolerability profile remained unchanged (see section 4.8) and the durability of the clinical treatment benefits were retained in patients dosed for 120 weeks in the ongoing OLE study PATHFNDR-2.

Study PATHFNDR-1

This 36-week study (PATHFNDR-1) enrolled 58 patients who were biochemically controlled on injectable depot octreotide or lanreotide somatostatin receptor ligand therapy. All patients were required to be biochemically controlled (defined as IGF-1 levels ≤1.0×ULN) during screening and at randomisation. Patients were randomised to receive either paltusotine (N=30) or placebo (N=28) for the 36-week treatment period. The dose could be titrated from 40 mg to a maximum of 60 mg based on IGF-1 value or decreased based on tolerability. After week 24, the paltusotine dose was maintained until the end of the randomised controlled period (week 36).

Fifty-five per cent (55%) of patients were female, 72% were White, 3% Asian, 5% Black or African American, 12% Other, 7% Unknown race. The mean age at time of enrolment was 55 years (28% were ≥65 years). The mean duration since diagnosis of acromegaly was 155 months with 86% of patients receiving pituitary surgery within a mean duration of 138 months prior to study participation. The baseline mean IGF-1 was 0.83×ULN with a baseline mean GH level of 0.90 ng/mL. Of enrolled patients, 59% were previously treated with octreotide and 41% previously treated with lanreotide. The majority of patients enrolled were on the mid or high doses of approved somatostatin receptor ligand therapy prior to screening.

The primary endpoint was met, with 83.3% of paltusotine-treated patients maintained biochemical control (IGF-1 level ≤1.0×ULN) at week 36 compared to 3.6% of placebo-treated patients (Table 6).

Table 6. Study PATHFNDR-1 overall efficacy results based on IGF-1 level:

Week 36 is the end of the randomised controlled portion of the study; if a patient received rescue therapy, the last assessment prior to rescue is used.
IGF-1=insulin-like growth factor 1, LS=least squares, SE=standard error, ULN=upper limit of normal.

Paltusotine demonstrated stable IGF-1 levels in patients who switched from prior somatostatin receptor ligand therapy, which was sustained through the end of the 36-week treatment period (IGF-1×ULN: 0.04±0.093). In contrast, patients randomised to placebo showed a rise in IGF levels (IGF-1×ULN: 0.83±0.096) at week 36 and the difference between groups at the end of the treatment period was statistically significant (p-value <0.0001) (Figure 2).

Figure 2. Study PATHFNDR-1 LS mean (±SE) IGF-1 (×ULN) change from baseline by visit for all patients:

The population includes all randomised patients based on multiple imputation methods.
IGF-1=insulin-like growth factor-1, LS=least squares, SE=standard error, ULN=upper limit of normal.

Target GH levels of <1.0 ng/mL were maintained in 87% of patients controlled at baseline in the paltusotine treated patients compared with 28% in the placebo-treated patients (p-value <0.0003) at week 34.

Study PATHFNDR-1 measured acromegaly clinical symptom severity in 7 items (headache pain, joint pain, sweating, fatigue, weakness in legs, swelling, and numbness or tingling) using the ASD. A preliminary threshold range to characterise meaningful within patient change for the ASD total is a -4 to -6 point change for improvement or worsening out of a total score of 70. At baseline, patients presented with mild to moderate symptoms. The change from baseline to week 36 in total ASD score showed an improvement of -0.606 for the paltusotine-treated patients compared to a worsening of 4.558 for the placebo-treated patients (p-value=0.0216) (Table 7).

Table 7. Change from baseline to week 36 in total ASD score in study PATHFNDR-1:

Week 36 is the end of the randomised controlled portion of the study; if a patient received rescue therapy, the last assessment prior to rescue is used. Baseline total ASD is the sum of the weekly average on or prior to day 1, and post-baseline total ASD is the sum of the weekly average on or prior to the scheduled visit date, inclusive of the date of visit, for 7 items (headache, joint pain, sweating, fatigue, weakness in legs, swelling, and numbness or tingling).At baseline, mean total ASD score was 13.21 in the paltusotine group, and 10.86 in the placebo group.

ASD=Acromegaly symptoms diary, CI=confidence interval, LS=least squares, SE=standard error.

Results by ASD individual item score change from baseline to week 36 showed for all 7 items a trend in favour of paltusotine, 2 of which were statistically significant (joint pain and numbness or tingling; p-value <0.05). No single ASD item predominantly affected the overall total ASD score, indicating there was improvement and stabilisation across acromegaly symptoms evaluated in the paltusotine treated patients compared with the placebo-treated patients.

The LS means (±SE) change from baseline to end of treatment in most bothersome symptoms were -0.530 (±0.360) in the paltusotine group and 0.617 (±0.381) in the placebo group, with a treatment difference of -1.147 (95% CI: -2.199, -0.094) in favour of paltusotine (nominal p=0.0335).

The observed safety and tolerability profile remained unchanged (see section 4.8) and the durability of the clinical treatment benefits were retained in patients dosed for 120 weeks in the ongoing OLE study PATHFNDR-1.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Palsonify in all subsets of the paediatric population in the treatment of acromegaly (see section 4.2 for information on paediatric use).