PALSONIFY Film-coated tablet Ref.[116079] Active ingredients: Paltusotine

In patients with acromegaly, there was a dose-dependent reduction in IGF-1 levels over the therapeutic dose range of 20 to 60 mg.

Paltusotine may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder stones or sludge [see Warnings and Precautions (5.1)].

Cardiac Electrophysiology:

At 4.6 times the maximum recommended dose of PALSONIFY, clinically significant QTc interval prolongation was not observed.

Paltusotine exhibited dose-proportional increases in exposures for doses ranging from 20 mg (lowest approved recommended dosage) to 120 mg (2 times the highest approved recommended dosage) in healthy participants. Apparent dose proportional increase was observed for mean steady-state trough concentrations up to 60 mg once daily in participants with acromegaly. Following once daily administration, paltusotine reaches steady-state exposure within one week.

Absorption

Following oral administration of paltusotine, the median time to maximum plasma concentration (t_max) is 1 to 4 hours regardless of post dose fasting duration.

Effect of Food

Relative to administration in the fasted state, administration of paltusotine with a high-fat meal (800 to 1000 calories, 50% to 60% fat) reduced the AUC by 85% and the C_max by 81%. Administration of paltusotine with a low-fat meal (400 to 500 calories, 25% fat) reduced AUC by 72% and the C_max by 68%.

Distribution

The volume of distribution (V_z) of paltusotine is 220 L. Paltusotine is highly plasma protein bound (99%).

Elimination

After maximal concentrations were attained, paltusotine concentration declined with apparent terminal half-life (t_½) of 28 hours.

Metabolism

Paltusotine is metabolized primarily in the liver via glucuronidation and oxidation. In vitro, glucuronidation was the major metabolic pathway and is primarily mediated by UGT1A1 and UGT1A9. Oxidation was a secondary pathway and was primarily catalyzed by CYP3A4/5 with a minor contribution from CYP2D6.

Excretion

Following oral administration of radiolabeled paltusotine, fecal excretion was the predominant route of elimination with observed mean recovery of total administered radioactivity being 90% in feces and 3.9% in urine. Unchanged paltusotine was a major component in excreta.

Specific Populations

Effects of Age, Body Weight, Sex, Race, Renal Function, and UGT1A1 Polymorphism

Based on population pharmacokinetics data, no clinically significant difference in the pharmacokinetics of paltusotine was observed based on age (18 to 84 years), body weight (45 to 138 kg), sex, race (White, Asian, Other), renal function (52 to 148 mL/min/1.73 m²; eGFR), or UGT1A1 polymorphism.

Hepatic Impairment

Paltusotine AUC did not change in participants with mild hepatic impairment (Child-Pugh A) compared to participants with normal hepatic function. Paltusotine AUC decreased by 25% in moderate (Child-Pugh B) and 10% in severe (Child-Pugh C) hepatic impairment.

Drug Interaction Clinical Studies and Model-Informed Approaches

Effects of Other Drugs on PALSONIFY

Strong CYP3A4 Inducers:

Paltusotine C_max and AUC decreased by approximately 44% and 70%, respectively, following concomitant administration of carbamazepine (a strong inducer of multiple enzymes and transporters [CYP3A4, UGT1A1, and P-gp]).

Moderate CYP3A4 Inducers:

Drugs such as efavirenz are predicted to decrease C_max and AUC of paltusotine approximately 5% and 30%, respectively.

Proton Pump Inhibitors (PPIs):

Paltusotine exhibited pH-dependent aqueous solubility. Paltusotine AUC was decreased by 21% with 20 mg dose and 42% with 60 mg dose levels.

Other Drugs:

Weak CYP3A4 inducers or inhibitors of CYP3A4/5, P-gp, or UGT1A1 are predicted to not cause clinically significant changes in paltusotine pharmacokinetics.

Effects of PALSONIFY on Other Drugs

Cyclosporine:

Concomitant use of PALSONIFY decreased cyclosporine C_max and AUC in whole blood by 53% and 35%, respectively.

Other Drugs:

Paltusotine did not show clinically significant changes in the pharmacokinetics of other drugs that were CYP3A4/5 or MATE substrates. Paltusotine is predicted to not cause clinically significant changes in the pharmacokinetics of other drugs that are CYP2D6 or P-gp substrates.

In Vitro Studies

In vitro studies suggest paltusotine is an inhibitor of CYP2D6, CYP3A4, and CYP2C19 and a weak inhibitor of UGT1A1, UGT1A3, and UGT1A9 but is unlikely to meaningfully inhibit these enzymes at clinically relevant concentrations. Paltusotine does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, UGT1A6, or UGT2B15. Paltusotine is not an inducer of CYP1A2, CYP2B6, or CYP3A4.

Paltusotine is a substrate of P-gp and BCRP transporters. In vitro studies suggest paltusotine is an inhibitor of P-gp, MATE-1, MATE2-K, and BSEP transporters but is unlikely to meaningfully inhibit these transporters at clinically relevant concentrations. Paltusotine does not inhibit OAT1, OAT3, or OCT1.

13.2 Phototoxicity

Paltusotine absorbs light at 203 to 350 nm wavelength and exhibited a positive phototoxicity signal in vitro as indicated by reduced viability of BALB/c 3T3 mouse fibroblasts. In a phototoxicity study in pigmented Long-Evans rats, oral administration of paltusotine for three consecutive days followed by ultraviolet radiation (UVR) exposure resulted in non-dose dependent ocular toxicities including corneal dystrophy, unilateral inferior focal retinopathy, and unilateral retinal degeneration/necrosis at systemic exposures approximately 2-times the exposure at the MRHD (based on body surface area). The clinical significance of these findings to humans is unknown.

Carcinogenesis and Mutagenesis

No carcinogenic potential was demonstrated in transgenic (rasH2) mice when administering paltusotine by oral gavage for 26 weeks at doses up to 300 mg/kg/day (2.8-times the clinical dose of 60 mg based on AUC). Additionally, no carcinogenic effects were noted when administering paltusotine by oral gavage for 88 to 90 weeks at doses up to 500 mg/kg/day (34-times the clinical dose of 60 mg based on AUC) in rats. Paltusotine was not genotoxic in the in vitro bacterial reverse mutation test (Ames), in vitro micronucleus assay, or in the in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

Animal studies have been conducted to evaluate the effect of paltusotine on fertility and early embryonic development of rats at doses of up to 500 mg/kg/day (18-times the clinical dose of 60 mg based on AUC). There were no paltusotine-related effects on any mating or fertility parameter in males or females at any dose. In addition, there were no paltusotine-related effects on reproductive organ weights or sperm parameters in males at any dose. Based on the finding of decreased corpora lutea in females at 500 mg/kg/day (which resulted in fewer implantation sites and live embryos/litter), the reproductive no-observed-adverse-effect-level (NOAEL) in females was considered to be 75 mg/kg/day (5-times the clinical dose of 60 mg based on AUC).

The effectiveness of PALSONIFY for treatment of adults with acromegaly was evaluated in two randomized, double-blind, parallel group, placebo-controlled clinical studies.

14.1 Study 1: Adults with Acromegaly Naïve or Previously Treated on a Somatostatin Analog

Study 1 (NCT05192382) enrolled 111 adult participants with biochemically uncontrolled acromegaly. Participants were either treatment naïve (n=46/111) or had no treatment within the previous 4 months prior to screening (n=36/111) ('Not Medically Treated' group) or were previously treated on a somatostatin receptor analog and then washed out of treatment during screening (n=29/111) ('Washout' group). The mean age at enrollment was 47 years (range: 18 to 80 years); 53% were female; and 52% were White, 31% Asian, 3% Black or African American, 9% Other, and 5% Unknown race. The mean duration since diagnosis of acromegaly was 87 months. Prior to study participation, 95% of participants had received pituitary surgery (mean duration 78 months prior to study participation). Of the 111 participants, 86 (78%) had macroadenomas (>10 mm), 9 (8%) had microadenomas (≤10 mm), and tumor size was unknown in 16 (14%) participants. In the 'Not Medically Treated' group, IGF-1 levels were required to be ≥1.3×ULN at screening. In the 'Washout' group, IGF-1 levels were required to be ≤1.0×ULN at screening and ≥1.1×ULN with at least a 30% rise in IGF-1 after washout. Participants were randomized to receive either PALSONIFY (n=54) or placebo (n=57) for the 24-week treatment period.

Dose

The starting dose was 20 mg daily, followed by dose increase to 40 mg daily after 2 weeks. The dose could be titrated from 40 mg to a maximum dose of 60 mg based on IGF-1 value during the first 12 weeks of treatment. After Week 12, the PALSONIFY dose was maintained until the end of the randomized controlled period of the study (Week 24). The dose could be down titrated at any time during the study based on tolerability. Rescue therapy with standard of care treatment was initiated if a participant had evidence of uncontrolled acromegaly based on IGF-1 levels and symptoms. Fourteen (13%) participants received rescue therapy during the study: one (2%) participant in PALSONIFY arm and 13 (23%) participants in placebo arm.

Efficacy Assessment and Results

The primary endpoint was the proportion of PALSONIFY participants achieving biochemical control (defined as IGF-1 level ≤1.0×ULN) compared to placebo-treated participants. At Week 24, 56% of PALSONIFY participants achieved biochemical control compared to 5% of placebo-treated participants (p-value <0.0001) (Table 5).

Table 5. Proportion of Participants Achieving Biochemical Control (IGF-1 Levels ≤1.0×ULN) at Week 24 in Adults with Acromegaly (Study 1):

^a The baseline mean IGF-1 was 2.3×ULN in the 'Not Medically Treated' group and 1.5×ULN in the 'Washout' group.
IGF-1=insulin-like growth factor-1; ULN=upper limit of normal
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 randomized controlled portion of the study; if a participant received rescue therapy, the last assessment prior to rescue is used.

The majority of participants who achieved IGF-1 normalization during Study 1 did so within the first 2 to 4 weeks following initiation of treatment, with sustained response through the end of the treatment period.

A posthoc subgroup analysis for the primary efficacy endpoint evaluating the response rate in participants who were naïve to medical treatment, who had not achieved biochemical control on prior medical therapy, or for whom prior biochemical control status was unknown (Group A) and participants who demonstrated prior response to medical therapy who were either washed out from the previous therapy prior to baseline or had documented biochemical control on prior medical therapy (Group B) is provided below (Table 6).

Table 6. Proportion of Participants Achieving Biochemical Control (IGF-1 Levels ≤1.0×ULN) at Week 24 in Adults with Acromegaly Based on Prior Biochemical Control (Study 1):

N=total number of participants per treatment arm; n=number of participants with event; Nx=total number of participants in the subgroup; CI=confidence interval
^a Continuity-corrected Newcombe-Wilson confidence limits were used for the 95% confidence interval.
^b Participants who were not medically treated recently and had not achieved biochemical control on previous medical therapy.
^c Participants who were not medically treated recently and for whom biochemical control on previous medical therapy was unknown.
^d Participants who were either washed out or not medically treated recently but had achieved biochemical control on previous medical therapy.

In Study 1, PALSONIFY-treated participants had numerically lower (versus placebo) severity of symptom scores associated with acromegaly as measured by the patient-reported symptom severity instrument, which assessed headaches, joint pain, sweating, fatigue, weakness, swelling, and/or numbness/tingling.

14.2 Study 2: Adults with Acromegaly Previously Controlled on a Somatostatin Analog

Study 2 (NCT04837040) enrolled 58 participants who were previously biochemically controlled (defined as IGF-1 levels ≤1.0×ULN during screening and at randomization) on injectable depot octreotide or lanreotide somatostatin analog formulations. The mean age at enrollment was 55 years (range: 29 to 84 years); 55% were female; and 72% were White, 3% Asian, 5% Black or African American, 12% Other, and 7% Unknown race. The mean duration since diagnosis of acromegaly was 155 months. Prior to study participation, 86% of participants had received pituitary surgery (mean duration 138 months prior to study participation). Of the 58 participants, 33 (57%) had macroadenomas (>10 mm), 11 (19%) had microadenomas (≤10 mm), and tumor size was unknown in 14 (24%) participants. Participants were randomized to receive either PALSONIFY (n=30) or placebo (n=28) for the 36-week treatment period.

Dose

The starting dose was 40 mg, and the dose could be titrated from 40 mg to a maximum of 60 mg based on IGF-1 value during the first 24 weeks of treatment. After Week 24, the PALSONIFY dose was maintained until the end of the randomized controlled period of the study (Week 36). The dose could be down titrated at any time during the study based on tolerability. Rescue therapy with standard of care treatment was initiated if a participant had evidence of uncontrolled acromegaly based on IGF-1 levels and symptoms. Eighteen (31%) participants received rescue therapy during the study: one (3%) participant in PALSONIFY arm and 17 (61%) participants in placebo arm.

Efficacy Assessment and Results

The primary endpoint was the proportion of PALSONIFY participants with biochemical response maintenance (i.e., IGF-1 ≤1.0×ULN) compared to placebo-treated participants. At Week 36, 83% of PALSONIFY participants maintained biochemical control compared to 4% of placebo-treated participants (p-value <0.0001) (Table 7).

Table 7. Proportion of Participants Maintaining Biochemical Control (IGF-1 Levels ≤1.0×ULN) in Adults with Acromegaly and Previously Maintained on a Somatostatin Analog Injection (Study 2):

^a The baseline mean IGF-1 was 0.83×ULN. Of enrolled participants, 59% were previously treated with octreotide and 41% previously treated with lanreotide. |
IGF-1=insulin-like growth factor-1; ULN=upper limit of normal
Week 36 is the end of the randomized controlled portion of the study; if a participant received rescue therapy, the last assessment prior to rescue is used.

In Study 2, PALSONIFY-treated participants had numerically lower (versus placebo) severity of symptom scores associated with acromegaly as measured by the patient-reported symptom severity instrument, which assessed headaches, joint pain, sweating, fatigue, weakness, swelling, and/or numbness/tingling.