Esbriet - Scientific Information
|Condition:||Idiopathic Pulmonary Fibrosis|
|Class:||Miscellaneous uncategorized agents|
|Ingredients:||Pirfenidone, Microcrystalline cellulose, Croscarmellose sodium, Povidone, Magnesium stearate, Titanium dioxide, Gelatin, Shellac|
|Description:||White to pale yellow crystalline powder|
|Solubility:||Freely soluble in methanol, ethyl alcohol, acetone, and chloroform. Sparingly soluble in 1.0 N hydrochloric acid, water and 1.0 N sodium hydroxide.|
|Melting point:||Between 106°C and 112°C|
|pKa||0.2 ± 0.6|
Study Demographics and Trial Design
The clinical efficacy of ESBRIET (pirfenidone capsules 267 mg) has been studied in three Phase III, multicentre, randomized, double-blind, placebo-controlled studies in patients with IPF (PIPF-004, PIPF-006 and PIPF-016).
PIPF-004 and PIPF-006 compared treatment with ESBRIET 2403 mg/day to placebo. The studies were nearly identical in design, with few exceptions including an intermediate dose group (1197 mg/day) in PIPF-004. In both studies, treatment was administered three times daily for a minimum of 72 weeks. The final follow-up visit was held 3 to 4 weeks after the treatment completion visit. The primary endpoint in both studies was the change from Baseline to Week 72 in percent predicted Forced Vital Capacity (FVC).
PIPF-016 compared treatment with ESBRIET 2403 mg/day to placebo. Treatment was administered three times daily for 52 weeks. The primary endpoint was the change from Baseline to Week 52 in percent predicted FVC.
|Study #||Trial design||Dosage, route of administration and duration||Study patients (n) Esbriet/Control||Mean age (Range)||Gender|
|PIPF-004||Randomized double-blind, placebo-controlled Phase III study to evaluate the efficacy and safety of ESBRIET in patients with IPF||2403 mg/day (three 267 mg capsules TID) ESBRIET vs. placebo, administered orally for 72 weeks.||174/174||65.7 years (45–80 years)||66.3 years (40–79 years)||32.2% female||26.4% female|
|PIPF-006||Randomized double-blind, placebo-controlled Phase III study to evaluate the efficacy and safety of ESBRIET in patients with IPF||2403 mg/day (three 267 mg capsules TID) ESBRIET vs. placebo, administered orally for 72 weeks.||171/173||66.8 years (45–80 years)||67.0 years (42–80 years)||28.1% female||28.3% female|
|PIPF-016||Randomized double-blind, placebo-controlled Phase III study to evaluate the efficacy and safety of ESBRIET in patients with IPF||2403 mg/day (three 267 mg capsules TID) ESBRIET vs. placebo, administered orally for 52 weeks.||278/277||68.4 years (47–80 years)||67.8 years (41–80 years)||20.1% female||23.1% female|
Forced Vital Capacity
In study PIPF-004, the decline in lung function, as measured by percent predicted FVC from Baseline at Week 72 of treatment, was significantly reduced in patients receiving ESBRIET (N = 174) compared with patients receiving placebo (N = 174; p = 0.001, rank ANCOVA). The absolute difference in the mean change in percent predicted FVC was 4.4% between treatment groups, representing a relative difference of 35.5%. Treatment with ESBRIET also significantly reduced the decline of percent predicted FVC from Baseline at Weeks 24 (p = 0.014), 36 (p < 0.001), 48 (p < 0.001), and 60 (p < 0.001). At Week 72, a decline from Baseline in percent predicted FVC of ≥10% (a threshold indicative of the risk of mortality in IPF) was seen in 20% of patients receiving ESBRIET compared to 35% receiving placebo (Table 2).
In study PIPF-006, there was no statistically significant difference between treatment with ESBRIET (N = 171) and placebo (N = 173) in the reduction of the decline of percent predicted FVC from Baseline at Week 72 (p = 0.501, rank ANCOVA). However, treatment with ESBRIET reduced the decline in lung function, as measured by percent predicted FVC from Baseline at Weeks 24 (p < 0.001), 36 (p = 0.011), and 48 (p = 0.005). At Week 72, a decline in FVC of ≥10% was seen in 23% of patients receiving ESBRIET and 27% receiving placebo (Table 2).
The primary endpoint analysis of the pooled population also showed an ESBRIET treatment effect on percent predicted FVC at week 72 (p = 0.005, rank ANCOVA). The absolute difference in the mean change in percent predicted FVC was 2.5% between two treatment groups, representing a relative difference of 22.8%. At Week 72, a decline from Baseline in percent predicted FVC of ≥10% was seen in 21.4% of patients receiving ESBRIET compared to 30.5% receiving placebo (Table 1).
|Number (% of Patients)|
|ESBRIET 2403 mg/d (n = 174)||Placebo (n = 174)||ESBRIET 2403 mg/d (n = 171)||Placebo (n = 173)||ESBRIET 2403 mg/d (n = 345)||Placebo (n = 347)|
|Decline of ≥10% or death or lung transplant||35 (20%)||60 (35%)||39 (23%)||46 (27%)||74 (21%)||106 (30%)|
|Decline of <10% but ≥0%||97 (56%)||90 (52%)||88 (52%)||89 (51%)||185 (54%)||179 (52%)|
|Improvement of >0%||42 (24%)||24 (14%)||44 (26%)||38 (22%)||86 (25%)||62 (18%)|
In study PIPF 016, the decline of percent predicted FVC from Baseline at Week 52 of treatment, was significantly reduced in patients receiving ESBRIET (N = 278) compared with patients receiving placebo (N = 277; p < 0.000001, rank ANCOVA). Treatment with ESBRIET also significantly reduced the decline of percent predicted FVC from Baseline at Weeks 13 (p < 0.000001), 26 (p < 0.000001), and 39 (p = 0.00002).
Progression Free Survival (PFS)
In the analysis of PFS in study PIPF-004, treatment with ESBRIET significantly reduced the combined risk of death or disease progression by 36% compared to placebo (HR 0.64 [0.44–0.95]; p = 0.023). Disease progression was defined as ≥10% decline in percent predicted FVC or ≥15% decline in percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO).
The reduction in risk was primarily due to differences in disease progression due to decline in percent predicted FVC. In study PIPF-006, there was no difference in PFS between the two treatment arms (HR 0.84 [0.58–1.22]; p = 0.355). In the pooled analysis, treatment with ESBRIET 2403 mg/day resulted in a 26% reduction in the risk of death or progression of disease compared with placebo (HR 0.74 [95% CI, 0.57–0.96]; p = 0.025).
In the analysis of PFS in study PIPF-016, treatment with ESBRIET significantly reduced the combined risk of death or disease progression by 43% compared to placebo (HR 0.57 [0.43–0.77]; p = 0.0001). Disease progression was defined as death, ≥10% decline in percent predicted FVC or ≥ 50 meters decline in six minute walk test (6MWT) distance.
Six Minute Walk Test Distance
In study PIPF-004, there was no difference between patients receiving ESBRIET compared to placebo in change from baseline to Week 72 of distance walked during a six minute walk test (6MWT) by the prespecified rank ANCOVA (p = 0.171). The difference in the mean decline in the 6MWT distance between the treatment groups at Week 72 was 16.4 meters, representing a relative difference of 21.3%.
In study PIPF-006, the decline in 6MWT distance from baseline to Week 72 was significantly reduced compared with placebo in this study (p < 0.001, rank ANCOVA). The difference in the mean decline in the 6MWT distance between the treatment groups at Week 72 was 31.8 meters, representing a relative difference of 41.3%.
In study PIPF-016, the decline in 6MWT distance from baseline to Week 52 was significantly reduced compared with placebo (p = 0.036, rank ANCOVA). The difference in the mean decline in the 6MWT distance between the treatment groups was 26.7 meters, representing a relative difference of 44.2%.
The overall survival was captured as an exploratory efficacy endpoint in pivotal studies. The cause of death was not adjudicated and the effect of ESBRIET on all-cause mortality is inconclusive.
In a pooled analysis of survival in PIPF-004 and PIPF 006 the mortality rate with ESBRIET 2403 mg/day group was 7.8% compared with 9.8% with placebo (HR 0.77 [95% CI, 0.47–1.28]).
In Study PIPF-016, the mortality rate with Esbriet 2403 mg/ day group was 4.0 % compared with 7.2% with placebo (HR 0.55 [ 95% CI, 0.26–1.15]).
The findings from a range of in vitro and in vivo primary pharmacodynamic studies suggested the anti-fibrotic and anti-inflammatory properties of pirfenidone. Bleomycin-induced pulmonary fibrosis has become an established model for human IPF and studies with pirfenidone in this model using mice, hamsters and rats demonstrated its activity in inhibiting the development and progression of fibrosis at exposures lower than that associated with the recommended human dose. In vitro and in vivo studies to date have not detected any activity of the major human metabolite, 5-caboxy-pirfenidone.
At concentrations higher than the Cmax seen in humans, pirfenidone may cause transient CNS depressant effects. Inhibitory effects on gastric emptying and small intestinal transport were observed in rats. An additional pharmacological effect was an arrhythmogenic effects in mice, rats and dogs.
Pirfenidone decreased "general activity and behavior" and "the central nervous system" in mice at an oral dose of 100 mg/kg or above. Pirfenidone had effects on "the respiratory and cardiovascular systems" in anesthetized rats at an intraduodenal dose of 30 mg/kg or above. Studies in mice and rats caused transient general activity and behavior effects (marked sedation and abnormal posture at oral doses of 100 mg/kg or above; at 300 mg/kg staggering gait, ptosis and a decrease in the body temperature), decreased the spontaneous motor activity and the body temperature at an oral dose of 100 mg/kg or above. At 300 mg/kg, significant potentiating effects of anesthesia, anticonvulsive effects (electroshock or PTZ-induced convulsions) and analgesic effects were observed and significantly reduced the blood pressure and significantly increased the respiratory volume and arterial blood flow in anesthetized rats at an intraduodenal dose of 30 mg/kg or above. At 100 mg/kg or above, pirfenidone caused a decrease in the respiratory rate, an increase in the heart rate, and occurrence of a premature beat.
In anesthetized rats, pirfenidone caused a transient increase in heart rate immediately after administration at 100 mg/kg. 300 mg/kg of pirfenidone caused a decrease in blood pressure and increase in heart rate lasting approximately 30 minutes. Pirfenidone caused premature ventricular contracts (PVC) and atrioventricular block at 100 mg/kg or above. Continuous PVC was also observed at 300 mg/kg.
Studies in anesthetized dogs demonstrated that an intraduodenal administration of pirfenidone at 100 mg/kg or more causes a decrease in blood pressure and an increase in heart rate.
Pirfenidone was converted to 5-hydroxymethyl-pirfenidone and 5-carboxy-pirfenidone by NADPH-fortified human liver microsomes. The result of experiments with human recombinant CYP enzymes implicated several CYP enzymes such as CYP1A2, 2C9, 2C19, 2D6, and 2E1 in the metabolism of pirfenidone. However, the results of the antibody inhibition experiments and correlation analysis suggest that CYP1A2 is the major CYP enzyme responsible for the conversion of pirfenidone to 5-hydroxymethyl-pirfenidone and 5-carboxy-pirfenidone in human liver microsomes. The overall results indicate CYP1A2 as the major CYP involved in the metabolism, however, results from experiments with human recombinant CYP enzymes and correlation analysis indicate that other CYP enzymes participate in the overall metabolism of pirfenidone.
Pirfenidone was found not to significantly inhibit CYP or MAO enzymes. However under one experimental condition examined using human liver microsomes, pirfenidone caused direct inhibition of CYP1A2, CYP2A6, CYP2D6 and CYP2E1, as approximately 34%, 27%, 21% and 27% inhibition was observed at 1000 µM. As well, CYP enzymes are not influenced by 5-carboxy-pirfenidone and only mildly influenced by pirfenidone (at 250 µM).
With the exception of phototoxicity, nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and toxicity to reproduction. Phototoxicity and irritation were noted in guinea pigs and mice after oral administration of pirfenidone and with exposure to UVA light.
In mice and rats the clinical signs observed at the maximum non-lethal doses included hypoactivity and abnormal gait. These clinical signs were observed in dogs in addition to vomiting, mydriasis and tremors. In a study with rats, the toxicity of pirfenidone was reduced when administered with food. Pirfenidone was more toxic to female rats and female dogs in which higher systemic exposures compared to males was observed.
|Species||Route||Maximum Non-Lethal Dose (mg/kg)||Minimum Lethal Dose (mg/kg)|
|Rat||Oral, gavage||500 (fasted); 1000 (fed)||1000 (fasted)|
|Dog||Oral, capsule||1000||Not determined|
In repeated dose studies, decreased body weight was observed in mice, rats and dogs administered oral pirfenidone. Increased liver weights were observed with hepatic centrilobular hypertrophy and increased CYP content in all species. In dogs, transient vomiting, abnormal gait, tremors, limb weakness, rigidity and hypoactivity were observed at doses 10-fold higher (Cmax) than the clinical dose. The toxic signs observed in these studies were reversible after pirfenidone administration was stopped.
|Mouse, B6C3F1||Oral, diet||13 weeks||0, 200, 600, 2000||↓ Body weight at the highest dose. ↑ Red blood cell indices, reticulocyte ratio and platelet count in males. ↓ Albumin (both sexes), A/G ratio (males), total protein (females) and cholesterol; ↑ BUN (males). Dose-related ↑ liver weight with centrilobular hepatocyte hypertrophy, and splenic extramedullary hematopoiesis in males at 2000 mg/kg/day.
NOAEL: 600 mg/kg/day
|Rat, F344||Oral, diet||13 weeks||0, 500, 1000, 1500||↓ Body weight and body weight gain, ↓ erythrocytes (RBC), haemoglobin, and hematocrit and ↑ MCV, platelets and reticulocytes in both sexes. ↑Total protein, albumin, glucose, BUN, cholesterol, calcium, and inorganic phosphorous; ↓ A/G ratio, triglycerides and chloride. ↑ Liver, kidney, adrenal, and testes weights. Dose-dependent centrilobular hepatocyte hypertrophy, kidney tubular epithelial regeneration (males only), and adrenal gland zone fasciculata hypertrophy (males only at 1500 mg/kg/day).|
|Rat, SD||Oral, gavage||6 months||0, 20, 100, 500, 1000||Salivation, ↓ activity, and respiratory rate at 500 and 1000 mg/kg/day during the first 6 weeks of treatment. ↓ Food consumption and body weight gain in high-dose males. ↓ RBC, haemoglobin, and hematocrit in females, and ↑ MCV and MCH in males, together with ↓ prothrombin time in males and ↑ activated partial thromboplastin time in females. ↑ Total protein, albumin, A/G ratio, creatinine kinase, amylase, cholesterol, calcium, and inorganic phosphorous; ↓ creatinine, triglycerides, and chloride. ↑ Liver weight (both sexes) and centrilobular hypertrophy in 2/12 males at 1000 mg/kg/day. ↑ CYP content and selected isoenzymes at 500 and 1000 mg/kg/day.
NOAEL: 100 mg/kg/day
|Rat, SD||Intravenous||4 weeks||0, 500, 1000, 1625||Ten deaths by Day 4 of treatment (1 female at 1000 mg/kg/day and 9 females at 1625 mg/kg/day). ↑ Absolute liver and kidney weights and hepatic centrilobular hypertrophy at 1625 mg/kg/day.
NOAEL: 500 mg/kg/day
|Dog, Beagle||Oral, capsule||3 months||0, 20, 70, 200||Mucous in faeces, salivation, vomiting, abnormal gait, difficulty in standing, rigidity, limb weakness, head shakes, vocalization and hypoactivity at the higher doses. ↑ Platelet counts at 200 mg/kg/day. ↑ Alkaline phosphatase at 70 and 200 mg/kg/day. ↑ Liver weight and reversible hepatocellular hypertrophy at 200 mg/kg/day. ↑ Submaxillary gland weight and acinar hypertrophy at 200 mg/kg/day. ↑ CYP content and microsomal enzyme activities at all doses.
NOAEL: 70 mg/kg/day
|Dog, Beagle||Oral, capsule||9 months||0, 20, 70, 200||Mucous in faeces (all doses), salivation, vomiting, abnormal gait, difficulty standing, rigidity, limb weakness, head shakes, vocalization and hypoactivity at the higher doses. ↓ Body weight (females), ↑ platelet counts, ↑ alkaline phosphatase, ↑ liver weight with reversible hepatocellular hypertrophy, ↑ submaxillary gland weight and acinar hypertrophy at 200 mg/kg/day. ↑ CYP content and microsomal enzyme activities at all doses.
NOAEL: 70 mg/kg/day
|Dog, Beagle||Oral, capsule||9 months||0, 20, 70, 200 (given as b.i.d.)||Excessive salivation and reddening of the inner ear skin. And ↑ alkaline phosphatase at the higher doses.
NOAEL: 200 mg/kg/day
A/G = albumin/globulin; MCV = mean corpuscular volume; MCH = mean corpuscular haemoglobin; BUN = blood urea nitrogen; RBC = red blood cells; SD = Sprague Dawley; NOAEL = no observed adverse effect level.
Reproductive toxicology studies demonstrated no adverse effects of pirfenidone on male and female fertility or postnatal development of offspring in rats. Rats exhibited prolongation of the estrus cycle and an increased incidence of irregular cycles at higher doses (≥450 mg/kg/day). Prolonged gestation and reduced fetal viability were observed in rats at high doses (≥1000 mg/kg/day). The placental transfer of pirfenidone and/or its metabolites occurred in animals with the potential for their accumulation in amniotic fluid. Dose-related increases in fetal incidences of soft tissue variations and skeletal variations were observed but were considered related to lower maternal food consumption and body weight. There was no evidence of teratogenicity in rats or rabbits at doses up to 4-fold higher than the clinical dose. Pirfenidone and/or its metabolites were also excreted in milk in lactating rats.
|Species and Strain||Route||Duration||Doses (mg/kg/day)||Results|
|Rat, SD||Oral, diet||50–69 days: Premating (28 days M and 14 days F) to Gestation Day 20||0, 450, 900||↓ Body weight and food consumption at both dose levels. ↓ Gravid uterine weights and foetal body weights.
NOAEL (fertility and foetal development): 900 mg/kg/day.
|Rat, SD||Oral, gavage||50–69 days: Premating (28 days M and 14 days F) to Gestation Day 17||0, 50, 150, 450, 1000||Transient hypoactivity, ptosis, limb weakness, abnormal gait, and hypopnea (both sexes) at 150, 450, and 1000 mg/kg/day. Dose-related prolongation of estrus cycle and high incidence of irregular cycles at 450 and 1000 mg/kg/day.
NOAEL (reproductive toxicity, males): 1000 mg/kg/day
NOAEL (reproductive toxicity, females): 150 mg/kg/day
NOAEL (foetal development): 1000 mg/kg/day
|Rabbit, Japanese white||Oral, gavage||Gestation Days 6 to 18||0, 30, 100, 300||Transient accelerated respiration, prone position, dilation of auricular blood vessels, sluggish startle reaction, ear drop, scant feces, salivation, and ptosis at 100 and 300 mg/kg/day. ↓ Food consumption and ↓ body weight gain. One animal at 100 mg/kg/day delivered prematurely on Day 28 and two animals aborted (Day 24 and Day 26) and another died (Day 27) at 300 mg/kg/day.
NOAEL (reproductive toxicity): 30 mg/kg/day
NOAEL (foetal development): 300 mg/kg/day
|Rat, SD||Oral, gavage||Gestation Day 7 to Lactation Day 20 (postpartum)||0, 100, 300, 1000||F0: ↓ activity, respiratory inhibition, salivation, and lacrimation at all doses. Prolongation of gestation period at 1000 mg/kg/day (22.7 days versus 22.2 days in control) and decreased foetal viability. F1: ↓ Body weights during pre-weaning period at 300 and 1000 mg/kg/day. F2: no effect on litter size.|
SD = Sprague Dawley; NOAEL = no observed adverse effect level.
Genotoxicity and Photogenotoxicity
Pirfenidone showed no genotoxic potential in standard in vitro and in vivo genotoxicity assays. However, under UV exposure, pirfenidone was positive in a photoclastogenic assay in Chinese hamster lung cells but was not mutagenic in the Ames test. The metabolite 5-carboxy-pirfenidone was not photomutagenic or photoclastogenic in similar assays.
|Type of Study||Test System||Method of admin.||Doses||Results|
|Ames||S. typhimurium, E. coli||In vitro||100–5000 µg/plate||Negative|
|Chromosome Aberration||Chinese hamster ovary cells||In vitro||1000–2800 µg/mL (no activation) 500–1400 µg/mL (with activation)||Negative|
|Chromosome Aberration||Chinese hamster lung cells||In vitro||231–1850 µg/mL (with and without activation) 116–925 µg/mL (without activation, 48 hr exposure)||Negative|
|Bone marrow micronucleus||Mouse, ICR||Oral, gavage (single dose)||200, 400, 800 mg/kg||Negative|
|Liver UDS||Rat, F344||Oral, gavage (single dose)||1000, 2000 mg/kg||Negative|
|Ames||S typhimurium strains TA102 and TA98, E coli strain WP2/pKM101||In vitro||39.1–5000 µg/plate (without activation, with UV exposure)||Negative|
|Chromosome Aberration||Chinese hamster lung cells||In vitro||560–1900 µg/mL (without activation, in the absence of UV exposure)||Negative|
|Chromosome Aberration||Chinese hamster lung cells||In vitro||1–120 µg/mL (without activation, with UV exposure)||Positive|
UDS = Unscheduled DNA synthesis
In long term studies, an increased incidence of liver tumours (hepatocellular adenoma) was observed in mice (≥800 mg/kg/day) and rats (≥750 mg/kg/day). At a pirfenidone dose of 1500 mg/kg/day (4-fold higher than the clinical dose), a statistically significant increase in uterine adenocarcinoma was observed in female rats. The results of mechanistic studies indicated that the occurrence of uterine tumours may be related to a chronic dopamine-mediated sex hormone imbalance involving a species specific endocrine mechanism in the rat which is not present in humans. The relevance of these findings to humans is unknown.
|Species and Strain||Route||Duration||Doses (mg/kg/day)||Results|
|Mouse, B6C3F1||Oral, diet||104 weeks||0, 800, 2000, 5000||↑ Liver tumours at all doses (both sexes): considered to be a rodent species-specific non-genotoxic effect due to hepatic CYP induction.|
|Rat, F344||Oral, diet||104 weeks||0, 375, 750, 1500||↑ Liver tumours at all doses (both sexes): considered to be rodent species-specific non-genotoxic effect due to hepatic CYP induction. ↑ uterine tumours at 1500 mg/kg/day: considered to be rodent species-specific due to chronic dopamine-mediated sex hormone imbalance.|
Pirfenidone was phototoxic in guinea pigs and mice inducing transient erythema at doses 4-fold higher than the clinical dose (based on Cmax). Sunscreens with SPF 50+ prevented pirfenidone induced phototoxicity in guinea pigs.
|Species and Strain||Route||Duration||Doses (mg/kg/day)||Results|
|Guinea pig, Hartley||Oral, gavage / topical||1 day / 2 weeks||0, 40, 160 (oral); 0%, 1%, 5% (topical)||No phototoxicity or photosensitivity|
|Guinea pig, Hartley||Oral, gavage||3 days||0, 2.5, 10, 40, 160||Reversible phototoxic effects.|
|Guinea pig, Hartley||Oral, gavage||Single dose||0, 160||Severity of phototoxic lesions ↓ over time after UV exposure and was minimal at 6 hours post-dose.|
|Guinea pig, Hartley||Oral, gavage||Single dose||0, 160||Severity of phototoxic lesions ↓ with ↑ grade of sunscreen. SPF 50 cream and SPF 50 lotion decreased the total toxicity score by 100% and 74%, respectively.|
|Mouse, HR-1 Hairless||Oral, gavage||28 days||0, 500||Local toxicity of skin: mild acanthosis and mild single cell necrosis in the epidermis of the auricle and the dorsal skin. These changes were not apparent after a 1-month recovery period.|
UV = ultraviolet; SPF = sun protection factor