PBI-4050: PBI-4050 is an orally active lead drug candidate with excellent safety and efficacy profiles confirmed in several in vivo experiments targeting fibrosis. Fibrosis is a very complex process by which continuing inflammation causes vital organs to lose their function as normal tissue is replaced by fibrotic scar tissue. The proof of concept data generated to date confirms our lead drug candidates’ anti-fibrotic activity in several key organs including the kidneys, the heart, the lungs and the liver.
Indications currently being pursued with PBI-4050:
Idiopathic Pulmonary Fibrosis:
Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, and ultimately fatal disease characterized by a progressive decline in lung function. It is a specific type of interstitial lung disease in which the small air sacs of the lung, the “alveoli,” gradually become replaced by fibrotic (scar) tissue and is the cause of worsening dyspnea (shortness of breath). IPF is usually associated with a poor prognosis. The term ‘idiopathic’ is used because the cause of pulmonary fibrosis is still unknown. IPF usually occurs in adult individuals of between 50 and 70 years of age, particularly those with a history of cigarette smoking, and affects men more often than women.
IPF affects about 130,000 people in the United States, with about 48,000 new cases diagnosed annually. Approximately 40,000 people die each year with IPF, a similar number of deaths to those due to breast cancer. The 5-year mortality rate for patients with IPF is estimated to range from 50% to 70%.
Currently completing a 12 weeks open-label, single-arm, exploratory Phase II study to evaluate the safety and tolerability of PBI-4050 in 40 patients suffering from IPF and to gather data on the effects of PBI-4050 on pulmonary function, disease progression and inflammatory/fibrotic markers. PBI-4050 has demonstrated early evidence of efficacy alone and in combination with one of the commercially approved drugs. In addition to demonstrating that PBI-4050 is safe and well tolerated in patients suffering from IPF, the objective of this study was to provide early evidence of clinical benefits of PBI-4050 treatment whether used alone or in addition to either nintedanib or pirfenidone. Forty patients are enrolled in the study in 6 sites across Canada. The Corporation has reported on the first 30 patients that have completed their 12 weeks of treatment.
The comparisons made between the results in this ProMetic study and the results of three other larger phase 3 studies undertaken by third parties (ie .ASCEND, INPULSIS-1 and INPULSIS-2) are only done to provide some guidance in terms of the potential clinical benefits of PBI-4050 for IPF patients. In the ASCEND and the two INPULSIS studies, IPF patients being treated with pirfenidone or nintedanib saw their Forced Vital Capacity (“FVC”) decline by approximately -25 ml to -30 ml after 13 weeks of treatment, whilst the FVC of those on placebo declined by -75 ml to -100 ml during the same period.
IPF patients in ProMetic’s ongoing clinical trial receiving PBI-4050 alone or PBI-4050 with one of the commercially available drugs (PBI-4050-Combo1) for 12 weeks have actually seen a slight improvement in their FVC (~ +10 ml).
Moreover, to date, none of the patients receiving PBI-4050 experienced a decline of ≥ 10% in FVC or death during the 12 weeks of treatment. In the phase 3 clinical trial ASCEND the authors reported that 7.5% of patients had a ≥10% decline in FVC or death after 13 weeks of treatment (5% on placebo and 2.5% on treatment).
Alström syndrome is a rare inherited autosomal recessive syndrome characterized by the onset of obesity in childhood or adolescence, Type 2 diabetes with severe insulin resistance, dyslipidemia, hypertension and severe multi-organ fibrosis, involving the liver, kidney and heart.
Alström syndrome is also characterized by a progressive loss of vision and hearing, a form of heart disease that enlarges and weakens the heart muscle (dilated cardiomyopathy), and short stature. This disorder can also cause serious or life-threatening medical problems involving the liver, kidneys, bladder, and lungs. Some individuals with Alström syndrome have a skin condition called acanthosis nigricans, which causes the skin in body folds and creases to become thick, dark, and velvety. The signs and symptoms of Alström syndrome vary in severity, and not all affected individuals have all of the characteristic features of the disorder.
Alström syndrome affects males and females in equal numbers. The exact incidence is unknown. Estimates have ranged from 1 in 10,000 to less than 1 in 1,000,000 individuals in the general population. Approximately 1200 affected individuals have been identified worldwide
PBI-4050 early efficacy results in a phase 2, open-label study demonstrated that the first five (5) patients (100%) who completed 12 weeks of treatment with PBI-4050 had a significant reduction of liver fibrosis, as measured by transient elastography (FibroScan®). This reduction was also sustained for the first patient, who continued to show reduced fibrosis after having completed 24 weeks of treatment. The initial efficacy results also demonstrate that those patients with the most elevated liver enzymes at baseline (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase) [ALP], had a significant reduction in all of these enzymes, to within normal ranges, after completing 4, 8 and 12 weeks of treatment with PBI-4050.
|Level of liver fibrosisat baseline||Fibroscan value at Baseline||Fibroscan value at Week 12||Fibroscan decrease from baseline (%)|
|Patient 1||Severe (F3)||9.9||7.1||- 28%|
|Patient 2||Significant (F2)||7.4||6.1||- 18%|
|Patient 3||Mild (F1)||6.1||4.5||- 26%|
|Patient 4||Significant (F2)||8.1||5.3||- 35%|
|Patient 5||Mild (F1)||5.1||3.1||- 39%|
The ongoing Alström syndrome phase 2 clinical trial is an open label, single arm and single center study investigating the safety, tolerability and efficacy of ProMetic’s small molecule lead compound PBI-4050 in a total of 20 patients. The trial is being performed at the specialty center for the care of UK patients with Alström syndrome at the Queen Elizabeth Hospital, Birmingham, UK. This center has recently published data showing that many of these patients show evidence of non-alcoholic fatty liver disease and advanced liver fibrosis at an early age, confirming previous publications showing a very high incidence of progression of NAFLD into liver cirrhosis with associated mortality in Alström patients.
Chronic Kidney Diseases/Diabetic Kidney Diseases:
Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. Professional guidelines classify the severity of CKD in five stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated. Stage 5 CKD is often called end-stage kidney disease, end-stage renal disease, or end-stage kidney failure, and is largely synonymous with the now outdated terms chronic renal failure or chronic kidney failure; and usually means the patient requires renal replacement therapy, which may involve a form of dialysis, but ideally constitutes a kidney transplant.
Twenty six million patients in the U.S. alone are diagnosed with chronic kidney diseases (“CKD”). Patients with severe CKD stages (3 and 4) suffer from a gradual and accelerated loss of their renal function (end stage renal disease or ESRD) leading to the need for maintenance dialysis or kidney transplant.
PBI-4050 has completed a randomized, double-blind, placebo-controlled, multi-dose phase Ib study to demonstrate the safety and tolerability of PBI-4050 and to determine the pharmacokinetic profile of PBI-4050 following multiple oral doses over 10 days in patients with stage 3b or 4 stable renal impairment. The trial was conducted in 8 patients with 6 patients receiving PBI-4050 and 2 patients receiving matching placebo. ProMetic anticipates filing an IND for a Phase II study in the first half of 2017.
Metabolic Syndrome and associated Type 2 Diabetes:
Metabolic syndrome is a major risk factor for cardiovascular disease and for Type 2 diabetes, and consists of the constellation of central (truncal) obesity, high blood triglycerides, low HDL (“good”) cholesterol, elevated blood pressure, and elevated blood glucose. Obesity is believed to cause a chronic inflammatory state, which leads to insulin resistance and so may in turn result in cardiovascular disease and/or Type 2 diabetes.
The International Diabetes Federation estimates that in 2013 there were 300 million diabetics world-wide, and that that number will increase to 600 million by the year 2035. The Centers for Disease Control estimates that 1 of 3 children born in the U.S. during the year 2000 will develop diabetes during their lifetime.
ProMetic has completed a Phase 2 clinical trial in patients with metabolic syndrome and type 2 diabetes. The Phase 2 trial has met its primary and secondary endpoints. In addition to safety and tolerability, the study was designed to evaluate the effect of PBI-4050 on metabolic syndrome parameters and on pro-inflammatory/fibrotic and diabetic biomarkers in blood and urine.
In this open label Phase 2 clinical trial, PBI-4050 (800 mg) was administered once daily to 24 patients for a period of 12 weeks. Ten of these patients were enrolled in an additional 12 weeks extension. PBI-4050 has been well tolerated with no serious drug related adverse events.
The fundamental physical criterion for the diagnosis of metabolic syndrome is waist circumference. The patients experienced a clinically and statistically significant reduction in waist circumference in 12 weeks, with a mean change of -1.5 cm (p = 0.009). A strong trend in weight and Body Mass Index (“BMI”) reduction was also observed (p = 0.06 and 0.07, respectively).
The pharmacological activity of PBI-4050 was confirmed through the clinically significant reduction in HbA1c between screening and Week 12. For instance, the 15 patients with a screening HbA1c ≥ 7.5 experienced a mean decrease of – 0.75% (p = 0.0004) while the 9 patients with a screening HbA1c ≥ 8.0% experienced a mean decrease of – 0.9% (p = 0.007). The 10 patients who participated in the study 12 week extension had a mean HbA1c of 7.7 at screening and experienced a reduction of – 0.8% at week 12 and this was maintained at week 24.
|Diabetes & Metabolic biomarkers in blood||Changes from baseline||P-value|
|Fasting insulin||– 19%||0.017|
|Fasting C-Peptide||- 11%||0.028|
Several biomarkers measured in blood or urine of patients and associated with a high incidence of cardiovascular complications and kidney injury when elevated in metabolic syndrome were significantly reduced by PBI-4050.
|Biomarkers for kidney (urine)||Changes from baseline||P-value|