The Small Molecule Therapeutics Segment is a small-molecule drug development business, with a pipeline of product candidates leveraging the discovery of two receptors involved in the regulation of the healing process. PBI-4050, the small molecules lead drug candidate has demonstrated excellent safety, tolerability and efficacy profiles in a large number of animal models of fibrosis affecting different organs, including the lung, liver, heart, kidney, and pancreas. The effects of PBI-4050 demonstrated in animal models have been replicated in Phase 2 clinical studies in IPF, in metabolic syndrome with type 2 diabetes and in Alström syndrome. PBI-4050 is entering pivotal placebo-controlled phase 3 clinical trials for the treatment of IPF.
The Plasma-derived Therapeutics Segment includes our plasma-derived therapeutics platform, which enables the development of our pipeline of biopharmaceutical candidates. This is achieved by leveraging our proprietary affinity technology, which enables a highly-efficient extraction and purification process of therapeutic proteins from human plasma. The Corporation’s primary focus is to develop plasma-derived therapeutics targeting unmet medical conditions and rare diseases in both established and emerging markets.
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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.
Acute exacerbation of IPF (AE-IPF) is defined as a sudden acceleration of the disease or an idiopathic acute injury superimposed on diseased lung tissue that leads to a significant decline in lung function. An AE-IPF is associated with a mortality rate as high as 85%, with mean survival periods between 3 to 13 days.
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%.
Prometic has announced positive results from its completed open label Phase 2 clinical trial in subjects suffering from idiopathic pulmonary fibrosis (“IPF”). In addition to demonstrating that PBI-4050 is safe and very well tolerated, an objective of this study was to seek early evidence of a clinical benefit with PBI-4050 treatment, whether administered alone or in addition to either of the drugs approved for the treatment of IPF, nintedanib or pirfenidone.
A total of 40 subjects were enrolled in the study conducted in 6 sites across Canada and all have completed the 12 weeks of treatment; 9 subjects received PBI-4050 alone, 16 received PBI-4050 & nintedanib and 15 received PBI-4050 & pirfenidone. The baseline characteristics of the subjects enrolled in this study were similar to those enrolled in prior IPF randomized controlled studies conducted by other pharmaceutical companies, namely ASCEND and INPULSIS.
As was demonstrated in these previously mentioned large clinical trials, IPF subjects typically experience a progressive decline in respiratory function. In contrast, in the ProMetic clinical study, the respiratory function of the subjects, measured as the forced vital capacity (FVC (ml)), remained stable after 12 weeks of treatment, in subjects treated with PBI-4050 alone and in those receiving PBI-4050 combined with nintedanib for the treatment of IPF and was superior to that of those subjects treated with PBI-4050 combined with pirfenidone for the treatment of IPF.
For further information on clinical trials, please click here.
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.
The on-going AS study is an open-label, single-arm, phase 2 clinical trial in which the patients are treated with PBI-4050 (800 mg) once daily. Each patient is evaluated against their respective baseline and against their respective historical disease progression trend whenever available, given the severity of their medical conditions. The clinical study has enrolled 12 subjects.
To date, the subjects have received 52 weeks of treatment with PBI-4050. PBI-4050’s safety and tolerability has been confirmed over this extended period. A brief summary of the most significant findings is presented below.
Fibroscan results from the 10 subjects who received at least 36 weeks of treatment showed a statistically significant improvement in the measure of liver stiffness, from a mean of 10.2 kPa at baseline to a mean of 8.1 kPa at last measurement, an absolute decrease of 2.1 kPa (p = 0.0219, 95% CI -3.52, -0.46). Fibroscan is a non-invasive technique for clinical assessment of liver fibrosis with a high degree of accuracy and reproducibility, especially in patients with established fibrosis (≥ F2) (Cassinotto 2016). FibroScan® measurements for all patients were carried out by a single, experienced operator. To ensure test reliability, a minimum of 10 valid readings were taken per patient, with a required success rate of at least 60% and an interquartile range of <=30% of the median value.
Liver MRI data also indicated a mean reduction of -11% in the T1-corrected score between baseline and last available measurement (p=0.0195, 95% CI: -92.3, -9.8), which supports an improvement of liver fibrosis.
In addition to the preliminary evidence of efficacy observed on liver fibrosis presented above, analysis of the interim cardiac MRI data indicates a reduction of cardiac fibrosis in each patient after initiation of treatment with PBI-4050 (p<0.001).
A major reduction of key urine biomarkers of ongoing kidney injury in the 12 subjects for whom Week 24 results are available was also observed. Finally, positive effects on other parameters of the liver and the fat tissue have also been observed and will be presented at forthcoming scientific conferences.
The Corporation also recently published summary liver and fat biopsies analysis data. Dysfunctional adipose tissue involving enlargement of fat cells, is known to increase cardiometabolic risk. In AS patients, fat tissue is characterized with significant enlargement and coalescence of adipocytes forming giant vesicular vacuolation/steatosis. After 24 weeks of treatment with PBI-4050, adipocytes were more distinct, were smaller in size and no coalescence was observed.
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.
For further information on clinical trials, please click here.
Plasminogen is a naturally occurring protein that is synthesized by the liver and circulates in the blood. Activated plasminogen, plasmin, is a fundamental component of the fibrinolytic system and is the main enzyme involved in the lysis of blood clots and clearance of extravasated fibrin. Plasminogen is therefore vital in wound healing, cell migration, tissue remodelling, angiogenesis and embryogenesis.
The incidence of Type-1 plasminogen deficiency is approximately 1.6 / 1,000,000 people, with roughly 5,000 - 10,000 patients worldwide.
In a phase 2/3 clinical trial for the treatment of congenital plasminogen deficiency, Ryplazim™ (plasminogen) met its primary and secondary endpoints following the intravenous administration of Ryplazim™ (plasminogen) to patients. In addition to being well tolerated and without any drug related serious adverse events, our Ryplazim™ (plasminogen) treatment achieved a 100% success rate of its primary end point, namely, a targeted increase in the blood plasma concentration level of plasminogen as a surrogate target. Moreover, all patients who had active visible lesions when enrolled in the trial had complete healing of their lesions within weeks of treatment, a 100% patient response rate for this secondary end point.
We disclosed new long term clinical data in July 2017 from its pivotal phase 2/3 trial of RyplazimTM (plasminogen) regarding the additional 36 weeks treatment period. The new data demonstrated that its plasminogen treatment prevented the recurrence of lesions in the 10 patients treated with Ryplazim TM (plasminogen) for a total of 48 weeks.
The current BLA filing includes the clinical data on 10 patients with 12 weeks of data for an accelerated regulatory pathway. Since filing the current BLA, Prometic has accumulated additional clinical data encompassing more than 3,200 infusions of RYPLAZIM™ (plasminogen) over treatment periods exceeding 48 weeks during which similar clinical activity and tolerability profiles, as previously reported, were observed. The original guidance from the FDA was for Prometic to submit such long-term clinical data in a supplemental BLA in order to secure full licensure in 2019. Full licensure would provide for the long-term efficacy and safety data to be included in the prescribing information of RYPLAZIM™ (plasminogen) which would further support Prometic’s claims of the strong health economics benefit associated with the use of RYPLAZIM™ (plasminogen). The company continues to supply RYPLAZIM™, to those patients enrolled in the original clinical trials.
The FDA’s review of the BLA raised no issues regarding the clinical data for the accelerated approval. The FDA has, however, identified the need for Prometic to make a number of changes in the Chemistry, Manufacturing and Controls (CMC) section of its BLA. These changes require the implementation and validation of additional analytical assays and “in-process controls” in the manufacturing process of RYPLAZIM™ (plasminogen). It will be necessary to manufacture additional RYPLAZIM™ (plasminogen) lots to support the implementation and validation of these process changes.
The FDA requested that such CMC data be submitted as an amendment to the current BLA and has invited Prometic to also submit the long-term (48-week) clinical data at the same time instead of through the originally agreed upon supplemental BLA process. This will allow the FDA to consider granting full-licensure under the current BLA. If granted, this is expected to allow a faster sales ramp-up from launch than could have been achieved had provisional licensure been obtained by the current PDUFA date.
The FDA indicated that the submission of the new CMC data will not impact the previously granted designations, including the Priority Review Status, the Orphan Drug Designation and the Rare Pediatric Disease Designation for RYPLAZIM™ (plasminogen) for the treatment of congenital plasminogen deficiency.
The Company continues to interact with the FDA regarding the filing of its BLA amendment. It has also engaged external consultants to assist with this, and will provide further updates as to timelines in due course.
‘Acquired plasminogen deficiencies’ occur in some medical conditions such as Acute Respiratory Distress Syndrome (ARDS) which affects 190,000 Americans every year. Patients experience an accumulation of fibrin or fibrous material in the lungs. Preclinical models have demonstrated that treatment with plasminogen helps overcome the accumulation of fibrin.
Prometic plans to initiate clinical programs in 2018 in North America for the potential use of Ryplazim™ (plasminogen) for the treatment of acute exacerbations in patients with ARDS or Idiopathic Pulmonary Fibrosis (IPF). Ryplazim™ (plasminogen) was granted Orphan Drug and Fast Track Designations by the FDA for the treatment of IPF.
Intravenous immunoglobulin is a preparation of antibodies purified from plasma donations from healthy individuals. It is indicated for the maintenance treatment of patients with primary immunodeficiencies (PID), including common variable immunodeficiency, X-linked agammaglobulinemia and severe combined immunodeficiency. It is also indicated for the treatment of immune thrombocytopenic purpura (ITP) and for many other autoimmune diseases, including Guillain-Barré syndrome, Kawasaki disease.
According to recent market data, Canada is ranked as the second country in the world after the United States for the average consumption of IVIG (measured in kilograms per million people), with sales exceeding $600 million in 2016. The global IVIG market CAGR is expected to reach 5-6% between 2016 and 2025 with Canada having one of the lowest IVIG self-sufficiency ratios (i.e. less than 20%).
Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 100 recognized PIDDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, autoinflammatory disorders, tumors, and disorders of various organs. There are currently no cures for these conditions; treatment is palliative and consists of managing infections and boosting the immune system
IVIG is the second biopharmaceutical arising from the plasma-derived therapeutics platform that is expected to be launched commercially, if approved. Currently being studied in a non-inferiority pivotal phase 3 open label, single arm, two-cohort multicenter clinical trial that is investigating the safety, tolerability, efficacy and pharmacokinetics of our plasma purified IVIG in a total of 75 patients suffering from PIDD, including 50 adults (cohort 1) and 25 children (cohort 2). The non-inferiority phase 3 clinical trial for IVIG in adults suffering from PIDD was completed in Q1 of 2018, meeting both the clinical primary and secondary endpoints, Prometic’s IVIG demonstrating comparable safety and efficacy data to existing commercial IVIG products without any significant drug related safety issues. The trial involving the pediatric cohort is expected to be completed in Q1 2019.
The primary end point is the rate of clinically documented serious bacterial infections (SBIs), defined as bacterial pneumonia, bacteremia and septicemia, osteomyelitis/septic arthritis, bacterial meningitis or visceral abscess. The FDA Guidance for Industry on studies required to support marketing of IGIV states: “…a statistical demonstration of a serious infection rate per person-year less than 1.0 is adequate to provide substantial evidence of efficacy”. Since there were no SBIs observed during the study, Prometic IGIV 10% met this requirement.
Secondary endpoints including episodes of fever (≥100.4°F), number of missed days, number of days of hospitalization due to infection, number of days on antibiotics, number of infections other than SBI, and trough IgG level were comparable between Prometic’s IGIV and commercial drugs. Only 4.94 days/subject/year were lost from work with Prometic IGIV 10%, which was significantly less than the rate observed while on commercial product.
For further information on clinical trials, please click here.
Other Products in Development
NAFLD is a condition defined by excessive fat accumulation in the form of triglycerides (steatosis) in the liver. A subgroup of NAFLD patients displays liver cell injury and inflammation in addition to excessive fat (steatohepatitis). The latter condition, designated NASH, is virtually indistinguishable histologically from alcoholic steatohepatitis (ASH).
Clinical activity observed on the kidney and liver of Alstrom patients supports the potential expansion of our clinical program in NASH. Such programs may be pursued with PBI-4050 and/or with follow-on analogues such as PBI-4547 and PBI-4425. These two drug candidates are amongst several analogues that have demonstrated similar or superior performance to PBI-4050 in preclinical models. This portfolio of follow-on analogues provides Prometic with the opportunity to specifically target specific indications such as NASH or Scleroderma with these two drug candidates and expand our commercial and partnering opportunities.
The manufacturing processes for both PBI-4547 and PBI-4425 have been scaled up to enable the commencement of their respective clinical programs in 2018.
Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot. Wound healing is an innate mechanism of action that works reliably most of the time. A key feature of wound healing is stepwise repair of lost extracellular matrix (ECM) that forms the largest component of the dermal skin layer. But in some cases, certain disorders or physiological insult disturbs the wound healing process. Diabetes mellitus is one such metabolic disorder that impedes the normal steps of the wound healing process. Many studies show a prolonged inflammatory phase in diabetic wounds, which causes a delay in the formation of mature granulation tissue and a parallel reduction in wound tensile strength.
Plasminogen is a naturally occurring protein that is synthesized by the liver and circulates in the blood. Activated plasminogen, plasmin, is a fundamental component of the fibrinolytic system and is the main enzyme involved in the lysis of blood clots and clearance of extravasated fibrin. Plasminogen is therefore vital in wound healing, cell migration, tissue remodeling, angiogenesis and embryogenesis.
According to the American Diabetes Association, the annual cost of diabetes, which affects 22.3 million people in the U.S., was $245 billion in 2012: $176 billion in excess health care expenditures and $69 billion in reduced workforce productivity. While much of the excess health care cost is attributable to treatment of diabetes itself, a substantial amount of the cost differential arises via treatment of chronic complications such as those related to the heart, kidneys, and nervous system.
One common complication of diabetes is the development of foot ulcers. Historically, foot ulcers have been estimated to affect 1–4% of patients with diabetes annually and as many as 25% of the patients with diabetes over their lifetimes. More recently, Margolis et al. have estimated that the annual incidence of foot ulcers among patients with diabetes may be as high as 6%.
The Phase 2 clinical trial is a prospective, dose escalation study of the safety, feasibility and initial efficacy of subcutaneous plasminogen for the treatment of DFU in 20 adult subjects. The study will be conducted in one study center in Sweden, under the supervision of Dr. Jan Apelqvist, an expert in the field of diabetic foot ulcers and hard to treat wounds from the Department of Endocrinology, Division of Clinical Sciences at Skane University Hospital in Malmö, Sweden.
A tympanic membrane perforation is a hole in the eardrum, which can result from ear infections, injury, and previous surgery such as ventilation tube placement.
It is estimated that as many as 70,000 children in the U.S. alone are diagnosed with chronic tympanic membrane perforations every year in the U.S
The chronic TMP clinical trial is a dose escalation, randomized, placebo-controlled study designed to investigate the safety, feasibility and initial efficacy of local injections of a novel and proprietary plasminogen formulation for the treatment of chronic tympanic membrane perforation. Up to 33 adult patients are expected to be enrolled. The study will be conducted at a single center in Sweden, under the supervision of Dr. Cecilia Engmér Berglin, MD, PhD from the Department of Otorhinolaryngology at Karolinska University Hospital in Stockholm, Sweden. The Karolinska University Hospital is the second largest ear/nose/throat center in the world.
Necrotizing enterocolitis (NEC) is a devastating inflammatory bowel condition that affects predominantly premature infants. NEC can ultimately destroy the wall of the bowel (intestine) and lead to perforation of the intestine and spillage of stool into the infant’s abdomen, which can result in an overwhelming infection and death. The cause of NEC is not well understood but appears to involve bacteria, injury to the bowel lining, inadequate oxygen supply to the bowel, and an abnormal immune response
Overall, NEC affects an estimated 8,000-12,000 live births each year in the USA. The disease has been reported to affect about 11 percent of very low birthweight infants born before 29 weeks of age. Mortality rates are high and range from about 15% to 30%.
NEC is the most commonly acquired gastrointestinal disease diagnosed in premature neonates and is one of the leading causes of death in neonatal intensive care units. The economic cost of NEC is high, accounting for approximately 19% of neonatal expenditures and an estimated $5 billion per year for hospitalizations in the United States alone.
Prometic’s IAIP for the treatment of NEC has been granted rare pediatric designation by the FDA which may make it eligible to receive a Priority Review Voucher (PRV) upon regulatory approval by the FDA. IAIP for the treatment of NEC has also been granted Fast Track status by the FDA and has been granted Orphan Drug designation by the FDA.
IaIp is the third biopharmaceutical that we are planning to launch commercially, if approved. It is currently in the pre-clinical development phase and the intent is to file an Investigational New Drug (IND) with the FDA in 2019.