Data for Promedior’s Idiopathic Pulmonary Fibrosis Drug PRM-151 Released

Promedior Inc., a clinical stage biotechnology company developing novel therapeutics for the treatment of fibrosis, has announced that retrospective quantitative imaging data from the company’s Phase 1b clinical trial of the drug PRM-151 for treatment of idiopathic pulmonary fibrosis (IPF), was presented in a poster at the 18th International Colloquium on Lung and Airway Fibrosis (ICLAF) , held Sept 20-24 at Mont Tremblant, Quebec — a small resort town located about one hour north of Montreal in the francophone region of Canada. This meeting brings together leaders, scientists, clinicians, fellows, students and patient advocates in lung fibrosis from around the world.

Despite its low profile in public consciousness, Fibrosis is quietly associated with an estimated 45 percent of U.S. deaths per year, including many of those attributed asthma, kidney disease, and congestive heart failure, which are only a sampling from among a broad class of more than 60 fibrotic diseases — painful, debilitating, chronic conditions for which neither cures nor U.S. Food and Drug Administration approved treatments currently exist.

The ICLAF colloquium was established more than 30 years ago by scientists and clinicians committed to enhance research in fibrosis and to improve care of patients with IPF. This year’s conference will present a wide range of top research in basic and clinical science, and organizers note that 2014 will be a very exciting year for the IPF community and the patients who suffer from this devastating disease, with everyone eagerly awaiting the results and impact of several crucial Phase 3 trials, which will hopefully result in worldwide approval and access to desperately needed IPF drugs.

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The Promedior data presented at the colloquium show that changes seen with structural and functional imaging of IPF patients’ lungs generally correlate with and appear complementary to pulmonary function tests. Both methods showed correlation with increases in Forced Vital Capacity (FVC) % predicted, normal lung, and lobar volumes in some subjects treated with PRM-151. In all placebo patients, decreases in both FVC % predicted and normal lung were observed, with decreased lobar volumes in some patients.

With a novel mechanism of action that is targeted to prevent and reverse fibrosis, PRM-151 has the potential to address the fundamental fibrotic pathology of IPF. Retrospective analyses of High Resolution CTs (HRCT) from the Phase 1b study assessed both volumetric quantification of interstitial lung abnormalities (ILA) and lobar volumes. The data support prospective use of these imaging techniques as biomarker endpoints to provide a more robust signal determination to support rapid development and require fewer patients in future clinical trials of PRM-151 in IPF.

The poster presentation at ICLAF entitled “Structural and Functional Quantitative Imaging Techniques are Complimentary in Retrospective Analysis of PRM-151 Data in Idiopathic Pulmonary Fibrosis (IPF)”, was coauthored by B. van den Blink, MD, PhD (Erasmus MC, Rotterdam, The Netherlands), J Burggraaf, MD, PhD (CHDR, Leiden, The Netherlands), L.D. Morrison, MD (Duke University Hospital, Durham, NC, USA), L.C. Ginns, MD (Massachusetts General Hospital, Boston, MA, USA), M.S. Wijsenbeek, MD, PhD (Erasmus MC, Rotterdam, The Netherlands), M. Moerland, PhD (CHDR, Leiden, The Netherlands), M.R. Dillingh, MSc (CHDR, Leiden, The Netherlands), B. Bartholmai, MD (Mayo Clinic, Rochester, MN, USA), R. Chamberlain, PhD (Imbio, Minneapolis, MN, USA), W. Vos, PhD (FluidDA, Kontich, Belgium and New Brunswick, NJ, USA), L. Nuyttens, MSc (FluidDA, Kontich, Belgium and New Brunswick, NJ, USA), J. Hanrahan (Grayfield Consulting, MA) and E.G. Trehu, MD (Promedior, Lexington, MA, USA).

The Phase 1b clinical trial was a randomized, double-blind, placebo-controlled study in 21 patients with IPF. In the study, PRM-151 doses of 1, 5 and 10 mg/kg or placebo were administered intravenously on days 1, 3, 5, 8 and 15. Patients were followed for 57 days after receiving their first dose. The study’s primary endpoint was safety and tolerability, and PRM-151 was shown to be generally safe and well tolerated across all study participants, with no serious adverse events. Additionally, the clinical study measured exploratory clinical endpoints, including Forced Vital Capacity (FVC), Diffusion Capacity of the Lung for Carbon Monoxide (DLCO), six minute walk test, quality of life, and several biomarkers of fibrosis.

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Earlier this year, Promedior, Inc. announced positive preliminary data from its Phase 2 trial of PRM-151 in patients with myelofibrosis which demonstrated biologic activity with improvements across clinically relevant measures, including bone marrow fibrosis, hemoglobin, platelets, spleen, and symptoms. Clinical data showed improvements in four independent treatment groups of myelofibrosis patients who received PRM-151 weekly or monthly, either as a single agent or in patients with no further improvements on a stable dose of ruxolitinib1. Importantly, PRM-151 demonstrated safety and tolerability both alone and in combination with ruxolitinib, with no evidence of the myelosuppression commonly observed with other treatments. Study results were presented at the American Society for Clinical Oncology (ASCO) 2014 Annual Meeting in June.

“These early clinical data with PRM-151 in patients with myelofibrosis are encouraging, and demonstrate the potential of the compounds novel mechanism of action,” says Srdan Verstovsek, MD, PhD, Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and Principal Investigator for this Phase 2 trial, in a Promedior release. “The improvements seen in patients who have either progressed on JAK inhibitors or were deriving no further benefit from ruxolitinib speaks to the need for new therapies that target fundamental mechanisms of the disease.”

“These findings are very promising and we are particularly excited to see improvements in bone marrow pathology in myelofibrosis patients receiving PRM-151. We believe PRM-151’s ability to precisely target the fundamental fibrotic pathology validates its broad potential to treat and reverse fibrosis in a wide range of fibrotic diseases,” says Suzanne L. Bruhn, PhD, President and Chief Executive Officer of Promedior. “We will continue to work to move as quickly as possible to bring PRM-151 forward as a potential new treatment option for patients with fibrotic diseases which have few, if any, treatment options today.”

Promedior reports that the preliminary Phase 2 data for PRM-151 were presented for 27 patients with myelofibrosis, 18 of whom completed 24 weeks of therapy. PRM-151 demonstrated a 50% reduction in symptoms according to the MPN-SAF2 Total Symptom Score in 7 patients, 5 of which have persisted for 12 weeks and are therefore confirmed IWG-MRT3 Clinical Improvement symptom responses; 5 reductions in bone marrow fibrosis by 1 grade, with 2 of 3 patients confirmed 12 weeks later and 2 patients pending confirmatory biopsy; a 20% reduction in spleen volume reduction in 5 patients with one 50% reduction lasting 8 weeks; and improvements in hemoglobin and platelets. Each treatment group demonstrated improvements that met the pre-specified efficacy criteria for further exploration of PRM-151 in the second stage of this adaptive Phase 2 trial. Fifteen out of 18 patients who have completed the 24 week study are continuing treatment in a study extension.

In this study, PRM-151 was safe and well tolerated on weekly and monthly dosing schedules, both alone and in combination with ruxolitinib, with no evidence of myelosuppression. Most adverse events observed in the study were Grade 1 or 2 and considered unrelated to PRM-151. Overall, there were 14 severe adverse events (SAEs) in 5 study patients, including 3 deaths, 2 from pneumonia and 1 from progressive multi-organ failure. Other SAEs were abdominal pain, bone marrow biopsy site hematoma, sialadenitis, gastroenteritis and respiratory syncytial virus. The Company expects to report the complete first stage results of this ongoing Phase 2 study by the end of 2014.

This Phase 2 trial is a multi-center, two stage, adaptive design study to determine the efficacy and safety of PRM-151 as a single agent or added to a stable dose of ruxolitinib in patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), or Post-Essential Thrombocythemia MF (post-ET MF). 27 patients were enrolled in the first stage of the study; up to 80 additional patients will be enrolled in the second stage.

The poster from ASCO, which was presented by the PRM-151 Phase 2 study Principal Investigator Srdan Verstovsek, is available on Promedior’s website at http://www.promedior.com/pdfs/posters/PRM-151-myelofibrosis-ASCO-2014.html

Participating investigators in the PRM-151 Phase 2 study include Srdan Verstovsek, MD, PhD (University of Texas MD Anderson Cancer Center, Principal Investigator for this Phase 2 trial), Jason Gotlib, MD (Stanford University), Ruben Mesa, MD (Mayo Clinic, Scottsdale), Vikas Gupta, MD (Princess Margaret Cancer Centre), John Mascarenhas, MD (Icahn School of Medicine at Mt. Sinai Hospital), Ronald Hoffman, MD (Icahn School of Medicine at Mt. Sinai Hospital), Ellen Ritchie, MD (Weill Cornell Medical College of Cornell University), Richard Silver, MD (Weill Cornell Medical College of Cornell University), and Lynda Foltz, MD (University of British Columbia).

PRM-151 has Orphan Designation in the US and EU for treatment of IPF and in the US for the treatment of myelofibrosis — a type of myeloproliferative neoplasm — a serious, life-limiting cancer that is characterized by fibrosis of the bone marrow. Replacement of the bone marrow by scar tissue prevents the normal production of blood cells, leading to anemia, fatigue, and increased risk of bleeding and infection. Production of blood cells shifts to the spleen and liver (extramedullary hematopoiesis), which become enlarged, causing severe discomfort, inability to eat, and weakness. Symptomatic myelofibrosis affects approximately 18,000 people per year in the US, with a median age of 61-66.4 The only potentially curative treatment is allogeneic bone marrow transplant, which results in reversal of fibrosis and all symptoms, but is a realistic option for only a small number of patients. Other currently available therapies address the symptoms, but have minimal if any impact on the underlying fibrosis.

PRM-151

Promedior’s lead product candidate PRM-151 is a recombinant form of human Pentraxin-2 (PTX-2) is a recombinant form of an endogenous human protein that is specifically active at the site of tissue damage. PRM-151 is an agonist that acts as a monocyte/macrophage differentiation factor to prevent and potentially reverse fibrosis. PRM-151 has shown broad anti-fibrotic activity in multiple preclinical models of fibrotic disease, including pulmonary fibrosis, acute and chronic nephropathy, liver fibrosis, and age-related macular degeneration. By acting as a master regulator upstream in the fibrosis cascade, Pentraxin-2 therapeutics harness the healing power of the innate immune system and open up new opportunities to treat a wide range of systemic fibrotic diseases for which there are no approved therapies.

Image caption: Pentraxin-2 therapeutics act as a master regulator of the complex fibrosis cascade, promoting healing and preventing disease progression – Image Courtesy Promedior

Phase 1a and 1b clinical studies in healthy subjects and IPF patients have demonstrated that PRM-151 was well tolerated. Additionally, a Phase 1b study in patients with IPF showed encouraging results in exploratory efficacy endpoints, which were presented in an oral session at the 2013 Annual Meeting of the American Thoracic Society. Recent clinical data in myelofibrosis demonstrated the potential of this immuno-oncology approach in fibrotic cancers.

Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a serious, progressive, irreversible, unpredictable and ultimately fatal lung disease characterized by fibrosis and scarring of the lung tissue. Replacement of normal lung tissue by scar tissue results in restriction in the ability to fill the lungs with air and decreased transfer of oxygen from inhaled air into the bloodstream. This decreased oxygen transfer results in lower oxygen delivery to the brain and other organs, and produces symptoms of shortness of breath, particularly with exertion; chronic, dry, hacking cough; fatigue and weakness, chest discomfort, loss of appetite and rapid weight loss.

IPF’s cause is not known (viz. “idiopathic”) and it inevitably leads to worsening lung function and exercise tolerance, and shortness of breath. Every IPF patient follows a different and unpredictable course and it is not possible to predict if a patient will progress slowly or rapidly, or when the rate of decline may change. Periods of transient clinical stability in IPF, should they occur, inevitably give way to continued disease progression.

IPF is a uniformly fatal disease, with the median estimated survival time from diagnosis two to five years, with a five-year survival rate of approximately 20-40 percent, which makes IPF more rapidly lethal than many cancers, including breast, ovarian, colorectal, pancreatic, lung, and liver cancers. IPF typically occurs in patients over the age of 50, and is more common in men than in women.

Once considered relatively rare, IPF is now recognized as the most common interstitial lung disease (interstitial refers to the tissue surrounding the alveoli). An estimated 50,000-70,000 people are living with IPF in the United States, and approximately 15,000-20,000 new cases are diagnosed annually.It is estimated that between 80,000 and 110,000 patients living with IPF in all of Europe and between 5,000 to 8,000 patients living with IPF in Canada.

Promedior is a Lexington, Massachhusetts based clinical stage biotechnology company pioneering development of targeted therapeutics to treat diseases involving fibrosis — a harmful process that occurs in many diseases, when normal healthy tissue is replaced with excessive scar tissue, compromising function and ultimately leading to organ failure. Promedior’s proprietary platform is based upon Pentraxin-2, an endogenous human protein that is specifically active at the site of tissue damage and, with an anti-fibrotic immunotherapy approach, works to prevent and reverse fibrosis.

Two biologists affiliated with Texas A&M University, Richard Gomer and Darrell Pilling, have collaborated in recent years on several SAP-related advances, from establishing  Promedior Inc. in 2006, and to celebrating its promising preliminary results in early clinical trials involving PRM-151.

Photo Caption: After initially discovering they had similar interests during lunch at a 2001 developmental biology conference in England, Texas A&M biologists Darrell Pilling (left) and Richard Gomer (right) teamed up to identify the blood protein serum amyloid P (SAP) as the key to controlling routine tissue-related processes from scarring to healing. The two have since collaborated on several SAP-related advances, from co-founding a company, Promedior Inc., in 2006 to celebrating its recent preliminary results in early clinical trials involving PRM-151, a recombinant form of SAP – Photo Courtesy Texas A&M University.

“Most of these fibrotic diseases can be fatal, and collectively, they kill more people than cancer,” Dr. Gomer notes. “They are associated with about 45 percent of all deaths in the U.S.”

“Scar tissue forms,” Dr. Gomer explains in a TAMU release, “as a normal and necessary response to wounds. In fibrotic diseases, however, this otherwise routine reaction goes haywire, creating extra, and often harmful, scar tissue around vital organs, such as the heart and lungs.”

Armed with their combined knowledge about biomedical science and related processes in the human body, Drs. Gomer and Pilling set out to find the cause by focusing on one of the body’s first lines of defense, white blood cells. They began with an initial experiment involving two groups of white blood cells, one in the presence of blood serum and one in a culture without.

In initial studies at Rice University in 2007, Drs. Gomer and Pilling noticed that SAP inhibited the differentiation of blood cells to fibrotic tissue. They theorized that if getting rid of the SAP in a wound were possible, more scar tissue cells would be available, thus enabling the wound to heal faster.

Dr. Gomer in lab – Photo Courtesy Texas A&M University

Dr. Gomer recalls they were fascinated by what they witnessed. Fibrocytes, the long, skinny cells responsible for the formation of scar tissue, quickly developed in the second group. None, however, developed in the group containing serum. By all appearances, something within the serum, later determined to be SAP, was inhibiting fibrocyte activity. They theorized that if getting rid of the SAP in a wound was possible, more scar tissue cells would be available, thus enabling the wound to heal faster.

To test their theory, the research collaborators devised an SAP treatment for lab mice that were given an irritant to cause fibrosis in the lungs. When those tests indicated that SAP treatment inhibited fibrosis, Gomer and Pilling realized they were in possession of a first-of-its-kind, groundbreaking medicinal discovery.

“What seemed to be happening is that the scar tissue cells go away,” Gomer said. “We don’t know if they die or just round up and leave. It looks like if you can prevent the new scar tissue formation, the old scar tissue will go away, and you can actually reverse fibrosis if it’s something you catch early on, which doctors generally do.”

“As it turns out, SAP binds like crazy to a sugar polymer made by seaweed thats used as a thickener in all kinds of stuff — chocolate milk, ice cream, lipstick, deodorant,” Dr. Gomer explains. “There are certain kinds of this agar made by seaweed that you can buy that will bind to SAP. So we made bandages of this seaweed polymer that would gobble up the SAP, resulting in faster formation of scar tissue.”

Promedior has successfully advanced its lead therapeutic candidate in human clinical trials, and is initially focused on rare fibrotic diseases, including myelofibrosis and idiopathic pulmonary fibrosis (IPF). Promedior is backed by leading global healthcare venture investors, has a significant intellectual property estate relating to the discoveries and applications of Pentraxin-2 therapeutics and is led by an experienced management team. For additional information about Promedior, visit:
http://www.promedior.com

Sources:
Promedior Inc.
Texas A&M University
American Society for Clinical Oncology (ASCO) 2014 Annual Meeting
18th International Colloquium on Lung and Airway Fibrosis (ICLAF)

Image Credits:
Promedior Inc.
Texas A&M University