Two Texas A&M University scientists and the biotechnology company they co-founded report encouraging progress in the fight against fibrotic disease.
Fibrosis is a harmful process that occurs with many diseases, and in which normal healthy tissue is replaced with scar tissue, compromising function and ultimately leading to organ failure. 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 to 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.
Thanks to the pioneering Texas A&M University scientists, however, relief may soon be in sight, a decade after their first identifying serum amyloid P (SAP) as a key protein in human blood that controls routine tissue-related processes from scarring to healing,
TAMU biologists Richard Gomer and Darrell Pilling have collaborated in recent years on several SAP-related advances, from establishing the biotech startup Promedior Inc. in 2006, to celebrating its promising preliminary results in early clinical trials involving PRM-151, a recombinant form of SAP.
“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 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 that is 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 is a clinical-stage biotechnology company pioneering the development of targeted therapeutics to treat diseases involving fibrosis. The company’s proprietary platform is based upon Pentraxin-2, an endogenous human protein that is a monocyte/macrophage differentiation factor specifically active at the site of tissue damage and works as an agonist with the potential to both prevent and reverse fibrosis.
Promedior’s lead product candidate is a recombinant form of human Pentraxin-2 called PRM-151, a recombinant form of an endogenous human protein, Pentraxin-2 (PTX-2), 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.
The company reports that 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.
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. PRM-151 has been shown to be generally safe and well-tolerated in healthy volunteers and in idiopathic pulmonary fibrosis (IPF) patients, with some encouraging exploratory efficacy signals seen in IPF. Clinical development is continuing in IPF as well as in myelofibrosis, currently in a Phase 2 study.
Dr. Gomer notes that in a recent 24-week study of 27 patients with myelofibrosis — a life-threatening scarring of the bone marrow — seven of the patients experienced a 50 percent reduction of symptoms with PRM-151, while five experienced a reduction in fibrosis. The results, initially revealed by Promedior at the June 2 2014 annual meeting of the American Society of Clinical Oncology in Chicago, have since been presented at additional conferences and symposia.
“More trials are definitely in the future,” Dr. Gomer says. “As for which of the 62 fibrotic diseases will be involved in the next trial, that’s a complicated business decision that depends on potential partners, among other factors.”
According to a TAMU profile, the origins of Dr. Gomer and Dr. Pilling’s breakthrough work in fibrosing disease therapy unfolded on an international stage, albeit a seemingly inconsequential one — a lunch table in a crowded cafeteria in England in 2001. During the interlude of a developmental biology conference, the two scientists — Richard Gomer, then a biochemist at Rice University, and Darrell Pilling, a British immunobiologist — discovered they had similar interests and agreed to collaborate on some future protein identification work.
“Unexpectedly, we ended up finding a human blood protein that looked like it might be a therapeutic for fibrosis,” Dr. Gomer explains in a TAMU Impact article.
Faced with the prospect of being able to save thousands of lives, Dr. Gomer says he reevaluated his professional priorities, making SAP his primary focus. In the process, he and Pilling both joined the Texas A&M Department of Biology shortly after co-founding Promedior to fast-track technologies and viable treatment options capable of halting or even eliminating the progression of fibrosis and, as a result, the future of other fibrotic diseases awaiting clinical trials and potential treatments.
You can watch an interview with Dr. Gomer and Dr. Pilling about their research and its life-changing potential on YouTube:
Dr. Gomer’s lab at TAMU is working on two areas of biomedicine. First, studying how the sizes of tissues and tumors are regulated, and how this can be manipulated for therapeutic purposes. As a model system, the researchers are using the simple eukaryote Dictyostelium discoideum, which allows them to combine techniques such as biochemistry, genetics, computer modeling, and cell biology to study tissue size regulation. They report having found that a secreted protein is the signal in a negative feedback loop that inhibits Dictyostelium cell proliferation, and they are now looking into the signal transduction pathway in order to understand similar mechanisms in the human biology.
Second, the team has found that a human blood protein called Serum Amyloid P (SAP) regulates a key step in the formation of scar tissue as well as the formation of the scar-like lesions in fibrosing diseases, like congestive heart failure, pulmonary fibrosis, and similar diseases. Both researchers are studying this mechanism, while also working in tandem with two biotech companies to develop both a new wound-healing material as well as a therapy for treating fibrosing diseases, both based on manipulating SAP levels.
“This all started with very basic research,” Dr. Gomer says. “The punchline is that this work didn’t come from deliberately trying to find a therapeutic. We probably never would have found one if that had been the case.”
Among the diseases that Gomer and Pilling are targeting is Myelofibrosis (MF), which is a type of myeloproliferative neoplasm. It is 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. At present, the only potentially curative treatment for the disease is an allogeneic bone marrow transplant, which has been shown to reverse fibrosis and all symptoms in the disease, but is an option for only a small number of patients who have Myelofibrosis. Other currently available therapies on the market address the symptoms of the disease, but have minimal, if any, impact on the underlying cause of the fibrosis.
At the end of May, Promedior, Inc. announced positive preliminary data from its Phase 2 trial of its PRM-151 anti-fibrotic immunotherapy in patients with myelofibrosis, which demonstrated biologic activity with improvements across clinically relevant measures, including bone marrow fibrosis, hemoglobin, platelets, spleen, and symptoms. The company reports that clinical data revealed improvements in 4 independent treatment groups of patients with myelofibrosis who received the experimental PRM-151 weekly or monthly, either in the form of a single agent or in patients with no further improvements on a stable dose of ruxolitinib1. Importantly, PRM-151 also demonstrated safety and tolerability both alone and in combination with ruxolitinib, with no evidence of the myelosuppression commonly observed with other treatments.
“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 Dr. 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. “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-151s ability to precisely target the fundamental fibrotic pathology validates its broad potential to treat and reverse fibrosis in a wide range of fibrotic diseases, comments Dr. 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.
The preliminary Phase 2 data for PRM-151 were presented for 27 patients involved in the study 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.
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)
While Promedior plans to conduct additional clinical studies to determine SAP’s potential as an anti-fibrotic therapy, Dr. Gomer says his work with the blood protein has gone as far as it can at this point — one at which he’s content simply to see what the future holds.
“It’s almost like a mother bird releasing her hatchling from the nest and seeing where it goes,” Dr. Gomer says. “Now, we’re just looking for more birds to raise.”
To learn more about Drs. Gomer and Pilling and their research, visit http://www.bio.tamu.edu/FACMENU/FACULTY/GomerR.php
For additional information about Promedior Inc., go to: