REALISTIC Trial to Test Efficacy of Bone Marrow Stem Cells on Liver Disease


Chronic liver disease is the fifth leading cause of death in the United Kingdom. With the long-standing shortage of donated, transplantable livers, the prognosis of such patients seems grim.

Several preclinical studies in animals have established that mobilization of bone marrow stem cells or direct injection of bone marrow stems into a damaged liver can augment healing and improve survival (Sukaida I, and others, Hepatology 2004;40:1304–11; and Yannaki E, and others, Exp Hematol 2005;33:108–19). Some small clinical trials have examined the use of a patient’s own bone marrow stem cells to prime the liver and stimulate its own internal healing mechanisms. These studies were small and varied in the manner in which the stem cells were delivered, but they di show that the stem cell treatments were safe and even improved the health of the liver significantly (Gordon MY, and others, Stem Cells 2006;24:1822–30; Terai S, and others, Stem Cells 2006;24:2292–8). Also, in patients with liver cancer who had to have portions of their livers removed, bone marrow stem cell treatments accelerated liver healing (am Esch JS, and others, Ann Surg 2012;255:79–85; am Esch JS, and others, Stem Cells 2005;23:463–70; and Furst G, and others, Radiology 2007;243:171–9).

Clearly there is a need for a larger, more systematic study of the efficacy of bone marrow stem cells as a therapeutic agent in patients with liver failure. To that end, Philip Newsome and his colleagues at the University of Birmingham, in collaboration with colleagues from Scotland, Newcastle, and Nottingham have initiated the REALISTIC trial, which stands for REpeated AutoLogous Infusions of STem cells In Cirrhosis.

This is a multi-center clinical trial and it will examine patients with Cirrhosis (fatty liver disease), regardless of the cause of that liver disease. Patients whose livers were damaged by excessive alcohol use, hepatitis B or C infections, or genetic conditions are all eligible for this study, but anyone who liver is too far-gone to be helped by a treatment like this or has had a liver transplant is not eligible.

Patients will receive injections of a drug called lenograstim (G-CSF) to mobilize bone marrow stem cells into the blood. These blood-based stem cells will then be collected and concentrated, and then implanted into the liver. Patients will be assessed at 3 months after the treatment and then followed-up for 1 year. Liver health will be assessed by means of medical imaging of the liver and various blood tests.

Patients will be evaluated using the Model for End-Liver Disease or MELD scoring system. Secondary tests will measure the degree of liver scarring, the degree of liver stiffness, blood tests, survival, and liver function.

Patients will also be placed into three groups. One group will only have the bone marrow stem cells mobilized from bone marrow without being collected. Another group will have the cells collected and implanted into the liver. The third group will receive standard care with not stem cells treatments.

There is a need for a study like this. I only hope that Newsome and his group can recruit the patients and get started collecting data as soon as they can.

New Liver Drug Gets Fast Tracked by the FDA


Liver scarring (fibrosis) and cirrhosis (deposition and build up of fatty deposits in the liver) are life-threatening events. We normally associate cirrhosis in our thinking with chronic alcoholism, but there are many other conditions that can cause liver fibrosis and cirrhosis. For example, chronic systemic lupus erythematosis, which is normally just known s lupus, can wreak havoc upon the patient’s liver. Likewise Crohn’s disease, chronic hepatitis infections, or even certain genetic can cause liver disease. Once a patient’s liver scars over to a certain point. The last stop for them is either a liver transplant, or Hospice.

Until now? A biotechnology company called Galectin Therapeutics has announced that the U.S. Food and Drug Administration (FDA) has granted their new drug, GR-MD-O2 (galactoarabino-rhamnogalacturonate – say that five times fast) so-called “Fast Track designation” as an experimental treatment for non-alcoholic steatohepatitis (NASH) with hepatic fibrosis, which is also commonly known as fatty liver disease with advanced fibrosis.

GR-MD-02 is an experimental name for a complex carbohydrate drug that targets galectin-3. Galectin-3 is a cell surface protein found on liver cells and it plays a critical protein in the pathogenesis of fatty liver disease and fibrosis. Galectin proteins are central players in those diseases that involve scaring of organs such as cancer, and inflammatory and fibrotic disorders. The drug binds to galectin proteins and disrupts their function. Preclinical data have shown that GR-MD-02 can reverse fibrosis and cirrhosis in kidney, lung, and liver.

Galectin-3
Galectin-3

What is “fast track” designation? Here how this works: Fast Track is a process designed by the FDA to speed up the development and review of drugs to treat serious conditions and fill an unmet medical need. The goal is to get important new drugs to the patient earlier. Determining whether a condition is serious is a matter of judgment, but generally is based on whether the drug will have an impact on such factors as survival, day-to-day functioning, or the likelihood that the condition, if left untreated, will progress from a less severe condition to a more serious one. The kinds of conditions that have qualified for fast tracking in the past include AIDS, Alzheimer’s, heart failure and cancer. .

To qualify for fast tracking, the drug must either treat or prevent a condition with no currently available, or if there are available therapies, a fast track drug must show some advantage over available therapy. These advantages would come in the following forms:

1. Show superior effectiveness (outcomes or improved effect on serious outcomes);
2. Avoid serious side effects of an available therapy;
3. Improve the diagnosis of a serious condition (in those cases where early diagnosis results in an improved outcome);
4. Decreases clinically significant toxicity of an available therapy
5. Ability to address emerging or anticipated public health need

If a drug is fast tracked, then is will receive more frequent meetings with FDA, more frequent written correspondence from FDA, or eligibility for Accelerated Approval and Priority Review, or some combination of these.

Galectin Therapeutics is currently conducting a phase 1 clinical trial to evaluate the safety, tolerability and efficacy for single and multiple doses of GR-MD-02 over four weekly doses of GR-MD-02 treatment in patients with fatty liver disease with advanced fibrosis. In this study, Galectin will enroll eight patients in each dose escalation cohort and there will be at least three cohorts and potentially up to five cohorts, with a maximum of 40 patients at six clinical sites in the US, which each have extensive experience in clinical trials in liver disease.

“Our preclinical data has shown that GR-MD-02 has robust treatment effects in reversing fibrosis and cirrhosis. Fast Track designation enables us to expedite the compound’s development and review process, with the ultimate goal of bringing a first-in-class treatment to the millions of Americans suffering from fatty liver disease with advanced fibrosis,” said Dr. Peter Traber, president, chief executive officer and chief medical officer of Galectin Therapeutics Inc. “We are very pleased that the FDA sees the clinical value of GR-MD-02 and seriousness of fatty liver disease, and we look forward to working closely with the FDA throughout this process.”