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.


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.”

New Liver Stem Cell Might Aid in Liver Regeneration

For patients with end-stage liver disease, a liver transplant is the only viable option to stave off death. Liver failure is the 12th leading cause of death in the United States, and finding a way to regenerate failing livers is one of the Holy Grails of liver research. New research suggests that one it will be feasible to use a patient’s own cells to regenerate their liver.

Researchers at the Icahn School of Medicine at Mount Sinai have discovered that a particular human embryonic stem cell line can be differentiated into a previously unknown liver progenitor cell that can differentiate into mature liver cells.

“The discovery of the novel progenitor represents a fundamental advance in this field and potentially to the liver regeneration field using cell therapy,” said Valerie Gouon-Evans, the senior author of this study and assistant professor of medicine at the Icahn School of Medicine. “Until now, liver transplantation has been the most successful treatment for people with liver failure, but we have a drastic shortage of organs. This discovery may help circumvent that problem.”

Gouon-Evans collaborated with the laboratory of Matthew J. Evans and showed that the liver cells that were made from the differentiating liver progenitor cells could be infected with hepatitis C virus. Since this is a property that is exclusive to liver cells, this result shows that these are bona fide liver cells that are formed from the progenitor cells.

One critical step in this study was the identification of a new cell surface protein called KDR, which is the vascular endothelial growth factor 2. KDR was thought to be restricted to blood vessels, blood vessels progenitor cells (EPCs), and blood cells.  However, the Evans / Gouon-Evans study showed that activation of KDR in liver progenitor cells caused them to differentiate into mature liver cells (hepatocytes).  KDR is one of the two receptors for VEGF or vascular endothelial growth factor.  Mutations of this gene are implicated in infantile capillary hemangiomas.

KDR Protein Crystal Structure
KDR Protein Crystal Structure

The next step in this work is to determine if liver cells formed from these embryonic stem cells could potentially facilitate the repair of injured livers in animal models of liver disease.

Isolating Mammary Gland Stem Cells

Female mammary glands are home to a remarkable population of stem cells that grow in culture as small balls of cells called “mammospheres.” Clayton and others were able to identify these stem cells in 2004 (Clayton, Titley, and Vivanco, Exp Cell Res 297 (2004): 444-60), and Max Wicha’s laboratory at the University of Michigan showed that a signaling molecule called Sonic Hedgehog and a Polycomb nuclear factor called Bmi-1 are necessary for the self-renewal of normal and cancerous mammary gland stem cells (Lui, et al., Cancer Res June 15, 2006 66; 606). The biggest problem with mammary gland stem cells is isolating them from the rest of the mammary tissue.

Mammary gland stem cells or MaSCs are very important for mammary gland development and during the induction of breast cancer. Getting cultures of MsSCs is really tough because the MaSCs share cell surface markers with normal cells and they are also quite few in number.

Gregory Hannon and his co-workers at Cold Spring Harbor Laboratory used a mouse model to identify a novel cell surface protein specific to MaSCs. By exploiting this unusual marker, Hannon and his team were able to isolate MaSCs from mouse mammary glands of rather high purity.

Camila Do Santos, the paper’s first author, said that “We are describing a marker called Cd1d.” Cd1d is also found on the surfaces of cells of the immune system, but is specific to MaSCs in mammary tissue. Additionally, MaSCs divide slower than the surrounding cells. Do Santos and her colleagues used this feature to visually isolate MaSCs from cultured mammary cells.

They used a mouse strain that expresses a green glowing protein in its cells and then made primary mammary cultures from these green glowing mice. After shutting of the expression of the green glowing protein with doxycycline, the cultured cells divided, and diluted the quantity of green glow protein in the cells. This caused them to glow less intensely. However, the slow-growing MaSCs divided much more slowly and glowed much more intensely. Selecting out the most intensely glowing cells allowed Dos Santos and her colleagues to enrich the culture for MaSCs.

“The beauty of this is that by stopping GFP expression, you can directly measure the number of cell divisions that have happened since the GFP was turned off,” said Dos Santos. She continued: “The cells that divide the least will carry GFP the longest and are the ones we characterized.”

Using this strategy, Dos Santos and others selected stem cells from the mammary glands in order to examine their gene expression signature. They also confirmed that by exploiting Cd1d expression in the MaSCS, in combination with other techniques, they could enhance the purity of the cultures several fold.

Hannon added, “With this advancement, we are now able to profile normal and cancer stem cells at a very high degree of purity, and perhaps point out which genes should be investigated as the next breast cancer drug targets.”

Will we be able to use these cell for therapeutic purposes some day?  Possibly, but at this time, more must be known about them and MaSCs must be better characterized.

Blood Vessel-Making Stem Cells Reprogrammed into Heart Muscle Cells That Improve Heart Function After a Heart Attack

Douglas Losardo at Northwestern University, Chicago, IL has done some extremely innovative work with transplanting bone marrow stem cells into the heart of human heart attack patients. His clinical trials have shown that human heart attack patients that receive infusions of their own bone marrow stem cells, on the average, show improved heart function, abatement of symptoms and improved prognosis.

In particular, Losardo has used CD34+ stem cells from bone marrow. CD34 is a cell surface protein that marks blood cell-making stem cells. CD34+ stem cells have been intensely studied and can form blood vessels in addition to red and white blood cells. The formation of new blood vessels in a sick heart improves the delivery of oxygen and blood to the heart, which improves heart function and recovery after a heart attack. Additionally, the CD34+ stem cells release a host of molecules that help the heart recover and function better.

The downside of CD34+ stem cells, is that they show limited ability to differentiate into heart muscle cells, and also do not survive terribly well in the heart after a heart attack. Therefore, Losardo has been on the hunt for a better technique for healing sick hearts, and a recent paper from his laboratory with mice provides a proof-of-concept of using reprogramming to form cells that can be used for regenerative therapies for the heart.

In this paper, Losardo and his team used a bone marrow stem cell called and “EPC,” which is short for “endothelial progenitor cell.” Endothelial cells compose blood vessels and EPCs make blood vessels. EPC infusions into a heart after a heart attack can improve heart function, but only modestly.

The first author of this paper, Melissa A. Thal, and her colleagues from Losordo’s laboratory treated EPCs isolated from mouse bone marrow with a cocktail of chemicals to move their gene expression patterns away from an EPC-specific pattern to that of a heart muscle cell. Their chemical cocktail contained either 5-Azacytidine, which changes the epigenetic profile of cells, and valproic acid, another epigenetic modifier, or a G9a histone dimethyltransferase called BIX-01294, which is also an epigenetic modifier. After soaking their EPCs in these chemicals for 48 hours, Genomic expression studies showed that pluripotency genes were expressed in these cells, as were genes for heart muscle and blood vessels. When cultured under the right conditions, these reprogrammed EPCs also formed good heart muscle cells.

These results were so remarkable that Losardo and his team decided to test these reprogrammed cells in the hearts of mice that have just experienced a heart attack. Transplantations of EPCs, or reprogrammed (REPCs) definitively showed that mice that had experienced heart attacks and did not have any interventions continued to deteriorate. However, EPC transplantations slightly improved the functional characteristics of the heart and tended to arrest the degradation of the heart. However, mice that had received REPCs had almost twice the % of blood ejected from the heart, significant reduction in the size of the damaged area, much less blood left in the heart after each pumping cycle, and better heart muscle function. Tissue examinations of the hearts showed that the REPC-transplanted hearts had grown new heart muscle whereas the EPC-transplanted hearts did not.

Thus this paper shows that it is feasible to reprogram EPCs from bone marrow into heart muscle cells and that it is also feasible to use these cells to repair the heart after a heart attack.

There were no significant side effects seen in the laboratory animals with the REPC transplantations. There were no tumors, no funky heart rhythms, and no sign of immunological rejection. Further work in animals will hopefully lead to human clinical trials and maybe even a commercially available treatment for heart attacks that use your own bone marrow stem cells. While that is a long way off, it is a hope that we all share.

Amgen’s New Drug Blinatumomab Shows Success in ALL Patients

Amgen Corporation announced updated results from its Phase 2 study with blinatumomab. Blinatumomab is a specially produced antibody that targets a protein called “CD19.” This antibody is made by an engineered cell line that produces one and only one kind of antibody. Such an antibody is called a “monoclonal antibody.” Monoclonal antibodies are made by antibody-making cells (B-lymphocytes) that are fused to tumor cells. The tumor cell immortalizes the B lymphocyte and this immortal cell now makes one type of antibody for its entire existence. Such a cell line that results from the fusion of a tumor cell with a B lymphocyte is called a “hybridoma” cell line.

CD19 is a cell surface protein that is made on the surfaces of B lymphocytes. Because B lymphocytes can over-grow and form blood-based tumors, an antibody that binds tightly to CD19 can specifically target B lymphocyte-based tumors. The binding of such antibodies also alerts other immune cells (T cells) to home to those cells and destroy them.

Blinatumomab, however, is an even more special molecule, because it binds CD19 at one end of the protein and a T cell-specific protein called CD3. Blinatumomab, therefore, acts as a bridge between tumor cells and T cells. It helps the T cells recognize the tumors as foreign. It is therefore an unusual type of chemotherapeutic agent called a bi-specific T-cell engager or BiTE. Another BiTE is MT110:, which is used to treat gastrointestinal and lung cancers, and is directed against the EpCAM antigen and the T cell surface protein B3.

Treatment with blinatumomab helped achieve a high-rate of complete response (CR) in 72% of all adult patients who were diagnosed with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL), and were treated in the study.

Full results of the study will be presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 4, 2012.

For more information on this Phase 2 single-arm dose-ranging clinical trial, 26 of the 36 patients treated with blinatumomab (across all of tested doses and schedules) achieved a complete response with partial recovery of their blood cell counts. All but two patients achieved a “molecular response..” Molecular response means that the presence of leukemic cells were not detectable with polymerase chain reaction (PCR) assays. There were also not treatment-related deaths or serious adverse events reported in this study.

Median survival was 9.0 (8.2, 15.8) months with a median follow-up period of 10.7 months at the time of the analysis. In the group of patients who received the selected dose of blinatumomab, the median survival time was 8.5 months, and the median duration of response in the 26 patients who responded to treatment was 8.9 months.

Max Topp, department of internal medicine II, University of Wuerzburg and chair of the study, said: “For these patients with limited treatment options, the remission rate observed in the trial is a vast improvement over the current standard of care. These results also represent significant progress in our research of immunotherapies; a new approach to fighting cancer that we believe could make a real difference for patients.”

Patients who received the selected dose and schedule, the most common adverse events were mild and included fever, (70%), headache (39%), shaking (30%) and fatigue (30%). Reversible central nervous system events led to treatment interruptions in six patients with two patients permanently discontinuing treatment.