Stem cells that make blood are heavily concentrated in the bone marrow. These cells are called "hematopoietic stem cells". When patients with leukemia are given a bone marrow transplant, they first receive high doses of radiation and chemotherapy in order to kill both the leukemic cells, as well as the healthy blood cells in the bone marrow. Subsequently the patients are given healthy bone marrow from a patient that has been matched immunologically. The new bone marrow contains high numbers of stem cells that take over the task of making new blood cells for the body. In some situations the leukemia comes back, however a bigger cause of mortality is when the blood cells made by the new bone marrow start attacking the recipient. This is a condition called graft versus host.
One of the advancements in bone marrow transplantation was the use of stem cells collected from the blood instead of the bone marrow. While under normal circumstances there are very little hematopoietic stem cells circulating in the blood, it was observed many years ago that after administration of certain compounds, the number of stem cells in the blood increases. This led scientists to try to find agents that can be used in patients that make stem cells leave bone marrow and enter circulation. There are three reasons why this would be important. Firstly, the process of extracting bone marrow from donors is very difficult. It involves sometimes more than 30 punctures into the hip bone. Secondly, there is some evidence that when the stem cells are collected from the blood, they have less potential to stimulate graft versus host disease. Thirdly, outside of the context of transplantation, it is known that bone marrow stem cells have ability to accelerate healing of tissues. Thus if there was a drug that could induce stem cells to leave the bone marrow and enter circulation, this drug would have many benefits.
The first stem cell mobilizer to be approved was granulocyte colony stimulating factor (G-CSF). This is a protein that is made by many cells in the body, especially by cells of the immune system. G-CSF specifically tells the bone marrow cell to make more granulocytes, these are cells that fight infections. In the process of infection, cells of the immune system called macrophages, start to produce G-CSF in response to bacteria and cause production of granulocytes which can then go and fight the bacteria. Interestingly, it was found that G-CSF also would instruct the bone marrow stem cells to exit the bone marrow and enter circulation.
This led to a variety of studies demonstrating that G-CSF "mobilized" stem cells can be collected from the blood of donors and used as an alternative to harvesting of donor bone marrow. In the majority of hospitals that perform transplants, donor collection is now performed by mobilization of stem cells.
Studies have reported that stem cells mobilized by G-CSF appear to have some beneficial effects in patients who have had heart attacks. Other studies have shown that stem cells mobilized by G-CSF may help patients with heart failure due to poor blood supply to the heart. For example, Maier et al. published a paper (Myocardial salvage through coronary collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial. Circulation. 2009 Oct 6;120(14):1355-63) in which 52 patients suffering from coronary artery disease were given either placebo or G-CSF for 2 weeks. Increases in the blood supply to the heart, and heart function were observed in the treated patients.
Currently G-CSF sells more than a billion dollars a year for use in a variety of diseases. Since the original patents on G-CSF have expired, there has been a great interest in the development of other stem cell mobilizers. However, to develop newer drugs that cause mobilization, it may be worthwhile to discuss the mechanisms by which G-CSF induces this process. It is known that in transplantation of stem cells, that the recipient can receive stem cells intravenously, but somehow they home to the bone marrow. This homing mechanism is mediated by the protein stromal derived factor (SDF)-1, which is made at a stable rate by the other cells in the bone marrow that are not stem cells. The hematopoietic stem cells recognize concentrations of SDF-1 based on receptors called CXCR-4. When G-CSF is administered, numerous biochemical pathways are activated that seem to converge, at least in part, to disrupting the interaction between the SDF-1 made by the bone marrow and the CXCR-4 that is on the stem cells.
The company Anormed recognized the importance of this interaction and started making chemical drugs that would block it. As we stated, G-CSF causes a variety of biological effects, however, by selectively targeting the essential interaction, the ability to increase mobilization should theoretically be more potent. Indeed, Anormed developed the drug Mozobil, which appears to be 10-100 times more potent than G-CSF at mobilizing stem cells, and was sold to Genzyme in a deal worth half a billion dollars. Mozobil received FDA approval and is currently used alone or sometimes in combination with G-CSF.
Recognition of the importance of the SDF-1-CXCR4 interaction led the company NOXXON to develop drugs to target this. However, unlike Anormed, which used conventional small molecules, NOXXON used a new technology called Aptamers, which are nucleic acids that can be engineered to specifically block interactions between proteins. The process of generating aptamers to target proteins involves selection in vitro, which can be accomplished at a more rapid rate as compared to what can be done for small molecules.
Today NOXXON announced that is has successfully administered its NOX-A12 aptamer-based mobilizer to healthy volunteers as part of a Phase I clinical trial. Usually the purpose of a Phase I trial is to determine the distribution of a drug in the human body, and to test for possible adverse effects. The dose chosen from a Phase I is then used to conduct Phase II studies in which biological effect is tested. The NOX-A12 trial was conducted in Germany with the approval of the Clinical Trial Application by the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM). The study is evaluating effects in 42 volunteers with the aim of assessing efficacy in patients with multiple myeloma or non-Hodgkin’s lymphoma in a Phase II trial that is planned for mid 2010. The company states that it plans to obtain marketing approval by 2014. Marketing approval for a drug is granted after 2 double blind, placebo controlled, Phase III studies are performed in which the primary endpoints show a statistically significant improvement over placebo.
The choice of multiple myeloma or non-Hodgkin’s lymphoma as conditions for evaluating NOXA-A12 may be due to the high incidence of patients with these conditions who are poor mobilizers. In these conditions, part of the protocols used clinically, involve mobilizing the bone marrow, administration of chemotherapy, and subsequent reintroduction of the bone marrow into the body.