A recent article criticizing NeoStem's (NBS) lead program AMR-001 described skepticism that the Phase II trial will yield positive data later this year. Unfortunately, the points that were brought up mischaracterize the program, with a misunderstanding of some important basics of the trial. In this article, I will walk through the arguments surrounding AMR-001 and provide an alternative argument for why the Phase II trial is designed appropriately, is based on science, and should be more carefully considered.
AMR-001 is an autologous stem cell therapy derived from a patient's own bone-marrow cells, which is delivered through the intracoronary artery after a heart attack. The goal of treatment is restoration of blood flow, reducing cardiac tissue damage, and improving heart function. The Phase II PreSERVE trial is a double-blind, placebo-controlled study that completed enrollment of 160 patients in December 2013. The primary endpoint is improvement in perfusion after 6 months. Secondary endpoints include other measures of cardiac function, including major cardiac adverse events (MACE) at several time points out to 3 years.
An important but mistaken point made about the trial is that enrollment was unacceptably slow. The argument is that doctors and patients are not interested in the trial because earlier, similar trials did not produce good results. This is an odd argument on its face, considering patients and doctors are always looking for ways to improve outcomes after a heart attack. More importantly, the real story is that the company simply overestimated the number of patients available for enrollment. One of the criteria for enrollment in the trial is that left ventricle ejection fraction must be less than 48% when measured at least 4 days after a stent procedure. NeoStem has conducted extensive preclinical and clinical work to establish the fact that treatment should begin after 4 days, rather than immediately after an event. However, ejection fraction after 4 days is not typically measured, so the company didn't know how many patients to anticipate. Apparently, there are not as many patients in this group as predicted, so NeoStem opened more sites and eventually completed enrollment. It is hard to say that slow enrollment is a knock against the trial, especially now that enrollment has been completed.
External Trial Data
Two studies have been highlighted as support that AMR-001 will not succeed, one published in Circulation in May 2013, and another published in the American Journal of Cardiology in July 2013. There are two basic reasons why these two publications are not sufficient evidence against AMR-001:
- In contrast to the cells described in the two publications, AMR-001 cells express particular cell surface markers (CD34+/CXCR4+), which are used for sorting.
- NeoStem's cells are delivered at the right time based on the evidence - between 5 and 10 days - and are delivered at a proper dose, established in earlier trials, to positively impact ischemia and cardiac function.
- Several other publications suggest that bone marrow-derived stem cells do positively impact cardiac function, which indicates that the literature is far from bearish on this topic.
The right cell surface characteristics: Much is known about heart attacks, including the causes, molecular consequences, tissue-level consequences, and repair mechanisms. The release of hypoxia-induced factor-1 (HIF-1) is a key component in the repair process following an event. HIF-1 stimulates the synthesis of stromal-derived factor-1 (SDF-1). SDF-1 is the ligand for CXCR4, a receptor found on the surface of a fraction of bone marrow cells. NeoStem's AMR-001 therapy consists of CD34+/CXCR4+ cells.
CXCR4 allows binding of the cells to SDF-1 at the site of ischemia, and CD34, a marker of hematopoietic stem cells, is important for the differentiation of the cells during angiogenesis. The cells used in the Circulation paper were bone marrow derived but unselected mononuclear cells. In fact, some small fraction of these cells are CD34+/CXCR+, but not enough to deliver a therapeutic effect, and they are mixed in with a large variety of other cells. The 10 trials analyzed in the American Journal of Cardiology paper used many types of cells, although mostly bone marrow derived mononuclear cells. CXCR4 is the key, and neither study included cells with this critical cell surface receptor.
The right time: SDF-1 is not secreted until several days after the ischemic event, which is why AMR-001 is delivered 5-10 days after a heart attack. The study reported in Circulation actually take this into account, and delivered cells either 5-7 days or 3-4 weeks post-heart attack. The American Journal of Cardiology paper was a meta-analysis, where the trials used a variety of administration protocols, so the exact delivery time was unique to each trial. The delivery time is key, and NeoStem has taken this into account in the PreSERVE trial, further separating AMR-001 cells from those described in the two papers.
The right dose: Just like any small molecule or biologic, an appropriate dose of cell therapy must be administered in order to provide a therapeutic benefit. NeoStem conducted a Phase I dose-finding study to determine that dose for AMR-001, finding that 10 million cells was the minimum number of cells needed to impact cardiac function. The conclusion was based on the fact that all patients receiving 10 million or more cells in the trial experienced an improvement in cardiac function at 6 months compared to baseline. Patients receiving placebo or 5 million cells actually had a decrease in perfusion. These are the data; data that establish 10 million or more cells as a clinically relevant amount. The problem with the papers highlighted in the article is that they use unselected or partially selected cell populations, making the fraction of CD34+/CXCR4+ cells delivered to the heart much lower than necessary to expect a strong impact on cardiac output.
Picking cherries: The funny thing about laying out the above argument for AMR-001 is that in reality, there are other papers not mentioned by the article that suggest CD34+ cells do significantly impact cardiac function. One meta-analysis published in the European Journal of Heart Failure in January 2012 examined 29 randomized, controlled trials. There was a significant association between bone marrow stem cell treatment and increased left ventricular ejection fraction (LVEF) both in the short-term (3-6 months) and long-term (12-18 months). Importantly, there was a significant correlation between the number of CD34+ cells administered and the benefit to LVEF, which emphasizes the benefits of purifying the right cell populations prior to treatment.
Another meta-analysis published in the journal Heart in February 2013 found that patients receiving bone-marrow stem cells had a significantly better LVEF at 6 months compared to those receiving placebo. Furthermore, there was a significant decrease in recurrent heart attacks in patients receiving cell therapy. These two papers highlight the fact that the literature as a whole does not support an argument against AMR-001, and a more thorough analysis can uncover support for NeoStem's treatment.
Data from NeoStem's Phase II PreSERVE trial are expected in the third quarter of 2014. Before deciding if you personally think the trial will succeed, it is best to examine the details very closely, making sure to take into account all of the facts on the ground, not just those that support a specific conclusion. A number of similar trials have been conducted that provide a deep pool of knowledge to draw from, and PreSERVE was designed with that experience in mind. While it is always possible to build an argument supporting one's conclusion, I believe that in this case the weight of evidence points to a reasonable likelihood that this trial will succeed. Please consider the features of AMR-001, including the Phase I dose-finding study, specific cell selection, and the accumulated literature on cell therapy for heart attack patients. You may find yourself on the side of AMR-001.
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.