NeoStem, Inc., a biopharmaceutical company developing novel cell based therapeutics, announced initial positive data from its 161 patient phase 2 PreSERVE AMI (or acute myocardial infarction) clinical trial. These data are based on all enrolled patients being treated and having received six month follow-up for imaging and twelve month median length follow up for mortality, adverse events, serious adverse events (SAEs) and major adverse cardiac events (MACE).
Highlights of the initial results include:
A statistically significant mortality benefit (p<0.05) in patients treated with NBS10 (also known as AMR-001) as compared to the placebo group; there were no deaths in the treatment group.
A statistically significant dose-dependent reduction in SAEs (p<0.05).
Observation of a dose-dependent numerical decrease in MACE. MACE occurred in 14% of control subjects, in 17% of subjects of who received less than 14 million CD34 cells, in 10% of subjects who received greater than 14 million CD34 cells, and in 7% of subjects who received greater than 20 million CD34 cells.
When correcting for the time to stent implantation in all subjects, patients treated with CD34 cells were seen to have a statistically significant dose-dependent improvement in their ejection fraction (p<0.05). Independent from time to stent implantation, a statistically significant improvement in ejection fraction (p<0.05) for patients treated with a dose of greater than 20 million CD34 cells compared to placebo was observed.
No meaningful difference in perfusion, as evidenced by SPECT imaging, between the treatment and the control group from baseline to 6 months in resting total severity score (RTSS) suggesting this may not be a future suitable tool to assess NBS10, which is consistent with US Food and Drug Administration (FDA) guidance that mortality and MACE are the appropriate approvable endpoints to determine efficacy of a cellular therapy for cardiac disease as opposed to imaging endpoints.
“For cardiologists, our key goal is to keep patients from progressing to worsening heart muscle function and death after a major heart attack,” said Dr. Arshed A. Quyyumi, Professor of Medicine at Emory University and Lead Principal Investigator of the PreSERVE AMI study. “It is encouraging to see clinically meaningful results this early in the study, and I look forward to future data readouts.”
Interestingly, prior to trial enrollment, patients subsequently randomized to the treatment group had experienced a significantly longer time to stent implantation after the onset of symptoms (931 minutes) compared to subjects subsequently randomized to the control group (569 minutes). This longer interval to reperfusion would ordinarily be expected to be associated with worse clinical outcomes.
Further supporting the potential efficacy of this product candidate, the results provide evidence that the positive effects observed were due to intracoronary administration of NBS10, and not endogenous CD34 cells. There was no relationship between high bone marrow CD34 cell counts and improvements in MACE, mortality, or ejection fraction in the control group.
“Similar to what was seen in phase 1, we have observed a relationship between the dose of CD34 cells administered and a positive effect on cardiac function. In our current trial, in addition to improved cardiac function, a CD34 dose-related reduction in serious adverse events was observed, highlighting the potential for clinical benefit,” said Dr. Andrew Pecora, Director and Chief Visionary Officer of NeoStem and co-inventor of the core technology upon which NeoStem’s Ischemic Repair Program is based.
Dr. Douglas W. Losordo, chief medical officer of NeoStem, stated that, “the demonstration by this study of a statistically significant reduction in mortality and a dose-dependent reduction in overall MACE in treated subjects provides us important direction as we move towards designing a pivotal trial that is consistent with FDA guidance.”
NeoStem’s subsidiary, PCT (Progenitor Cell Therapy), a leading contract development and manufacturing organization in the cellular therapy industry, developed the manufacturing process for NBS10, and has provided all of the manufacturing of product for both its phase 1 and phase 2 trials. Over the last two years, PCT has worked to further optimize the yield of CD34 cells in order to maximize the dose that can be delivered to patients.
“By refining the methods for collecting and purifying CD34 cells for the PreSERVE AMI trial, we believe that we can facilitate providing doses of a sufficient number of CD34 cells for most patients from a single harvest,” said Dr. Robert Preti, NeoStem’s chief scientific officer, president of PCT, and co-inventor of the core technology upon which NeoStem’s Ischemic Repair Program is based. “The Engineering and Innovation Center at PCT continues to refine the process to provide for high quality, scalable and sustainable manufacturing at an optimal cost of goods for wide-scale commercial production.”
Patients with AMI are at significant risk of downstream adverse events, including chronic heart failure, recurrent AMI, significant arrhythmias, premature death or acute coronary syndrome. A report from Agency for Healthcare Research and Quality (2011) surveyed the most expensive hospitalization conditions by payor, and lists AMI as the sixth most expensive condition treated in US hospitals, with a national hospital bill of more than $37 billion annually.
“Heart attacks and cardiovascular disease are a significant physical and economic burden on society, and it is encouraging to see what we believe to be a meaningful impact on patient outcomes at this early point in the trial,” said Dr Robin Smith, chairman and CEO of NeoStem. “While perfusion is important in the pathophysiology of a damaged heart, SPECT imaging may not be sensitive enough to measure differences. Additionally, the FDA has taken the position that such analysis should not be relied upon as an “approvable” endpoint for a cellular therapy for cardiac disease. As we continue to develop NBS10, we will continue to consult with the FDA, external advisors and future partners to determine the best path forward for the future.”
NeoStem is developing therapies to address ischemia through its Ischemic Repair Program (the Program), using CD34 cell technology. Ischemia occurs when the supply of oxygenated blood in the body is restricted. The Company’s therapeutics seek to reverse this restriction through the development and formation of new blood vessels. The Program’s lead product candidate is NBS10, a chemotactic hematopoietic stem cell product comprised of autologous bone marrow derived CD34/CXCR4 cells selected to treat damaged heart muscle following AMI (or heart attack). NBS10 is thought to work by increasing microvascular blood flow in the heart muscle via the development and formation of new blood vessels, thereby reversing the restriction of blood supply caused by a heart attack and rescuing at-risk cardiac tissue from eventual cell death.
PreSERVE AMI is a randomized, double-blind, placebo-controlled clinical trial of intracoronary infusion of autologous CD34 cells in patients with left ventricular dysfunction post-ST elevation myocardial infarction (STEMI). The trial included 161 subjects at 60 sites in the United States, randomized 1:1 between treatment and placebo arms. Eligible patients presented with acute STEMI, had successful stenting of the infarct-related artery and had left ventricular dysfunction 4 days after AMI. Primary endpoints include occurrence of SAEs and MACE (defined as cardiovascular death, re-infarction, heart failure hospitalization, and coronary revascularization) through 3 year follow-up, occurrence of SAEs through 3 year follow-up, and 6-month change in myocardial perfusion (RTSS) measured quantitatively by gated SPECT myocardial perfusion imaging. Other endpoints include cardiovascular magnetic imaging resonance (CMR) to measure left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), left ventricular end-systolic diameter (LVEDV), regional myocardial strain, infarct/peri-infarct regional wall motion abnormalities and infarct size (baseline and six months) and quality of life measures (KCCQ and SAQ). While all 6 month data has been collected, it is subject to ongoing analysis, and results reported at this time, although promising, are preliminary. There can be no assurance that further analysis may not reveal negative, or less promising, results.