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NeoStem (NYSE MKT: NBS), The Nexus Between Curative Regeneration And Personalized Medicine

Harnessing the body's untapped mechanisms to preserve and restore function to regenerating tissues and organs

NBS's focus on stem cell therapies targets the nexus between curative regeneration and personalized medicine. NBS breadth spans from harnessing the body's untapped mechanisms to preserve and restore function to regenerating tissues and organs. With NBS' lead product, AMR-001; this path should transform the practice of medicine and trigger product developers and investors to embrace the field.

In the first hours of an acute infarction, myocardial necrosis occurs. Therapies and processes of care developed over the past few decades halt this process and limit that initial phase of necrosis. In higher risk infarcts, those featuring ST segment elevation (STEMI), a large infarction is accompanied by a significant region of surrounding tissue with inadequate blood supply that is also working harder to compensate for the neighboring dead, non-functioning myocardium.

This peri-infarct region - hit by this ischemic insult - responds via biologically conserved mechanism to signal the body of its need for perfusion. Within weeks, if there is no response, this tissue begins the process of apoptosis which expands the infarction, triggering changes throughout the ventricle in structure and function. This so called remodeling is the driver of disease progression in these patients, similar to how tumor growth and metastases drive outcome in cancer patients. The scientific literature and our phase 1 study1 support the view that AMR-001 will address this need blocking infarct expansion and preserving cardiac function.

According to the American Heart Association, almost 1 in 5 patients of MI older than 45 will be dead within a year.2 While the prognosis for patients with acute MI is improving, analysis by Kaiser Permanente reports that the outlook for STEMI patients is not improving and revascularization rates are rising most sharply in STEMI patients.3 For MI patients with LVD, the prognosis is particularly worrisome.

For over a decade, the scientific literature featured reports of the promise of stem cell therapies for patients suffering from and following myocardial infarction. It's no mystery why this clinical scenario receives so much attention; cardiovascular disease is the major driver of suffering, lost productivity and health care costs. As reflected by the 3 meta-analyses, whose outcomes agree with other met-analyses that are not attached, bone marrow derived stem cells, improve ventricular function.

Within these meta-analyses, there are several critical points that amplify the promise of AMR-001.

  • First, in addition to the study showing reduction in risk of a composite endpoint of morbidity and mortality…The totality of data in these meta-analyses show that in parallel to improved ventricular function, patients receiving bone marrow derived mononuclear cells via intracoronary delivery early after myocardial infarction appear to be at lower risk of clinical events, including reinfarction, heart failure hospitalization and revascularization;
  • Second, the single meta-analysis that evaluated correlates of the effect of bone marrow stem cells demonstrates a statistically significant relationship between the number of CD34+ adult stem cells the improvement in ventricular function.7 There was no relationship between the total number of bone marrow cells and change in ejection fraction7 pointing to the importance specifically of CD34+ cells.;
  • Third, dose and potency matter. While dose of unselected marrow cells appears important,* it is the CD34+ that matters most. This relationship between dose of CD34+ cells and effect on preserving myocardium parallels two other data sources. When bone marrow derived mononuclear cell mobility was measured in a clinical trial measuring the effect of therapy of infarct size measured by MRI 6 months after treatment, those patients treated with more mobile cells did not show as much infarct expansion, and therefore, would lead to preservation of ventricular function. In the AMR-001 Phase 1 trial, the number of mobile cells correlated with improvements in perfusion and blocking of infarct expansion, findings which served as the basis for expansion of NBS' IP portfolio.

The science tells us that the impact of AMR-001 in particular in these high risk patients, those with left ventricular dysfunction following acute STEMI, should not be a surprise. When the peri-infarct zone signals its need for perfusion, it does so using mechanisms that start with release of hypoxia inducible factors (HIF-1), and features prominent tissue levels of stromal derived factor-1 (SDF-1) starting within days and continuing for several weeks.10 11 SDF-1 is the ligand that matches to a surface protein present on approximately 20-25% of CD34+ cells, CXCR4. And this receptor-ligand match serves as a driver for CD34+ cells to move towards this region of ischemia with high levels of SDF-1, release their exosomes and thus trigger capillary formation that starts within hours.1112

NBS' intellectual property portfolio provides the rights to use CD34+ adult hematopoietic stem cells with CXCR4 receptor expression for the treatment of ischemic tissue. The CXCR4/SDF-1 relationship is what provides these angiogenic and anti-apoptotic cells the "navigation" to create the capillary bed where the body needs it, and because our IP portfolio includes composition of matter claims, we believe AMR-001 and NeoStem are ideally positioned.

When considering investments, partnerships and collaborations, the level of risk must be identified and mitigated where possible. One of the lessons evident in drug development is the danger of even a single adverse event.

  • The clinical trials of Armodafinil for ADHD showed promising efficacy, but a single case of suspected Stevens-Johnson syndrome shut down the program. A single case of Torsades would likely shelve most new products in development. When developing an autologous therapy, particularly when the product is manufactured by NBS' subsidiary, Progenitor Cell Therapy, such rare cases are not significant risks. A risk assessment for an allogeneic therapy cannot conclude the same way.

Give credit where it is due … Thanks … to Dr. Jonathan Sackner-Bernstein, MD, the articles author and VP Clinical Development and Regulatory Affairs at NeoStem.

The Bottom Line: The promise of AMR-001 is rooted in the models used for its development, leveraging off drug development paradigms. Thus AMR-001 is manufactured to assure purity (of CD34+) and potency (mobility to SDF-1 gradient). The context of dose-effect relationships for cardiovascular therapeutic development programs serves as critical lessons for CD34+ cells6 and specifically for AMR-0011. As opposed to the direct relationships between escalating dose of AMR-001 and benefit, other cell based therapies demonstrate that doses administered have a flat or inverted effect curve, similar to that seen in such therapies as endothelin antagonists and natriuretic peptides.

The importance of this component to drug and biologic therapeutic development is underscored by the FDA Guidance Document on the issue (joint CBER/CDER) as well as its prominence in the Guidance Document for CDER's End of P2 Meetings. AMR-001 is an angiogenic and antiapoptotic therapeutic in a P2 advancing trial, with proposed indication of preventing infarct expansion and preserving ventricular function, leading to improved clinical outcome. Worsening ventricular function for a patient post MI is of the import of tumor burden to a cancer patient or viral load to those infected with HIV.

NBS expect to show that AMR-001 halts the driver of disease in patients post MI, and by preserving ventricular function, reducing the risk of morbidity and mortality, and transforming the natural history of disease - thereby establishing the utility of stem cell therapies for human disease.

NBS closed at $0.61, down a penny with a larger volume day and … anemic RegMed universe movement. I can't say it any better … from a Seekingalpha article from A. John Hodge …"After a 4 month rally of 160% between April and August, NeoStem (NBS) has since pulled back and found a steady trading range between $0.61 and $0.68. In the process, the company has had one positive announcement after the other, and was pushed higher because of these announcements. Now, with several looming catalysts in 2013 and a stock that is priced attractively, it is very possible that this stock will break its range and trade higher.There is no particular reason that NeoStem has pulled back and traded flat for the last four months, except for the fact that all stocks eventually find a trading range after a large rally. These trading ranges provide investors with a good safe buying price, as almost always such stocks will trade higher with the appropriate catalyst, which NeoStem has into 2013." . NBS continues a "BUY" as I have <also> been iterating for a while!

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.