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Cytomedix, Inc. Message Board

  • philphillyguy philphillyguy May 14, 2013 7:55 AM Flag

    Informative read from Zacks...

    An excerpt from Zacks…
    The Cytomedix Solution
    Cytomedix is developing ALDH-Br cells for the treatment of stroke and other ischemic disorders. ALDH-Br cells are autologous bone marrow derived cells that have been sorted from the patient's own bone marrow by FACS. The technology takes advantage of the observation that the ALDH enzyme is found in all stem cells, whereas the cell surface markers traditionally used to isolate stem cells, such as CD35, are only found in specific subsets.
    By sorting bone marrow cells based on their ALDH status rather than based on a cell surface marker, Cytomedix generates a mixture of adult stem cells capable of providing a variety of supportive functions that the company believes will demonstrate superior properties to those of more narrowly selected cell types. These cells are directed directly into the patient without any expansion, thus minimizing the lag time between bone marrow collection and the availability of therapeutic product. In contrast to MultiStem, which is intended for use during the subacute period beginning 1-2 days post-stroke, the Cytomedix product is administered two weeks post-stroke with the goal of supporting neuronal viability and neurogenesis in the post-acute period.
    ALDH-Br cells have demonstrated impressive activity in an animal model of stroke. Mice treated with ALDH-Br cells two weeks after an induced stroke showed statistically significant improvement in motor function of 41% after 2 weeks, compared to 11% in a control group. Significant effects were also seen in reducing brain volume loss. In a second study, the brains of mice treated with ALDH-Br cells two weeks after an induced stroke exhibited superior blood flow four weeks after treatment relative to control mice.
    ALDH-Br cells exert their cytoprotective activity via a combination of promoting improved blood flow, and by directly inhibiting necrosis and apoptosis (Liisa Smith et al, ASH Annual Meeting Abstracts, 2009, 114: Abstract 3056). In vitro, ALDH-Br cells migrate toward cells that have been exposed to hypoxia, and attach themselves to hypoxia and nutritionally stressed cells with greater avidity than to non-stressed cells.
    Gene array and protein expression studies have shown that ALDH-Br cells express high levels of several angiogenic growth factors, cytokines, and signaling molecules involved in matrix remodeling. These inc
    In related applications, the safety and efficacy of ALDH-Br cells in heart failure and limb ischemia have been examined in Phase I trials. These trials were not powered to demonstrate efficacy, but treatment was safe and trends toward improved blood flow and function were observed. In the critical limb ischemia trial, four of 11 patients achieved improved function such as to no longer meet the diagnostic criteria for critical limb ischemia, and the one year rate of limb amputation was dramatically reduced relative to historical standards. In the heart failure trial, treated patients experienced an improvement in maximum oxygen consumption relative to the placebo group. These results support the safety of ALDH-Br cells and provide support for their ability to improve outcomes in ischemic disease.Cytomedix is currently conducting a Phase II trial of ALD-401 in ischemic stroke. The Phase II RECOVER trial (ClinicalTrials.gov # NCT01273337) is enrolling 100 patients with first time ischemic stroke and persistent neurological deficits. Patients in the active arm (n=60) will be treated with a single intracartoid infusion of ALDH-Br cells and compared to a sham treated group (n=40) with a primary efficacy endpoint of recovery of mental and physical function at 3 months, with durability and safety endpoints at 3, 6, 9, and 12 months. Enrollment in the trial has been proceeding slowly. As of May 10, 2013, only 30 patients have been enrolled. In May 2012, Cytomedix announced that an independent data safety monitoring board (DSMB), after reviewing the safety data from the first 10 patients, had recommended that the phase 2 trial continue as designed. That means only 10 patients have been enrolled over the past year. However, we note that enrollment of the first 10 patients took place at three clinical sites in the U.S. Safety data presented in October 2012 at the World Stoke Congress in Brazil showed procedure was safe and yielded no serious adverse events. Enrollment has now been opened to a total of 10 sites, with another 5 expected to come online in the next few weeks. Besides this, there are reasons to believe enrollment will accelerate in the coming months. For the previous 15 months, it seems that the entry criteria for enrollment had been too strict, and that two key issues where holding patients back. The first was age of enrollment. The trial previously capped the age of subjects at 75 years. The new protocol now allows for enrollment of patients up to 83 years of age. Management believes this change will help increase the pace of enrollment by 20%. The second change is the allowance of patients with subcortical stroke. The previous entry criteria only allowed cortical stroke patients, a far more restrictive hurdle. The new protocol now allows both cortical and subcortical stroke patients to be enrolled. Management believes this change should speed enrollment by 50%.
    A combination of easing the entry criteria and adding six new sites should help quicken the pace of enrollment throughout 2013. However, Cytomedix tells us the biggest hurdle to enrollment of patients is the bone marrow aspiration procedure required to extract the cells. Surprisingly, it is not the angiography and intracartoid infusion. Both of these are common practice in stroke patients regardless.
    To generate the 3 mL of ALDH-Br cells for ALD-401 to be infused back into the patient two days later, a total of 150 mL of bone marrow must be extracted. Although this is not an enormous amount - note that bone marrow transplant procedures require 500 to 700 mL - it is still more than most hematologists or neurosurgeons are accustomed to. Traditional bone marrow aspiration procedures may be only as much as 50 mL. A goal for Cytomedix is to work to increase yield and cell selection on the ALDH-Br cells so that the volume of bone marrow required to generate 3 mL of ALD-301 can be reduced. We know the company is working on this, although we do not expect the procedure to change during this clinical trial. Besides the procedure and volume of bone marrow required, scheduling and the ability to return two days later for infusion are key limiting factors to enrollment. We note these are somewhat limiting factors for Athersys as well.
    Nevertheless, management at Cytomedix believes they can complete enrollment at 100 patients before the end of the year. Data should follow four months later, perhaps in April 2014. We remain skeptical of that timeframe, but note that more important than the month of the data is the actual data itself.

    Conclusion
    The perception by investors with respect to these two programs is one of competition - which company will succeed and which technology is superior? However, we see no reason to believe that the success of one company will mean the success or failure of another. We view these trials are mutually exclusive events. In fact, we see no reason why one patient cannot receive both MultiStem and ALD-401.

    - Athersys is dosing patients 1-2 days post moderate-to-severe stroke (ages 18-79) with an IV injection of over 1 billion cells.

    - Cytomedix is dosing (note the bone marrow harvest takes place 2 days prior to dosing) patients 13-19 days post stroke (ages 30-83) with persistent neurological deficit 7 days after stroke with an intracartoid infusion of roughly 5 million cells.

    Multiple seems to offer advantage in entry and enrollment criteria, potential cost of therapy, and scalability of the commercial product. A popular misconception is that Athersys' MultiStem offers advantages in dosing number of cells and delivery. We strongly disagree. Dosing 1 billion cells isn't necessarily better than dosing 5 million cells - it's not how many cells, it's what the cells do once they are dosed. It is clear that an IV injection is far less invasive than an intracartoid infusion, but for neurosurgeons and stroke patients, angiography and intracartoid infusions are not outlandish procedures. In fact, they are quiet common.

    Comparing the protocols of these two trials on ClinicalTrials.gov (ATHX & CMXI), investors can see the enrollment and entry criteria for Athersys is far less restrictive than for Cytomedix. Cytomedix must enroll patients that have the ability to withstand a bone marrow aspiration procedure and catheterization for localizing arteriograms for intracarotid/MCA delivery of the cells. Patients must remain overnight for observation. Patients cannot have 50% stenosis or ulcerated plaque in the cortid artery, or recent cardiovascular events or renal insufficiency. Things like hemoglobin and platelet counts must all be within normal ranges. All concomitant medications must be stopped, such as warfarin, heparin, immuno-suppressants, and anti-angiogenic drugs. We simply do not see this level of restriction on the Athersys program. This clearly explains the hurdle that Cytomedix has yet to overcome with respect to enrollment.

    However, despite the challenges that Cytomedix faces with patient recruitment, delivery, and scale, we favor the mechanism of action for ALD-401 over MultiStem. MultiStem is designed to work on the basis of the cells migrating to the site of ischemic damage and releasing multiple proangiogenic, cytoprotective, and immunomodulatory factors. The cells could lead to increases in VEGF, BDNF, or other neuroprotective agents. The key question for Athersys is: Do the cells get to where they need to be and elicit the type of response seen in preclinical and in vitro studies?

    We are not convinced that systemic delivery of any therapeutic agent make sense for a localized and acute event inside the brain. In a paper by Detante et al (2009) entitled, "Intravenous Administration of 99mTc-HMPAO-Labeled Human Mesenchymal Stem Cells After Stroke: In Vivo Imaging and Biodistribution," the authors found that IV-injected hMSC are eliminated in urine (~61%), or transiently trapped in lungs (~26%), kidneys (~7%), and liver (~3%) at 2 hours. Only 0.05% of the total IV injected cells were found in the brain (left + right) 2 hours later. The percent drops to 0.03% at 20 hours.

    However, the authors did find that more cells are found in the brain of rats with middle cerebral artery occlusion (MCAo) than in control rats at 20 hours. This suggest a mechanism for which hMSC migrate to the site of an ischemic injury in the brain. The literature supports dosing something like MultiStem intravenously, but it is clear that the large majority of cells ( 99%) do not end up in the brain. It is a misconception that more cells are better. The preclinical data for both Athersys and Cytomedix are equallty impressive, and Cytomedix dosed on average 1/100th of total number of cells. That being said, systemic IV administration appears to be safer and easier than local brain grafting or intracartoid infusion.

    For Cytomedix, the mechanism of action is one of promoting cytoprotective activity via a combination of promoting angiogenesis, inhibiting necrosis and apoptosis, and expressing high levels of growth factors, cytokines, and signaling molecules involved in matrix remodeling. The intracarotid/MCA delivery, although a complex surgical procedure, guarantees the cells end up where they are needed to perform the function they are hypothesized to perform. The key question for Cytomedix is: Can they convince enough patients to enroll in the trial to generate the data?

    Both companies have impressive and exciting preclinical animal data. Both companies have opportunities outside of stroke. Athersys is also studying MultiStem in graft vs. host disease, inflammatory bowel disease, and cardiovascular indications. The Athersys pipeline clearly expands beyond stroke. Besides stroke, the Cytomedix pipeline includes programs for critical limb ischemia and heart failure. Plus, Cytomedix has two FDA approved medical devices in Angel and AutoloGel. The company should record $10 to $11 million in revenues in 2013 based on these two products (based on Q1 reported financials).

    We will be watching the outcomes of both these trials closely. Data should come first from Athersys, followed by Cytomedix six months later (highly dependent on enrollment rates in 2013). Athersys has a market capitalization of $111 million, whereas Cytomedix has a market capitalization of only $49 million (both based on basic share count). Both stocks have tremendous upside if their respective trials succeed.

    Co-Authored by John Tucker, PhD

    Sentiment: Strong Buy

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