NeoStem: Understanding Research And Its Implications To Clinical Trials

On September 11, a report published in the European Heart Journal Advance Access essentially validated the workings of NeoStem's (NBS) Phase II AMR-001, or at least the approach that NeoStem is using. The report flew somewhat under-the-radar, because a few days later, a negative article on Seeking Alpha questioned AMR-001, and caused NeoStem's stock to fall drastically. As a result, I reached out to NeoStem's Chief Medical Officer and CD34+ cell specialist Dr. Douglas Losordo who clarified the controversy quite nicely and completely tore down the author's argument in this Instablog post.

However, the report in European Heart Journal was quite important to NeoStem, yet no one seemed to notice. One reason is likely because these research reports are written in a way that very few retail investors (or analysts) can understand. Therefore, once more, I reached out to the company, hoping that this seemingly positive research report can be summarized for investors to understand. Hence, here is a short Q&A with the company's PCT segment's CMO Dr. Andrew Pecora, and his take on the report.

Note: I have added a few notes (in bold) for clarification and for important points.

Nichols

How do the results of this study compare with other related studies that have released either final or interim data? From a size, safety, and efficacy point of view.

Dr. Pecora

Pretty much the same. All studies have shown that if an adequate number of CD34 cells are administered (either isolated or admixed with marrow) during the window phase after inflammation has subsided (days 5-12 post acute myocardial infarction (AMI) there is a consistent finding of increased LVEF, preservation of heart muscle function and less adverse remodeling. One study also showed significantly fewer clinical events. (Essentially, Dr. Pecora is saying that when trials are done correctly, and the threshold dose is used, the outcome is consistent, which also goes hand-in-hand with NeoStem's goal in its Phase II trial)

Nichols

Can you elaborate on the significance of this statement within the research report?

"There was no difference in LVEF improvement between patients treated with cell infusion ,7 days from primary PCI compared with =7 days (1.46%, 95% CI: 0.41 to 2.51 vs. 2.69%, 95% CI: 1.80 to 3.58, P 1/4 0.08). Furthermore, we found no difference in LVEF improvement comparing patients with number of injected mono- nuclear BMC of ,108 compared with = 108 (2.80%, 95% CI: 0.79 to 4.80 vs. 0.58%, 95% CI: 20.44 to 1.59, P 1/4 0.05), Table 2. Studies, using MRI as LV function assessment had a smaller treatment effect in LVEF when compared with non-MRI studies (0.16% 95% CI: 20.88 to 1.20 vs. 4.67%, 95% CI: 3.69 to 5.66, P, 0.001)."

Dr. Pecora

This is a meta-analysis so data of this kind will not pick up small differences and probably cannot be used to conclude this fine a point. In regard to the days post PCI we know there is no difference in effect if cells are given day 5 vs. day 8 but there is no effect if given day 3 so one would need to know how the actual day of delivery is weighted in the cut they did (the day administered is very important to outcome). There is no good correlation between the number of mononuclear cells infused which is irrelevant and the number of CD 34 cells which are a constituent of the mononuclear cells and the cells that cause the effect. In addition further confounding this analysis is that the more mononuclear cells infused the more cells there are to get in the way of the CD34 cells. MRI has less variability than standard echo and what is important is not effect size (i.e. how much the LVEF goes up) it is the percentage of patients that do not have a drop in LVEF that matters. What matters is preservation of heart muscle function (preservation of heart muscle function was shown, and is the goal of NeoStem's Phase II study).

Nichols

Can you expand on the importance of the trial size and impact it has on being able to analyze subgroup data?

Dr. Pecora

It is more than adequate for the general effect assessment and conclusion that bone marrow derived cells administered after an AMI via the coronary artery preserve heart muscle function and prevent adverse remodeling

Nichols

From an investor's perspective, what do you feel is the single most important take away from this report?

Dr. Pecora

In regard to AMR-001, in our study we are administering a much greater number of CD34 cells than prior studies and not admixed with mononuclear cells. In our study we have limited entry to patients with persistent cardiac dysfunction (LVEF <48% on day 4), which would indicate that most of our patients fall into the <40% category in this analysis (because the LVEF is taken before day 4 in these studies and tends to improve by day 4). Thus if an effect is observed in most studies used for this meta analysis than our study should result in a similar effect at minimum and could be greater because we are giving a greater number of potent cells to a sicker population.

Final Thoughts

Now, hopefully Dr. Pecora's response made this study easier to follow/understand. Unfortunately, retail investors tend not to pay attention to reports such as this, and only show interest at the end of Phase III trials when a study either "met" or "did not meet" primary and secondary endpoints. However, reports such as this can give you, as an investor, a better idea of future success, or a lack thereof. Then, you aren't as likely to respond to the daily volatility that is created with such stocks, and will feel better about your investment.

Disclosure: I am long NBS. 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. (More...)

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Implications Of The Pfizer Business Split

Details of the split

Pfizer (PFE) announced that it will split its business into three parts. While the separation of its genetics business into a separate unit had been widely anticipated, the split of its remaining business into two separate units took many analysts by surprise. Each of the three units will have its own emerging markets operation and the separation of the financials is expected to begin with the 2014 fiscal financial statements of Pfizer. The generics business will now be called the"value products group," and will include brands that have lost patent protection and products that will lose patent exclusivity by 2015. This business unit will also incorporate the company's portfolio of biosimilars. This is believed to be the precursor of a spinoff or a sale though the company refused to comment. The generics business will also handle partnerships for growing the off-patent business, including partnerships with Mylan Pharmaceuticals in Japan, China's Zhejiang Hisun Pharmaceutical and Laboratorio Teuto Brasileiro in Brazil.

The second unit will include drugs with patent protection beyond 2015 and will be called "innovative products." The third unit which was not expected in the course of the reorganization will include vaccines, oncology and consumer healthcare products. The company explained that the rationale for the third unit is that the products are operationally and commercially distinct with their own culture, research facilities and research focus. The company also did not want the vaccine business to be part of a larger primary care business.

Pfizer had already kicked off the reorganization process by spinning off its animal health unit Zoetis and taking it public. The IPO combined with a share swap meant that the company was able to avoid potentially large tax expenditures. The company also sold Capsugel in a deal worth $2.4 billion in 2011 to Kohlberg Kravis Roberts and its infant nutrition business in 2012 to Nestle (NSRGY.PK) for $12 billion and the sale proceeds were used to enhance its share buyback program.

Benefits of the split

Frank D'Amelio, Pfizer's chief financial officer, summarized the new strategy as follows: "This is all about getting these three businesses to hum internally, to operate with excellence inside the company." Analysts believe that this is a clever move that will provide investors with more clarity and transparency and allow an accurate valuation of the different parts of the company. It would also provide investors with value because some of the businesses after the split could well trade at P/E multiples in excess of the approximately 12.5 times at which the stock is currently trading. This strategy of separating a large diversified healthcare company into smaller pure play businesses has worked well for other companies. Abbott Laboratories (ABT), like Pfizer, was much too diversified to be able to control its risk and reward tradeoff. As a result, it spun off its blockbuster treatment, Humira, and its experimental pipeline drugs into a separate company, AbbVie, while retaining the other businesses. This worked very well for many investors. Conservative ones, concerned at the impending end of patent protection for Humira and Androgel, got to sell AbbVie and more adventurous ones were able to buy AbbVie because of the blockbuster potential of its pipeline drugs.

The urgency for the split

Pfizer had to do something drastic in order to resume its growth. It recently reported second quarter earnings of $0.56 per share, beating the Thomson Reuters consensus estimate of $0.55 per share but declining 10% from the same quarter of the previous year. Revenue also declined 7% to $12.97 billion, short of the consensus analysts' estimate of $13.01 billion. Much of the revenue decline can be attributed to the loss of patent exclusivity for the blockbuster Lipitor a treatment for high cholesterol, and volatile emerging markets. This decline was however partly offset by a 28% increase in cancer drugs especially the newer ones such as Inlyta and Xalkori. A large portion of second quarter income came from the public spinoff of animal health business Zoetis.

Over the last few years, generic manufacturers such as Actavis (ACT) and Teva Pharmaceutical Industries (TEVA) have turned into major threats to leading pharmaceutical companies because they have used business models based on lower margins but higher volumes. They have benefited from generic versions of Pfizer's treatments such as Viagra in nine important European markets where patent protection expired this year. Plenty of other manufacturers have announced plans to launch a generic version of Viagra which generated over $2 billion in revenue for Pfizer last year, most of it from the United States where it is protected until 2020. Spinning off the generics business will allow it to focus on growth at its own pace.

The investment thesis

The company says it does not intend to spin off or sell the three new business units until 2017 but this does not preclude other large companies offering to buy the generics business. I cannot see the company not selling especially if the price is attractive. The split will take time to accomplish and add value to the stock price. You should not expect much short term capital appreciation but console yourself with a stable stock price and the 3.3% dividend yield. Keep an eye on the performance of the three separate businesses with a view to future investment.

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

Business relationship disclosure: The article has been written by an Analyst at ResearchCows, ResearchCows is not receiving compensation for it (other than from Seeking Alpha). ResearchCows has no business relationship with any company whose stock is mentioned in this article. Any analysis presented herein is illustrative in nature, limited in scope, based on an incomplete set of information, and has limitations to its accuracy. The author recommends that potential and existing investors conduct thorough investment research of their own, including detailed review of the company's SEC filings, and consult a qualified investment advisor. The information upon which this material is based was obtained from sources believed to be reliable, but has not been independently verified. Therefore, the author cannot guarantee its accuracy. Any opinions or estimates constitute the author's best judgment as of the date of publication, and are subject to change without notice.

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Knockout mouse grows larger, but weaker, muscles: Finding has implications for age-related muscle loss

Main Category: Bones / Orthopedics
Also Included In: Seniors / Aging
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Knockout mouse grows larger, but weaker, muscles: Finding has implications for age-related muscle loss

Although muscle cells did not reduce in size or number in mice lacking a protective antioxidant protein, they were weaker than normal muscle cells, researchers from the Barshop Institute for Longevity and Aging Studies at The University of Texas Health Science Center San Antonio found.

The scientists, who are faculty in the university's School of Medicine, are studying how oxidative stress in cells impacts sarcopenia - a loss of muscle mass and strength that occurs in all humans as they age.

Protein knocked out selectively

The antioxidant protein is called SOD1. The researchers developed mice that did not have SOD1 in their muscles, though it was still present in other types of cells. Then they asked the question: Is lack of SOD1 at the muscle enough to cause atrophy?

Surprisingly, the total muscle mass in this mouse was larger. "We think that lack of SOD1 could be priming the muscle to use all of its survival skills," said Holly Van Remmen, Ph.D., professor of cellular and structural biology in the School of Medicine and associate director for basic research at the Barshop Institute. "The muscle knows things aren't quite right. Its rescue mechanisms are pulled into play."

But even though the muscles were not atrophied, they were still weak.

Sarcopenia and oxidative stress

Sarcopenia in people has two components: loss of muscle mass and loss of function (weakness). This study supports the idea that oxidative stress has a role in these detrimental effects. If a way can be found to curb the effects, then healthier, more productive aging could result, Dr. Van Remmen said.

The oxidative stress theory of aging holds that oxidation from molecules called "free radicals" causes damage to cells over time, resulting in sarcopenia and other decline.

The study is described in The FASEB Journal. Future research will assess whether limiting oxidative stress can effect muscle regeneration, Dr. Van Remmen said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our bones / orthopedics section for the latest news on this subject.

This work was supported by U.S. National Institute on Aging grant AG-020591.

CuZnSOD gene deletion targeted to skeletal muscle leads to loss of contractile force but does not cause muscle atrophy in adult mice, The FASEB Journal, Yiqiang Zhang, Carol Davis, George K. Sakellariou, Yun Shi, Anna C. Kayani, Daniel Pulliam, Arunabh Bhattacharya, Arlan Richardson, Malcolm J. Jackson, Anne McArdle, Susan V. Brooks,_,1 and Holly Van Remmen, doi:10.1096/fj.13-228130

University of Texas Health Science Center at San Antonio

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Study of melittin-based pore formation has implications for fighting cancer and bacteria

Main Category: Cancer / Oncology
Also Included In: Infectious Diseases / Bacteria / Viruses
Article Date: 17 Aug 2013 - 0:00 PDT Current ratings for:
Study of melittin-based pore formation has implications for fighting cancer and bacteria

A new study by Rice University biophysicists offers the most comprehensive picture yet of the molecular-level action of melittin, the principal toxin in bee venom. The research could aid in the development of new drugs that use a similar mechanism as melittin's to attack cancer and bacteria.

The study appears in the Proceedings of the National Academy of Sciences.

Melittin does its damage by penetrating the outer walls of cells and opening pores that allow the contents of the cell to escape. At low concentrations, melittin forms transient pores. At higher concentrations, the pores become stable and remain open, and at still higher doses, the cell membrane dissolves altogether.

"This strategy of opening holes in the cell membrane is employed by a great number of host-defense antimicrobial peptides, many of which have been discovered over the past 30 years," said Rice's Huey Huang, the lead investigator of the study. "People are interested in using these peptides to fight cancer and other diseases, in part because organisms cannot change the makeup of their membrane, so it would be very difficult for them to develop resistance to such drugs."

But the clinical use of the compounds is complicated by the lack of consensus about how the peptides work. For example, scientists have struggled to explain how different concentrations of melittin could yield such dramatically different effects, said Huang, Rice's Sam and Helen Worden Professor of Physics and Astronomy.

In the new study, Huang and Rice graduate student Tzu-Lin Sun partnered with colleagues Ming-Tao Lee at the National Synchrotron Radiation Research Center (NSRRC) in Hsinchu, Taiwan, and with Wei-Chin Hung at the Republic of China Military Academy in Fengshan, Taiwan. The team used a combination of experiments to zero in on the molecular activity of melittin at the "minimal inhibitory concentration" (MIC), the lowest concentration that's been shown to slow the growth of target cell populations. The MIC for melittin is a dose that results in stable pore formation, rather than complete dissolution of the membrane.

"We want to understand how pore formation works at this critical concentration, including both at the molecular scale -- what are the shapes of the pores themselves -- and the cellular scale -- how are the pores arranged and distributed over the surface of the membrane," Huang said.

To find the answer, the team correlated the results of two different types of experiments. In the first type, which was conducted at Rice, the team used confocal microscopy to film "giant unilamellar vesicles" (GUVs), synthetic membrane-enclosed structures that are about the same size as a living cell. The outer surface of the GUV became green when bound to melittin that was labeled with a fluorescent dye. The GUV was filled with a solution that contained a red fluorescent dye.

In the experiments, Sun used a needle-like glass pipette to partially aspirate and grab dye-filled GUVs, which were then placed into a melittin-infused solution beneath the microscope. Time-lapse videos of the experiments show that dye-labeled melittin begins sticking to the surface of the GUV within seconds. Within about two minutes, so much melittin binds to the outside of the GUV that the outer surface area increases by up to 4.5 percent. At a critical threshold, the expanding surface changes configuration to accommodate the increased load of melittin. At this point, pores form across the entire surface of the GUV. On the video, the bright red dye within the GUV rapidly leaks out at this critical pore-forming stage.

"The experiment shows how the MIC brings about a new physical state that results in cell death," Huang said. "By correlating these findings with other data about the molecular characteristics of the pores themselves, we get the first complete picture of the process of stable, melittin-induced pore formation."

The molecular level data came from a series of X-ray diffraction experiments performed by Lee at NSRRC. In those experiments, samples of multilayered membranes were bombarded with X-rays. Each layer contained an ordered arrangement of pores, and the stacked layers contained a 3-D lattice of regularly arranged pores. By examining how X-rays scattered away from the sample, Lee and Hung were able to determine the precise contours of the melittin-induced pores.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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