Neuralstem Announces Topline Results Of Phase II ALS Trial

GERMANTOWN, Md., March 12, 2015 /PRNewswire/ — Neuralstem, Inc. (NYSE MKT: CUR) announced top line data from the Phase II trial of NSI-566 spinal cord-derived neural stem cells under development for the treatment of amyotrophic lateral sclerosis (ALS). The study met primary safety endpoints. The maximum tolerated dose of 16 million transplanted cells and the surgery was well tolerated.

Secondary efficacy endpoints at nine months post-surgery indicate a 47% response rate to the stem cell treatment, as measured by either near-zero slope of decline or positive slope of ALSFRS score in seven out of 15 patients and by either a near-zero decline, or positive strengthening, of grip strength in seven out of 15 patients. Grip strength is an indicator of direct muscle strength of the lower arm. ALSFRS is a standard clinical test used to evaluate the functional status of ALS patients. The average ALSFRS score for responders at 9 months after treatment was 37. Non-responders scored an average of 14. These scores represent 93%, versus 35%, of the baseline score retained, respectively, by the responders versus non-responders at 9 months, which is a statistically significant difference. As measured by an average slope of decline of ALSFRS, responders’ disease progression was -0.007 point per day, while non-responders’ disease progression was -0.1 per day, which was again statistically significant. Lung function as measured by Seated Vital Capacity shows that responder patients remained within 94% of their starting scores, versus 71% for non-responder patients. The trial met its primary safety endpoints. Both the surgery and cells were well-tolerated, with one patient experiencing a surgical serious adverse event.

“In this study, cervical intervention was both safe and well-tolerated with up to 8 million cells in 20 bilateral injections,” said Karl Johe, PhD, Neuralstem Chief Scientific Officer. “The study also demonstrated biological activity of the cells and stabilization of disease progression in a subset of patients. As in the first trial, there were both responders and non-responders within the same cohort, from patients whose general pre-surgical presentation is fairly similar. However, we believe that through the individual muscle group measurements, we may now be able to differentiate the responders from the non-responders.

“Our therapy involves transplanting NSI-566 cells directly into specific segments of the cord where the cells integrate into the host motor neurons. The cells surround, protect and nurture the patient’s remaining motor neurons in those various cord segments. The approximate strength of those remaining motor neuron pools can be measured indirectly through muscle testing of the appropriate areas, such as in the grip strength tests. We believe these types of endpoints, measuring muscle strength, will allow us to effectively predict patients that will respond to treatment, adding a sensitive measure of the therapeutic effects after treatment. Testing this hypothesis will be one of the primary goals of our next trial.” The full data is being compiled into a manuscript for publication.

“We believe the top-line data are encouraging,” said Eva Feldman MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System, and an unpaid consultant to Neuralstem. “We were able to dose up to 16 million cells in 40 injections, which we believe to be the maximum tolerated dose. As in the first trial, the top-line data show disease stabilization in a subgroup of patients. Perhaps equally as important, we believe the top-line data may support a method of differentiating responders from non-responders, which we believe will support our efforts as we move into the next, larger controlled trial expected to begin this summer.”

“The top-line data look very positive and encouraging. If this proportion of patients doing well after treatment can be corroborated in future therapeutic trials, it will be better than any response seen in any previous ALS trials,” said site principal investigator, Jonathan D. Glass, MD, Director of the Emory ALS Center. “Elucidating which factors define a patient who may have a therapeutic response to the stem cell treatment will be the next key challenge. We are hopeful that a set of predictive algorithms can be established to help pre-select the responders in our future trials.”

“We were very excited to participate as a site in this clinical trial,” said  Merit Cudkowicz, MD, Chief of Neurology, Massachusetts General Hospital and Co-Chair of the Northeast ALS Consortium (NEALS). “We are hopeful with respect to the top-line results and we need to move swiftly and safely forward to confirm the responder effect and identify people who might benefit from this treatment approach.”

The open-label, dose-escalating trial treated 15 ambulatory patients, divided into 5 dosing cohorts, at three centers, Emory University Hospital in Atlanta, Georgia, the ALS Clinic at the University of Michigan Health System, in Ann Arbor, Michigan, and Massachusetts General Hospital in Boston, Massachusetts, and under the direction of principal investigator (PI), Eva Feldman, MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System. Dosing increased from 1 million to 8 million cells in the cervical region of the spinal cord. The final trial cohort also received an additional 8 million cells in the lumbar region of the spinal cord.

The company anticipates commencing a later-stage, multicenter trial of NSI-566 for treatment of ALS in 2015. Neuralstem has received orphan designation by the FDA for NSI-566 in ALS.

About Neuralstem

Neuralstem’s patented technology enables the production of multiple types of central nervous system stem cells in FDA GMP commercial quantities. These stem cells are under development for the potential treatment of central nervous system diseases and conditions.

Neuralstem’s ability to generate human neural stem cell lines for chemical screening has led to the discovery and patenting of compounds that Neuralstem believes may stimulate the brain’s capacity to generate neurons, potentially reversing pathologies associated with certain central nervous system (CNS) conditions. The company has completed Phase Ia and Ib trials evaluating NSI-189, its first neurogenic small molecule product candidate, for the treatment of major depressive disorder (MDD), and is expecting to initiate a Phase II study for MDD and a Phase Ib study for cognitive deficit in Schizophrenia in 2015.

Neuralstem’s first stem cell product candidate, NSI-566, a spinal cord-derived neural stem cell line, is under development for treatment of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). The primary endpoints were met in Phase II. In addition to ALS, NSI-566 is also in a Phase I trial in chronic spinal cord injury at UC San Diego School of Medicine. NSI-566 is also in clinical development to treat neurological diseases such as ischemic stroke and acute spinal cord injury.

Neuralstem’s next generation stem cell product, NSI-532.IGF, consists of human cortex-derived neural stem cells that have been engineered to secrete human insulin-like growth factor 1 (IGF-1). In animal data presented at the Congress of Neurological Surgeons 2014 Annual Meeting, the cells rescued spatial learning and memory deficits in an animal model of Alzheimer’s disease.

For more information, please visit http://www.neuralstem.com or connect with us on Twitter, Facebook and LinkedIn

Cautionary Statement Regarding Forward Looking Information:
This news release contains “forward-looking statements” made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995.  Such forward-looking statements relate to future, not past, events and may often be identified by words such as “expect,” “anticipate,” “intend,” “plan,” “believe,” “seek” or “will.” Forward-looking statements by their nature address matters that are, to different degrees, uncertain. Specific risks and uncertainties that could cause our actual results to differ materially from those expressed in our forward-looking statements include risks inherent in the development and commercialization of potential products, uncertainty of clinical trial results or regulatory approvals or clearances, need for future capital, dependence upon collaborators and maintenance of our intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in Neuralstem’s periodic reports, including the annual report on Form 10-K for the year ended December 31, 2013 and Form 10Q, for the period ended September 30, 2014.

Algae-based oral recombinant vaccines

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In this journal article, the authors present to us plant-based vaccines as a real solution to impacting worldwide death rate due to infectious diseases. Infectious diseases directly account for 25% of deaths in the world. Traditional vaccines are expensive to administer from all points of view, let it be from availability, infrastructural, development, and medical personal availability. Furthermore, this high associated cost of vaccine delivery hinders the development of new vaccines for diseases that could be prevented.

The added value of plant-based vaccines is that it is orally administered and thus elicits both mucosal and systemic immunity. Additionally, they avoid the associated high costs, the need for trained medical personnel, reduce the risks of infections associated with syringes utilization and improved safety compared to traditional recombinant vaccine since there is no risk of infections by mammalian pathogens. It was estimated that the cost of plant-produced vaccines might be as much as a thousand times less than traditional vaccine production.

However, plant-based vaccines have still not made it through licensing except for one product, a veterinary injectable vaccine against Newcastle disease virus in poultry made from purified antigen expressed in cultured tobacco cells. This is explained by the low yield of the protein, less than 1% total soluble protein (TSP) in lettuce, tomato, potato, and tobacco. Even with the help of improved techniques in recombinant viral vectors or Agrobacterium mediated transformation, the end product has still a low yield and is unstable (uneven expression across the plant).

Plant-based vaccines are still the subjects of many researches as plant cells are attractive for oral vaccines. Their rigid cell walls protect the antigen through the stomach into the intestines so that they can access the gut-associated lymphoid tissue. Unfortunately, the inedible tobacco plants have proven to be the highest-yielding plant in the land species.

Green microalgae has recently attracted the interest of many industries. It has proven to be a very competent protein production platform even when dealing with complex proteins.  It has also showed that it can yield product as high as 10% TSP with a sophisticated cellular folding machinery. It has already been used to produce full-length human antibodies with varying expression rate.

The advantages conferred by those unicellular green algae are many. They have all the qualities of plant systems and numerous unique ones over terrestrial plant as vaccine production manufactory.  Indeed, the utilization of algae allows for rapid biomass accumulation and the entirety of the biomass is utilized for target protein production without having to waste energy on supporting tissue that do not produce the target protein or can’t be harvested. The authors also remind us of the importance of the fact that algae are not restricted by season, soil fertility and cross contamination risks. Furthermore, they can easily be grown in enclosed bioreactor for higher yield production, withstand long storage period at room temperature when dried, and can endure the harsh conditions of the stomach such as low pH with low antigen degradation, making them the perfect host to produce edible vaccines.

Algae have been used as vaccine production host in the past with some success. It was discovered that codon optimization was critical for high yield and for the oral administration to be effective, the antigen had to be fused to a known mucosal adjuvant such as the beta subunit of cholera toxin (CTB). During a pre-clinical trial, mice were fed freeze-dried algae for 5 weeks and 80% of them survived a lethal challenge with Staphylococcus aurea that killed all control mice within 48hrs.

The authors summarize all the algae produced vaccine up to this day and enumerate the progresses that have been done on algae research; however, the predominant problem is still the low yield of target gene. It is important to note that all those experiments were done for the most part on the same alga model organism C. reinhardtii, and that we are still in early research phase of algae produced vaccines (less than 11 years). The authors also remind us that the advances made on this model organism can be readily applied to other organisms more suited for mass vaccine production. Furthermore, algae have proved to be having a complex folding machinery for heavily disulfide-bonded proteins and are reliable—keep in mind there is no glycosylation machinery in algal chloroplasts.

There is no doubt in the authors’ minds that algae are the right hosts to produced complex vaccine antigens, and that this point was proven repeatedly in the past. For the authors, it is a question of fine-tuning the method. Indeed, even though CTB is the favored adjuvant, fusion of the protein with this adjuvant has been suggested to impair CTB’s activity. This led to many other adjuvants being researched for oral administration. The authors suggest that future work should be directed into finding the proper antigen adjuvant fusion combination as well as optimization the expression levels.

For the authors the future of algae produced vaccine is not to be questioned, but defined and refined. Indeed, given the low associated costs and logistical requirements, the authors go as far as stating that plant or algal production may be the only available option for large scale inexpensive and efficient vaccination. The authors call for investors and the pharmaceutical industry as well to seriously consider this avenue and give it the attention it deserves.

What do you think?

Y.S.H.

Induced Pluripotent Stem Cells from Bone Marrow-Derived, Peripheral Blood-Derived Hematopoietic Cells and Cord Blood.

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As mentioned in a previous article—Public and Private Cord Blood Banking: United We Stand!—umbilical cord blood obtained from the umbilical cord and placenta is a rich source of MSPC’s and HSPC’s; the latter can be used for transplantation to treat a range of malignant, genetic, metabolic, and immune disorders. In fact, it was shown that cord blood HSPC’s are more proliferative and have a greater chance of matching family members than stem cells from bone marrow. Additionally, cord blood is not only widely available and easily accessible—collection is relatively non-invasive, safe and painless—but its derived HSPC’s can even be safely infused when they are an incomplete match for the recipient due to their immunologically naïve quality.

Given the importance of bone marrow and cord blood transplants, the growing numbers of patients requiring them, their growing availability and the quality of those units, one can only wonder if those cells wouldn’t make better candidates for not only inducing pluripotency but also in making pluripotent cells of better quality for clinical use once the difficulties discussed in the previous article are overcome. Indeed, nuclear and mitochondrial mutations in adult stem cells and differentiated somatic lineages appear to accumulate over a lifetime and have been suggested to contribute to aging and cancer formation.

After many efforts, it was found that mature bone marrow derived hematopoietic cells were indeed reprogrammable into pluripotent cells, however it was more difficult than in fibroblast cells. Indeed, they initially required previous transdifferentiation into adherent macrophage-like cells through retroviral overexpression of the myeloid transcription factor CCAAT/enhancer-binding protein-beta. It was later found that less mature bone marrow derived hematopoietic cells were more easily reprogrammable into pluripotent cells.

Peripheral blood derived hematopoietic cells were found to be very bad candidates for inducing pluripotency as they are predominantly nonadherent and slow-cycling. Indeed, researchers were initially simply unable to induce pluripotency unless using G-CSF-mobilization of HSCs, however that was expensive, time consuming and was found to potentially have detrimental effects on individual donors. After many efforts, and without prior stem cell mobilization, several groups were able to induce pluripotency of different mouse and human blood lineages. However, the observed reprogramming efficiencies were typically lower than for fibroblasts.

It was found that cord blood endothelial cells were superior cells for the induction of pluripotent stem cells based on the criteria that they were adherent and actively dividing cells. Furthermore, Giorgetti et al. demonstrated that even frozen cord blood could be used to generate iPSCs with overexpression of OCT4 and SOX2 only. These cells have biological superiority and, thus, could be made available quite rapidly for thousands of patients. For example, children born with cardiac malformations could benefit from CB-iPSC-derived tissue transplants.

In conclusion, it was found that hematopoietic cells from cord blood represent an easily accessible cell source for the derivation of clinically useful iPSCs. Indeed, allogeneic and autologous cord blood from public and commercial CB banking may provide a superior and almost unlimited juvenescent cell source for the production of clinically useful iPSCs.

Y.S.H.

Applying Induced Pluripotent Stem Cells in Treating Brain Diseases

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The work conducted by the Yamanaka lab led to the discovery that somatic cells can be reprogrammed into pluripotent cells (hiPSCs’s) by introducing four transcription factors (TFs): Oct4, Sox2, Klf4 and c-Myc—the infamous gene believed to be linked to cancer. Given the highly controversial role of c-Myc, additional studies were conducted to see if those factors could be replaced. It was found that only Oct4 and Sox2 are crucial to induce pluripotency, however, the efficiency suffered significantly. The exact mechanism by which this induction happens is still poorly understood today. It is believed that the expression of the two transcriptions factors among others—that are still being tested—leads to epigenetic modifications in the cell, from which little is known, resulting in inducing a pluripotent state within said cells. This process takes several weeks before yielding a very small percentage of pluripotent cells. This poses a serious problem, which needs to be resolved before using hiPSC’s in therapeutic applications.

Another difficulty, which will also have to be addressed, is the reprogramming technique itself.  Indeed, the three most used reprogramming methods all have flaws that forbid them from being used in therapy.

The initial techniques used were done with lentiviral or retroviral transduction. They were and still are very efficient methods of inducing pluripotency, however, both vectors were found to integrate into the genome. This has for consequence to disrupt the gene at site of entry often leading to tumourigenesis. Furthermore, the expression of the TFs themselves must be regulated, as they are only needed for a set period of time, this leads to problems with differentiation. In order to respond to the difficulties engendered by this method, adenoviral vectors have been developed that do not integrate into the genome. However, the efficiency suffers and prolonged expression of the TFs remains a problem.

Given the difficulties encountered when using viral methods, non-viral methods were developed. Plasmid vectors containing the TFs’ complementary DNA’s were transfected into the cells and resulted for the most part with non-genomic integration. Because of contradictory results, another method was used: fusion of the TFs proteins to a membrane permeable peptide (constructs recombinant cell-penetrating reprogramming proteins). These peptides are broken down by the cell itself and nothing of the constructs remain inside the cells. It is labor intensive however as it requires multiple rounds of addition of recombinant proteins to ensure sufficient presence of the TFs proteins for long enough.  A new method is showing great promises with microRNAs (miRNAs), the regulatory RNAs that repress the expression of a large set of target genes post transcriptionally. It was shown that reprogramming with miRNAs was faster and approximately 100-fold more efficient than with standard viral vectors. However, viral vectors are still used to deliver the miRNAs to the cell. There are ongoing works to overcome this problem with very promising results.

Once the reprogramming techniques perfected, methods to accurately measuring pluripotency must be in place in order to determine if the end product is achieved or not after reprogramming. This in itself is a difficulty as stemness must be clearly defined before being able to qualify an iPSC as having achieved an embryonic stem cell (ESC) like state: stemness is still ill understood and poorly quantified. For those reasons, molecular assays have been created to identify ESC-like condition as well as the epigenetic status of the hiPSCs based on the detection of mRNA associated with pluripotency and promoter activity. However, even after extensive testing it is still difficult to draw conclusive results about the success of the reprogramming technique as even if resemblance to ESCs is attained it might just be that in end, resemblance. Additionally, the efficiency of the reprogramming technique, percentage of viable hiPSC colony forming cells, is usually very low and is dependent on a combination of cell state and reprogramming strategy making the entire process that much more complicated.

Nonetheless, the application of hiPSCs in cell replacement therapy for neurodegenerative diseases including PD, Alzheimer’s Disease and ALS has been the subject of great interest given its potential to repair the damaged brain. And more importantly they can be obtained from the patient own somatic cells and thus bypass immune rejection issues, the ethical issues surrounding ESCs and the very invasive protocols to obtaining neural stem cells.

In the case of PD there were very positive outcome of several studies for developing cell therapies and therefore the use of hiPSCs is being explored extensively. Different labs are trying to optimize in vitro protocols to produce large amounts of functional dopaminergic cells. There are no clinical trials for PD as of yet, but animal studies have shown promising results. Indeed, transplantation performed with iPSC-derived dopaminergic neurons improved motor function in a rat model of PD, and even resulted in an improvement of PD signs, both functionally and behaviorally. There is one major issue however the survival rate of transplanted cells is often low.  Another disease where the use of hiPSCs might be very useful is in vanishing white matter disorder (VWM), a progressive disease in which the white matter of the brain becomes increasingly abnormal and eventually virtually disappears. Indeed, the disease-causing mutations are known and, thus, genetic modification is possible using hiPSCs expanded in sufficient numbers in-vitro before transplantation. Of course the procedure still lacks safety and efficiency and no clinical trials or animal testing is underway as of today since there are no confirmed animal model of the disease yet.

In conclusion, even though hiPSCs show great promises in treating neurodegenerative diseases while avoiding the ethical concerns of ESCs and the problematic immune rejections, there are still many limitations preventing using hiPSCs in clinical settings. Furthermore, even if we overcome the known limitations, we must be aware of potential novel issues arising from using hiPSCs. Indeed, new ethical issues would have to be addressed, such as using patient-specific iPSCs derived cells without the consent of the donor, especially in the production of gametes for reproductive purposes, and, also, we would still need to confirm that differentiated hiPSCs would not trigger an immune response in the patient as well.

Y.S.H.

Regulatory Strategy in Biopharmaceuticals: Centerpiece of Corporate Planning

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As you all know, the costs associated with the development of a new drug have been and still are extremely high. Furthermore, the process itself is very risky, very lengthy and highly regulated. Nonetheless, it is still an endeavor all the big biopharmaceutical companies undertake regularly and start-ups are created everyday with similar objectives. Just to give you rough numbers, in 2009, the total dollar amount spent on research and development of new medicines by pharmaceutical companies was of approximately $65 billion ($65,300,000,000)! The average cost to develop one drug was estimated to be of about $1.3 billion in 2005 and the time required to make said medicine was, and still is, of about 10-15 years.  Additionally the number of new medicines that reaches the break-even point or makes a profit is in the number of 2 out of the 10 that actually made it through. And each drug results from the screening of about 5,000-10,000 compounds and has no more than 12 years of effective patent life… and there is always the risk of a similar product hitting the shelves at the same time or few years later or even worse, few years earlier!

So why do biopharmaceuticals invest so much in drug development and why so many start-ups are being created? Well, the returns on the 1 drug that succeeds are huge and keep on increasing.  For example, Humira, the anti-TNF inhibitor from Abbott, had annual sales amounting to $9.3 billion for the year 2012, more than 7 times the cost of developing it in just one year!

Given these huge investments and potential returns, you can imagine that the critical factors for those kinds of endeavors are to get to the market quickly, ahead of competition and in the safest and most effective way possible: welcome to the science of regulatory intelligence and strategies.

Contrary to common beliefs, regulatory affairs is not just about preparing, submitting, and maintaining an investigational new drug application, and then submitting adverse event reports if needed and then just coordinating other routine communications with the FDA. It is not just about ensuring compliance… it is much more than that. Regulatory affairs is intertwined with every department in the company, and proper cooperation and coordination is of essence to insure corporate success. Indeed, regulatory affairs guides the direction of various corporate activities from a regulatory point of view with serious implications on the management and growth of the entire company or department. It is of the upmost necessity for corporate management to include regulatory thinking and planning in day-to-day decisions, as they not only affect drug development plans but also market determination, marketing, business development, finance, human resource, technology, manufacturing, risk management, insurance policies, etc.

Regulatory strategy is based on those exchanges with different internal, external and regulatory influences and is an ever changing, highly dynamic and determining science for any biopharmaceutical company, no matter its size. Indeed, it is the regulatory strategy that determines the plan for developing the drug with the objective of obtaining the right regulatory approval in the target market faster, safer and in a more cost effective manner than anyone else while properly managing and maintaining the life cycle of the drug after the approval was obtained.

The regulatory group must be aware of the very frequent changes in regulations and must be able to comply with or make use of them in the case they encompass the drug their company is developing—in consequence guiding the corporate management to take the appropriate measures to show that the drug does indeed meet expectations of the newly adopted regulations. The regulatory group must do so in record times while maintaining cost efficiency and safeguarding the competitiveness of their product compared to the competitors. A very good example of a regulatory influence that drastically changed drug development to treat serious diseases and fill an unmet medical need is the FDA Fast Track Development Program.

The reason behind why the FDA introduced that program was to get important new drugs on the market faster to patients suffering from a serious disease. The FDA considers a disorder serious on a case per case basis. However, it is generally centered on the impact the drug will have on clear factors such as survival, day-to-day functioning, or on the probability that the disease might progress from a less severe condition to a more severe one if left untreated. Examples of disorders considered serious are AIDS, Alzheimer’s, heart failure and cancer. Though, epilepsy, depression and diabetes are considered serious disorders as well. Unmet medical need on the other hand is defined as introducing a therapy, which was nonexistent or is potentially superior to the existing one(s), i.e. any drug to treat or prevent a disease which has no treatment available would qualify. Furthermore, even if there are existing therapies, the drug would still qualify for the Fast Track designation if it showed superior effectiveness, avoided grave side effects of the existing therapies, improved the diagnosis of a serious disease resulting in an enhanced outcome, or decreased accepted significant toxicity of available treatments.

That designation is quite useful and very sought-after by pharmaceutical companies since, if the drug qualifies for it, it becomes eligible for early and more frequent meetings with the FDA in order to ensure the drug’s development plan and collection of the needed data in order to support drug approval. But there is much more! The drug becomes entitled to more frequent written correspondence from the FDA about matters like the design of the proposed clinical trials. The drug can also become eligible for the Accelerated Approval regulation where surrogate endpoint—an indirect laboratory measurement that is used in clinical trials to represent a clinically meaningful outcome, such as survival, without however being itself a direct measure of it—becomes sufficient to likely predict clinical benefits of the drug, i.e. it shortens considerably the time required prior to receiving FDA approval… we are talking years shorter! Additionally, the drug becomes also eligible for Rolling Review where the biopharmaceutical company can submit completed sections of its New Drug Application for review by the FDA without having to wait until every section of the application is completed before the entire application can be reviewed—The New Drug Application does not usually starts before the company has submitted the entire application to the FDA! And of course, any drug in the Fast Track Program receives a Priority Review, and we all know how important that is when it comes to the FDA.

The pharmaceutical company can request the Fast Track designation at any time during drug development and, usually, the FDA will make its decision available within 60 days! It is important to note however, that the FDA requires the biopharmaceutical company to conduct additional clinical trials after it receives approval under the accelerated approval program, and while its drug is on the market, to confirm the drug’s direct benefits and validity.The regulatory affairs group cannot elaborate a strategy the same way when aiming for Fast Track designation as it would for the normal track. The average time saved using the Fast Track is between 3 and 6 years compared to the normal track—and sometimes half the time of the normal track is sufficient to have the new drug on the shelves with the associated cost savings and that much longer effective patent life! In fact, the strategy elaborated by the regulatory affairs group will determine how corporate management will handle company growth, day-to-day decisions, finance, human resource, technology, research and development, marketing, etc. In truth, the regulatory affairs group is in the “hot seat” in the drug development process.

Y.S.H.

Social Entrepreneurship in Biotechnology

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We all know the biotech start-up life cycle and how it is valued. It all starts when the founders meet with the seed investors. The founders are usually people with technical expertise from academic institutions or even large biopharma companies who possess the intellectual property of a new technology, discovery or even simply to an innovative idea that is generally valued at an average of $1M. The seed capital usually comes from the 3F—friends, family and fools—or from angel companies or even government grants. The usual amount needed is of $2M, which put the start-up company at a value of $3M; 33% shares for the founders and 67% for the seed investors. The company is then brought to maturity if all goes well by going through the infancy and adolescence stages—raising additional funds, advancing drug candidates, building a strong structure and management team till the company has led candidates in phase 2/3 trial and is robust. Usually, at the maturity stage, the company is valued at about $24M, with 62% of the shares for the venture investors, 25% for the seed investors and 13% for the founders. At this stage, the start-up is either acquired and assimilated by one of the large biopharma companies for 150% of its market value, or it becomes an independent public biotech company in hope of conquering the market for the duration of its patent(s)—in order for the investors to make their money back, usually they sell their shares during the IPO for 4-6 times its market value. This is typically how a new biotech company functions…it is all about return on investment…you would be surprised at how many discoveries and new technologies go down the drain every year because investors can’t see the adequate return on investment on them. But what if there were a different way, a better way to create and value a new biotech company?

The recent years have seen a growing trend in the bioscience field, the partnership of the public and private sector in order to mobilize resources to be able to develop new technology based solutions to incur long and lasting positive social development and changes: Social Entrepreneurship. I know you probably think that it is just another social initiative created to generate some kind of awareness to raise funds, in other words, for most of you social entrepreneurship merely provides a different “social” setting in which to implement a new entrepreneurial project…and you might be right…might be. Social entrepreneurship is still in its infancy and is barely understood. Without any available real empirical knowledge to set it apart from anyone who claims to be bringing in social changes and still lacks a successful model even though there are plenty of successful social entrepreneurs today all around the world. Those people have not only impacted positively on their communities, their cities, but also on their countries and even on the world. But before we tackle social entrepreneurs who should be taken as an example, let me first try to better define social entrepreneurship, or at least try to!

First, it is good to remember that starting a business, according to economists Say and Schumpeter, is not the main goal of entrepreneurship. Stimulation of economic progress through innovation and action is actually the main objective of entrepreneurship. Social entrepreneurship on the other hand is about compassion for humankind and about inducing positive social changes. Social entrepreneurship should not be confused with charity, as social entrepreneurship is about investing in social ventures, which can then generate their own revenues to sustain themselves without relying heavily on donor funds. Social entrepreneurship aims to bridge the gap between business and benevolence by applying conventional entrepreneurship in the social sphere; it integrates economic and social value creation in order to achieve a long heritage and a global presence…how do you integrate economic and social value creation do you ask?

Well, economic value is basically a measure of return on investment, deb/equity ratios, price/earning ratios and various other econometrics. Social value on the other hand is created when resources, inputs, processes or policies are combined to result in improvements in the lives of individuals or society as a whole, such as anti-racism efforts, community organizing, and environmental protection. Social value is difficult to quantify into dollar value. In order to integrate both values, a social enterprise must be able to increase the value of the resources or inputs it utilized and then generate cost savings and/or revenues for the public sector—its community. By doing so, it is possible to quantify and monetize the elements of an activity’s social value. Indeed, these cost savings and revenues can be achieved in decreased public dollar expenditures and in increased revenues to the public sector through additional taxes collected, effectively translating the enterprise’s activity’s social value into socio-economic value.

It is not an easy task for a social entrepreneur to achieve such a goal, and it is even more difficult to convince potential investors to become social investors at the price of sacrificing financial return in favor of social return—the social investor takes on more financial risks compared to the traditional investor, twice or even thrice the risk, in order to achieve social or environmental impact. Social entrepreneurs and social investors are different breeds of people altogether. A social entrepreneur is by definition an individual, group, network, organization, or alliance of organizations that seeks sustainable, large-scale change through pattern-breaking ideas in what or how the governments, nonprofits, and businesses do to address significant social problems. Social investors are people, more often than not called philanthropists, who wish to invest their money in causes they feel most passionate about in order to incur social changes.

One of the most famous social entrepreneurs of our time would be Virgin founder Sir Richard Branson, and one of his latest “folly”, Virgin Stem Cell Bank, one of the pioneer hybrid model of cord blood banks, was created in order to respond to the fact that an increasing number of children were dying through lack of umbilical cord blood. Initially, Sir Richard had offered 3 million pounds to the National Health Service (NHS) to help them increase their storage capacity, but the NHS was not comfortable accepting funds from private sources, so Sir Richard decided to set up a company to do the job with a unique approach: “an individual’s cord blood is harvested at his expense and divided in two, one will go into a national blood center where anybody can get access to; the other half will be stored for the child. Furthermore, the generated profits will go to a charity to help groups who have difficulty sourcing cord blood due to lack of sample matching.”

So readers, what say you? Is social entrepreneurship in bioscience real or does it merely provide a different “social” setting in which to implement a new entrepreneurial project? If you think it is real, what are you waiting for? Stop looking for the right opportunity to fall on your lap and start creating it for your community and yourself!

Y.S.H.

Public and Private Cord Blood Banking: United We Stand!

cordbloodunit

The recent years have been witness to revolutions in the medical fields in many aspects, and more specifically in the development of applications in regenerative medicine. One of the most promising and fastest growing fields of regenerative medicine is cellular therapy for both personalized and generalized treatments. Indeed, incredibly innovative approaches have been and are being developed to treat degeneration of tissues and organs due to aging or damage using stem and progenitor cells. This led to an increase in cell therapy revenues from $410M in 2008 to $5.4B in 2012, truly marking our entry into the age of the cell and making cell-based therapeutics the next pillar of medicine; virtually every branch of medicine will see direct application of cell therapies.

Stem and progenitor cells are undifferentiated cells, which, under the right conditions, can differentiate to become virtually any type of cell that makes up the tissues and organs in the body. This ability makes stem and progenitor cells ideal for use in proven and novel clinical therapies to replace defective or damaged cells resulting from a variety of disorders and injuries as well as for use in research. Stem and progenitor cells provide the foundation for cell therapies and, amongst the different types of stem and progenitor cells, none has been more researched, funded and commercialized than mesenchymal and hematopoietic stem and progenitor cells (MSPC’s & HSPC’s respectively) typically found in bone marrow in large quantities.

Recent data show however that umbilical cord blood obtained from the umbilical cord and placenta is a rich source of MSPC’s and HSPC’s; the latter can be used for transplantation to treat a range of malignant, genetic, metabolic, and immune disorders. In fact, it was shown that cord blood HSPC’s are more proliferative and have a greater chance of matching family members than stem cells from bone marrow. Additionally, cord blood is not only widely available and easily accessible—collection is relatively non-invasive, safe and painless—but its derived HSPC’s can even be safely infused when they are an incomplete match for the recipient due to their immunologically naïve quality. In spite of this, cord blood is still routinely discarded as hospital waste along with the umbilical cord and placenta following birth when it should be collected, processed, tested and banked for future therapeutic use, especially since, until now, 50 percent of all patients seeking a transplant cannot find a match.

There have been more than 30,000 transplants worldwide using cord blood derived HSPC’s and the demand is still growing fast. Indeed, the National Marrow Donor Program estimates that by the year 2015, there will be 10,000 cord blood transplants worldwide per year as opposed to 3,000 per year in 2010. From 23 active cord bloods as of 2005, the Bone Marrow Donors Worldwide (BMDW) currently list 44 public cord banks from 26 different countries and there are approximately 225 private cord blood banks worldwide. That is an eleven fold increase (1,100 percent) in the companies involved in the industry over only a seven year period, and yet, the market is far from being saturated as the offer still cannot meet the demand—both in number and quality.

There are two main types of cord blood banks: licensed public banks, which ask mothers to donate their umbilical cord blood—only the umbilical cord blood—for future use by anyone who may be a potential match, and private or family banks, which will store cord blood, tissue and/or MSPC’s from either or both the umbilical cord and placenta for future use by the donor or matching family members for an average fee of $1,600 per item plus an annual storage fee of around $100 per item. Historically, public banks have been not-for-profit while private or family banks have been for-profit enterprises. The private cord blood industry has been criticized by a number of professional bodies including the EU ethics Committee and the Royal College of Pediatrics because the medical utility of private cord blood banks is believed to be more potential than actual and, thus, private cord blood banks threaten the supply of cord blood units to the public system which is based on actual needs and not potential ones.

It is important nonetheless to point out that the private banks are founded on the autologous (cells derived or transferred from the same individual’s body) business model, where cells are harvested from the patient to be treated in a facility before being shipped back to the physician for delivery into the same patient, who is thus both the donor and recipient. The allogeneic (cells derived from separate individuals of the same species) business model on the other hand is based on mass production of aliquots of cells from a single healthy donor to be shipped to the physicians for subsequent delivery into the patient—the allogeneic model being the preferred one by the big biopharmaceuticals companies of course. Against common belief, the autologous business model is far from being unsupported or unsound since there are currently over 650 FDA clinical trials involving autologous and allogeneic applications of MSPC’s and HSPC’s with a clear bias to autologous approaches as they don’t provoke an immunological response by the patient. In fact, recent data have shown that, in reality, it is not autologous vs. allogeneic but autologous and allogeneic as there is room for both therapies in treating patients, even within a single diagnosis.

Until recently, only one alternative existed to both the public donation and private storage: directed donation of cord blood donated to public banks to siblings who have an existing condition that may in the future require an allogeneic transplant. This alternative nonetheless was simply not good enough for parents who wanted to take a form of biological insurance to safeguard their children’s future and who understood the potential of autologous therapies and the advantages early-stage stem cells as opposed to adult stem cells—many studies showed greater proliferative capacity and greater plasticity of newborn stem cells as opposed to same types of stem cells harvested from adults. Furthermore, with the growing awareness of parents of stem cell therapeutics, a deeper commitment to research and development of stem cell therapeutics by the banks was expected: regenerative medicine is to be included in the world of tomorrow today. This situation gave rise to new kinds of umbilical cord blood banks—hybrid models that combine aspects of both the public and private systems with a clear commitment to research and development in the field of stem cell therapeutics.

The hybrid models can be classified into two broad categories: the cord blood banks that offer both options, either private storage or public donation, and the cord blood banks that make the privately stored cord blood available to the public system. The first category is the most prominent one in North America and Belgium and keeps gaining popularity with the recent announcement that the major public banks have agreed to expand their services to offer private storage. The second category is the most popular one in Spain, Turkey, the U.K. and Germany, each with its own characteristics. Indeed, In the Turkish model, according to government legislation, 25 percent of all privately stored cord blood is donated to the public system. In the Spanish model, cord blood stored in a private bank is registered on the Official Spanish Register of Bone Marrow Donors and should a patient in need of a transplant find a match in a private bank, parents are obliged to donate said cord blood and the storage fee is reimbursed. In the U.K., the Virgin model comes to mind where 80 percent of the privately stored cord blood is donated to the public system for allogeneic transplantation. And finally, in Germany, should a patient needing a transplant find a match in a private bank, the bank asks for permission to the parents for release, however, as opposed to the Spanish system, the parents are under no obligation to accept.

No matter the outcome of which hybrid model is the best, both public and private cord blood banks are now working together to implement new stem cell therapeutics and allow for a greater number of patients needing a transplant to actually find a matched donor.

Y.S.H.