Israel and Stem Cells

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In the Israeli stem cell arena – contrary to what many expected – adult stem cells (ASCs) seem to be outdoing the embryonic ones (ESCs). Israeli researchers were among the pioneering developers of ESC technologies, due in part to relatively unrestricted government and societal support.

Unlike the US and many European countries, where political leaders opposed the use of human embryonic cells for research on the basis of Christian religious beliefs, in Israel, rabbinical authorities supported scientific exploration in this area for a positive reason, as well as for the lack of a negative one. Orthodox Jewish belief maintains that a human does not come into being until about 30 days after conception; there was a strong positive, since the same doctrine takes a very activist line about using every possible means to ‘save human lives.’

Consequently, Israel soon became the leading publisher of stem cell research per capita in the world (as reported in a 2006 German study by the Central Library of the Research Center Julich), and a national academic-industry consortium known as Bereshit (Genesis) was formed.

But despite a flurry of academic research, few ECS startups materialized. Currently only one company, Cell Cure Neurosciences, seems to be within reach of a clinical study. Cell Cure today is focused on an ESC product for age-related macular degeneration (AMD).

While the number of ESC technology-derived companies remains small, a substantial number of ASC companies have sprung up. Among them: Gamida Cell, with a Phase III trial underway for patients with blood cancers, such as leukemia and lymphoma, who cannot find a family-related matched bone marrow donor; Pluristem, preparing Phase II trials for placenta-derived stem cell products for the treatment of Peripheral Artery Disease and Critical Limb Ischemia; and TheraVitae with a product in a clinical trial for the treatment of angina pectoris.

Now, another ASC company is on the verge of a clinical trial: BrainStorm Cell Therapeutics, developer of an autologous technology that produces differentiated stem cell products, is about to begin a PhaseI/II study for Amyotrophic Lateral Sclerosis (ALS). The trial has garnered much attention, both because of its stem cell technology and as a consequence of the closely watched indication that is its initial target.

ALS is known to many as Lou Gehrig’s Disease, in reference to the famous American baseball player who was stricken at the height of his career in 1939 at age 36 and died two years later. The disease has completely frustrated researchers ever since, with no therapy being able to stop the almost certain and rapid deterioration that was also the fate of the protagonist in the American best-selling book, Tuesdays With Morrie.

BrainStorm has shown promising preclinical results with a technology that processes adult human mesenchymal stem cells derived from the patient’s own bone marrow. The treated stem cells are differentiated into astrocyte-like cells capable of releasing neurotrophic factors, including glial-derived neurotrophic factor (GDNF). The astrocyte-like cells are intended to be neuroprotective and have a positive impact on ALS as well as on other neurodegenerative conditions like Parkinson’s disease, multiple sclerosis and spinal cord injury.

BrainStorm’s trial will be the first differentiated stem cell human study in Israel, and only the second stem cell trial for ALS in the world, after the US-based Neuralstem clinical trial, using fetal neuronal stem cells, which began last year.

Although BrainStorm has yet to start its trial, it could actually finish ahead of the Neuralstem trial. The latter involves injection of stem cells into the spinal cord of the patient and the trial is moving ahead at a carefully monitored and measured pace. BrainStorm, with a relatively simpler and safer autologous technology involving injection into the muscles or spinal cord, could have preliminary results within 6 months of the start of its trial, scheduled to begin shortly.

It is still too early to say whether it will be an ASC or ESC technology that produces the first commercial product to reach the market; but researchers from both sectors agree that they all owe a fair amount to each other, as there has been a great deal of information sharing and cross-pollination of ideas. Despite the differing sources of the stem cells, many of the processes employ similar methods.

The pooling of Israel’s stem cell resources could gain an additional boost from an international source. According to a news report published earlier this year in the Globes financial daily, Roche Holding AG is about to fund the establishment of a new Israeli stem cell consortium. The consortium will be created in partnership with the local Pontifax VC fund and will based on the intellectual property rights of Israeli universities, in particular the research of Prof. Joseph Itskovitz-Eldor of the Technion Institute of Technology, and Prof. Nissim Benvenisty of the Hebrew University of Jerusalem.

Bernard Dichek

Implications of Financing Your Biotechnology Start-up

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Starting a biotechnology company requires thoughtful strategies for the development of your product, and for your intellectual property portfolio, team, and many other areas. One such key aspect is your financing strategy. Deciding on what types of capital to raise and how much financing is required has major implications for the type of business you can operate, the amount of control the founders retain, and the types of exits available. In this post, I discuss the implications that financing has on two critical aspects of your business: the dilution of founder’s equity and the exit options available after financing is secured.

Dilution. When an entrepreneur takes money from an investor, the investor receives a percentage of the company that is proportional to the amount invested. For example, say you and your investor agree that your company is valued at $500,000 (this is called the pre-money valuation), and that the investor will give you $1,000,000 to operate your business for the next 12 months. Following investment, your company will have a valuation of $1,500,000 (the post-money valuation = pre-money valuation + investment cash) and your ownership will be diluted to 33% from 100% of the company. Dilution is an inherent aspect of equity financing, however this affect has the greatest impact when the company is at its youngest and has its lowest valuation. In the accompanying figure, I outline four scenarios that demonstrate the significance that the ratio of money raised to pre-money valuation has on the resulting founders’ percent ownership.

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Figure 1: Dilution following financing. Red indicates investor’s funds and resultant investor equity; blue indicates pre-money valuation and resultant founder’s equity.

In most areas of biotech, particularly in therapeutic, medical device, and diagnostic areas (where the regulatory burden requires significant capital investment), it is expected that investor financing will be required and that investors will become significant shareholders of the company. In fact, most companies require multiple rounds of financing, which can compound the dilution effect. As such, entrepreneurs should put in efforts at the earliest stages of their companies to fund their work using alternative financing sources in replacement of, or in addition to, traditional investors. These ‘non-dilutive’ sources include academic grants, government funds, industrial partnerships, making sales, etc., and allow entrepreneurs to retain control of the company while providing much needed operating cash. A savvy entrepreneur will use these funds to conduct critical proof-of-concept work that can increase the company’s valuation, leading to reduced dilution in future financings. In upcoming posts I will more specifically outline potential sources of non-dilutive funds in North America and give examples of how companies, including my own, are primarily funded by such sources. I will also discuss the cons of these monies, which can include an increased effort to secure, constraints on the use of capital, reporting requirements, and others.

Exit options available. A less well appreciated aspect that financing has on your business is how it can dictate the exit options available to your company. For example, compare two founding teams, NewCo A that raises $1 million from investors and NewCo B that raises $10 million. For simplicity, assume that in both cases the companies have a $1 million pre-money valuation, and both sets of investors expect to receive a 10x return on their investment upon exit. As shown in the table below, the two investments create very different business requirements for these companies.

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Whereas it may take a successful entrepreneur 3 – 4 years to build a $10 – 20 million company, it will likely take 7 – 12 years to build a company to a >$100 million valuation, and the probability of achieving such a level of success is lower. Considering that the founding team will receive the same absolute return upon exit (10 x $1 M = $10 M), the founders’ incentives for these two scenarios needs to be carefully considered. In addition, the methods of exit of the two companies are very different. For the smaller company, NewCo A the exit will likely be through an acquisition from either a large or medium sized company looking to expand their businesses or product line. The larger company, NewCo B, may exit through an initial public offering (IPO) on a public stock exchange or through a large acquisition by a large company. Based on the financing strategy chosen, the management team will need to align their skills and other elements of their business with these very different outcomes.

In summary. The capital requirements of your business will determine the amount of money that needs to be raised. Although simplistic, the financing scenarios I outline above start to demonstrate the impact that a financing strategy will have on your business. Alternative business models or the use of non-dilutive funding sources can help to reduce the amount of investor money required at the earliest stages of your company. In future posts I will describe alternative funding sources and the advantages and the costs associated with these monies.

Further reading. To have an understanding of how financing and dilution impact a business and its founding team, have a look at the resources put together by Venture Hacks (includes workable cap-table in spreadsheet format).

Basil Peters, an entrepreneur turned angel investor based in Vancouver and Silicon Valley, has written extensively about the impact financing has on exit strategy. I highly recommend both his book Early Exits and blog Angel Blog.

(For further opinions and insight into biotechnology, technology, financing, and innovation please see my blog at: www.persistentchange.com ; twitter: @jtbiotech)

James Taylor