The News Net

This week in the Net: bioentrepreneurism gets a boost from initiatives in Dubai and Cuba; and an incubator hatches in Moscow. Happy weekend reading.

 

 

  • The government of Dubai’s ongoing efforts to become the major biotech hub in the Middle East is spotlighted in GEN. Among the 120 companies now installed at DuBiotech and taking advantage of its 22 million square feet of space and “purpose-built” features are Pfizer, Bristol Meyer Squib, CHR Hansen and Firmenich.
  • Cuba’s government has created a new biotech-pharma combine made up of 38 companies. The group, called BioCubaFarma, will be guided by “business principles” in line with recent reforms enacted by Cuba’s Communist Party to update the country’s socialist model. The reforms also include broadening the scope for private business and plans to lay off 500,000 state employees through 2015. Read the story from FOX News here.
  • The Moscow Times reports on Formula BIO, the first Russian biotechnology incubation program designed to boost innovation and commercialization in the sector. Set up jointly with the Russian Venture Co., Formula BIO is focused on helping medical and biotech startups. Read the full article here.

Alma As Example

Biotech entrepreneurs looking for new ways to start a company on the global stage may find the example of Alma Bio Therapeutics inspiring and instructive.

The start-up with a platform technology in the field of auto-immune and inflammatory diseases was established in December 2011 by Irun Cohen, a professor emeritus at Israel’s Weizmann Institute; Raanan Margalit, an expert in preclinical drug development; and Dr. Binah Baum, an experienced biotech executive who is well-networked in the European bio-community.

The three Israeli founders established their business in the Basel Biotech Incubator in Switzerland and financed a preclinical trial out of their own pockets. In doing so, they have shown it is possible to establish a company outside of one’s  home turf and get to proof-of-concept without relying on outside investors.

Baum explains the choice of the Swiss location as being related to access: several big pharmas that are likely candidates for collaboration are in that area or nearby in Germany, Austria and France. Also, the European venue increases the startup’s visibility among angels and private investors. In Israel, by contrast, she notes that VCs are primarily focused on medical devices rather than early stage biopharma, though she says it’s possible they might establish a presence in Israel later on.

The company’s IP is based on original research by Prof. Cohen at the Weizmann Institute. Several years ago, that IP was reassigned back to the inventor by the Institute’s technology transfer agency.

As a combined result of the previous and current studies, Alma has already obtained six major patents. The company chose inflammatory bowel disease (IBD) as its initial autoimmune indication. At a later stage, it plans to apply its platform to chronic pathological inflammatory diseases.

Alma’s technology is built around leveraging heat shock proteins (HSPs) that are implicated in the immune system’s control over inflammatory diseases. Discoveries made in this area by Prof. Cohen have already led to the development of a drug by Andromeda Biotech for Type I Diabetes; it is currently in Phase III.

Alma’s goal is to treat IBD in a curative and non-toxic manner by introducing heat shock proteins in the patient’s body that can regulate the level of inflammation in a controlled manner. Rather than use recombinant proteins, the HSPs are introduced through changes in the DNA coding.

The entrepreneurs note there is no disease-modifying therapy available for IBD, a condition currently attracting intensive R&D efforts in the pharmaceutical industry.

Upon reaching Phase I/II, Alma’s founders are confident that investors are likely to gain a relatively fast and high multiple return once a deal is made with a pharma company.

Bernard Dichek

The S-3 Barometer

Access to capital is essential for development-stage biotechs, yet the capital markets for public and private biotech companies are notoriously fragile. For private companies, venture investing in the life sciences has recovered from a rough patch in the ’08-’09 span to the robust financing environment in last year and a half. In the public markets, IPOs haven’t fully rebounded to historical levels, but follow-on financings and debt deals have been brisk as the biotech sector has performed extraordinarily well in 2012. Indeed, the NASDQ biotech index is up ~35% YTD at the end of the third quarter.

Public biotech companies have a mechanism, a shelf registration statement (or S-3, as it is known in SEC terminology), to register securities in advance of their issuance. The securities are “put on the shelf,” generally speaking, allowing them to be sold at any point within the 3-year lifespan of the shelf registration statement. One would think that having an active shelf registration on file is a must-half for public biotechs; they exist in a topsy-turvy macroeconomic environment compounded by the highs and lows of product development. Allowing them to raise money opportunistically and take advantage of strong capital markets or simply strong interest in their stock should be a good thing.

However, this is not the typical view. The filing of a shelf registration statement is often met with derision, and considered a bad omen that shareholder dilution is around the corner. If you follow any of the biotech stock watchers on Twitter, you know what I mean. My sense is that complaints arise primarily for three reasons:

  1. Investors seek to avoid dilution, and the issuance of new shares via draw downs from a shelf dilutes existing shareholders.
  2. Filing of an S-3 shelf registration signals to the market that a financing is forthcoming, thus creating an overhang on the stock, depressing its performance. In other words, why should big institutions buy shares in the open market if they can simply wait and buy in an upcoming follow-on financing?
  3. An active shelf is like a credit line for management that can be tapped at their discretion, so incentives are not fully aligned with shareholders if shelves are utilized haphazardly.

I don’t like dilution either, and I don’t like the artificial feel to the market cap increases that result from the issuance of more shares. But is there empirical support to the notion that S-3 filings predict subsequent financings? Is filing an S-3 a reflection of management and corporate strategy or a fact of life for R&D stage biotechs?

To address these questions, I looked at new shelf registration statements filed between Q2 2008 and Q2 2012 by US-based small cap biotech companies devoted to new drug discovery and drug development. I defined “small cap” as less than $1 billion, as this captures the vast majority of pre-commercial companies. I restricted the list to drug discovery and development companies because a) their value is largely “technology value” — the value ascribed to their development programs above the cash balance, and b) their cost of capital is heavily influenced by the perceived value of their technology.

During this period, I tallied 269 new shelf registration statements by 180 companies (some companies filed more than one, a replacement to an existing shelf that was either depleted or not). By my calculation, there are approximately 340 US-listed, small cap drug development companies in the sub-$1 billion range, so around 50% of these utilize shelf registration statements. Filing S-3s are not a universal capital-raising strategy.

But S-3 filers are a diverse group, with market caps at filing of between $11 million and $840 million. Further, the size of the shelf (that is, the total amount of capital that can be raised by the securities contained in the shelf) varied as well, though there was a slight trend for larger market cap companies to file larger S-3s. Of course, shareholders are interested in “implied dilution,” or the dilution that would occur if the entire shelf was drawn down. As expected, the implied dilution, or the ratio of the shelf size to market cap at filing, tends to be larger for small companies, but as shown in the figure (click to enlarge), there are some significant outliers. I assume that shelf size is related to the cost-intensiveness of future development plans, but perhaps I’m giving management too much credit. 

Is an S-3 filing a harbinger of a near-term financing? The data say: Yes. Of the 269 shelves, 207 (77%) have raised money. Of those 244 S-3s filed before January 1, 2012, that number rises to 82% (199 of 244). If one excludes those companies that were acquired with an active shelf in place (e.g., ISTA, ANDS, INHX, CLDA, ISPH, ADLR, MITI, PRX, PPCO), the number is closer to 85%.

The average time to the first financing was 207 days, with a median of 240 days. The magnitude of the first drawdown covered the full range, from 1% of the shelf to the full 100%. As shown in the figure, the majority of the first financings raised 50% or less of the full shelf value.

 

Taken together, the data around S-3s in recent years, a period of economic hardship, indicate that:

  1. Only about half of small cap therapeutics companies file shelf registrations
  2. For those that do, the overwhelming majority utilize them, usually in about 6 months
  3. The first drawn down is usually 50% of the shelf or less, which could give shareholders an estimate of the extent of dilution at a first raise.

Of course, as I noted above, raising money is a necessity for biotech, so noting here that they do, via the shelf mechanism, is somewhat self-evident; if a company files a shelf, why not use it? More important is when and how.  Ideally, shelves are utilized at opportunities when share price is high. Remember that S-3 remain active for three years, so market cap at the time of shelf drawn downs is perhaps a more important metric than market cap at the time of filing. If share price rises (and so market cap) during that time, the implied dilution would decrease.  These are questions to explore in future posts.

I should note that, in the process of compiling these data, I put together a fairly extensive spreadsheet with numerous metrics related to S-3 filers, such as stock performance, extent of insider holdings, estimated runway at the time of filing/draw-down, share price at first raise, etc. If any readers are interested in a particular question, please let me know in the comments below or via direct message on Twitter and I’ll see if I can address it with my database.

Adam Bristol

Unlocking the Molecular Diagnostic Interpretation Bottleneck

As noted in the news feature Direct-to-consumer genomics reinvents itself, 23andMe has filed to secure 510(k) clearance for some of its genetic tests, which poses the question of whether a foot in the door at the FDA will increase demand and re-energize the direct to consumer (DTC) genomics market?

FDA approval is undoubtedly an important step, but it will not address the most fundamental bottleneck to growth of the DTC market. The far more fundamental problem to the evolution, growth and value of genomic testing, whether DTC or through a physician-driven model, is the inability to scale the interpretation of these tests and the need to improve, by several orders of magnitude, the speed and quality of interpretation and variant classification.

For decades, clinicians have been running tests of a single gene or a small panel of genes for tightly defined phenotypes. These tests have emphasized clinical validation or confirmation of a clinical hypothesis, and the tests have generally been limited to genetic variation associated with broadly accepted clinical guidelines and benefits. Even so, a small- to medium-sized lab employs five to 10 medical geneticists and pathologists to interpret, score and report on these tests.

As the industry moves to testing with larger gene panels, exomes and whole genomes, and as we target these tests to more complex and multiple phenotypes, the time and complexity of interpreting these tests will grow exponentially.  Add to this the desire to run millions of tests per year, and the interpretation becomes intractable with current solutions. No clinical geneticist can handle the enormous complexity, and no testing lab can hire enough medical geneticists to scale and address the need with currently available solutions.

The bottom line is that for the DTC and molecular diagnostic market to grow much beyond its current state and realize its full potential, the industry needs to develop fundamentally new content and software solutions that deliver many orders of magnitude improvements in the time, quality and cost to interpret and classify genetic variation.

At Ingenuity, we think in terms of comprehensive curation of all known human phenotype variations from peer-reviewed literature and computationally tractable models of biology that allow us to more fully understand the impact of genetic variation on the biological system.

Easy-to-use software that enables clinical geneticists or pathologists to quickly and with high confidence produce test reports with clinical relevance and impact is the solution. Until innovative companies and the scientific community solve this problem, no amount of FDA clarification, sequencing technology improvement or reduction in the cost per test will materially alter the market dynamics. By every estimate this is a daunting task, but science had the ingenuity to drop the price of sequencing faster than Moore’s law over the past 10 years, and now together we need to focus our attention on unlocking the full market and clinical potential by addressing the interpretation bottleneck before it becomes a showstopper.

Jake Leschly, CEO, Ingenuity Systems