The Inescapable Gravity Of Biotech’s Key Clusters: The Great Consolidation Of Talent, Capital, & Returns

Posted March 21st, 2017 in Bioentrepreneurship, Biotech financing, Boston Cluster, Talent | 5 Comments

Two key geographic clusters dominate the biotech landscape today. These two areas, Boston and San Francisco, combine a unique blend of biomedical science, venture capital, entrepreneurial talent, risk-taking culture, and geographic density. Other regions have some or all of these elements, but not in the same magnitude or momentum that Boston and San Francisco have today – and the gap is just getting bigger.

Last year, GEN ranked Boston #1 and San Francisco #2 in their biotech clusters report (here). Others have covered these clusters and the rivalry between them (here), as the Economist did with “Clusterluck” earlier in 2016. But rather than draw distinctions between them, I’d like to focus on these key clusters relative to the rest of the biopharma ecosystem.

Context

Relative to the US biotech scene, Europe is often viewed as a laggard in the biopharma space from an entrepreneurial perspective. Of course, there are notable exceptions – like Actelion’s incredible success – but, by and large, there’s limited funding, limited R&D-veteran entrepreneurship and risk-taking, and limited prospects for scaling companies. While there is great science across many world-class research institutions in Europe, the commercialization of their science into local startups and emerging biopharma companies remains a challenge.

Two relevant analyses were captured in the data-rich report from HBM Partners on the M&A environment which highlight the essence of this challenge from a venture perspective: US-based biotechs drove faster exits (here) with higher investment return multiples (here) than their EU counterparts.

These data are striking.  But how much of this outperformance was driven by the two key clusters in Massachusetts and San Francisco? (I’ll refer to them as the “key clusters” from now on). In an attempt to answer this, I’ve worked with Pitchbook to assemble some data on these two key clusters relative to the rest of the US, as well as Europe.

The quick conclusion is that the rest of the US should likely use the Euro as its biotech currency; outside the key clusters, the rest of the US biotech sector performs and looks a lot like the European ecosystem.

As shown in the charts below, examining either M&A or IPO events between 2013-2016, biopharma startups from the key clusters were roughly two years faster at the median to get to that exit outcome (left chart): 7-7.5 years to M&A or IPO versus 9-9.5 years.  The quartile ranges are shown as well.  Similar timeline differentials are evident in prior time periods over the past decade as well.

In terms of value, biopharma startups in the key clusters have outperformed both on the median upfront M&A and the median IPO pre-money valuations during 2013-2016 (right chart). The average dramatically skews the distribution upwards in the key clusters (due to big outliers). Again, this differential in value also exists during other time windows of the past decade.

Holding periods and valuations at exit are reasonable but only directional proxies for investor returns. The actual returns depend on pricing of each of the venture rounds, as well as timing of stock sales, etc.  But it’s reasonable to assume based on these data that biotech returns in the two key clusters have outperformed other regions.

Why is differential in performance happening?

Biotech historians in the future might call it the “Great Consolidation of Talent and Capital.” While Silicon Valley quickly emerged in Tech a few decades ago as the nexus of all things IT and venture capital, in biotech it’s been far more geographically egalitarian in the past.  San Francisco and Boston were clearly important leaders in the early decades of the field, but so were other biotech clusters: Seattle, San Diego, Raleigh, Philly/NJ, Colorado, etc…  Most of these also had legacy Pharma or big Biotech footprints that were important for cultivation of talent.  And great firms grew out of places well beyond Boston and San Francisco: early winners like Immunex, IDEC, Centacor, Medimmune, and Celltech, just to name a few – and firms like Celgene (San Deigo, NJ) and Amgen (Thousand Oaks) – all born in other geographies.

In recent years, this has changed – Boston and San Francisco are now the preeminent biotech clusters.  And their gravity in the ecosystem is only getting stronger.

Beyond having great science and the right “pixie dust” in the local environment, two fundamentally important ingredients to the success of any cluster are capital and talent – and both are aggregating into the two key clusters.

Capital

Over the past decade, startups in the key clusters have been consuming ever-greater portions of the global biotech venture capital pie.

As shown in the chart below, since 2012, these two key clusters have increased their share by more than 50%, now securing nearly half of the global venture capital funding budget for biotech. In the US alone, depending on the data source, the two clusters are now receiving 60-70% of the country’s venture pie. Both the rest of the US and the EU have shrunk on a relative basis as a response.  The percent change in absolute dollars reflects this – nearly 130% increase in five years into the two key clusters, with the other regions relatively flat or down. Looking back to 2007, most of the change has occurred in the past five years – the distribution of capital across geographies were nearly the same between 2007-2012.

On top of the flow of venture capital, other funding sources are also consolidating into these geographies. Take NIH funding, for instance: California and Massachusetts rank first and second in terms of total NIH funding to its institutions.  And Massachusetts ranks a far-and-away first with regards to NIH funding per capita, nearly 3x higher than most other strong states (like CA, NY, PA, NJ, etc). Five of the top six NIH-funded independent research hospitals are in the Boston area (here).  Fund flows like these further contribute to the consolidation of biomedical activity into the key clusters.

However, it’s important to call attention to the disconnect between where scientific discoveries are made and where startups are formed. Many of the new companies that get created or launched in the two key clusters do not have scientific roots in those regions. As an example from our own portfolio here at Atlas Venture, despite nearly all of our startups being located/formed in Cambridge MA, the founding science is sourced from all over the globe: Unum came from Singapore, AvroBio from Toronto, Padlock from Florida, Quartet from EPFL in Switzerland, Delinia from San Francisco, etc… About a third of our new startups have roots or connections into Boston’s research institutions, a third with institutions across the rest of the country, and a third outside of the US. So the concentration of capital doesn’t mean scientific sources have shrunk; in fact, it’s increasingly clear to us that science competes on a global stage and we need to access the best substrate wherever it may be – but put the startup where it can take advantage of the benefits of a key biotech cluster.

Talent

It’s much harder to quantify the talent metrics, but one only has to see all the cranes in Cambridge MA to know that big things are happening here. Nearly every major biopharma company has a research footprint in the region.  Same goes for the Bay Area, though much more spread out around the region.

To get a sense for the consolidation of talent, here’s a chart that attempts to capture the change in biopharma R&D employment in the three geographic groupings.  The key clusters have seen R&D employment grow by 30% in past decade, versus shrinking in the other major biopharma states (like PA/NJ). Europe, according to their pharma trade group, is flat – though I suspect the metric is actually down in Pharma R&D organizations and up in the CRO R&D world.  As a macro point, these data reflect the intuitive sense we have of recruiting talent from other regions into Boston: with regards to R&D teams, prior Pharma hubs are shrinking rapidly while Boston is growing. We’ve even recruited a few sun-loving San Diego biopharma vets to move to the Boston market recently.

As this implies, for startup biotechs, larger biopharma companies are the lifeblood of the talent flows (prior blog on topic is here). Most of our early stage startups are led by teams with experiences inside of larger R&D organizations. The serial cycle of biotech entrepreneurship – starting companies, recruiting talent, discovering new medicines, and getting acquired (or going public) – is accelerated in high density clusters. The entrepreneurial diaspora enabled by biotech M&A is just much larger and more vibrant in these clusters (here). As shown by the data above, faster timelines, more acquisitions, and more R&D talent flows just add more and more water to the millrace, powering the wheel of the biotech mill churning out startups in these key clusters.

As these data suggest, the great consolidation of talent and capital into the two key clusters has clearly been happening in the past decade – and shows no signs of abating any time soon. While the prior return metrics of time and value are clearly lagging indicators of an ecosystem, as they reflect the value creation pace and trajectory in the past few years, metrics around talent and capital flows into startups will most definitely shape the future of these ecosystems.

So what are the implications of this consolidation for different stakeholders in the ecosystem?  Here are a few thoughts.

If you are a sector or civic leader in one of the key clusters, some simple advice: don’t get complacent. Make sure the local infrastructure doesn’t fail you at the most critical moment. Congestion, commutes, and chaos can only lead to an exodus over time of those interested in a better quality of life. Further, building capacity to grow will be important; scarce lab space has already driven rents in Cambridge to outlandish levels. We’re seeing startups begin to move back out to the Rt 128 corridor. While still part of the greater Boston ecosystem, those locations are less hyper-connected to the benefits of the density and proximity of the Kendall biotech scene. Lastly, make sure you keep importing ideas and talent into the cluster from around the world or you risk becoming insular; ideas are global, talent is mobile – so keep focusing on bringing them into the region.

If you aren’t in a cluster today, different stakeholders might think about this challenge differently. A few themes:

  • Can’t beat ‘em, join ‘em. One school of thought would suggest that rather than fighting the consolidation, work to benefit from it.  If you are an academic investigator interested in founding a new company, and you want to maximize its chances of success, you might consider putting the startup in a key cluster and create virtual links back to your lab elsewhere in the US or Europe (we’ve done this successfully many times). You’ll need connections into those clusters, but some creative use of email and social media can usually get you that. If you are a tech transfer executive, you might also work to build connectivity with venture creation firms in the key clusters.
  • Give them an offer they can’t refuse. The alternative for economic development minded folks in other regions is to enable your local startups with “extra” advantages. Provide R&D credits or funding, like Texas did with CPRIT grants – these significant funding infusions lower the cost-of-capital for young startups and let them progress with less equity investment (since its less available outside of clusters). Unclear whether these are sustainable in the long run, but they could help prime the pump. It’s also important to cultivate more anchor tenants to remain or build in the region; easier said than done, but the revolving door of talent from larger biopharma into smaller companies is a crucial component to a successful cluster. Along those lines, facilitating the return of your regions biopharma diaspora could help; many exec’s in the key clusters hail from other parts of the country or world, and some wouldn’t mind returning “home” like former California investor JD Vance recently did with Ohio. I’m sure tax deductions to successful returnees would spur lots of interest. At the end of the day, in the face of this ongoing consolidation, regions need to figure out how to give their startups a leg up to compete without a major disadvantage.
  • Be the big fish in the small pond. This is a riff off the age-old contrarian investor thesis. Much like biotech has been a recent contrarian bet in venture capital amongst many LP’s, creating or investing in startups outside the key clusters could offer some advantages – fewer competitors for the regions talent and capital, even if scarce, means that you could attract more of them. And there’s less threat of losing talent if there’s few other places for them to go. Further, operating costs are lower – both people (salaries) and fixed costs (rents, etc) are often far less expensive outside the clusters. Most of these other regions remain under-appreciated, and a local champion might get a reasonable cut of the “best” ideas in the smaller pond.  But you’ll need to figure out how to evolve these businesses into global competitors over time – and one idea is to have a satellite office inside one of the major clusters to access the talent and capital advantages of those markets (which we’ve done with numerous startups in the recent past, like here).

The current trends around capital and talent flows strongly suggest that Boston and the Bay Area will be the preeminent biotech clusters for the foreseeable future – and the global biotech startup scene needs to figure out how to adapt to that reality.

 

 

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The Hunt For Novel Treatments Against Deadly Bacteria:  Spero Therapeutics And Its Potentiators

Posted March 16th, 2017 in Portfolio news, Science & Medicine | Leave a comment

This guest blog was written by Troy Lister, Head of Chemistry, and Cristina Larkin, Chief Commercial Officer, of Spero Therapeutics, as part of the From The Trenches feature of LifeSciVC.

A national security threat equivalent to terrorism?  This is how Britain’s chief medical officer described drug-resistant bacteria.  Dr. Thomas Frieden, recently retired director of the CDC, referred to drug resistant bacteria as one of the most serious health threats that “has the potential to harm or kill anyone in the country, undermine modern medicine, to devastate our economy and to make our health care system less stable.”

The CDC estimates that every year, at least 2 million people are infected with drug resistant bacteria and that the number of deaths resulting from these infections is equivalent to one fully loaded jumbo jet crashing each week.  We have also seen a lack of novelty in treating these infections.  In fact, 40 years have lapsed since a novel antibiotic class was approved for use against Gram-negative infections.

The lack of novelty is by no means an indication of lack of effort devoted to this cause.  Indeed, across the public, private and academic industries many extensive and protracted drug discovery endeavors have been undertaken, only to come up short of a novel therapeutic. The reason for these numerous failures lay not in a lack of quality molecular targets or even a lack of inhibitors of such targets, but rather the inability to get these good inhibitors to their targets in Gram-negative bacteria.  In fact, it is predominantly the physiology of Gram-negative bacterium, specifically the make-up of the outer-membrane of these bacteria that has hindered innovation. Whilst Gram-positive bacteria possess a single phospholipid cell membrane, Gram-negative bacteria have both a phospholipid inner membrane (akin to the Gram-positive membrane) and an outer membrane bilayer composed primarily of phospholipid at the inner surface and lipopolysaccharide (LPS) at the outer leaflet. It is this layer of highly polar, negatively charged LPS that excludes many excellent target-based inhibitors including to a trove of wonderful, clinically useful Gram-positive antibiotics from entering Gram-negative bacteria to do their work. Unfortunately, a distinct incongruence between chemical properties required for Gram-negative penetration (both membranes) and that imposed by many of the known (and novel) bacterial targets means that simple (or complex) medicinal chemistry tactics have not been able to provide a solution.

Spero Therapeutics hopes its adjunctive, Potentiator approach (SPR741) to LPS disruption will be the solution.

SPR741-First new approach to gram-negatives in 40 years

SPR741, Spero’s lead Potentiator candidate, is currently progressing through Phase 1 clinical trials. SPR741 is an analog of the well-known natural product antibiotic, Polymyxin B (PMB).  PMB, as a single agent, is an efficient killer of Gram-negative bacteria, but unfortunately, this molecule is also associated with severe, dose-limiting kidney toxicity, and the chemical attributes that make PMB an efficient antibiotic are complicit in the observed toxicity. SPR741 was specifically designed to utilize one of PMB’s favorable attributes, namely interaction with Gram-negative LPS, while being devoid of the safety liabilities. SPR741 does not directly kill bacteria, but very potently interacts with LPS, essentially disrupting this barrier to entry for many antibiotic classes. Indeed, preclinical studies of SPR741 in combination with many Gram-positive antibiotics have shown success in reducing the bacterial burden of infections caused by several common drug-resistant pathogens,The mechanism of action (MOA) of SPR741 is captured in a stunningly visual representation below. In this experiment, E. coli bacteria have had their outer membrane labeled with a fluorescent red dye (you can see the characteristic rod shape) and these bacteria are ‘swimming’ in a pool of green fluorescently tagged azithromycin. On the top, SPR741 is not present, and azithromycin is unable to penetrate the bacterium and concentrate enough to be visualized. On the bottom, a small amount of SPR741 has been added, and now the azithromycin enters the cell, concentrated and is visualized. The inability of azithromycin to enter Gram-negative bacteria renders it incapable of killing these organisms. Simply, the addition SPR741 allows azithromycin to freely translocate the outer membrane and ultimately kill Gram-negative bacteria.

Spero has also investigated the impact SPR741 has on the cell surface structure of Gram-negative bacteria using atomic force microscopy (AFM). AFM employs an exquisitely sensitive technique to scan the surface topology of a biological specimen. Spero employed this technology to map the impact exhibited by SPR741 on the topology at the outer membrane of Gram-negative bacteria. The image below on top shows the natural, relatively smooth topology of the cell envelope of an E. coli bacterium. Below, the E. coli was exposed to a small amount of SPR741 leading to significant perturbation of the surface as seen by the dramatic change in topology.  This disruption allows an opening for the adjunctive antibiotic to enter the cell and exert its antimicrobial activity.

Spero has taken a very broad approach to understanding and characterizing the capacity of SPR741 to potentiate other agents. Combinations of SPR741 with a host of generic and novel (clinical and pre-clinical) molecules have been assessed for enhanced antibiotic activity. These activities have demonstrated a vast capacity for SPR741 to potentiate activity, which we classify into two categories.  First, molecules that are dramatically potentiated from a complete lack of Gram-negative activity to a profile encompassing activity against multiple Gram-negative bacteria, including drug-resistant variants at clinically relevant concentrations.  Examples include large and/or lipophilic molecules like the rifamycins, pleuromutilins, macrolides, mupirocin and fusidic acid whose activity can be increased up to 5 orders of magnitude.  Second, are a group of molecules that penetrate the Gram-negative outer membrane reasonably well, but that can still see benefit from the addition of SPR741 by expanding the coverage of organisms that may be intermediate or resistant to the antibiotic alone.  Examples include the well-established and trusted cephalosporins, carbapenems, and quinolones.

Upon successful completion of its Phase 1 evaluation of SPR741, Spero will introduce first combination product to emerge from this franchise, namely a combination of SPR741 with a generic Gram-positive antibiotic. This combination exhibits potent efficacy against life threating Gram-negative organism including E. coli, K. pneumoniae and A. baumannii, including drug resistant variants like extended-spectrum beta-lactamases (ESBLs), and Carbapenem-resistant Enterobacteriaceae (CRE). Additionally, this approach will enable Spero to leverage a deep safety database and broad usage/availability across the world in the partner antibiotic and the combination will qualify for various regulatory incentives including accelerated 505b2 filing, and Qualified Infectious Disease Product (QIDP) designation, which allows for fast track approval and 5 additional years of exclusivity.

Given the broad potentiation exhibited by SPR741, we expect this to be the first of multiple combinations to enter clinical use akin to the experience of combining beta-lactamase inhibitors with multiple generic and novel beta-lactams.

Certainly significant focus and energy has been spent over the past 2 years taking SR741 from concept to clinical stage asset, but Spero has also spent time building knowledge and deployable technologies to further refine our understanding of structure-activity and structure-toxicity relationships of these unique molecules. In so doing, Spero has assembled a platform of assets capable of addressing multiple areas of unmet need.

The future of SPR741, and Potentiators broadly, is an exciting one and all of us at Spero are excited at the potential to significantly impact the practice of infectious disease medicine and provide clinicians and patients alike more options.

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