News from Old Neighborhoods

Five years ago, the initial band of scientists at my current employer had just moved from the offices of our venture capitalist sponsor, Third Rock Ventures, into lab space in Cambridge sublet from Blueprint Medicines.  The Athenaeum Building is a large brick-faced building which once held the publishing house by that name.   Eleven Biotherapeutics was trying to engineer new immune-modulating proteins, initially focusing on a treatment to dry eye.  Some of their IP I understand was pulled from the wreckage of Codon Devices.  Also on the floor was Verastem, a company spun out of work from Robert Weinberg and Eric Lander on cancer stem cells. In the last few months, major news has been announced by Third Rock, Blueprint, Eleven and Verastem which illustrates many of the forces that make life in early discovery interesting (as in "may you live in interesting times").
When we were there, the Athenaeum Building was separated from Binney Street, a major auto thoroughfare through the Kendall Square district, by a huge parking lot.  This older building was build in dribs and drabs during the 19th and early 20th centuries, resulting in a complex warren of rooms and not always matched dimensions for ceiling heights (and apparently a very byzantine HVAC system, according to the facilities guy).  On our floor were two somewhat older startups.  A number of other biotech and software companies were in the building, with a gym on the first floor and a professional cooking school on several floors.  The latter was fun sometimes, as their final projects would be served to us buffet style in the main lobby. The cooking school shut down a year or so after we moved out, and a huge glassy building nearing completion now occupies the old surface lot.

But back to our floor.  Being in incubator-type space, it is valuable to have good neighbors, and I found both Verastem and Eleven to be helpful.  For example, soon after we moved in we thought we were all set for PCR, but had forgotten to order adhesive seals for the plates.  Eleven was nice enough to spot us a few until our order came in.  Another time, we were out of dry ice with no delivery scheduled for a few more days, and Verastem gifted us enough to get a package of DNA shipped.  Verastem also let us come look at some equipment we were considering buying when we moved to larger space.  Eleven let us latch onto their flu vaccine clinic.  

Alas, Eleven had multiple clinical disappointments with their drugs.  Around the time we decamped to our current starbase, Eleven sadly dropped their entire research and development group.  We snagged one senior leader, but the tough talent competition in Cambridge had us beaten for several other scientists and research associates we targeted.  Still, Eleven persevered in reduced form to see their compounds through all their trials.  That path had come to an end, so Eleven really had no future.  But they did have one valuable asset, their stock listing, so a reverse merger was executed in September with a company called Viventia Bio.  The Eleven name will remain, but the management of Viventia will take over and push forward Viventia's clinical program.

One consequence of that merger is that Eleven's CEO, Abbie Celniker, was now without a full-time job (though she will remain a director of Eleven).  Abbie was at Millennium and recently gave a talk at our company's offsite.  She is an extremely seasoned researcher and executive now, with experience stretching back to the early days of antibody development back at Genentech.  Abbie won't be idle at all, as Third Rock made her a partner for a new fund.

That fund, which raised an eye-popping $616 million in an oversubscribed solicitation, will continue Third Rock's aggressive investments in early stage therapeutic and diagnostic companies.  This Halloween announcement (now that's some serious trick-or-treating!) marked their fourth fund, with quite a few huge successes coming from their first three, but also some clear failures and perhaps a few deep space ventures that can't be clearly classified either way.

One of those new companies was just announced.  Magenta Therapeutics, represents a merger of efforts by both Third Rock and Flagship Ventures to create a company.  Their founding CEO, Jason Gardner, wrote a very readable and detailed blog post on Magenta's plan, which I find very exciting.  I've mentioned before that I knew someone who died of CLL a few years before Gleevec arrived on the scene.  Technically, she died not of the disease but of the treatment attempted for it: bone marrow transplantation.  To implant a new, good marrow, one must first kill off the old marrow that is spewing out leukemic cells, plus if both are present the risk of them fighting disastrously is omnipresent.  The old way of doing this was with very high doses of radiation. The patient is left highly immunocomprised for an extend period and must live in a special isolation unit in the hospital.  The person I knew died from a latent infection which took advantage of her immunocompromised state.  Magenta wants to use much more targeted approaches to ablating bone marrow, offering the hope of lower risk.  Should that risk be lowered, then these sorts of transplantation methods would be opened to more diseases.  Magenta wants to also improve the harvesting of hematopoetic stem cells from donors, which should increase success rates and make this approach more feasible for gene editing approaches.  

Speaking of stem cells, Verastem was founded to target cancer stem cells.  These hypothesized cells are very rare and hence contribute little to the bulk of the tumor, but can re-generate tumors.  I haven't kept up with this contentious field, but there were a number of observations which suggested their existence, though I know not everyone was convinced.  Robert Weinberg and Eric Lander have historically represented very different approaches to cancer biology, with Weinberg focused on small-scale focused experiments and Lander being one of the best known proponents of high-throughput 'omic approaches.  But, they had published a paper together on an approach to screen for compounds targeting cancer stem cells, and from this Verastem was born.

Verastem has gone through its own rough path, and even before we moved to our larger quarters they had shed a number of researchers.  While their own efforts have yielded compounds they are pursuing, they were apparently eager to leapfrog their program.  Their recent announcement is that they have licensed a late-stage clinical compound from yet another Cambridge company which desired to shed it in order to focus on one remaining early stage compound.  This sort of horse-trading of compounds is not unusual; depending on a company's goals, aspirations, cash position and size, it may well be rational for one company to trade off an asset to another, even if both companies view the chance of success of that asset equally.  Should final approval for this company be handed down by the FDA, then Verastem can become an actual pharmaceutical company selling a drug.

The other company in that transaction: my old employer Infinity Pharmaceuticals.  I had written an elegy for the company this past summer, as it had just shed its entire research staff.  As I noted then the somewhat shocking cause of this was a clinical success, not a clinical failure as is typical.  It's just that duvelisib is not longer expected to compete well in a rapidly changing clinical landscape for non-Hodgkin's lymphoma.  

A bit later, there was some controversy over the size of retention bonuses that Infinity had promised the remaining staff there, up to $1 million for some of the top executives.  These bonuses would be paid on two future dates should those employees still be employed at those times.  Promising extra money to highly paid executives can be seen as a bitter pill by investors, but there's a stark reality there.  Biopharma is booming, particularly in Cambridge. Anyone with many years of experience who becomes available, or who is thought might be available, quickly has their phone ringing constantly.  Companies such as Infinity inspire great loyalty, but absolute loyalty is hard to maintain, particularly if you are ambitious.  Passing up a great opportunity in the name of loyalty to a foundering ship is a noble act, but one that might be greatly regretted should the ship fully capsize.

Infinity will further shrink; I think one report had the final count around 20 employees remaining after the duvelisib program is fully handed off to Verastem.  The one remaining Infinity asset, like duvelisb, is an inhibitor of what are known as phosphoinositide-3-kinases (PI3Ks), which are important enzymes in regulating a number of cellular processes.  Humans possess 4 different versions of PI3Ks, alpha, beta, gamma and delta.  Duvelisib inhibited both gamma and delta forms.  IPI-549 is more specific, targeting only gamma.  Infinity and its academic collaborators just published back-to-back papers in Nature showing the importance of PI3Kgamma to suppressing immune responses and how inhibiting PI3Kgamma may be useful for enhancing the immune therapies for cancer known as T-cell checkpoint inhibition.  So Infinity's deal with Verastem is an attempt to focus all their efforts into this one potentially exciting compound while still retaining an economic interest in duvelisib [I will emphasize again I hold no stock in Infinity and can't benefit from this].

So in all these events around old friends and employers we can see many of the forces that buffet small discovery companies.  Eleven effectively folded, its only asset of note a stock ticker symbol.  Eleven's CEO dances over to Third Rock Ventures, which routinely breeds new companies such as Magenta.  At the other end of the hall, Verastem partnered with Infinity in a deal which may enable Verastem to mature more quickly while giving Infinity cash and focus to try to drive their last promising compound through the clinic.  Waxing and waning companies, the reality of life in biotech.