The wild story behind a promising experimental cancer drug

Today, Pharmacyclics is a $5.3B company, a value attributable largely to its promising lead compound, ibrutinib, currently in late clinical development for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma, and under investigation for a range of other B-cell malignancies.  A joint development and marketing deal with J&J was announced in late 2011, valued at nearly $1B, including $150M upfront plus significant milestone payments.  Analysts are already pegging future sales in the billions.

Ibrutinib's emergence as a promising oncology drug - "The Gleevec of CLL," as one oncologist described it to me - is an almost absurdly improbable story embracing the Human Genome Project on the one hand, and Scientology on the other.

A "Most Wondrous Map"

In 1998, a radically inventive biologist, J. Craig Venter, founded a company called Celera, with the goal of sequencing the human genome within three years.  He was competing against a much larger, well-funded public effort, led by Human Genome Project Director Dr. Francis Collins, who is now Director of the National Institutes of Health.

Both efforts succeeded; the initial draft map of the human genome was famously announced on June 26, 2000 by President Clinton, joined by Venter and Collins.  Clinton said, "Today the world is joining us here in the East Room to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wondrous map ever produced by humankind."

In 2002, Venter stepped down as President of Celera, and over the next four years, its promise progressively evaporated.  Turning information into value - arguably the key challenge of the genomic era - proved elusive.  The company's attempts to try its hand at drug development - kick-started by the acquisition of Axys Pharmaceuticals in 2001 - had largely fallen short.  Electing to focus on diagnostic testing, the company unloaded its early stage assets - a phase 1 HDAC inhibitor and a few other preclinical molecules, which in 2006 were picked up for a pittance by a small struggling company called Pharmacyclics.

A Useful Tool

Included among the preclinical assets were small molecules targeting a signal transduction molecule called Bruton's trysosine kinase - BTK - an enzyme that sits downstream of the B-cell receptor, and was targeted by Celera because of its putative role in autoimmune diseases such as rheumatoid arthritis (a thoughtful discussion of "immunokinase" drug discovery can be found here).  The BTK gene itself - tied through "classical" genetics to the disorder X-linked agammaglobulinemia (XLA) - was first identified in 1993.

As part of their efforts to screen candidate BTK inhibitors, Celera researchers created a "tool compound," a molecule that would bind BTK permanently (i.e. covalently), and could also be fluorescently labeled.  This tool would help the company identify compounds that could bind BTK tightly, but not covalently, since drug developers traditionally shy away from compounds that permanently bind their target, concerned about their "potential for off-target reactivity," as a recent review nicely summarizes.  That said, many drugs, both ancient- such as aspirin - and recent - such as clopidogrel (Plavix) and esomeprazole (Nexium) - work through a covalent mechanism.

As Celera researchers pursued BTK inhibitors, they made two important discoveries: first, they learned that their molecules seemed to show activity in arthritis models; second, they progressively appreciated that their tool compound seemed more promising than any of the other molecules emerging from their screens.  It was at this point that Celera's assets were sold to Pharmacyclics.

Developing Science

Meanwhile, elegant experiments in mice by Harvard immunologist Klaus Rajewsky highlighted the importance of B-cell receptor signaling for B-cell development, stimulating cancer researchers to wonder whether inhibiting B-cell receptor signaling might help treat B-cell cancers.  In rapid succession, scientists from Stanford, Harvard, and other universities reportedly reached out to a small Bay-area biotechnology company called Rigel to request permission to study one of their lead compounds, fostamitinib, an inhibitor of the Syk kinase which is also in the B-cell receptor signal transduction pathway.

The initial results were promising but not stellar, although encouraging responses were seen in some patients, according to Dr. Jeff Sharman, who at the time was a Stanford oncology fellow in the legendary lab of Ronald Levy, and an early proponent of inhibiting B-cell receptor signaling in B-cell cancers.  (In 2010, Rigel partnered fostamitinib with AstraZeneca, and it is currently in late-phase development for rheumatoid arthritis).  Sharman (disclosure: we trained together at MGH) recalls that a frequent visitor to the Levy lab was Dr. Richard Miller, an oncologist and entrepreneur who at the time was CEO of a local drug development company: Pharmacyclics.

Local Hero

Richard Miller was already a bit of a legend in the Bay area; in 1984, he co-founded IDEC with Stanford colleague Levy, UCSD immunologist Ivor Royston, San Diego bioentrepreneur Howard Birndorf, and a trio of top-tier VC investors led by Brook Byers of KPCB (he's the "B"), and including Tony Evnin of Venrock and Pitch Johnson of Asset Management; IDEC integrated an existing company, Biotherapy Systems, that Miller and Levy had founded in Mountain View.   In 1997, IDEC delivered rituximab, the first monoclonal antibody approved by the FDA for cancer treatment; it is also used for the treatment of rheumatoid arthritis.  IDEC merged with Biogen in 2003.

Miller ultimately left IDEC, and in 1991 teamed up with chemist Jonathan Sessler to co-found Pharmacyclics, a collaboration that reportedly began when Miller was treating Sessler for cancer at Stanford in the early 1980's.  The company was initially focused on a class of molecules called "texaphyrins," synthesized by Sessler (who had moved on to the University of Texas); the name may reflect either the UT origins or the resemblance of the structure to the five-point star of Texas.

While initially promising, the lead molecule,  motexafin gadolinium (Xcytrin), was unfortunately not panning out in clinical studies of brain metastases (eventually leading to a much-publicized dispute between Miller and the FDA), prompting Pharmacyclics to start thinking about a Plan B.  Enter Celera.

A Prepared Mind

The opportunity to pick up potentially promising assets from Celera - essentially, acquire an early-stage pipeline - was appealing to Pharmacyclics; while the deal apparently was initially focused only on the Phase 1 HDAC asset, Miller reportedly was keen for the BTK inhibitor program to be included as well; it was an easy request to grant, as its perceived value at the time was just about zero.

Additional studies of autoimmune disease seemed to confirm the potential of the "tool" BTK inhibitor, now designated PCI-32765; however, Miller was eager to explore its potential in B-cell cancers.  The problem was that it was hard to find appropriate models to use, either cell lines or animal models, as it was felt essential to find a model in which growth was explicitly dependent upon B-cell receptor activation, rather than bypassing it as was more commonly the case in model systems.  Ultimately, the team decided their only option was to study the drug in spontaneously occurring lymphomas in dogs, and obtained results that were suggestive, but not overwhelming.  A partial response was observed in several animals, stable disease was seen in several others.

The team struggled with what to do next.  For starters, they had reached the limits of what they felt they could learn from preclinical studies, and needed to decide, in the words of a researcher, "whether it was worth $1M" to figure out whether the promising but shaky preclinical results would translate into patients.

In addition, the team was also agonizing about whether to move forward with a molecule that worked by forming an irreversible, covalent bond; perhaps it would make more sense to go back to the chemistry lab, and try to identify a BTK inhibitor that worked by a more traditional, non-covalent mechanism.

"I Have Patients Who Are Dying"

Reportedly, Miller asked the team what were the risks of moving ahead with the covalent mechanism, and when he received vague responses, he reportedly told his colleagues, "I have patients in clinic who are dying, and need something right away.  I can't tell them they'll need to wait around for another year because we have a concern we can't even articulate."

Hence, the clinical study was initiated, and while at first it was slow to recruit, it ultimately was completed and viewed as strikingly successful.  The drug - now in phase 3, and called ibrutinib - is not a magic bullet, but may emerge as a promising option for some patients with some B-cell cancers.

On The Road Again

In another strange twist, Miller hasn't been around to see this; he was dismissed in 2008 by the chairman of the board, Robert Duggan, who is perhaps best known as Scientology's biggest donor.  While a Bloomberg report seems to suggest Miller's departure reflected Duggan's disappointment in the Xcytrin program, and his preference for focusing on B-cell cancers, I've also heard a very different account, suggesting it was Duggan who was keen to pursue Xcytrin, and Miller who refused, preferring instead to focus on the promising BTK inhibition program.

Miller promptly teamed up with UCSF chemist Jack Taunton to co-found Principia Biopharma, a company that focuses on "reversible covalent" molecules - drugs that form covalent bonds that release when the target protein denatures; VC backers include New Leaf, OrbiMed, Morgenthaler, SR One, and the UCSF early stage fund Mission Bay Capital.

In 2010, Miller signed on with the University of Texas as "Chief Commercialization Officer."  However, according to reports, this role ended abruptly with his resignation less than two years later "after UT officials insisted that Miller divest his ownership interest in three startup companies that intended to license tech discoveries from the school."   He is said to be working on a new company focused on a novel drug delivery technology.

Lessons Learned?

  1. Limitations of experimental models.   In this case, the team had the insight, and the confidence, to recognize that available model systems for the study of B-cell cancers wouldn't accurately enable assessment of their B-cell receptor-dependent mechanism, and rather than force the molecules through traditional assays (and get a false negative result), they tried to use a less traditional approach (e.g. spontaneous lymphoma model in dog), and then proceed rapidly to the clinic.
  2. Value of a translational champion: This is evident on both the academic side (e.g. inquisitive physicians such as Sharman) and on the industry side (e.g. Miller's ability to see the clinical potential of research compound developed for different indications).
  3. Courage to value clinical need over conventional wisdom, and empiricism over theory.   Miller challenged traditional pharmaceutical reticence about covalent mechanisms in order to speed an important new drug to patients.
  4. It helps to be lucky.  For each of the lessons here - and particularly, for each of the "brave" and "bold" choices - I can easily envision how following this exact approach might have led to a far less favorable outcome, and a very different narrative (e.g. "cavalier physician imperils patients in reckless pursuit of flawed vision").

Bottom Line: Discovering impactful new drugs is far more difficult - and far less linear - than is typically recognized.  It's wonderful to celebrate success; our challenge is finding a way to repeat it.

 

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About the Author

 

David
Shaywitz
  • Dr. Shaywitz trained in internal medicine and endocrinology at MGH, and conducted his post-doctoral research in the Melton lab at Harvard. He gained experience in early clinical drug development in the Department of Experimental Medicine at Merck, then joined the Boston Consulting Group’s Healthcare and Corporate Development practices, where he focused on strategy and organizational design. He is currently Director of Strategic and Commercial Planning at Theravance, a publicly-held drug development company in South San Francisco. He recently wrote Tech Tonics: Can Passionate Entreprenuers Heal Healthcare With Technology? 

  • Email: davidshaywitz.aei@gmail.com

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