Forbes Magazine
April 5, 2013
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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