PETER YOUNIS
`
`options that are available as pills. These include
`next­generation BTK inhibitors, agents directed
`against other B­cell targets and combinations of
`these strategies, which can be offered in addi­
`tion to or as a replacement for chemotherapy
`for lymphomas of all stripes. “Ibrutinib trans­
`formed the landscape,” says haematologist
`Simon Rule of the University of Plymouth in the
`UK. “What it’s allowed us to do is think about a
`totally different treatment paradigm.”
`Younis is a living testimonial to this new
`world of lymphoma therapy. Had he relapsed
`just a few years earlier, he would probably have
`had little choice but to roll the dice on another
`round of chemotherapy. Instead, when his can­
`cer returned in 2014, ibrutinib was entering its
`pivotal phase III trial for treating Waldenström’s
`— regulators around the world would later
`make the drug the first therapy approved for
`treating people with the condition. (A second
`drug, rituximab, was approved by US regulators
`in August for people with Waldenström’s, but it
`must be used in combination with ibrutinib.)
`In addition, there was a newly launched first­
`in­human trial of zanubrutinib, a more potent
`and potentially safer BTK inhibitor.
`Because Younis’s only access to ibrutinib
`would have been through a placebo­controlled
`trial — and he didn’t like the idea that he might
`not be getting the real thing — he opted instead
`to enrol in an early­stage, open­label safety trial
`of zanubrutinib. He was one of the first people in
`the world to be treated with this BTK inhibitor.
`Younis has now taken that drug for four years,
`with no apparent side effects. His cancer has
`not returned. Other than having to travel four
`times a year to Melbourne for blood testing, says
`Younis, “I live a completely normal life.”
`
`TOOL OF THE TRADE
`The US Food and Drug Administration (FDA)
`led the world’s regulators in approving ibrutinib
`in late­2013 for people with previously treated
`mantle­cell lymphoma, an aggressive non­
`Hodgkin’s lymphoma that forms in the outer
`edge of lymph nodes. Additional approvals soon
`followed for chronic lymphocytic leukaemia in
`2014, Waldenström’s macroglobulinaemia in
`2015 and several other indications after that.
`The drug is now taken by tens of thousands
`of people worldwide, and brings in around
`US$5 billion a year for its makers. But that out­
`come was far from certain. In fact, the molecule
`almost never made its way out of the laboratory.
`Chemists at Celera Genomics in Alameda,
`California, created ibrutinib in 2005 as a ‘tool
`compound’ to study BTK function, but they
`never considered it to be a suitable drug can­
`didate. After all, it formed permanent covalent
`bonds with the BTK protein, and the general
`consensus among drug developers at the time
`was that irreversible binding with unintended
`targets would lead to unacceptable toxicities.
`So a year later, when Celera decided to get
`out of the drug­development game and focus
`instead on diagnostics, the company offloaded
`ibrutinib for a pittance. Pharmacyclics in
`
`Peter Younis was one of the first people to have his lymphoma treated with a type of targeted inhibitor.
`
`THERAPEUTICS
`
`A life-changing
`innovation
`
`How the success of one targeted therapy ushered in a new
`era of lymphoma treatment.
`
`BY E L I E D O LG I N
`
`When doctors first diagnosed Peter
`
`Younis with Waldenström’s macro­
`globulinaemia in 2004, there were
`few drug options available. Like most people
`with this rare type of non­Hodgkin’s lym­
`phoma, Younis, a cattle veterinarian from
`Port Campbell, Australia, received a regimen
`of three chemotherapy agents.
`Nearly a decade later, his cancer returned. But
`in the intervening years, the treatment land­
`scape had changed dramatically. Clinical testing
`was under way for a new class of targeted agents
`called Bruton’s tyrosine kinase (BTK) inhibitors.
`
`These precisely block a molecule in the signal­
`ling pathway that turns B cells, a type of white
`blood cell, cancerous in most lymphoma cases.
`Leading the BTK inhibitor pack was ibruti­
`nib. Several other targeted agents were in the
`works that blocked different points of B­cell
`receptor signalling, but harsh side effects either
`limited their clinical uptake or scuttled their
`development entirely. Ibrutinib, by contrast,
`proved fairly mild. Moreover, it brought about
`swift and sustained remissions across a range
`of lymphoma types, even in patients whose
`disease relapsed after they tried other therapies.
`The clinical success of ibrutinib has led
`to a growing number of non­chemotherapy
`
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`© 2018 Springer Nature Limited. All rights reserved.
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`OUTLOOK
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`

`Sunnyvale, California, put up $2 million
`plus an equity stake to acquire the bulk of
`Celera’s therapeutic assets.
`The most promising drug candidate was an
`inhibitor of histone deacetylase that Celera
`had just taken into first­in­human trials. It
`worked by blocking a chromosome­remodel­
`ling enzyme in tumour cells, thereby trigger­
`ing their self­destruction, and Pharmacyclics
`advanced the drug into phase II testing for
`people with various forms of lymphoma. Yet
`the company opted not to pursue the therapy
`further. “Based on the overall pipeline data that
`were available, including early research with
`the BTK inhibitor,” says Pharmacyclics spokes­
`person Bret Coons, the firm strategically chose
`to “concentrate its efforts and resources” on
`ibrutinib. And this drug proved to be the real
`prize of the deal — even though it was included
`in the transaction almost as an afterthought.
`As Pharmacyclics co­founder and former chief
`executive Richard Miller explains: “It was just
`a chemical that they had in their refrigerator.”
`Even if targeting BTK to treat lymphoma
`was not Pharmacyclics’ initial priority, Miller
`saw potential in the strategy. A haematologist–
`oncologist by training who now runs a start­up
`called Corvus Pharmaceuticals in Burlingame,
`California, he knew of a rare genetic disorder
`in which children born with mutations in the
`BTK gene never develop B cells, and thus have
`frequent infections. If these children lacked
`B cells for genetic reasons, Miller reasoned,
`then therapeutically wiping out BTK could
`bring about the same effect for people with
`cancer by destroying the overactive B cells that
`go rogue in lymphoma. “Mother nature did the
`experiment for us,” Miller says.
`Chemists at Pharmacyclics tried to tweak
`ibrutinib to make it bind reversibly to its target.
`But time and again, the chemical derivatives
`performed worse than the original molecule in
`lab experiments. Finally, the company decided
`to move forward with ibrutinib as is — indus­
`try dogma about covalent drugs be damned.
`Dogs are a preferred animal model for
`lymphoma (see page S50), so Miller and his
`colleagues tested the drug in eight dogs with a
`naturally occurring form of the disease1. Three
`dogs displayed tumour shrinkage and another
`three showed no further growth. “We were very
`excited with the results,” says Doug Thamm,
`a veterinary oncologist at Colorado State Uni­
`versity in Fort Collins who collaborated on the
`research. “This was the first time that we had
`observed any kind of objective response to a
`targeted agent in canine lymphoma.”
`Despite the promising data, Miller couldn’t
`find a major pharmaceutical firm willing to
`partner with Pharmacyclics to take ibrutinib
`forward. No one liked the drug’s chemical prop­
`erties. As Pharmacyclics’ former chief medical
`officer Ahmed Hamdy puts it, the industry had
`an “allergic reaction to covalent compounds”.
`It wasn’t until the Pharmacyclics team deliv­
`ered impressive initial phase I results2, showing
`safety and efficacy across various lymphoma
`
`subtypes in humans, that big pharma came
`calling. In 2011, Janssen Biotech in Raritan,
`New Jersey, entered a co­development deal
`worth nearly $1 billion. Four years and three
`FDA approvals later, the bio pharmaceutical
`giant AbbVie in North Chicago, Illinois, paid
`$21 billion to buy Pharmacyclics outright.
`
`BETTER MOUSETRAPS
`Following the clinical and financial success of
`ibrutinib, attention in the drug industry shifted
`to finding other ways of jamming B­cell­
`receptor signalling through different molecular
`targets or better BTK blockers.
`One strategy involves targeting phospho­
`inositide 3­kinase (PI3K), a node in the B­cell­
`receptor pathway. Another goes after a key
`cell­survival protein called B­cell lymphoma 2
`(BCL2), which renders many lymphoma cells
`resistant to destruction. “Knowing what target
`to hit is pretty challenging,” says Kristie Blum, a
`haematologist at Emory University in Atlanta,
`Georgia. “There are just so many different tar­
`gets that are aberrantly unregulated, and all
`these pathways have multiple proteins in them.”
`The FDA has approved three PI3K inhibitors
`and one BCL2 blocker. Now, dozens of trials are
`ongoing to test whether combining any of these
`newer agents with ibrutinib will yield improved
`responses. Other clinical studies are evaluating
`the potential of giving ibrutinib as an add­on
`for people undergoing immunotherapy.
`“These are all complementary strategies that
`can be combined,” says Adrian Wiestner, a hae­
`matologist at the US National Heart, Lung and
`Blood Institute in Bethesda, Maryland. The
`challenge now, he says, is getting past the “steep
`learning curve about how to use these new
`agents for maximum benefit”.
`Several drug companies are also working on
`BTK inhibitors that are more selective for the
`target — and thus may
`be less toxic than ibruti­
`nib. Although ibrutinib
`is better tolerated than
`any lymphoma drug
`that came before it, it
`still triggers side effects
`such as debilitating
`diarrhoea and bleed­
`ing. “Many patients end
`up stopping the therapy,” says haematologist
`Jeff Sharman at the Willamette Valley Cancer
`Institute in Eugene, Oregon.
`The first next­generation BTK inhibitor to
`hit the market was acalabrutinib from Acerta
`Pharma in South San Francisco, California.
`Although acalabrutinib binds and blocks BTK
`in much the same way as ibrutinib, it is thought
`to be more potent and less likely to inhibit off­
`target enzymes. “That could make it better and
`safer,” says Hamdy, who co­founded the com­
`pany after leaving Pharmacyclics in 2011.
`A large head­to­head study is now testing
`whether acalabrutinib is indeed more effica­
`cious and tolerable than ibrutinib in people
`with high­risk chronic lymphocytic leukaemia.
`
`“You’re
`going to see
`chemotherapy
`slowly fade
`away in
`the next 10
`years.”
`
`In a similar vein, zanubrutinib from the Bei­
`jing­based biopharmaceutical company Bei­
`Gene — the drug that Peter Younis continues
`to take on an experimental basis and that is
`thought to offer many of the same pharma­
`cological benefits as acalabrutinib — is being
`evaluated against ibrutinib in a phase III trial
`for people with Waldenström’s macroglob­
`ulinaemia. Other BTK inhibitors are also in
`earlier stages of development for patients who
`develop resistance to ibrutinib.
`For now, most BTK inhibitors are reserved
`as second­line treatments for lymphoma, used
`only after the disease has relapsed following
`chemotherapy. But clinical evidence of the effec­
`tiveness of these drugs is piling up. Constantine
`Tam, a haematologist (and Younis’s physician)
`at the Peter MacCallum Cancer Centre in
`Melbourne, Australia, thinks that, at least for
`some types of lymphoma such as Walden­
`ström’s, “you’re going to see chemotherapy
`slowly fade away in the next 10 years”.
`Not every form of lymphoma has been
`equally responsive to BTK inhibition. In a
`phase II trial of ibrutinib in people with fol­
`licular lymphoma, only 23 out of 110 par­
`ticipants responded. And when given as an
`add­on to chemotherapy in people with dif­
`fuse large B­cell lymphoma (DLBCL), the most
`common form of lymphoma, the drug failed
`to outperform chemotherapy alone in a large
`phase III study.
`According to Louis Staudt, director of the
`Center for Cancer Genomics at the US National
`Cancer Institute in Bethesda, some people
`with DLBCL might still benefit from ibrutinib.
`Doctors just need to take a more personalized
`approach, he says.
`Over the past decade, Staudt’s work with cell
`lines, mouse models and patients has shown
`that B­cell­receptor signalling is chronically
`active in one subtype of DLBCL with specific
`gene mutations. Patients who display these
`genetic markers are therefore particularly
`responsive to ibrutinib therapy. Earlier this
`year, Staudt and his colleagues worked out why.
`They showed that several proteins expressed
`by the mutated genes form a complex that
`cooperates with a cancer­causing protein to
`promote cancer­cell survival3. But this interac­
`tion is dependent on BTK. Block that molecu­
`lar crosstalk with ibrutinib, and the cells tend
`to shrivel and die.
`“This is all starting to make some coor­
`dinated sense,” Staudt says. The challenge
`remains to turn these basic biological insights
`into predictive assays that can identify the
`patients most suitable for BTK­blocking ther­
`apy. Those will come, he says. “It will just take
`a little bit more time.” ■
`
`Elie Dolgin is a science journalist in
`Somerville, Massachusetts.
`
`1. Honigberg, L. A. et al. Proc. Natl Acad. Sci. USA 107,
`13075–13080 (2010).
`2. Advani, R. H. et al. J. Clin. Oncol. 31, 88–94 (2013).
`3. Phelan, J. D. et al. Nature 560, 387–391 (2018).
`
`1 5 N O V E M B E R 2 0 1 8 | V O L 5 6 3 | N A T U R E | S 4 7
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`© 2018 Springer Nature Limited. All rights reserved.
`
`LYMPHOMA OUTLOOK
`
`SAN EX 1017, Page 2
`
`