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By Ludwig Burger and John Miller
FRANKFURT/ZURICH, Jan 6 (Reuters) - Dozens of drugmakers are
conducting human trials for a record 89 therapies that pair
antibodies with toxic agents to fight cancer, evidence of
renewed confidence in an approach that has long fallen short of
its promise, an analysis compiled for Reuters shows.
These antibody-drug conjugates, or ADCs, from companies
including AztraZeneca and GlaxoSmithKline, are described by
researchers as "guided missiles" packing a powerful anti-cancer
punch.
They are engineered to zero in on tumours and then release
cytotoxins that deliver up to 10,000 times the potency of
standard chemotherapy, while minimizing damage to healthy
tissue.
The approach has for decades been a major biotech industry
focus. Many experimental ADCs, however, failed due to the
complexity of pairing the right antibody with the appropriate
toxic agent. Some were abandoned as too weak; others were too
harmful.
From 2000 to 2018, only five ADCs won approval. Just one,
Roche's Kadcyla, approved in 2013 for breast cancer, has
surpassed $1 billion in annual sales after data last year showed
it boosted disease-free survival for some patients compared with
the standard treatment, Roche's Herceptin.
Over time, however, scientists devised better ways to
connect payloads and antibodies and more precisely reach
tumours. There is a growing understanding, too, of how to design
ADCs to kill even surrounding cancer cells that previously
evaded destruction.
"What we're seeing now are the benefits of the science
becoming mature," said ADC pioneer Chris Martin, CEO of
Switzerland's ADC Therapeutics. "It took at least a
decade, probably more like 15 years, to really begin to turn the
art into a science."
In 2019, U.S. regulators approved three ADCs, the most ever
in a single year, as last-ditch treatments based on studies
showing they helped patients whose survival outlook was bleak.
They include AstraZeneca's and Daiichi Sankyo's
breast cancer drug, Enhertu, which was shown to help
patients who had failed numerous previous treatments survive a
median of more than 16 months before their disease worsened.
Astellas' and Seattle Genetics' bladder
cancer drug, Padcev, also received expedited approval in
December, based on evidence that 44% of patients who had failed
immunotherapy showed improvement, and in some cases, no evidence
of cancer, when they were assessed after treatment.
Roche's Polivy was green-lighted against lymphoma in
June after producing complete response rates, with no signs of
disease, in 40% of patients when combined with two other
therapies.
NEW RECORD
While all three drugs must prove their mettle in further
studies, the industry is growing optimistic that ADCs' time may
have arrived.
The number of ADC drug candidates is at unprecedented
levels, according to data from consultancy Beacon Targeted
Therapies compiled for Reuters, based on a review of companies'
pipelines. Dozens more ADC prospects are in pre-clinical review.
London-based Beacon advises drugmakers on targeted
therapies, helping them decide whether to pursue prospective
drugs or redirect efforts, based on industry trends.
Current ADC projects include GlaxoSmithKline testing
its belantamab mafodotin against multiple myeloma.
ADC Therapeutics, part-owned by private equity firm Auven
Therapeutics, has several studies on experimental drugs,
including with Danish partner Genmab, on blood cancers
and solid tumours.
U.S. biotech Immunomedics' market capitalization
gained more than 60% to $4.3 billion in the last six months,
ahead of the U.S. Food and Drug Administration's late-December
decision to review its ADC against triple-negative breast
cancer, which is hard to treat and has poor prognosis.
Massachusetts-based ImmunoGen, hit by past trial
failures, got a lift in December for its ADC against ovarian
cancer when the FDA indicated it may become a candidate for
accelerated approval.
The surge in ADC investment has been fueled, in part, by
improvements in the so-called "linker" technology that binds the
antibody to its cancer-killing toxins, keeping them stable in
the circulatory system until the poison can be unleashed on the
targeted tumour.
ADCs are generally delivered via repeated infusions, similar
to chemotherapy.
"There is a revival again because there is a new generation
of molecules in which the linker is more efficient," Giuseppe
Curigliano, clinical director of early drug development at
Milan's European Institute of Oncology, told Reuters.
BETTING ON GROWTH
This optimism has contract manufacturers like Merck KGaA
and Lonza ramping up facilities, in hopes
drugmakers will farm out complex ADC production.
Merck expects the overall ADC market to grow by more than
20% in coming years, boosting its business, which includes
manufacturing of monoclonal antibodies, linkers and cytotoxic
agents.
Rival Lonza, which helps make Roche's two ADCs and sees
annual 9% growth for the so-called bioconjugates market, is
investing millions of dollars in its Swiss site, where it
produces ADCs for other drugmakers.
"What we see over time at Lonza is a good request for
capacity," said Iwan Bertholjotti, Lonza's bioconjugate
commercial development head. "That's a good sign that the market
is booming."
Still, enthusiasm is not universal.
AbbVie in August abandoned its ADC candidate Rova-T
after flunking a lung cancer trial and wrote off most of the
$5.8 billion it paid for the drug's developer, Stemcentrx, in
2016.
Roche, which helped pioneer ADCs with Kadcyla and Polivy,
has also backed off. In 2013, the Basel-based company had about
a dozen experimental ADCs. Today, only one remains, and it is
being developed for Staph infections, not cancer.
"We have shifted our technology priorities," Roche CEO
Severin Schwan told Reuters. "Maybe others will be luckier, but
we failed to master the complexity."
AstraZeneca aims to do just that.
In March, the Cambridge, England-based drugmaker struck a $7
billion deal with Japan's Daiichi Sankyo for rights to Enhertu,
getting $1.35 billion up-front, and more if it challenges Roche
drugs' dominance in breast cancer.
Some industry analysts see Enhertu sales eventually reaching
up to $7 billion annually.
"Our plan is to expand the number of studies in different
tumour types," said Gilles Gallant, head of oncology R&D at
Daiichi Sankyo. "This agent has potential."
(Reporting by Ludwig Burger in Frankfurt and John Miller in
Zurich; Editing by Michele Gershberg and Dan Grebler)
