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`https://www.wsj.com/articles/merck-keeps-striking-out-on-expanding-its-cancer-drug-juggernaut-637c83d4
`
`HEALTH
`
`Merck Keeps Striking Out on
`Expanding Its Cancer-Drug Juggernaut
`The company needs combinations to extend Keytruda sales after
`patent expires
`
`By Jared S. Hopkins Follow
`April 26, 2023 8:00 am ET
`
`Merck says it has been doing deals and developing new drugs to reduce its dependence on Keytruda
`for sales. PHOTO: DAVID CROSLINGEPAEFESHUTTERSTOCK
`
`The gold rush from pioneering cancer immunotherapy Keytruda is about to run
`out for Merck & Co. 
`
`Keytruda, one of the world’s top-selling drugs, powered its maker for the past
`decade. The therapy’s annual sales neared $21 billion last year, about a third of
`Merck’s revenue. Yet a drop in sales looms after Keytruda’s main patent expires
`in 2028.
`
`To extend sales further, Merck has been seeking to combine Keytruda with other
`drugs, which could get new patents if proven to work. Most haven’t, however,
`intensifying pressure on the company to find other sources of revenue and
`contributing to a risky and costly deal-making spree.
`
`Keytruda has failed as a combination therapy in 21 late-stage studies spanning
`nine different partner drug technologies, according to SVB Securities LLC.
`Researchers also didn’t advance at least 66 combination studies after early or
`midstage trials.
`
`“The track record has been horrible,” said Daina Graybosch, an SVB Securities
`pharmaceuticals analyst. 
`
`JHU 2078
`Merck Sharp v. Johns Hopkins
`IPR2024-00650
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`Counting on Keytruda
`The cancer immunotherapy's sales are about one-third of Merck's revenue
`
`Keytruda Sales
`
`Merck Sales
`
`Forecast
`2023
`
` billion
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`
`
`
`
`
`
`
`
`
`
`
`
`
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`Source: FactSet
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`Some Keytruda combinations have panned out. Doctors use the drug with
`chemotherapy for about a half-dozen cancers, and U.S. health regulators recently
`cleared a pairing with a targeted treatment for advanced bladder-cancer
`patients. This month, researchers found that Keytruda and a cancer vaccine
`from Moderna Inc. helped prevent relapses in high-risk melanoma patients in a
`midstage study. 
`
`Merck is also testing a tweaked version of Keytruda, which is currently infused
`intravenously, so it can be injected under the skin. And the company is studying
`the drug in new tumors and earlier stages of various cancers. 
`
`“We’ve learned a lot and certainly that gives us a leg up on our future
`development programs for our next generation of anticancer drugs, but it’s still
`always going to be a game of chance,” said Eliav Barr, Merck’s chief medical
`officer. “Every cancer is different, and every setting within the cancer can be
`different.” 
`
`The approved combinations don’t promise to generate the revenue Merck needs
`to offset a roughly 40% drop in sales that the company could lose within two
`years if competitors launch their own off-brand versions of Keytruda, analysts
`said. 
`
`Merck has been making deals and developing new heart, immune-disease and
`other cancer drugs that will reduce the company’s dependence on Keytruda and
`could add billions of dollars in sales, the company said.
`
`Immunotherapies such as Keytruda belong to a class that lifts a natural brake on
`the immune system, allowing it to attack cancer cells. Bristol Myers Squibb Corp.
`secured the industry’s first approval of the class in 2011. 
`
`Keytruda, which was cleared three years later to treat melanoma, became the
`go-to of the class in large part because it performed better than Bristol’s rival in
`lung-cancer study subjects. The drug has earned 35 approvals across 16 types of
`cancer. 
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`Merck says that failures are part of drug development. PHOTO: BRENDAN MCDERMIDREUTERS
`
`Companies including Merck, academics and others are now conducting 1,935
`clinical trials involving the drug, more than any other approved immunotherapy
`treatment, according to the Cancer Research Institute.
`
`Merck scientists and other researchers have been especially interested in
`combining Keytruda with other agents because the drug alone doesn’t help a
`sizable percentage of patients.
`
`Combinations would also help extend sales because health insurers would agree
`to pay for Keytruda in addition to its partner drug. Merck could also package the
`combination under a new brand protected by new patents.
`
`Yet researchers said Keytruda’s early success might have encouraged Merck and
`its partners to move too quickly. After getting promising results in early studies
`in people, the companies sometimes skipped the next phase of studies, which
`could have helped sort out whether and how the pairings could work.
`
`Some physicians and analysts also faulted certain study designs that, for
`instance, explored combinations in the wrong types of cancer patients or
`administered the pair of drugs in ways that hurt the response.
`
`A patient receives an infusion of Keytruda. PHOTO: JAMES BORCHUCKTAMPA BAY TIMESZUMA WIRE
`
`“The field perhaps got overoptimistic and expected all of these combinations to
`work in people,” said Gordon Freeman, a professor at Dana-Farber Cancer
`Institute in Boston who helped pioneer research of immunotherapy.
`
`Merck said it balances the need for a midstage trial with the urgent needs of
`patients.
`
`The most recent misfire involved Keytruda’s combination with Eisai Co.’s
`Lenvima. The pair have been approved to treat forms of kidney and uterine
`cancers, but failed in pivotal studies against five other tumors. 
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`A setback in liver cancer last year might have happened in part because Lenvima
`targets a receptor that plays a smaller role in liver cancer than kidney cancer,
`said Toni Choueiri, director of the Lank Center for Genitourinary Oncology at the
`Dana-Farber Cancer Institute, who was involved in the kidney-cancer trial. 
`
`Dr. Barr of Merck said it was unclear why study subjects responded to the
`combination, but not enough to generate a positive result. Eisai said the
`combination worked but not enough to demonstrate superiority statistically.
`
`Merck and partner Amgen Inc. jumped to a late-stage study of a combination of
`Keytruda and an agent called Imlygic in advanced melanoma subjects, after a
`small, first-stage trial succeeded. In 2021, the larger trial failed.
`
`Jason Chesney, director of UofL Health-Brown Cancer Center in Louisville, Ky.,
`who was involved in the trial, said the companies took a gamble bypassing a
`midstage trial and might have been successful if they tested the cocktail in
`patients who previously failed Keytruda, rather than as a first-line treatment for
`patients. 
`
`The companies later started testing the combination in people who had
`previously failed immunotherapies such as Keytruda, and recently presented
`promising midstage study results. Amgen said that it jumped to a late-stage
`study based on other immunotherapy and Imlygic research. Merck said the
`program was based on solid science, and “not everything works in clinical
`trials.”
`
`In 2018, a combination of Keytruda and Incyte Corp.’s epacadostat failed to
`perform better than Keytruda alone in a later-stage trial in melanoma subjects.
`
`Michael Atkins, an oncologist at the Georgetown Lombardi Comprehensive
`Cancer Center who has studied immunotherapy trial designs, said the
`companies could have learned the combination didn’t provide a benefit and
`avoided the larger trial if they designed an earlier trial differently and tested the
`cocktail against Keytruda alone, rather than test only the combination.
`
`He also said the companies should have tested Incyte’s drug as a single agent
`against melanoma to verify that it worked by itself. 
`
`Steven Stein, Incyte’s chief medical officer, said epacadostat didn’t appear to
`block its targeted enzyme strongly enough. Merck said the companies only
`tested the combination during the midstage study to be efficient and failures are
`part of drug development. The company said it is doing more randomized
`midstage studies and limiting study of drugs that don’t work alone. 
`
`Write to Jared S. Hopkins at jared.hopkins@wsj.com
`
`Appeared in the April 27, 2023, print edition as 'Drug-Trial Failures Press Merck'.
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