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It might sound like a strange complaint against an industry often accused of scrimping on research to fund marketing efforts, but some executives and scientists say drugmakers are doing too many clinical trials in the hot new field of immunotherapy. Merck and Bristol-Myers Squibb have dominated the first wave of immunotherapy with their “checkpoint inhibitors”, which release brakes in the immune system so that it can attack tumours, while Roche, AstraZeneca and Pfizer are trying to catch up by launching rival versions. Almost $9bn worth of these checkpoints have been sold since they went on sale two years ago. Early enthusiasm for the medicines has given way to a determination to push response rates substantially higher. Although a minority of about 20 to 30 per cent of patients respond extremely well to the drugs — living for months or years longer than their doctors would expect — the majority derive no benefit. “There is some pushback,” said Jill O’Donnell-Tormey, chief executive of the Cancer Research Institute. “Are there too many trials? Are we just throwing spaghetti at the wall, by taking compound ‘X’ or ‘Y’ and adding it together just to see what happens?” Most scientists say checkpoints do not need to be replaced with something else, but rather augmented with new drugs that can further cajole the immune system into fighting cancer. This has led to an unprecedented amount of clinical research sponsored by drugmakers, which are combining checkpoints with other medicines to try to find a magic bullet to treat cancer. The sheer number of studies has sparked fears that some companies are engaging in a medical gold rush, hoping to chance upon the right cocktail without doing the appropriate scientific groundwork. Almost 800 clinical trials involving a checkpoint are under way in the US, according to a government database, more than 700 of which are testing the drugs in combination with one or more additional medicines. This compares with about 200 in 2015. Some investors are unnerved by such haste, says Brad Loncar, who runs an exchange-traded fund focused on immunotherapy: “People are concerned there is not as much scientific rigour as there should be.”
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Pascal Soriot, chief executive AstraZeneca, which is trialling its own immunotherapy combination, admitted as much in a recent interview with the Financial Times. “The field is very competitive. Right now you have a lot of companies that take bets . . . without a lot of data,” he said. “So we also have to consider the speed, and sometimes we’re going to have to take educated risks with maybe not as much conviction or data to support the clinical programme, but enough of it.” While Mr Loncar believes that the recent surge in clinical trials is fundamentally a good thing for patients, he says the field should move at a speed that allows scientists to fully understand the reasons behind a particular success or failure. “When trials fail there’s not enough time or effort to look at the details to understand why things are not working,” he says. With five checkpoints on the market, the class of medicines is well-established, but many drugmakers are nonetheless developing their own versions, such as Novartis, Eli Lilly and Regeneron. In total, there are roughly 50 of these medicines, pejoratively known as “me too” products, in the pipeline. Some executives say the latecomers may find it increasingly difficult to fill their trials with “naive” patients who have not already been treated with a checkpoint. Many will have taken the drugs already, either because they have completed one of the hundreds of existing studies, or because their doctor has prescribed the medicine to them on an “off-label” basis, whereby they are given an immunotherapy to treat a cancer for which it is not approved. “The level of pre-treatment and controlling for that is something we want to be cognisant of, because we want to ensure we have a consistent set of baseline patients to evaluate,” says Vas Narasimhan, global head of drug development at Novartis. “And I would say that’s getting more complex.” Theoretically, it should not be difficult to recruit participants given that only 4 per cent of cancer patients end up on a trial in the US. But the pharma industry has struggled to widen the pool beyond highly educated people who live in urban centres. Patients can also be reluctant to enter a randomised trial because they might end up in the control group that does not receive the drug, a fear that some companies have tried to assuage by allowing people to cross over into the treatment arm once their cancer worsens. Designing trials in this way can cloud the results significantly, however. Dr Roger Perlmutter, the top scientist at Merck, has little sympathy for laggard companies, arguing they should instead focus their efforts on unearthing new drugs or looking for biological clues that might predict which patients are most likely to respond. “It’s going to be difficult for those who are coming in late, but really that’s the way it should be,” he says. “The world doesn’t need any more [checkpoints]. We need other things. We should be finding a way to develop other medicines beyond these.”
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And some investors fear that the proliferation of checkpoints could end up commoditising one of the most promising drug classes in years. The rush to develop so many “me-too” drugs is best explained by the widely held belief that checkpoints will form the backbone of combination immunotherapies in the future. Those companies without their own in-house versions will have to strike deals with a rival company every time they discover a promising molecule that might be used in a cocktail, reducing their flexibility and wasting time in a highly competitive field. “We fully recognise there are others out there, but we decided to develop our own because we felt it was a necessary ingredient,” says Dr Israel Lowy, a vice-president at Regeneron. “We wanted the flexibility to trial it in combinations.” He adds: “There is a lot of room to improve if we do come up with the right combination. That’s the future. We are only at chapter one in the book of immunotherapy.” Cost concerns There is a huge excitement about the promise of experimental combination immunotherapies, which contain two or more medicines designed to encourage the immune system to attack cancer. Several companies unveiled encouraging early data on such cocktails last month at the annual meeting of the American Society of Clinical Oncology, the world’s largest gathering of cancer experts. Merck presented favourable results from a small trial combining its immunotherapy, Keytruda, with a drug made by biotech group Incyte: 35 per cent of patients with a certain type of lung cancer responded when given both drugs, about double the rate that doctors would expect if they were taking Keytruda alone. And Bristol-Myers unveiled early data that suggested a new cocktail containing a medicine known as “Lag 3” could help melanoma patients who have already tried an immunotherapy but failed to respond. However, with the price of a single immunotherapy already running at $150,000 per patient each year, many fear that cash-strapped healthcare systems will be unable to bear the cost of treatment regimens that combine two or more drugs. “The individual drugs are very expensive and the system won’t bear adding one on top of another,” says Brad Loncar, founder of an exchange-traded fund focused on immunotherapy. “The combo itself will have to be marketed as a single thing,” he adds, predicting that drugmakers will offer significant discounts for patients who end up taking a cocktail containing several medicines. Mr Loncar predicts that such cost pressures will lead to further consolidation in the immunotherapy field, as companies try to ensure they own all the ingredients in a cocktail so that they can set the price. “The only way to offer these discounts is if you own every component of the combination yourself,” he adds.
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