• Biotech and pharma giants look to bispecifics as alternative
  • Roche's O'Day sees potential to leapfrog CAR-T therapies

This is a tale of two cancer therapies, each championed by one of the world’s biggest drugmakers.

Novartis AG has made a priority of an experimental therapy that reprograms a patient’s cells and put them back into the body to fight tumors. It’s part of a new class of custom treatments that have investors excited. News of high remission rates in early studies sent stocks soaring early last year and stirred hope for transformative cures. 

Roche Holding AG, Novartis’s crosstown rival in Basel, Switzerland, is bypassing that approach. Instead, Roche is pursuing a technology that offers the promise of custom-cell therapy without having to extract or pump in any living cells.

Called bispecifics, these treatments have two distinct arms to grab onto proteins on the surfaces of different cells. One end hooks onto the cancer and one end latches onto the immune cell. Once they’re connected, the immune cell moves in for the kill.

Playing Leapfrog

"If we are successful with this, we think that’s definitely a leapfrog" over custom cell treatments such as chimeric antigen receptor cells, or CAR-Ts, Daniel O’Day, Roche’s head of pharmaceuticals, said in an interview. "You’re essentially doing the same thing that you’re doing outside the body in CAR-T, inside the body."

Some CAR-T results have been stunning. One Novartis therapy wiped out an aggressive blood cancer in 93 percent of children and young adults who received it -- and 18 of 59 patients were cancer-free after 12 months. Treatments from Juno Therapeutics Inc. of Seattle and Kite Pharma Inc. of Santa Monica, California, have shown similar promise.

But the approach may prove a little too unwieldy, according to O’Day, as it requires numerous procedures and intensive manufacturing processes for each patient, unlike more typical one-size-fits-all drugs.

“Ninety-six percent of cancer patients were treated outside of academic institutions,” O’Day said. “They are not going to have access to these sophisticated centers that do CAR-T cell therapy.”

Side Effects

There can also be serious side effects: CAR-T therapies can push the immune system into overdrive, causing a potentially fatal immune reaction called a cytokine storm. A fraction of the patients in trials by Juno, Kite and Novartis have experienced severe cytokine release syndrome, and a few have died of the condition. Researchers now treat patients with drugs that can calm the overactive immune system.

"People are beginning to understand that the cell-based therapies that have been so interesting to everyone, including me, CAR-T cells and other derivatives of other cell-based therapies, may have some way to go," said Sean Harper, head of research and development at Thousand Oaks, California-based Amgen Inc. "Some of the hype is beginning to fade."

Making bispecifics work hasn’t been easy, either. Often built with large, complex molecules welded together, the drugs fall apart easily. The first bispecific approved by U.S. regulators, Amgen’s Blincyto, is so fragile that it’s swept out of the body in just a few hours. To compensate, patients are hooked up to a pump for a month, continuously infused with the drug. 

Fragile Drugs

Amgen says Blincyto, which is approved for a small subgroup of patients with blood cancer B-cell acute lymphoblastic leukemia, is just the beginning for bispecifics, and companies are trying to make them more durable.

In a key clinical trial, about 42 percent of those who took Blincyto had the disease wiped out. Yet there is still risk: Across the drug’s clinical trials, about 65 percent of patients suffered serious side effects, including 15 percent of patients who had fatal adverse events. Patients on Blincyto have also experienced cytokine release syndrome, though at a much lower rate.

Smaller companies including Xencor Inc. and MacroGenics Inc. are also staking out claims to be able to build more effective bispecifics. And industry giant Regeneron Pharmaceuticals Inc. is testing its own version, trying to build the drugs to look like a single protein so that they last longer and work more effectively. Roche has designed a new format for bispecifics, and in 2014 acquired technology that the company says results in “excellent stability and good manufacturing properties.”

Hedging Bets

In people whose immune systems have been so depleted that they have virtually no T-cells remaining, CAR-Ts may work where bispecifics cannot, according to Scott Koenig, chief executive officer at MacroGenics in Rockville, Maryland. And though it’s committed to bispecifics, Amgen last year signed a deal with Kite to get access to CAR-Ts in case they truly have the edge in some cancer cases.

Meanwhile, Juno has said it’s trying to speed up its manufacturing process so that it may take as little as two days.

"Bispecifics are very promising," Juno CEO Hans Bishop said. "Whether they can get to the level of efficacy that CARs can remains to be seen."

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