To battle B-cell cancers, drugmakers are going beyond the covalent bond

Credit: RCSB PDB

An X-ray crystal structure shows pirtobrutinib bound to the kinase domain of the enzyme Bruton tyrosine kinase (BTK).

In the battle against B-cell cancers, drugs that target the enzyme Bruton tyrosine kinase (BTK) have transformed treatment. Before the first BTK inhibitor, ibrutinib, came on the market in 2013, people with B-cell malignancies would have to endure harsh chemotherapy regimens. Ibrutinib was followed by the second-generation BTK inhibitors acalabrutinib and zanubrutinib, and all three drugs can extend lives for years.

But these drugs’ strength is also their weakness. Each of the three makes an irreversible covalent bond to C481, a cysteine residue in BTK’s active site. In doing so, the drug blocks BTK’s enzymatic activity, preventing BTK from participating in the signaling pathway that’s key to the development of B cells.

Over time, though, the interaction between BTK and these so-called covalent BTK inhibitors becomes a flaw. That’s because BTK mutates so that C481 is replaced by an amino acid that no longer forms a covalent bond to the drugs. The covalent BTK inhibitors lose their potency, and the disease becomes resistant to treatment.

Structure of pirtobrutinib.

Seeking to give patients options when covalent BTK inhibitors fail, drugmakers have been pursuing noncovalent BTK inhibitors—compounds that block BTK’s activity without forming a covalent bond to the enzyme. In 2023, the US Food and Drug Administration granted conditional approval to the first of these: pirtobrutinib, which is marketed by Eli Lilly and Company as Jaypirca. Another noncovalent BTK inhibitor, Merck & Co.’s nemtabrutinib, is in Phase 3 clinical trials.

Choosing the course

B-cell malignancies develop when the body’s B cells, which are part of the immune system, grow out of control and crowd out normal cells. Examples include chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. CLL is the most common form of leukemia in the US. Doctors typically identify the disease from a high white blood cell count. But the diagnosis often comes as a surprise.

“The white blood cell count is identified to be elevated in a blood draw for something else, like for a routine physical,” says Omar Abdel-Wahab, a physician-scientist at Memorial Sloan Kettering Cancer Center who specializes in leukemia and consults for companies in the pharmaceutical industry. When doctors try to understand what’s causing the elevated white blood cell count, they find that CLL is to blame.

On average, a person is diagnosed with CLL at the age of 70, and more than 20,000 people in the US will be diagnosed with the disease this year, according to estimates from the American Cancer Society. But CLL is very treatable, says Catherine Coombs, a hematologist and oncologist at the University of California, Irvine, School of Medicine who consults for several drug companies. People with CLL can do well on a covalent BTK inhibitor for 8 years or more, she says.

“The two major issues that come up are intolerance or resistance,” Coombs says. Roughly half of people taking ibrutinib find that its side effects, such as diarrhea and fatigue, are intolerable and stop taking it. “That ends up being a little bit better now that we have drugs that are more selective for the target BTK,” Coombs says, referring to acalabrutinib and zanubrutinib.

But all three covalent BTK inhibitors share the same mechanism of action and therefore the same mechanism of resistance. “That’s where pirtobrutinib is uniquely poised to fulfill an unmet need,” she says.

We’re hoping that with these noncovalent BTK inhibitors that we’re going to be able to provide better disease control for a longer period of time than with the covalent inhibitors.

Gregory Lubiniecki, vice president of oncology clinical research, Merck & Co.

Noncovalent BTK inhibitors like pirtobrutinib offer people with CLL a lifeline when covalent BTK inhibitors no longer work. “I’ve seen many patients that really benefited from that treatment option,” Abdel-Wahab says. What’s more, pirtobrutinib is taken as a pill at home and has few side effects. Before the drug was available, patients whose disease had become resistant to a covalent BTK inhibitor were left with treatments that had to be given as infusions and required an inpatient stay. “So it’s kind of a big deal,” he says.

A noncovalent approach

Pirtobrutinib was first made by chemists at Redx Pharma. Nicolas Guisot, Redx’s vice president of drug discovery, says scientists at the company took note of how effective ibrutinib was but also that many people taking it reported intolerable side effects. Redx researchers thought they could make a more selective BTK inhibitor that still formed a covalent bond but had fewer off-target effects.

But then data emerged about mutations that killed ibrutinib’s potency. At Redx, scientists decided to focus on compounds that were highly selective for BTK but didn’t make a covalent bond. All the BTK inhibitors have similar structural features, Guisot says. With that knowledge, they tweaked the structure to make it more selective for BTK and, once they had a promising molecule in hand, modified it further to improve its pharmacokinetic properties.

Structures of ibrutinib, acalabrutinib, and zanubrutinib.

The scientists first synthesized their clinical candidate, RXC005, in June 2016. The company disclosed the compound at an American Society for Hematology meeting in December of that year.

Guisot says the Redx team pushed hard to develop the compound in the face of competition from other companies working on noncovalent BTK inhibitors. “We made it pretty quickly to the front of the pack, and I think for a small company like us it was really important not to lose the momentum,” he says.

Researchers at Loxo Oncology (now owned by Lilly) also saw that people taking ibrutinib were developing mutations at the C481 position in their BTK enzymes. “That was an obvious tell that the cancer is evolving beyond this medicine,” says Jake Van Naarden, who was chief operating officer at Loxo in 2016 and is now an executive vice president at Lilly and president of Loxo@Lilly.

Although people were developing resistance to ibrutinib, the data told Van Naarden that BTK was still a good drug target. B cells need BTK, whether it has C481 or a different amino acid at that position, for development. “It remains a druggable target through the course of one’s disease,” he says. But because C481 could mutate, drugmakers needed to find an approach that doesn’t rely on bonding to that amino acid.

At Loxo, Van Naarden says, scientists thought about trying to build their own noncovalent BTK inhibitors. “It would take us years because that’s just how long these hard projects take,” he says.

But then Van Naarden saw Redx’s RXC005. “What I liked about it was that it was deliberate,” he says. The compound had excellent pharmacokinetic properties such that people would have to take it only once a day, and it was designed to specifically bind to BTK.

“It turns out that product profile is exceptionally difficult to deliver chemically,” Van Naarden says, because BTK’s adenosine triphosphate–binding pocket is incredibly similar to the pocket on hundreds of other kinases.

In 2017, Loxo paid Redx $40 million for the full rights to RXC005. Lilly then acquired Loxo in 2019 for $8 billion. The deal included the drug candidate, which was eventually renamed pirtobrutinib.

Pirtobrutinib has been an exciting medicine to work on, Van Naarden says. Because it was approved conditionally, the development program is ongoing, and several more clinical trials are waiting to read out. “It’s still sort of in the early days, despite being an approved drug,” he says.

Awaiting approval

Another noncovalent BTK inhibitor making its way through clinical trials is Merck’s nemtabrutinib. This molecule was first synthesized in 2012 by chemists at Daiichi Sankyo in collaboration with scientists at ArQule. But the molecule was not seen as a success, and Daiichi Sankyo returned it to ArQule, where it was known as ARQ 531.

Structure of nemtabrutinib.

Back at ArQule, the then director of chemistry Jean-Marc Lapierre saw something special in ARQ 531. The compound was remarkably good at shrinking tumors in rodents. Lapierre started trying to convince his managers that the compound was worth following up on. “It took a good year of work to get them to approve going into the clinic with it,” he says.

Lapierre says the scientists didn’t initially understand why the compound worked so well in their rodent studies. “It was equivalent to ibrutinib. But of course there is no moiety on the molecule to bind covalently to the protein. But it acts like it does.”

Crystallographic studies showed that the molecule’s tetrahydropyran noncovalently interacts with both BTK and its most common mutant, which occurs when C481 mutates into a serine.

“It was only when we realized that this moiety on the molecule interacts with either the cysteine or the serine, in the mutant BTK, that we realized that we had something of high value,” Lapierre says. “It’s actually as potent against the mutant as it is against the wild type.”

Based on the promise of ARQ 531, Merck acquired ArQule in 2019 for $2.7 billion. The molecule eventually became known as nemtabrutinib.

Gregory Lubiniecki, Merck’s vice president of oncology clinical research, says that because nemtabrutinib inhibits unmutated BTK and the most common mutant, patients should be able to take it for longer.

“We’re hoping that with these noncovalent BTK inhibitors that we’re going to be able to provide better disease control for a longer period of time than with the covalent inhibitors,” Lubiniecki says.

Potential pitfalls

Not all noncovalent BTK inhibitors in development for B-cell malignancies have been successful. In 2020, Sunesis Pharmaceuticals decided not to advance the noncovalent inhibitor vecabrutinib after the drug candidate didn’t prove to be effective in an early clinical trial in people with B lymphoid cancers, including CLL. Likewise, Roche didn’t continue clinical trials of the noncovalent BTK inhibitor fenebrutinib for people with CLL or B-cell non-Hodgkin’s lymphoma. But the company continues to pursue the compound as a multiple sclerosis treatment.

Another potential pitfall of noncovalent BTK inhibitors is that, like with the covalent versions, the kinase can mutate, but at sites other than C481. While doctors have seen evidence of pirtobrutinib resistance, UCI’s Coombs says that patients are prone to develop resistance when their disease has relapsed, and those are the patients on whom pirtobrutinib was tested.

“I don’t think it’s fair to extrapolate what we’ve seen with the patients who have developed pirtobrutinib resistance,” Coombs says, since they differ from people who get pirtobrutinib in an earlier line of therapy. People who get the drug earlier in the course of their treatment may never have BTK mutations, or the mutations could take a decade to develop, she says.

Structures of vecabrutinib and fenebrutinib.

Several companies are also looking at a strategy where they use targeted protein degradation, as opposed to simple inhibition, to go after BTK. But it’s early days for BTK degraders, says Memorial Sloan Kettering’s Abdel-Wahab, who recently published work on a BTK degrader along with Justin Taylor, a physician-scientist at the University of Miami Miller School of Medicine.

“It’s not clear that they necessarily are going to have the same level of efficacy as the inhibitors. Also, safety is still unknown. These are still Phase 1 clinical trials,” Abdel-Wahab says.

Ultimately, Taylor says, it’s most important to consider “which treatment might be best for each patient.” Today, an alternative to BTK inhibitors is to take the drug venetoclax, which has a different mechanism of action, in combination with an inpatient infusion of an antibody for a limited period of time, usually 2 years. “Many patients favor the BTK inhibitors because of their ease of administration,” Taylor says.

Noncovalent BTK inhibitors offer people with CLL a treatment option they didn’t have before that prolongs survival. With multiple drugs now available, CLL can be seen as chronic disease, like diabetes or hypertension, Taylor says, “where you’re managing it, and you go about your life normally with a few extra doctor visits.”


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