Excerpt from For Blood and Money: Billionaires, Biotech, and the Quest for a Blockbuster Drug

The First Patients

Imbruvica and BTK inhibitors revolutionized the treatment of chronic lymphocytic leukemia. A new book, FOR BLOOD AND MONEY, shows the crucial role patients played in the development of this groundbreaking cancer medicine. By Nathan Vardi

On the very same day Bob Duggan publicly announced that the biotechnology company he ran, Pharmacyclics, had successfully completed a crucial stock offering on Wall Street—August 5, 2009—an eighty-two-year-old woman showed up at a tiny medical clinic in Springfield, Oregon.

Located in a single-floor building of a strip mall anchored by an Albertsons grocery store, the clinic was a satellite office of the Willamette Valley Cancer Institute, headquartered in nearby Eugene. The woman had been suffering from chronic lymphocytic leukemia, or CLL, which had returned after chemotherapy treatment, causing the lymph nodes in one of her armpits to inflate to the size of a golf ball.

The most common form of adult leukemia, CLL is diagnosed in 21,000 mostly older Americans annually, representing more than one-third of all new US leukemia cases each year. While defined as a relatively rare cancer, it is not rare enough. Because CLL is a slow progressing disease, about 186,000 Americans deal with it at any given time. The median age of patients is seventy-one, but it’s not just an old person’s disease. As many as 11 percent of CLL patients are under the age of fifty-five, so the absolute number of younger patients is still significant.

For doctors, treating CLL was both monotonous and abysmal, and to make matters worse, there had been no major medical advancements in CLL for a long while. The cancer grew slowly in most patients, who initially just kind of lived with it. Their doctors would typically see them every six months and tell them their blood tests looked good. But eventually, things would go south and one of these appointments would result in a recommendation for treatment. The tempo and conversation would then change rapidly, and there were mostly only two tools available. First off, there was the carpet bomb of chemotherapy that indiscriminately kills both good cells and bad. The second option was rituximab, the monoclonal antibody treatment. These therapies were often administered in a combination treatment program. Remissions rarely lasted for long.

For a subset of patients with a specific genetic mutation, a more brutal chemotherapy could be more effective, but even then, only the younger patients could tolerate it. Otherwise, the cancer would normally come back within two to four years. As malignant B cells collected in the lymph nodes of patients, these bean-sized glands in the armpits, neck, or stomach would swell up to the size of an orange. Patients would often lose weight and feel terrible. Some opted for bone marrow transplants to deal with associated bone marrow failure. For most patients, the disease would no longer be treatable and they would succumb to CLL or the complications from it and the chemotherapy that ravaged their immune system.

This was the situation the eighty-two-year-old woman who arrived at the Willamette clinic found herself in. Chemotherapy was no longer a viable option for her. But one of the two oncologists on-site, Jeff Sharman, suggested she participate in a new study; it was being run by Pharmacyclics for an experimental treatment code named PCI-32765. The drug was a small molecule that medical science referred to as a BTK inhibitor. It targeted and infiltrated malignant cells and blocked an enzyme, Bruton’s tyrosine kinase, that helped cancer cells multiply and stay alive.

A lot of random events had come together to produce this moment. Sharman knew all about Pharmacyclics and its drug. He had known Richard Miller, the founder of Pharmacyclics, at Stanford, where as a thirty-one-year-old hematology-oncology fellow Sharman had first worked in Ron Levy’s lab on the idea of impairing B cell receptor signaling in blood cancer. Miller frequently visited the lab, where Sharman had originally impaired B cell receptor signaling, not by blocking BTK, but by hitting a different tyrosine kinase called Syk. Some Stanford doctors thought that Sharman’s work had helped inspire Miller to test a BTK inhibitor in lymphoma patients in the first place. And before he left Pharmacyclics, Miller had ended up including CLL patients in the first-in-human trial of PCI-32765 in order to more easily do assays.

Sharman had arrived in Oregon a year earlier to start a career as a practicing doctor at the Willamette Valley Cancer Institute. Meanwhile, at Pharmacyclics, the trial of PCI-32765 had been expanded to include a few new physician-scientists, clinical investigators who could recruit patients to the trial. Sharman had signed himself up, and he was now convincing the elderly woman suffering from CLL to be treated with Pharmacyclics’ BTK inhibitor.

Sharman entered the patient into a database so she could get access to the experimental drug. He also called Ahmed Hamdy, Pharmacyclics’ chief medical officer. Sharman warned Hamdy that the patient’s white blood cell count might increase. More white blood cells normally meant the cancer was advancing, but Sharman knew from his experience inhibiting Syk at Stanford that the white blood cell counts could eventually come down.

“Don’t get alarmed,” Sharman said.

The next day, the patient returned to the clinic to get her blood drawn, revealing that her white blood cell count had indeed shot up just as Sharman had anticipated. Standing in his muddy backyard that evening, Sharman called Hamdy to talk to him about it. Hamdy freaked out. Was the drug making the cancer worse?

“Are we causing a hyper-progression?” Hamdy barked into the phone.

But Sharman felt something else was going on, a signal beneath the noise.

“I could feel her armpit lymph nodes and they’re smaller,” Sharman responded.

For Sharman, swollen or firm lumps under the skin were the most surefire symptom of blood cancer, indicating that large numbers of cancerous white blood cells had gathered in the lymph nodes. The fact that the lymph nodes had shrunk meant that something good was happening. Sharman expressed confidence that the white blood cell count would begin to come down over time, just like it had with the Syk inhibitor he had worked on at Stanford, a drug called fostamatinib.

Hamdy ordered a CT scan. And indeed, the imaging showed a reduction in the patient’s swollen lymph nodes of more than 25 percent.

Not long afterward, the elderly patient’s lymph nodes shrunk by more than 50 percent, and she was noticeably feeling better. Her white blood cell count declined during her week off treatment. As a result, the patient was recorded to have had a partial response to the drug. Later in the fall, Sharman enrolled another relapsed CLL patient, a sixty two-year-old who for years drove a taxi cab in Juneau, Alaska. He also experienced a partial remission while taking PCI-32765.

Back at Pharmacyclics’ headquarters Sunnyvale, California, word of the partial responses was greeted with a sense of relief. For the first few months of the trial, there had been no indication the drug was doing anything. It had not resulted in any harm, which was good, but there was no patient improvement either.

When Duggan heard at a Friday meeting about the first partial remission, he jumped up on the conference room table and danced an Irish jig. Duggan would later deny ever doing the dance. But for Glenn Rice, Pharmacyclics’ president, the moment was unforgettable.