Post ASCO, talk turns to prepping BMS therapy for launch

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As the big cancer meeting wound down, talk turned to the best way to prepare Bristol-Myers Squibb's anti-PD-1 antibody, a potential blockbuster, for launch.

While they are early studies, three clinical data presentations on the PD-1 pathway discussed at the American Society of Clinical Oncology and published online over the weekend confirmed analysts' belief in BMS-936558 as a very potent way of mobilizing the patient's own immune system to fight cancer.

“BMY's Anti-PD-1 Turns Heads in Oncology,” was the title of a June 4 investor note from Credit Suisse analyst Catherine Arnold. “While this weekend's ASCO Meeting was full of oncology advances, we believe BMY's Anti-PD-1 (‘558) garnered the most interest,” she observed.

She and others were duly impressed by rates of tumor shrinkage seen in three refractory metastatic cancers: 18% in those with non-small cell lung cancer, 28% in melanoma and 27% in renal cell cancer—responses that are two or three times stronger than those typically seen with standard of care.

The data inspired Arnold to raise her ‘558 forecast from $200 million to $1.8 billion. She predicted a 70% chance of success, launch in 2016, and use in NSCLC (squamous only, an area of unmet need), melanoma and RCC. By 2020, she wrote in her note, the antibody could account for 7% of BMS revenue. The forecast was in line with others'.

One reason '558 is picking up more fans among the analyst and KOL community is that it opens up a new class of immunomodulators—drugs that rally the body's own defenses to stave off cancer. “We thought enthusiasm among KOLs attending the meeting was palpable,” noted analysts from Leerink Swann, who were among early fans of the anti-PD-1 approach, in a recap for investors which reaffirmed their forecast of $2 billion in sales by 2020.

PD-1 (programmed death 1) is a protein on the surface of activated T cells, the advance guard of the body's immune system. Some tumor cells generate a related protein, PD-L1, which binds to the PD-1 on T cells and cripples their ability to fight the tumor. A monoclonal antibody, ‘558 blocks PD-1 from binding to PD-L1.

Boosting the immune system can lead to side effects. There were nine cases of a serious side effect, including three deaths from inflammation of the lung that seemed to be related to the drug. Oncologists, wrote Barclay's analyst Tony Butler, feel that in most cases the effect, called pneumonitis, is reversible, and he too continued to support a $2-billion peak sales estimate and likely launch in 2016. Butler pointed out that the agent appears “less toxic than Yervoy,” the BMS drug for stage IV melanoma approved in March 2011.

More compelling than the response rates, wrote the Leerink Swann analysts, was evidence suggesting that PD-L1 expression in tumors could represent “a powerful biomarker for guiding patient selection.” Several presenters cautioned that the data on anti-PD-L1 in lung and renal cancer were not mature and limited to only a few patients (75 and 17 patients, respectively). “Nonetheless, we believe a predictive biomarker that ‘concentrates' ‘558's efficacy would be a grand-slam for reimbursement and uptake,” the analysts wrote.

BMS acquired rights to develop and sell ‘558 in 2009 with its takeover of Medarex. It's the second likely blockbuster besides Yervoy to come from the legacy company. Other drugmakers with PD-1 blockers in development include Merck and Teva.

The drug's potential leads to questions on the best way to prepare it for launch. With respect to biomarkers, many approaches can be taken. “It's incumbent on companies developing these types of treatments to look for biomarkers that are relevant to immunological modulators,” said Sandra Silberman, VP, translational medicine for Quintiles, the contract research organization.

These could include a companion diagnostic. “It's very likely you are going to get a companion diagnostic looking at PD-L1 IHC [immunohistochemistry] or utilize a FISH test,” said Brad Smith, Quintiles VP, translational medicine, integrated clinical services.

In addition, ‘558 could be “sequenced” with chemo, or paired with Yervoy or other targeted agents to enhance its effect. “Most importantly, rational combinations with, for example, a cancer vaccine and an immunomodulator might be useful,” said Smith.

So-called cancer vaccines provide specific antigens rather than non-specifically stimulating the immune system. Dendreon's Provenge, a vaccine for treating prostate cancer, involves a process where patients' immune cells are harvested and antigens (proteins) found in prostate cancer are added, producing cells that can better stimulate the patient's own T cells when re-injected. In the case of Provenge, combining it with the new non-specific immunomodulators may or may not improve value for the patient. Nevertheless, said Silberman, “Use of specific and non-specific immunological agents together needs to be explored."

In other research presented at ASCO, data from a trial funded by Johnson & Johnson's Janssen unit, maker of prostate cancer drug Zytiga, showed the drug more than doubled the period from the start of treatment to when subjects' metastatic cancer worsened. Zytiga provided a 25% benefit in survival in chemo-naïve patients who have the disease, and in this same setting it more than doubled the response rate among pre-metastatic subjects.

Many believe the trial, known as study 302, was stopped too early (at 43% of total events). Nevertheless, the data bode well for Zytiga's approval and launch in Provenge's pre-chemo setting, which would be in addition to its existing approval for use with prednisone to treat patients whose cancer has resisted other treatments. Another prostate cancer drug being developed by Medivation, MDVN 3100, is also being tested in the pre-chemo setting  but would likely not reach market for that indication before 2015, according to Credit Suisse analysts.

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