How Pembrolizumab Became Oncology’s Closest Thing to a “Silver Bullet”

Are genius molecules a product of nature or nurture?

How you spend your CI budget is as important as how much you are spending; therefore, it is vital to assess the upfront value associated with each potential project in order to ensure your money goes where it should and that the management team is happy.

Kevin Baruzzi, Dr. Arun R. Shrivats and Daria Andreeva

Among the available cancer treatments, pembrolizumab is an industry bellwether: A drug that is as close to a “silver bullet” as the industry has ever had in history. Here are some of the facts about pembrolizumab that have given it a hero status among oncology patients worldwide:

In the last five years, pembrolizumab has received 13 tumor approvals and 35 indication approvals at a staggering rate of ~4 approvals per year over the last three years.

Pembrolizumab has opened up new paradigms in oncology treatment, including a shift toward a molecule-based paradigm (TMB, MSI-H) from a tumor biology-based paradigm. It has also successfully led the charge on a precision, biomarker-based approach to immunotherapy, which has been the province of targeted therapies until now.

Projections suggest pembrolizumab is clearly still an ascendant product: Its sales in 2019 were $12 billion, with analysts estimating this figure will reach $22 billion by 2025.

When a game-changing drug such as pembrolizumab appears on the horizon, one must be intellectually curious and ask how it came into being.

Was pembrolizumab a special molecule – a find of nature – that heralded, perhaps via the minutest alteration, an immunotherapy breakthrough, a chemistry miracle?

Or was pembrolizumab a talent that fell into the right hands and was housed in labs where scientists knew exactly how to nurture it?

To layman eyes viewing the image below, the temptation may be to see the remarkable similarity between pembrolizumab nivolumab (BMS’ compound) and say “nature”.

Yet, literature suggests there are notable structural differences in terms of how the two molecules bind to PD-1, with the epitope region of pembrolizumab showing a much greater overlap with the PD-L1 binding site than that of nivolumab. Beyond structure, preclinical and early clinical pharmacology of pembrolizumab are similar to that of nivolumab and give no clue to its special destiny. Indeed, one can argue there is little reason to believe they are not interchangeable based on preclinical and early clinical data.
So, while structural, preclinical and early clinical data tell us that something is special about pembrolizumab, they are not conclusive. Empirically, the drug as found in nature may not be “one of a kind”, yet its status today befits that description. How did that happen?

Like all genius successes, this brings us to a critical ingredient: The way pembrolizumab has been nurtured, and the credit here goes to Merck, perhaps even more so to Merck Research Labs (MRL). MRL-led studies have defied industry expectations on probabilistic success and failure.

There is a personality at play here too. Merck has not always taken the first shot on goal, but has instead chosen to wait to get the shot right when the company eventually took it (e.g., using PD-L1 expression to select the regimen). There is clearly genius also in the choices Merck has made related to trial design and patient selection, which led to the “separation of curves” between pembrolizumab and the rest of the drugs in the space.

Are there learnings here for pharmaceutical companies in general? The answer is a resounding yes.

Every major pharmaceutical company faces the breakthrough imperative, and perhaps the lesson here is that breakthrough drugs are not only born but are also made. More importantly, is there a repeatable model? The answer to this is more complex.

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