Every so often, a technology quietly (and seemingly suddenly) crosses the line from an intriguing scientific idea into a paradigm capable of changing an entire industry. That’s precisely what’s happening with biocatalysis: the use of natural or engineered biological systems—specifically enzymes or whole living cells—to accelerate and direct chemical transformations.

For decades, researchers dreamed of harnessing engineered enzymes to manufacture medicines that conventional chemistry simply couldn’t produce. Today, that vision has arrived, and its first contribution to medicine has the potential to make a significant splash. In this episode of Behind the Breakthroughs, David Thaisrivongs, PhD, executive director and head of Biocatalysis at Merck, shares the decades-long story behind one of the field’s defining milestones: the approval of enlicitide, the first oral macrocyclic peptide PCSK9 inhibitor.

But this isn’t just the story of a new cholesterol drug. It’s the story of how a generation of advances in enzyme engineering, process chemistry, and manufacturing converged to create an entirely new therapeutic modality.

Thaisrivongs explains how Merck evolved naturally occurring enzymes into precision manufacturing tools capable of orchestrating multi-enzyme reaction cascades, making some of the pharmaceutical industry’s most structurally complex molecules at commercial scale. He explores why conventional small molecules repeatedly failed against PCSK9, how macrocyclic peptides occupy a “Goldilocks” space between small molecules and biologics, and why that middle ground could open the door to oral therapies for diseases long thought treatable only with injectable biologics.

Along the way, he offers a rare behind-the-scenes look at what it actually takes to build a breakthrough medicine: choosing the right scientific problems, surviving years of skepticism, solving manufacturing challenges that discovery scientists never see, and recognizing the moment when an ambitious experiment finally becomes a viable drug.

If the last era of pharmaceutical innovation was about discovering new biology, the next may be about learning how to build—and manufacture—entirely new kinds of medicines.

This interview has been edited for length and clarity.

 

IPM: Biocatalysis has suddenly become one of the hottest areas in pharmaceutical manufacturing, but this has really been decades in the making. Can you explain what changed and why the field is reaching an inflection point now?

Thaisrivongs: I think it’s important to appreciate that people have been working on biocatalysis for a generation, but it hasn’t been until relatively recently that the potential of this technology—using engineered enzymes to perform chemical transformations—has really been translated into practice and become a valuable manufacturing tool.

I’m really proud of the work the team here at Merck has done to demonstrate, first, that it was even possible to pull off this kind of ambitious idea: creating an engineered enzyme that performs a useful function. Then we showed that you could scale production of that enzyme.

We also showed that you could scale the process in which it performs its function and, more recently, that you could do more than just one reaction. Because enzymes are often compatible with one another—as they are in every living organism, including the enzymes allowing me to answer this question—we can combine multiple enzymes in a single reaction vessel and carry out truly remarkable manufacturing processes using these novel catalysts.

One of the great things about working at Merck is that it isn’t just about developing the enzyme. It’s also about developing the manufacturing process in which that enzyme performs its function. The collaboration between the biocatalysis group, process chemists, chemical engineers, and analytical scientists is what allows us to solve the bigger problem: how to manufacture a molecule reliably enough to bring it into the world.

 

IPM: Enlicitide sits in an interesting space between traditional small molecules and biologics. Why was a macrocyclic peptide the right solution for PCSK9 when conventional small molecules had repeatedly failed?

Thaisrivongs: Enlicitide is a great example of why this kind of approach can be so important. When I joined Merck, the pharmaceutical world was largely divided into two categories: small molecules and large molecules. You were either a small-molecule scientist or a biologics scientist. Today, it’s clear that there’s a lot more gray area between those two extremes.

PCSK9 was identified more than 20 years ago as a highly promising target for reducing cardiovascular risk. Many companies, including Merck, spent years trying to develop a conventional small-molecule inhibitor—and we all failed.

The first successful therapies targeting PCSK9 were large molecules because of the biology itself. PCSK9 interacts with the LDL receptor through what’s known as a protein-protein interaction. Those interfaces are often broad and relatively flat, making them extremely difficult for traditional small molecules to disrupt. Small molecules generally work best when they bind within a well-defined pocket or cleft on a protein.

After years of unsuccessful efforts, we stepped back and changed our strategy. Instead of asking whether a conventional small molecule could solve the problem, we asked whether a somewhat larger molecule—still much smaller than an antibody—might be able to engage that flat protein surface.

That’s where macrocyclic peptides became so compelling. They’re significantly larger than traditional small molecules but still remarkably small by pharmaceutical standards. Enlicitide, for example, is roughly one percent the molecular weight of a typical monoclonal antibody. That turns out to be something of a Goldilocks solution. The molecule is large enough to disrupt the protein-protein interaction but still small enough to be orally bioavailable.

In that sense, macrocyclic peptides combine many of the advantages of both worlds: the potency, selectivity, and safety profile often associated with large molecules, together with the convenience of oral administration that’s traditionally been limited to small molecules. PCSK9 is only the first target we’ve pursued with this approach. There are many other disease targets that have historically required injectable biologics, and we’re excited about the possibility that macrocyclic peptides could make those therapies available as oral medicines. 

 

IPM: How much of this approval is about enlicitide itself, and how much is really proof that an entirely new class of medicines has arrived?

Thaisrivongs: The approval was based on two Phase III studies that we’ve already shared publicly, which generally showed reductions in PCSK9 and LDL cholesterol comparable to those seen with the injectable therapies. We’ve published the clinical data in detail, so I’d rather defer questions about the efficacy results to the clinical experts. Dr. Christie Ballantyne, for example, is a much better person to speak to about those findings.

What I can say is that we’re incredibly excited about what this new option represents for patients. We believe it has the potential to make this class of medicines much more accessible around the world.

Beyond enlicitide itself, I think this approval demonstrates something much broader. It shows that there is an important class of molecules that sits between traditional small molecules and biologics and that these intermediate-sized molecules can provide meaningful benefits for human health. More importantly, molecules like enlicitide have the potential to bring therapies that have historically required injectable biologics to many more patients through oral medicines. That’s what excites me most—the possibility of making these kinds of treatments substantially more accessible. 

 

IPM: Not every disease target is suited for a macrocyclic peptide. How do you decide which biological problems are actually worth pursuing with this technology?

Thaisrivongs: I think one of the most important leadership principles, regardless of your field, is problem selection. Even at a company like Merck, where our resources are substantial, they’re still finite. Time is probably the most precious resource of all. We spend a great deal of effort deciding where to invest—not only across therapeutic areas and modalities, but also within specific technologies like macrocyclic peptides. The key question is always, “Where can this modality have the greatest impact?”

Not every biological target is well suited to a macrocyclic peptide. One of the reasons PCSK9 proved to be such a compelling opportunity is that it’s an extracellular target. That means the molecule can engage its target without needing to cross a cell membrane. It was also an area where patients had few alternatives beyond injectable biologics. That created an opportunity to develop an orally available therapy that could offer comparable performance while providing a meaningful advantage in convenience and accessibility. If an equally effective oral small molecule had already existed, I’m not sure we would have spent the better part of a decade developing a macrocyclic peptide.

Those are the kinds of questions we ask. Where can we have the greatest impact? What are the needs of the patients? Where is the target expressed? What type of molecular interaction is required? All of those factors feed into the complex decisions about where we choose to invest in drug discovery. 

There are so many new therapeutic modalities emerging today that simply didn’t exist when I was in school—antibody-drug conjugates, targeted protein degraders, molecular glues, bispecific antibodies, and many others. These are fascinating molecules with tremendous biological potential. We still have a great deal of science and experimentation ahead of us to fully understand what’s possible.

But I’d come back to the point you raised earlier. The first challenge was simply proving that we could design a molecule with the right biological properties—that it could engage its target, be orally bioavailable, and be well tolerated.

The discovery team at Merck accomplished something extraordinary by creating an unprecedented macrocyclic peptide with the properties we believed were necessary to achieve our goal of developing the most potent and accessible oral cholesterol-lowering therapy possible. Achieving that performance, however, required an exceptionally complex molecular structure. That created an entirely new challenge for the development organization.

Once discovery handed us this remarkable molecule, the question became, how do we actually manufacture it in a way that allows patients to benefit from it? That’s been our focus for many years. The first time we synthesized this molecule, it felt like a military campaign—it took years of work just to produce milligram quantities. Our challenge was to transform that heroic laboratory synthesis into a robust, scalable manufacturing process capable of supplying patients around the world. That’s where biocatalysis proved to be uniquely suited to unlocking the full potential of what the discovery team had created. 

 

IPM: Was there a specific point during development when you realized this wasn’t just an interesting scientific experiment—that it could actually become a medicine?

Thaisrivongs: We’ve been working on PCSK9 for well over a decade, and the development of enlicitide itself has taken nearly that long. I think it’s important for people to appreciate just how much time, effort, and persistence it takes to bring a single medicine across the finish line.

The real “aha” moment came when we saw the Phase I data. Up to that point, the discovery team had succeeded in making enough of these molecules to perform the initial preclinical studies. The potency looked promising, the absorption assays were encouraging, and there was enough evidence to justify advancing what would eventually become enlicitide into clinical development. Even so, I think it’s fair to say that many people—perhaps even most people—at Merck remained skeptical that a molecule like this could actually be orally bioavailable. Nothing quite like it had been done before.

There was relatively little doubt that, if the molecule reached its target, it would do what it was designed to do. It showed excellent potency and target engagement. The real question was whether it could survive the gastrointestinal tract, be absorbed, and reach systemic circulation. When the Phase I data came back, the project transformed overnight. It was no longer just an ambitious scientific proof of concept—it suddenly looked like it could become a real medicine.

One advantage of working on PCSK9 is that the downstream biomarker is LDL cholesterol, which is straightforward to measure. Even in Phase I, we saw excellent target engagement accompanied by substantial reductions in LDL cholesterol. Decades of cardiovascular research have established the relationship between LDL cholesterol and cardiovascular risk. Once we saw oral absorption, target engagement, and meaningful cholesterol lowering all coming together, we knew we had something very special. At that point, we were off to the races. 

 

IPM: Where do you see biocatalysis heading over the next decade? What are the next frontiers that excite you most?

Thaisrivongs: One thing worth reflecting on is that the examples Merck has published—from enlicitide to some of the earlier work I mentioned—still have important connections to biology. These aren’t naturally occurring molecules, but they resemble classes of molecules that do exist in nature. Nucleosides, for example, are fundamental biological building blocks, and while enlicitide isn’t a naturally occurring peptide, it incorporates many peptide-like structural features. That gave us a path forward. We could begin with naturally occurring enzymes and evolve them to work on these more complex, non-natural substrates.

I don’t want to minimize how much work that required—it was an extraordinary scientific effort—but there was a clear conceptual bridge between nature and what we were trying to accomplish.

I think the next frontier for biocatalysis is extending that capability to molecules that bear almost no resemblance to anything found in biology. We’re already seeing exciting examples of this, both at Merck and elsewhere. Researchers are taking naturally occurring enzymes and evolving them into catalysts capable of performing chemistry on molecules and intermediates that look nothing like anything nature ever evolved to process.

As we continue expanding the range of reactions engineered enzymes can perform—and the diversity of molecular structures they can act upon—we’ll dramatically broaden the reach and impact of biocatalysis in pharmaceutical manufacturing.