MOMA Makes an Art of Targeting ATPases

Molecular machines known as ATPases are one of the cell’s most important workhorses. Through stepwise contortions, each move fueled by the combustion of an ATP molecule, these enzymatic motors drive vast vital functions. Embedded in cellular and mitochondrial membranes, ATPases pump ions into neighboring spaces to charge cells electrochemically, excrete acids into the gut, and survey the expanses of cytoplasm and the nucleus for protein folding and DNA replication.

With more than 400 family members, ATPases represent attractive drug targets. Drugs targeting these enzymes—such as the heartburn medication omeprazole (a proton-pump inhibitor) and the chemotherapeutic and topoisomerase inhibitor doxorubicin—are in widespread clinical use. However, many of these drugs were found serendipitously, not through a systematic understanding of the ATPases.

MOMA Therapeutics is dedicated to developing the next generation of precision medicines by focusing on the molecular machines implicated in disease. Based in Boston, the biopharmaceutical company is developing a platform to exploit a critical weakness shared by all enzymes in the class: their reliance on well-coordinated, sequential changes in protein structure. Named after the molecular machines that are their clinical targets of interest, MOMA aims to develop high-impact, precision medications for people with unmet medical needs by focusing its platform on disease-causing molecular machines.

Founded in 2020, MOMA Therapeutics is a private firm backed by a prominent group of life sciences investors. In early May, the biopharmaceutical company announced the completion of a $150-million Series B financing led by Goldman Sachs Asset Management, with participation from Section 32, Pavilion Capital, Invus, and LifeSci Venture Partners. All of MOMA’s Series A investors, including Third Rock Ventures, Nextech Invest, Cormorant Asset Management, Casdin Capital, Rock Springs Capital, Creacion Ventures, Alexandria Venture Investments, also participated in the round.

GEN Edge sat down with MOMA CEO Asit Parikh, MD, PhD, to understand how MOMA is making headway in creating pharmaceuticals for a notoriously tricky drug class of enzymes.

GEN Edge: What is the core mission at MOMA Therapeutics?

Parikh: We have one goal at MOMA: to pursue life-changing medications for patients by unlocking a class of enzymes, or molecular machines as we call them colloquially—ATPase proteins.  MOMA was launched just a little over two years ago. I committed to come on in January 2021 and started formally in March 2021. MOMA was founded around the concept that this set of specific proteins catalyzes functions in the body present in all cells, yet they’ve been difficult for people to drug. With all the drugs that have come out in the last 15–20 years, this class of enzymes is the toughest to target. It’s not that they’ve never been drugged. There are some fantastic examples in this class. But there are 450–500 of them in the human genome, half of which have been linked to disease; only about a dozen have ever been drugged.

These are generally very large enzymes. They work in complexes and are sometimes present inside specific compartments within the early drug discovery spectrum that we excel in at MOMA.

GEN Edge: Is MOMA a platform company?

Parikh: If we focus on just the ATPases linked to disease, we can start making associations across the class and start making that process of the early drug discovery within the class much more efficient. That should manifest shorter times to identify lead projects to become clinical development candidates, a higher likelihood of technical success at each stage of the discovery process, and a greater number of enzyme targets for drug discovery. That’s what we’ve done. When the company was launched, there was this focus on building out this platform and the tools and pulling them together to work on this class of molecules.

But the company also reasoned not just to build a platform. We have to have real projects that will become drugs. We had to pick it up somewhere. It was a vision that these enzymes are targetable and build the tools to target them. There were three projects picked out that we thought we could get traction on. All three projects are in the oncology space. Each of the targets we’re going after is genetically linked to a specific type of cancer where we could, in theory, screen which patient would benefit from what we’re addressing our drugs. In other words, personalized medicine.

The perfect projects out there are the ones that are not too easy and not impossibly hard. There’s a sweet spot in there where if you have the tools. Not many people can get there, but if you get there, you get a lot of differentiation because it’s going to be very hard for people to follow because of what you had to build up to get there.

 GEN Edge: How will MOMA make use of the recent funding round?

Parikh: This funding round permits us to have about 2.5 years of runway to get us into the clinic. 2.5 years is a long time. There are many degrees of freedom. We have a broad but very early-stage portfolio. But we’re going to have to be super focused on getting that portfolio into the clinic and as far into the clinic as we can. There’s not a clear sign that the market will suddenly pickup, nor should we wait around for that. It’s great if it does, but I think that, more likely, it could stay very similar to where it is or even potentially go down. We need to be ready for all of those scenarios.

How do we get this exciting portfolio, still early, into the clinic with $150 million? It may seem like a lot of money today. Still, it will have to be spent very wisely because it’s not an inexpensive proposition to do what we do: put together all the tools in biochemistry, chemistry, structural biology, and computational biology on challenging targets.

 GEN Edge: How will MOMA approach manufacturing and commercialization?

Parikh: We haven’t built all that up yet. Some of it needs to be thought about now, and some can wait a little bit. We just met with our leadership team where we talked about what the next stage of build would look like in preclinical science, because our molecules have to go into animals before they can go into people. Most of what we’ve done so far has been in cells or in vitro. Now it goes to animals before it can go to people. That requires some different skill sets that we need to either bring on from a consulting basis or bring on full-time, in a way that works well within our system and produces what we need on time and within budget.

GEN Edge: How is MOMA’s approach for targeting ATPases working pharmacologically?

Parikh: We do expect that we should be able to make oral drugs. These are small-molecule drugs—the classic pill. I think there’s still a space for these, even with all the ultra-high-tech stuff invented in the last few years like cell therapy. We’ve seen excellent, transformative examples of these new technologies. That’s one kind of innovation. The old technologies still have a place for the proper biology and the right patient and unmet clinical need. You can still put together a small molecule drug that can do some pretty incredible things as well. And we’ve seen examples of that from others just in the last few years. I fully expect there will be a lot of learnings for us. Fortunately, we have a seasoned leadership team. We’ve spent many years in preclinical and clinical development across the team at many other institutions and in pharma and biotech, working with contract laboratories to produce high-quality output.

Many people want to jump on the bandwagon of something innovative, and it was probably the first person that got there—hats off to them—because they probably took some significant risk. Still, then the second person wants to follow along. Maybe there’s a piece of the action for them. [Then you get] a bunch of people saying ‘I want to go where that person did’, but it’s not so novel anymore. You have to ask: is there enough meat on the bone or a big enough problem to solve?

There’s a reason we still eat cereal with a spoon after all these years! You could come up with a completely different tool if you wanted to, but you still have to get the cereal into your mouth. It’s practical. The people who jumped into MOMA early had some very conducive skills to this structure-based design. A lot of companies use structure-based design. You learn the structure of an enzyme and then you use that structure to pinpoint where on the enzyme you want to block or modulate its activity. Sometimes you can even activate and get it to do something.

I don’t think that those people believe that that’s the only correct answer. They were very good at that. That was conducive to the first vision, which was to modulate this class in a way that impacts human disease. We knew that inhibiting ATPases would be necessary, at least for a handful of them, and very likely to succeed based on some genetic data we had seen in databases.

By bringing together the people that were willing to take a crack at it—added onto the fact that this is how we’re doing it right now and will be down the road —could MOMA start thinking about some of these other modalities to target proteins in this class in a different way where it made sense.

There are a lot of really bright people out there. But the most significant achievements are when people have to do something as a team. The only way to make a drug is as a team, where people work well together. We will be hiring another ten or so people in the coming year, and probably about the same amount next year. We’re looking for people who share the desire to be active contributors to a team doing critical things for suffering people. That’s a shout-out to our scientists because they’ve embodied that day-in, day-out. The only reason we could raise $150 million in this environment is because of what they produced.

We’ve got a long way to go. This Series B funding is terrific, but the day we got the financing wasn’t any different than a typical day. We’re now past the fundraising, now we just have to deliver.