Inside J&J's Many-Indication mAb
By Tyler Menichiello, contributing editor and Matt Pillar, chief editor
Leona Ling, Ph.D.’s relationship with the investigational monoclonal antibody nipocalimab is defined by curiosity, perseverance, and commitment.
Dr. Ling, who currently serves in a weighty position with the equally weighty title of Head, Translational Science Autoantibody Pathway Area Stronghold at Johnson & Johnson Innovative Medicine, is humble. She’s not quick to declare that her journey with nipocalimab began when she herself discovered it. She is, however, quick to fondly reminisce about the days, more than ten years ago, when she was charged with leading the project that led to its discovery.
Ling says addressing HDFN was a good fit for Momenta’s history of innovative development paths, a compelling fit for nipocalimab, and the right fit for her. “Momenta had an unusual complex generics portfolio that was the basis for its expertise in glycosylation, which spawned the company’s interest in IgG Fc function in autoantibody and alloantibody diseases,” she says. “I had worked in novel drug discovery at Biogen for a long time. A unique company like Momenta was exactly what I was looking for.”
Molecular Discovery, Design Partnership
Ling and the team she led, with its deep expertise in glycosylation and Fc biology, worked quickly to discover the molecule known today as nipocalimab, but Momenta needed some help. “We had a lot of diverse expertise, but heavy-duty antibody discovery expertise wasn’t among it,” she says. As such, Momenta partnered with AnaptysBio, which created some of the initial molecules that Ling and her team characterized, formatted, and optimized. That team selected the final candidates, discovering one optimal molecule for development, and nipocalimab was born.
Ling describes the molecule as a well-behaved one, and thus, she says CMC development and manufacturability studies didn’t pose any significant challenges. “The job of this molecule is simply blocking that FcRn-IgG binding site. The activity of the molecule suits the diseases for which it is being developed,” she says. The molecule doesn’t exhibit glycosylation, it’s stable, and it’s productive. All that said, the very premise of blocking IgG gave rise to some heavy questions. While there existed parallel treatments to clear antibodies—plasmapheresis and immunoadsorption, for instance—which provided a rough proof of concept, those are episodic treatments that aren’t applied consistently. To treat HDFN, Ling and her team wanted to lower IgG for the duration of pregnancy, and potentially, in other indications, for even longer durations. “The real big question we needed to ask ourselves was,” says Ling, “is it really a great idea to lower IgG?”
Ling and her team did extensive due diligence in the clinical immunology arena, consulting with experts and researching IgG-lowering therapies that were in clinical studies for other indications. The team confirmed its hypothesis that lowering IgG doesn’t create the same effect as having primary immunodeficiency. “That took us some time to understand. We simply didn’t have clinical experience with it until we started doing some Phase 1 studies in humans,” she says. That’s when the real “aha” moment came. “It became clear that this molecule is very consistent and very predictable. We could figure out how to dose it, we knew we could build clinical studies, and we had expanded to three different diseases, including HDFN, myasthenia gravis and warm autoimmune hemolytic anemia, to pursue in those studies,” she says.
Big Bio Comes Calling: Enter J&J
Ling says the world of IgG pathogenic antibody indications seems to be expanding every day. Momenta put itself in a strong position when it chose to chase one of the toughest of those indications in HDFN. It treated pregnant patients early in their second trimester, as IgG doesn’t cross into the fetus during the first trimester, and the fetus isn’t yet developed enough to suffer from hemolytic anemia. But, the fetus is only about the size of a plum at the start of the second trimester. If it becomes anemic due to HDFN, the fetus must be treated with an incredibly risky intrauterine transfusion, which introduces complications to the pregnancy and carries a high risk of fetal death.
It’s no surprise that, because Momenta thwarted much of that risk with nipocalimab, and in the process contributed a great deal to the industry’s understanding of the FcRn-IgG mechanism, J&J took notice.
In 2020, J&J acquired Momenta in an all-cash deal worth $6.5 Billion. Nipocalimab was the prize J&J was after. And J&J took the molecule on in a package deal that included Leona Ling.
Fast-forward to present day. You’ll find J&J pursuing multiple autoimmune indications with nipocalimab, six of them in phase 2 or 3 clinical trials, and Dr. Ling still heavily involved in its research and development.
Approaching An Acquisition From Both Sides
Terence Rooney. Ph.D., VP Disease Area Stronghold Leader, Rheumatology at Johnson & Johnson Innovative Medicine has spent the bulk of his career working on immunology product development. He knows FcRn and IgG science, knows the molecule, and much like Dr. Ling, appreciates its behavior, predictability, and manufacturability. In fact, none of the three biggest challenges he cites when addressing the addition of nipocalimab to the J&J portfolio are related to the molecule or its manufacturing. Instead, they relate to the acquisition itself, and the indications J&J would pursue with its newly-acquired asset.
“On that first challenge, the integration of Momenta and J&J, we took the bull by the horns, and it went quite well,” says Dr. Rooney. He cites the onboarding of Dr. Ling and the rest of the nipocalimab discovery team as critical to the continuity of the program.
When it comes to combining companies of two very different sizes, Rooney says, “It should be an integration, not a grab.” The bigger company needs to try to understand the culture, operating model, and practices of the smaller company, as well as transmit its own story, culture, and operating models, “so the folks coming in have a clear vision of what to expect.”
“I think the biggest, most important thing is to take that time to listen and learn, seek to understand, but then educate a little bit about where the members of the bigger company are coming from and then take the time to bring people aboard, map them into positions that make sense for them. Take the time to do all the necessary training and education about the systems and the bigger company and things can go well. If it's rushed, and you don't take the time to listen and explain, the outcomes tend to be less good,” he says.
It's important to remember that despite sizes and potential differences in culture, both companies are united in a shared goal — bringing a novel therapy to patients and changing lives for the better. After an acquisition, Rooney says, it helps if the bigger company explains why the deal was done and what attracted the company to the asset. “Explaining the story and the things that make you excited are another way of engaging and bringing people together,” he says.
Picking Indications For A Well-Rounded mAb
Challenge number two, whittling down the indications J&J would pursue, proved a bit more formidable. “There are more than 80 auto- and allo-antibody-related disorders affecting maybe 240 million people worldwide, and the vast majority of those diseases have no approved therapies,” says Rooney. Auto-antibody disorders occur when, as is the case in myasthenia gravis, the body creates antibodies against some component of the person themselves. Depending on the organs involved, the resulting inflammation and damage to tissue that occurs can have mild to life-threatening consequences. To land on the specific indications it’s settled on in the near-term, J&J applied what Rooney calls a three-part filter. “We analyze unmet need, actionable science, and value creation,” he says.
That first filter—a large patient population with unmet needs—spawned the challenge of pursuing multiple indications in parallel. “That meant creating new ways of working on the operational side, and a recalibration of our internal staffing, including but not confined to the doctors and scientists who design, execute, analyze, and report on the trials. We had to scale up a bit to accommodate all those multiple indications in parallel,” he says.
The third challenge Rooney cites is specific to just one of those selected indications, Sjögren's disease. The condition was new to J&J, and with no approved therapies, the company knew the clinical path would be long. “We have lots of experience in R&D and clinical trials in the bigger disorders in rheumatology, like rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and arthropathy. These are indications that we've developed medicines for and taken all the way to market in the past,” he says. Because Sjögren's disease was relatively new to the company, Rooney says it had to wrap its arms, and its operational systems, around a new disorder that doesn't have a particularly mature investigative space or regulatory path. “We've been fortunate to get to where we are, on the right side of positive mid-stage data and looking forward to next steps,” he says.
Perseverance As A Prerequisite
Both Ling and Rooney would surely agree that drug development is not for the faint of heart. Behind every product, every acquisition, and every deal are fiercely passionate people who carry on despite the overwhelming odds of failure inherent in drug development.
Drugs fail for any number of reasons. It could be from running out of money; it could be from poorly planned clinical trial execution. Sometimes, perhaps often, a drug may fail through no fault of its own.
“You can apply as much persistence as you want, but you won’t always succeed,” Ling says. “But I think that you’ll always learn something that’s going to help the next time around.”
Surrounding yourself with people that share this resilient, bounce-back mindset, she believes, makes all the difference in the world.