'It's the right call': GSK expresses no regrets on abandoning cell therapy as oligo strategy heats up

Summarizing GSK’s vision to investors last month, CEO Emma Walmsley reaffirmed that the British Big Pharma had decided to “end our investment in cell and gene therapy.” While this was hardly news to the audience—especially coming months after GSK axed cell therapy deals with Lycell and Immatics—it still served as a stark reminder that the company's development portfolio is swimming against the industry tide.

But rather than racing to get an “off-the-shelf” CAR-T into the clinic or going all-in on a solid tumor strategy, GSK believes its genetic expertise will offer the smoothest path to market success.

John Lepore, GSK
John Lepore, M.D. (GSK)

“About 70% of the entire GSK portfolio now has strong human genetic underpinning and even higher than that in the research phase,” the company’s head of research, John Lepore, M.D., tells Fierce Biotech in an interview.

The theory is that genetically validated targets have at least a twofold higher chance of becoming medicines.

“It's not a cure-all,” says Lepore. “But on a portfolio basis, if you can have a twofold inflection, that's fundamental for our company and for the industry in general—and we’ve made significant progress on that.”

It sounds simple, but there’s a reason not every Big Pharma is betting the house on genetic targets. Lepore says that as novel potential targets are identified through genetics, half of them can't be targeted with a small molecule or an antibody.

That’s where oligonucleotides come in. These short strands of synthetic DNA or RNA can reduce, restore or modulate RNA through several different mechanisms. Biotechs like Alynlam and Ionis were among the early pioneers in the field, but “the science of the platform of oligonucleotides is growing beyond what those two companies originally started with,” says Lepore.

Riding the wave

It’s for this reason that GSK spent $170 million upfront in December to collaborate with Wave Life Sciences. Wave’s pitch is that it’s the only oligonucleotide platform offering three RNA-targeting modalities, in the form of editing, splicing and silencing. “As we look at the range of potential drug targets coming out of genetics, all three of those modalities are of interest to us,” Lepore says.

A major attraction for GSK is the belief that Wave’s chemistry could broaden the use of subcutaneously delivered oligonucleotides beyond the liver, where these therapies have primarily been limited to until now.

“The chemistries are starting to show evidence of the molecules being able to be directed towards other organs: kidney, lung, etc.,” he says. “As we have insight into drug targets from genetics in those organs, we think we can leapfrog to starting to have oligonucleotide therapies for those.”

The deal with Wave has the potential to cover up to eight targets from GSK’s side. While Lepore won’t go into details on the targets they have in mind, “our ambition clearly is for targets in liver and beyond liver,” he says.

As well as those potential future targets, the crown jewel in the Wave deal was WVE-006, a preclinical RNA editing therapy targeting alpha-1 antitrypsin deficiency, an inherited disorder that can cause lung and liver disease.

Mel Paff, GSK
Melanie Paff (GSK)

“It's really cool because it's an oligonucleotide that actually corrects gene defect at the RNA level, and therefore allows normal production of the alpha-1 antitrypsin protein,” says Lepore. “[It] could be an oligo therapy that obviates the need for replacement of this protein, which is what patients are stuck with now. So it's a really neat proof of principle of what the technology could look like over time.”

While exciting, WVE-006 will for the time being remain at the back of the pack when it comes to GSK’s oligonucleotide pipeline. Leading the charge is bepirovirsen, a collaboration with Ionis that is now in a pair of phase 3 trials as a potential “functional cure” for hepatitis B virus infection.

By using olignucleotides as an antisense, bepirovirsen’s modality is the opposite of WVE-006, explains Melanie Paff, who heads up GSK's hepatitis B program. “So we're trying to knock down protein, knock down the virus.”

Bepirovirsen’s dual activity of knocking down the hepatitis B surface antigen as well as having an innate immune activity is “absolutely unique,” Lepore adds.

Results from the phase 2 B-Clear trial showed that 9% of patients with chronic hepatitis B on stable nucleoside/nucleotide analogue (NA) treatment and 10% of those not on NA treatment achieved the study’s primary outcome of a sustained clearance of their hepatitis B surface antigen levels and hepatitis B virus DNA levels. At the time, GSK was keen to point out that even a 10% effectiveness rate among patients is around tenfold higher than the current standard of care.

Now, the company is pursuing patients with lower baseline hepatitis B surface antigen levels, a cohort that the previous study suggested responded best to the therapy. The hope, according to Paff, is to see a higher response in this patient group. 

The plan is to have an interim readout on a regimen of bepirovirsen and a pegylated interferon treatment “sometime mid this year,” followed by final data ready for an international congress toward the end of 2023, according to Paff.

“Oligonucleotides have actually been around for a very long time,” Paff says. “But they've been relegated to rare disease settings, very small volume plays. Bepi is one of the first big pipeline plays to come across. And now that we've … figured out the manufacturing, that really opens it up to allow us to go into broader and broader disease areas.”

Coming up behind is GSK4532990, a collaboration with Arrowhead that’s about to enter phase 2 for the notoriously tricky liver indication nonalcoholic steatohepatitis. And it doesn’t sound like the oligonucelotide pipeline will be limited to three therapies for too long. Lepore makes no secret of the fact that GSK is “thoughtful about potential business development in this space.”

“It's a really important area for us, where the technology of oligos fits so nicely with our expertise in genetics and novel targets, and we're going to be looking to optimize that,” he adds. “You can envision all sorts of business development deals, ranging from single asset acquisitions through to additional platform plays.”

Sticking with antibiotics

Oligonucleotides aren’t the only research area where GSK seems to be going against the grain. November saw the pharma announce positive results from two new antibiotics—for tuberculosis and urinary tract infection—with the latter candidate slated for FDA submission this year.

Despite the looming threat of antimicrobial resistance, Big Pharmas have been giving antibiotics a wide berth for decades due to the low return on investment.

“It's an area that someone absolutely has to continue to develop,” Paff says. “We can't let that go.”

There are also other headline grabbers coming up this year, including a May FDA decision for the respiratory syncytial virus vaccine, which—if approved —could be the first to market, ahead of close rival Pfizer. With all this considered, do the executives still think the company has made the right decision to turn away from the red hot research areas of cell and gene therapy?

“For us it is the right call,” Lepore says. “This is a capital allocation question for GSK.”

While there have been big wins targeting CD19 and CD20 against liquid tumors, the space has become “very crowded,” he explains. “The prospect of expanding to solid tumours has become more challenging than we originally thought. And for us to stay in, with all the manufacturing costs and the risk, it's not the best place for GSK to put its capital at the moment.”

So far, it doesn’t sound like the Big Pharma has any regrets about its genetics focus or sending back its cell therapy programs to “the companies that we think could bring them further better than we can.”

“Over time, you're going to see more and more proof points coming from GSK of molecules with genetic validation, coming through to clinical development with positive data,” Lepore adds.