Eli Lilly has expanded its genetic medicines pipeline and capabilities, agreeing to partner with Ascidian Therapeutics to develop RNA exon editors intended to treat inherited kidney diseases, through a collaboration that could generate more than $1.9 billion for the Boston biotech.
The companies have agreed to launch a global research collaboration focused on discovering and developing treatments for undisclosed monogenic kidney diseases, with the option to expand into additional targets.
At the heart of the collaboration are Ascidian’s RNA exon editors, which are designed to repair genetic instructions causing disease. A single RNA exon editor can address multiple mutations spanning multiple exons, resulting in the editing of multiple disease-causing exons simultaneously.
“What that allows us to do is to replace many exons at once, thousands of bases at a time, and use endogenous cellular machinery,” Michael Ehlers, MD, PhD, Ascidian’s president and CEO, told GEN. “We’re not editing letters in the genetic code. We’re rewriting whole chapters at the kilobase scale.
“It’s a very versatile technology to address a fairly wide-ranging set of genetic diseases, and potentially beyond as well,” he added.
Since only exons need to be replaced within the diseased protein, the exon editing payload is small enough to fit in an adeno-associated virus (AAV) or in other viral or nonviral delivery vehicles, including lipid nanoparticles.
Michael Ehlers, MD, PhD, president and CEO of Ascidian Therapeutics [Credit: Kevin Trimmer, courtesy Ascidian Therapeutics]“The therapeutic is an AAV that expresses the designed RNA exon editor. The AAV infects the target cells. The episome of the AAV dwells in the nucleus and expresses this engineered RNA molecule, our exon editor, that then conducts the trans-splicing,” Ehlers explained. “We very intentionally, across programs and things, really emphasized being a differentiated cargo company in designing these RNAs, and tried where we can to use precedented clinical delivery.”
During the transcription of DNA into RNA, noncoding introns are usually removed, while exons that remain are spliced together to form messenger RNA (mRNA) that can be translated into protein. Mutations result in malformed proteins that cause disease.
Ascidian’s RNA exon editors are designed to bind to target pre-mRNA through what the company calls a highly specific binding domain. The editor molecules are delivered as a DNA construct and transcribed into mutation-free, exon-only RNA, designed with a highly specific binding domain.
Trans-splicing process
Through a binding process called pre-mRNA trans-splicing, exon editors replace disease-causing exons, leading to what Ascidian said is expression of wild-type mRNA and protein at proper levels, in the right cells at the right time.
The exon editors are designed to address large genes or genes with high mutational variance.
“There are other excellent targets which are dominant genes, where maybe you’re uncertain whether the disease-causing mutations are dominant because they’ve got a dominant toxic gain-of-function phenotype, or they’re dominant because it’s a haploinsufficiency. The nice thing about RNA exon editing is that it doesn’t really matter to us. We simply replace the sequence with wild type, so we don’t have to worry about whether you need allele-specific knockdown in those cases, or whether you are at risk of having a haploinsufficiency phenotype,” Ehlers explained.
The exon editing approach, Ascidian said, represents a sea change for RNA therapy, which has seen treatments incorporating antisense oligonucleotides, adenosine deaminase acting on RNA (ADAR)-mediated editing, and mRNA as applied in vaccines such as those for COVID-19, and in in vivo chimeric antigen receptor T-cell (CAR-T) therapies.
“RNA exon editing is really quite different, because you can target and dodge RNAs, and instead of editing one base at a time, you’re changing big swaths of sequence at a time, and unlike a lot of other forms of editing, whether DNA or RNA—not all, but for many—there’s no need to introduce exogenous enzymes or exogenous proteins to be able to conduct the editing,” Ehlers said. “That allows Ascidian to use RNA exon editing to go after a different set of diseases, a different set of disease genes, and potentially a larger patient population.”
In kidney disease, for example, more than 60 genetic diseases are known or suspected to affect the kidneys, with over 3.5 million Americans living with severe inherited kidney disease.
“I would not say all of them are treatable, but a reasonable portion of them are, and we’re prioritizing some that are clearly important, ones where RNA exon editing is particularly uniquely suited, we believe, to addressing the underlying genetic cause,” Ehlers said.
Undisclosed targets
Ascidian has granted Lilly exclusive, target-specific rights to Ascidian’s RNA exon editing technology for undisclosed kidney disease targets. The number of targets was also not disclosed. Ascidian has agreed to lead discovery and specified preclinical activities, with Lilly agreeing to oversee additional preclinical work, clinical development, manufacturing, and commercialization. Ascidian said it retains rights to pursue other kidney-focused targets, independently or with additional partners.
Ehlers said the Lilly collaboration resulted from conversations with the pharma giant held over several years that started with Ascidian discussing its research, and over time became more focused on the companies developing the research plan and programs that they agreed to work on.
“About a year and a half ago, I would say, we kind of got really quite a bit more specific about, well, what would be some interesting areas that might fit with Lilly’s strategic interests and capabilities, where Ascidian’s technology and know-how in RNA biology and splicing biology and using RNA exon editing could apply,” Ehlers recalled.
Genetic medicine expansion
Ascidian’s RNA research and technologies fit with Lilly’s commitment in recent years to expand in genetic medicines. Lilly launched the $700 million Institute for Genetic Medicine in 2021 in Boston’s Fort Point section as part of a strategy of advancing gene and gene editing therapies, and RNA- and other nucleic acid-based therapeutics. The Institute operates in Boston and New York City, where Lilly-owned neuroscience gene therapy developer Prevail Therapeutics is based. Prevail was acquired in 2021 for up to $1.04 billion.
A year later, Lilly expanded an RNA-focused collaboration with ProQR into a potential nearly $4 billion partnership to target disorders of the liver and nervous system by applying ProQR’s RNA-editing Axoimer platform. Lilly also snapped up another gene therapy developer, buying hearing loss-focused Akouos for up to $610 million, while last year Lilly purchased gene editing therapy developer Verve Therapeutics for up to $1.3 billion
This year, among its numerous acquisition and collaboration deals, Lilly announced plans in February to buy out circular RNA cell therapy developer Orna Therapeutics for up to $2.4 billion, targeting advancements in cell therapy, and last month acquired nonviral DNA delivery-focused drug developer Engage Biologics for up to $202 million cash.
In its latest collaboration with Ascidian, Lilly agreed to pay the biotech up to $1.9 billion, to consist of an undisclosed upfront payment and payments tied to achieving development and commercial milestones, as well as tiered royalties on global commercial sales.
Targeting Stargardt
Ascidian’s website discloses eight pipeline candidates, the most advanced of which is its sole clinical-phase candidate ACDN-01, a first-in-class RNA exon editing therapy designed to halt the progression of Stargardt disease or other ABCA4 retinopathies by targeting their genetic cause.
ACDN-01 contains a healthy copy of exons of ABCA4 RNA, designed to replace the sections of the ABCA4 RNA that contain mutations, thus creating healthy ABCA4 RNA in the retina. According to Ascidian, this is intended to produce normal ABCA4 protein that can then help clear the eye of toxic waste products. The FDA has granted ACDN-01 its Fast Track and Rare Pediatric Disease Designations.
“I anticipate this will be, by and large, the way that we will deliver exon editors. Although, in principle, it can be agnostic to the delivery method, it’s just whatever it takes to get that RNA exon editor into the cell, into the nucleus, effectively trans-splicing at the target.”
ACDN-01 is under study in the Phase I/II STELLAR trial (NCT06467344), an open-label, single ascending dose clinical study assessing the safety, tolerability, and preliminary efficacy of the treatment candidate when delivered subretinally in participants with ABCA4-related retinopathies. Last month, Ascidian said it had completed the adult dose escalation portion of the STELLAR trial and expanded the study to subjects over 12 years of age.
“We’re working as effectively as we can to get that up and going, so I’d say in the coming months,” Ehlers said when asked about the timing of the expansion.
Ascidian is also conducting an observational prescreening study called STARPATH (NCT06445322), which is designed to identify children ages 5+ and adults with Stargardt who may be eligible for future clinical trials evaluating ACDN-01.
ACDN-01 is among numerous candidates in clinical development to treat Stargardt. These candidates include genetic therapies such as:
Ocugen’s OCU410ST (AAV5-hRORA), a modifier gene therapy that uses an adeno-associated virus serotype 5 (AAV5) delivery platform to deliver the RORA (RAR-Related Orphan Receptor A) gene to the retina.
SpliceBio’s SB-007, a dual AAV gene therapy designed to restore expression of a functional, full-length ABCA4 protein in the retina through a protein splicing intein platform using two AAV serotype 8 (AAV8) vectors to overcome the size limitations of conventional AAVs, reconstituting biologically active ABCA4 through protein trans-splicing in target photoreceptor cells.
VeonGen Therapeutics’ VG801, a dual AAV gene therapy enabled by the company’s vgAAV capsid and vgRNA REVeRT large-gene delivery platform, which delivers the full-length functional ABCA4 gene.
Single vector approach
Ehlers said ACDN-01 would stand out from the other genetic therapies because of its single vector approach to delivery: “I’d say the others, because the nature of the ABCA4 gene, it’s too large just for gene replacement in a single vector. All the others have to use dual vector technologies to try to address that.”
“You can imagine a single vector approach being potentially simpler and more technically feasible,” he added. “But of course, what matters is clinical data, and all these programs will play out in the clinic.”
Also in Ascidian’s pipeline: A second retinal program in lead identification phase; four neuro and neuromuscular programs in phase from lead identification to lead optimization; and two lead identification-phase programs in undisclosed “other areas.” Ascidian is also partnering with Roche to discover and develop RNA exon editing therapeutics against undisclosed neurological targets, through an up-to-$1.842 billion collaboration ($42 million paid initially) launched in 2024.
Following two years in stealth mode, Ascidian was formally launched in 2022 by venture capital firm Apple Tree Partners (ATP), which incubated the company and funded it with $50 million in Series A financing. Ehlers led that incubation as the company’s founding CEO, then chaired the company’s board while Romesh Subramanian, PhD, served as Ascidian’s president and CEO. After Subramanian left the company, Ehlers returned to Ascidian’s helm in 2023, when it closed on $40 million in Series A extension funding from ATP, with the goal of financing the development of ACDN-01 and other pipeline programs.
Since then, Ascidian has grown its workforce to about 40 people, Ehlers said.
“For a clinical stage editing company, to be in the clinic with $90 million in equity financing and have 40 people plus or minus is no small feat, and I think it has been accomplished by having the focus that we’ve had, and having just one of the best scientific teams that I’ve ever had the fortune of working with,” Ehlers said.
“We might have little bits of growth here and there to be able to support this [Lilly] collaboration, to be able to expand the technology, but I’m not anticipating substantial growth,” he added. “We’ve built the company to be efficient and focused, and we’re going to maintain that going forward.”
Lilly’s hot streak
The Ascidian collaboration continues a hot streak of collaboration and acquisition deals for the pharma giant, which is flush with cash from sales of its blockbuster glucagon-like peptide 1 (GLP-1) receptor agonist drug tirzepatide, marketed for type 2 diabetes as Mounjaro® and for obesity as Zepbound®.
So far this year, Lilly has either acquired or is acquiring 10 biotechs, most recently three privately-held developers of vaccines for infectious diseases purchased for a combined up to $3.83 billion cash—Vaccine Company for up to $1.55 billion, Curevo for up to $1.5 billion, and LimmaTech Biologics for up to $780 million.
The Ascidian collaboration is Lilly’s third partnership with a biotech, announced just this week. The other two, totaling a combined amount of up to $4.304 billion-plus, were announced with Asian partners.
Seoul-based Hanmi Pharmaceutical said Lilly had agreed to license from it the rights to develop, manufacture, and commercialize sonefpeglutide (LAPSGLP-2 analog), a Phase II glucagon-like peptide 2 (GLP-2) receptor agonist, worldwide excluding South Korea. Hanmi is now studying sonefpeglutide in a global Phase II trial (NCT04775706) in short bowel syndrome (SBS).
Lilly agreed to pay Hanmi $75 million upfront, and up to an additional $1.185 billion in payments tied to achieving clinical development, regulatory approval, and commercialization milestones, plus royalties on sales following product launch.
Beijing-based Haisco Pharmaceutical Group announced a licensing and research collaboration with Lilly to develop treatments across multiple undisclosed therapeutic areas. Haisco agreed to oversee discovery and identification of up to five “innovative target” programs, while Lilly agreed to lead IND-enabling studies, clinical development, and commercialization. Lilly will obtain exclusive global rights for some programs, as well as exclusive rights worldwide, excluding China, Hong Kong, Macau, and Taiwan, for the other programs.
Lilly agreed to pay Haisco up to $87 million in upfront and near-term payments, up to $2.967 billion in unspecified milestone payments, and single-digit tiered royalties on future product sales.
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