Regeneron Pharmaceuticals will use Mammoth Biosciences’ CRISPR-based ultracompact gene editing platform to develop in vivo therapies for tissues and cell types beyond the liver, the companies said, through a collaboration that will expand Regeneron’s genetic medicines presence with more gene editing programs.

The collaboration is designed to combine Mammoth’s platform with Regeneron’s effort to develop adeno-associated viral vectors (AAVs) that use antibody-based targeting to enhance delivery of genetic medicine payloads to specific tissues and cell types.

With gene editing having shown success delivering therapies into the liver, Regeneron and Mammoth seek to expand into other tissues and organs.

“Our most advanced delivery capabilities are in terms of muscle and CNS [central nervous system],” Leah Sabin, PhD, executive director, Regeneron Genetic Medicines, told GEN Edge. “Those are our most advanced delivery platforms, but we have a number of up-and-coming new delivery antibodies that we’re exploring to access additional tissues beyond that.”

Muscle and CNS were two therapeutic areas Mammoth co-founder and CEO Trevor Martin, PhD, told GEN Edge last year that the company was excited about exploring after starting with liver disease.

“That’s why it’s a great collaboration, right?” Martin said this week. “Because it is just so well paired scientifically in terms of optimal delivery, optimal cargo. It just makes a lot of sense.”

Sabin said Regeneron has been developing two complimentary platforms designed to use antibodies to redirect viral particles. One relies on physically conjugating antibodies to the surface of capsids using a protein tagging system. The other relies on the company’s bispecific technologies, engineered to bind two different molecular targets; one or more arms of the antibody bind to the capsid, while one or more arms bind to a target on a target tissue or cell type.

“We see advantages to each,” Sabin said.

When would one platform be used over another?

“We are actively working on the CMC [chemistry, manufacturing, and controls] aspects of this, and that might be a deciding factor,” Sabin replied. “There are advantages to having one entity where they are physically together, and they can be characterized as such. But from a manufacturing perspective, we can envision an advantage where you can generate an AAV, you can generate an antibody, mix the two together, and move forward.

“The advantage that approach gives is that we could actually have the potential to apply our bispecific antibodies to existing therapeutic programs where an AAV already has been made and developed, and all of the CMC has been worked out, and we can add in our antibody to give better on target efficacy,” Sabin added.

Equity, upfront payments

Regeneron’s delivery antibodies will be combined through the collaboration with the platform developed by Mammoth to develop CRISPR-based, gene edited therapies. Under the collaboration, Regeneron will pay Mammoth $100 million consisting of a $95 million equity investment and a $5 million upfront payment. Mammoth could generate up to $370 million in milestone payments per target developed.

The companies have not specified how many targets they plan to pursue.

Regeneron and Mammoth have agreed to jointly select and research collaboration targets, with Regeneron leading subsequent development and commercialization efforts.

Martin co-founded Mammoth in 2017 with Janice Chen, PhD, the company’s CTO; Lucas Harrington, PhD, the company’s CSO, and CRISPR pioneer Jennifer Doudna, PhD, a 2020 Nobel laureate.

Initially focused on CRISPR-based diagnostics, Mammoth has expanded its reach to CRISPR-based therapies incorporating novel Cas enzymes that are smaller than Cas9 in the company’s toolbox. They include Cas12, which targets double-stranded DNA and Cas13, which targets single-stranded RNA; as well as Cas14, which targets single-stranded DNA; and Casɸ, which is encoded exclusively in the genomes of huge bacteriophages.

At 1,368 amino acids (aa) long, Cas9’s size makes it a challenge to fit into AAVs and other delivery vehicles for treatments. By contrast, Cas12 enzymes range from Cas12a (1,200–1,500 aa) to Cas12f (400–700 aa), CasΦ members average about 750 aa, and Cas14 members, about 500 aa.

Mammoth has exclusively licensed foundational IP around novel CRISPR Cas12, Cas13, Cas14, and Casɸ systems from the University of California, Berkeley. The systems were discovered in Doudna’s lab.

“It’s so complimentary with the work that’s being done at Regeneron. And this really great marriage of innovation on the delivery side and innovation on the cargo side, I think that’s how we’re going to unlock the true potential of genetic medicine, and actually go after all these genetic diseases, instead of collapsing on the same targets over and over and over again,” Martin said.

Surmounting packaging limitations

Mammoth’s smaller enzymes attracted Regeneron to Mammoth’s technology, Sabin said, because of their ability to surmount the challenge of the packaging limitations of AAVs as delivery vehicles.

“We have a lot of expertise now in developing cell type specific promoters. We have put a lot of tech dev[elopement] into that. Yet even a really great promoter cuts down even further on the size that one can accommodate in an AAV,” Sabin explained. “Mammoth’s ultra-compact systems are really special in that not only is there a base nuclease for formation of double-strand breaks that’s very, very small. The ability of having a base enzyme, but having the additional functionality that can be built in and still fall within the packaging limits of an AAV is an extremely important advance to the technology.”

Mammoth is building a pipeline of CRISPR therapies, starting with a lead program focusing on a target within the liver—the company has yet to offer specifics. The company has identified several potential therapeutic areas in addition to liver disease, including autoimmune diseases, cardiovascular, hematology, immuno-oncology, liver disease, neurology and neuromuscular diseases, and ophthalmology.

“With our ultra compact systems we can have something that is a third or less the size of those legacy Cas systems like Cas9. Not only can you more easily fit them into an AAV, but most importantly, you have all this extra space, so you can be very creative,” Martin said.

Tissue-specific promoters are one example that can increase efficacy and safety, as is going beyond double-stranded breaks by combining a CRISPR protein with an additional protein carrying out any of several newer editing modalities, such as base editing or gene writing or epigenetic editing.

“At Mammoth, we uniquely have the ability to do an all-in-one single AAV base editor, gene writer, epigenetic editor, and that’s a huge unlock. Then, when you combine it with these AAVs that have been innovating on the actual ability to get into all types that you want, I think that’s a super powerful combination.”

The companies are not wedded to a specific editing modality.

“We are interested in pursuing all of the tools in their [Mammoth’s] toolbox and really trying to match the different types of editing systems to the different types of disorders that we might want to go after. And I can envision utility in every single one of the systems that they’ve been developing,” Sabin said.

Six programs, three modalities

Regeneron’s genetic medicine presence includes six clinical-phase programs in three modalities, according to its pipeline posted on its website.

In gene editing, Regeneron is developing two programs with Intellia Therapeutics through a collaboration that began in 2016 at up to $125 million for Intellia, with the company receiving a $100 million upfront cash and equity investment from Regeneron in 2020. Last October, the companies again expanded their partnership to develop additional in vivo CRISPR-based gene editing therapies focused on neurological and muscular diseases. The companies extended their collaboration through April 2026, with Regeneron agreeing to pay Intellia a $30 million extension payment.

Regeneron and Intellia are partnering on a Phase III program to develop the in vivo CRISPR-based therapy NTLA-2001 for Transthyretin amyloidosis with cardiomyopathy (ATTR-CM), as well as a Phase I program for ATTR amyloidosis. Recently, the first patient was dosed in the Phase III MAGNITUDE trial (NCT06128629), designed to assess NTLA-2001 vs. placebo in participants with ATTR-CM.

Designed to inactivate the TTR gene that encodes for the transthyretin (TTR) protein, NTLA-2001 is the first CRISPR therapy candidate to be administered systemically to edit genes inside the human body.

In 2021, Regeneron and Intellia published the first-ever clinical data that supported the safety and efficacy of in vivo CRISPR genome editing in humans. In a study published in The New England Journal of Medicine, researchers from the companies and their clinical partners showed that NTLA-2001 generated a dose-dependent sustained reduction of protein linked to ATTR amyloidosis following a single dose in six patients living with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).

With these data, we believe we are truly opening a new era of medicine,” Intellia president and CEO John Leonard, MD, declared at the time.

The rest of Regeneron’s genetic medicines pipeline consists of three gene silencing programs and a single gene therapy program.

In gene silencing, Regeneron has ALN-HSD, a metabolic associated steatohepatitis (MASH) candidate targeting HSD17B13 that is wholly owned and now in Phase II. Regeneron is also partnering with Alnylam to develop two Phase I candidates: ALN-APP, an early-onset Alzheimer’s disease treatment designed to target APP; and ALN-PNP, a metabolic associated steatohepatitis (MASH) treatment designed to target PNPLA3.

Regeneron’s sole gene therapy program, DB-OTO, is a Phase I/II cell-selective, AAV-based treatment designed to provide durable, physiological hearing to individuals with profound, congenital hearing loss caused by mutations of the otoferlin gene. Regeneron inherited DB-OTO when it acquired the gene therapy’s original developer, Decibel Therapeutics last year for up to $213 million.

In October 2023, Regeneron announced preliminary positive safety and efficacy results from the first patient (under age 2) dosed with DB-OTO in the Phase I/II CHORD™ trial (NCT05788536).

Additional data from the CHORD trial is expected to be reported at the American Society of Gene and Cell Therapy (ASGCT) annual conference, to be held in Baltimore.

Also at ASGCT, Regeneron will present data from 10 abstracts, including six oral presentations, detailing Regeneron’s efforts to address obstacles to clinical administration of genetic medicines that range from pre-dosing, to delivery, to long-term sustained expression.

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