Regeneron and Mammoth Biosciences Forge $340M CRISPR Collaboration to Advance In Vivo Gene Editing Beyond the Liver

On April 26, Regeneron and Mammoth Biosciences announced a collaboration agreement with an upfront payment of $100 million. The two companies will jointly research, develop, and commercialize in vivo CRISPR gene editing therapies for various tissues and cell types.

According to the terms of the agreement, Mammoth will receive $100 million (approximately 720 million yuan) in funds, including an upfront payment, and is also eligible to obtain up to $370 million (approximately 2.68 billion yuan) in development, regulatory, and commercial milestone payments for each target. Additionally, they will receive royalties ranging from single-digit percentages to 15% of future net sales of all collaborative products. Meanwhile, over a five-and-a-half-year term, Regeneron will gain broad usage rights to Mammoth's editing technology, excluding certain excluded candidate therapies, and has the option to extend the usage rights by two years upon payment of additional research extension fees. Both parties will jointly select and study collaborative targets, after which Regeneron will lead their development and commercialization process.

The liver is a common target organ for gene therapy of monogenic inherited diseases, mainly because the liver plays an important role in various basic functions such as substance metabolism, detoxification, coagulation, digestion, and immunity, providing direct support to major organs and tissues throughout the body. According to incomplete statistics, most of the approved gene therapies use adeno-associated virus (AAV) as the delivery vector. In addition to local administration, AAV products for systemic administration, including Novartis' Zolgensma, have shown clinical pharmacokinetics.All showed liver enrichment of viral vectors.

But in fact, the market for targeting extrahepatic tissues/organs is much broader. Although extrahepatic targeted delivery remains a challenge, many pharmaceutical companies have regarded it as the key to breaking through the "ceiling." Currently, pharmaceutical companies inside and outside China are mainly exploring two approaches to achieve breakthroughs in extrahepatic targeted delivery. One approach is to explore and optimize injection sites/administration methods, such as avoiding systemic toxicity or first-pass metabolism through localized administration. The other approach involves exploring methods like covalent conjugation and nanocarriers, as well as corresponding tissue-specific receptors, to increase accumulation and uptake in specific tissues and cells and prolong circulation time in the body.

According to a Mammoth press release, Regeneron is developing adeno-associated virus (AAV) vectors, utilizing antibody-based targeting technology to enhance the ability to deliver gene therapy payloads to specific tissues and cell types; Mammoth is developing novel ultracompact nucleases and related gene editing systems, which possess various editing capabilities but are much smaller in size compared to other CRISPR-based systems (including first-generation Cas9 nucleases). By combining Regeneron’s expertise in AAV and antibody engineering with Mammoth’s technical proficiency in ultracompact gene editing systems, the two teams will jointly develop disease-modifying drugs capable of being delivered to tissues beyond the liver.

Mammoth Biosciences, co-founded by CRISPR pioneer and 2020 Nobel Prize in Chemistry laureate Dr. Jennifer Doudna, aims to leverage novel editing modalities (including base editing, reverse transcriptase editing, and epigenetic editing) with greater specificity for in vivo gene editing in hard-to-reach tissues. To date, Mammoth has raised over $260 million in multiple financing rounds. In addition to several well-known investment institutions, Mammoth has also received funding from individual investors such as Brook Byers, Tim Cook (CEO of Apple), and Jeff Huber (former Vice President of Engineering at Google), solidifying its status as a leading CRISPR unicorn.

Mammoth's CRISPR platform can discover and engineer novel Cas enzymes with unique properties, such as ultra-small size, enhanced thermal stability, faster reaction kinetics, and more flexible targeting of alternative PAM sequences. According to publicly available information, the platform is currently focused on two ultra-compact Cas enzymes: Cas14 and Casɸ. Cas enzymes are the core components of the CRISPR gene-editing system. Due to the limited cargo capacity of AAV, smaller-sized Cas enzymes are easier to deliver and hold promise for expanding the scope of in vivo gene editing.

Based on the core technology platform of CRISPR, prior to reaching a collaboration with Regeneron worth up to nearly $500 million, Mammoth Biosciences has maintained an "achievement" of partnering with one multinational corporation (MNC) almost every year since 2020.

In 2020, GSK Consumer Healthcare, part of GlaxoSmithKline (GSK), announced an agreement with Mammoth Biosciences to jointly develop a CRISPR-based test for the novel coronavirus.

In 2021, Vertex Pharmaceuticals and Mammoth Biosciences announced a collaboration to develop in vivo gene editing therapies for two genetic diseases using Mammoth's CRISPR system. Under the terms of the agreement, Mammoth will receive an upfront payment of $41 million and is eligible for up to$650 millionR&D and commercial milestone payments.

In 2022, Bayer announced a strategic collaboration with Mammoth Biosciences to develop next-generation in vivo gene editing therapies using the latter’s CRISPR system. Under the terms of the agreement, the collaboration between the two companies will initially focus on liver diseases. Bayer has obtained a license to use Mammoth’s novel gene editing technology and will pay Mammoth an upfront fee of $40 million. If specific research, development, and commercial milestones are successfully reached for five selected liver disease indications in the future, Bayer will pay certain target option exercise fees as well as additional payments exceeding...$1 billionmilestone payments. In addition, Bayer will also provide research funding and tiered royalties in the low double digits.

In addition, Mammoth also receives funding from organizations. For example, in 2021, the U.S. Defense Advanced Research Projects Agency (DARPA) signed a four-year contract worth up to $36.7 million with Mammoth and IDbyDNA to develop CRISPR diagnostics and biosurveillance technologies for various diseases using their proprietary pathogen database and algorithms to address a range of diseases.

It is worth mentioning that, in addition to Dr. Jennifer Doudna, Mammoth's co-founders also include Trevor Martin, Janice Chen, and Lucas Harrington—three young yet senior researchers—who were under 30 when they founded Mammoth. Trevor Martin, Janice Chen, and Lucas Harrington were jointly selected for the 2018 Forbes Healthcare "30 under 30" list and were also named as global young leaders in the biopharmaceutical industry under the age of 40 by Business Insider in 2020.