Mammoth Bioscience’s CRISPR systems technology will be used by Vertex Pharmaceuticals  to develop in vivo gene-editing therapies for two undisclosed genetic diseases, in a deal that has the potential to generate as much as $695 million for Mammoth, the two companies announced today.

“We are focused on developing in vivo gene-editing therapies in two indications for specific serious and/or life-threatening diseases with the Vertex team,” Peter Nell, Mammoth’s Chief Business Officer and Head of Therapeutics Strategy, told GEN.

Mammoth and Vertex did say, however, that they will apply Mammoth’s CRISPR platform consisting of a proprietary toolbox of novel Cas enzymes—what the company calls the largest toolbox of CRISPR proteins on earth.

These include Cas12, which targets double-stranded DNA; Cas13, which targets and recognizes single-stranded RNA; Cas14, which targets single-stranded DNA; and Casɸ, which is encoded exclusively in the genomes of huge bacteriophages.

Mammoth has exclusively licensed foundational IP around novel CRISPR Cas12, Cas13, Cas14, and Casɸ systems from the University of California, Berkeley, where, they were discovered in the lab of Nobel laureate and Berkeley-based researcher Jennifer Doudna, Ph.D.

Doudna is a co-founder of Mammoth Biosciences along with CEO Trevor Martin, Ph.D.; Janice Chen, Ph.D., the company’s CTO; Lucas Harrington, Mammoth’s CSO; and Ashley Tehranchi, Ph.D., who served as CTO until May 2019.

Cas14 and Casɸ are the smallest known CRISPR systems. Their sizes—530 amino acids for Cas14a and 757 amino acids for Casɸ-2—are less than half those of commonly used variants of Cas9 [1368 amino acids for SpCas9] and Cas12 [1,300 amino acids for FnCas12], offering numerous potential advantages for the therapies Mammoth plans to develop, Martin told GEN Edge last month, after the company announced the completion of $195 million in new financing completed over the past year.

The additional financing—consisting of $150 million in Series D financing and a $45-million Series C round whose investors included Amazon—brought Mammoth’s total capital raised from investors to more than $255 million., propelling the company to a “unicorn” valuation of more than $1 billion.

In addition, Mammoth said, it is building out its IP portfolio by discovering novel CRISPR systems within and beyond the  foundational work. The company has yet to disclose those systems or other Cas enzymes under development.

“The combination of Mammoth’s unique technology with Vertex’s unmatched experience in serious disease research and development will only accelerate programs with the goal of reaching patients with high unmet medical need,” Nell added. “We believe our novel ultra-small CRISPR systems have the potential to be game-changers when it comes to systemic and targeted delivery of in vivo gene-editing therapies.”

Area of focus for Vertex

CRISPR-edited therapies have been an area of focus for Vertex. Late last year, the company and CRISPR Therapeutics reported positive data from a pair of Phase I/II trials for their CRISPR-Cas9 gene-edited therapy CTX001™ showing consistent and sustained positive response in 10 patients treated for a pair of blood disorders, sickle cell disease (SCD) and beta thalassemia.

The companies in April amended their collaboration agreement to give Vertex leadership in global development, manufacturing, and commercialization of CTX001 with support from CRISPR Therapeutics, in return for CRISPR receiving a $900 million upfront payment and a potential additional $200 million milestone payment upon CTX001 regulatory approval. Two months later, during the Joint European Hematology Association-American Society of Hematology (EHA-ASH) Symposium, researchers presented additional clinical data showing CTX001 to have delivered a consistent and sustained response to treatment in 22 patients in two ongoing Phase I/II trials.

“We see tremendous potential for CTX001,” Stuart A. Arbuckle, Vertex’s executive vice president and chief commercial and operations officer, told analysts July 29 on the company’s quarterly earnings call following release of second-quarter results. He cited an estimate of more than 150,000 patients in the United States and Europe, who have beta thalassemia, or sickle cell disease, approximately 32,000 of whom have severe disease; plus another 25,000 severe sickle cell disease patients, the vast majority of which were in the United States.

“We believe that a gene-editing approach which holds the potential for a one-time curative treatment will be highly valued by patients, physicians, and payers,” Arbuckle said. “Consistent with our own internal market research, published physician surveys in the United States consistently indicate that they expect a quarter to a third of their sickle cell disease patients would be good candidates for a one-time curative approach using the current conditioning regimen, which is in line with the estimates of the numbers of severe patients.”

With gentler conditioning regimens in the future, Arbuckle added, “we expect CTX001 to be an attractive option for a much larger proportion of the 150,000 beta thalassemia and sickle cell disease patients.”

To launch its collaboration with Mammoth, Vertex has agreed to pay the Brisbane, CA,-based company $41 million upfront, including an investment in the form of a convertible note, and up to $650 million in potential future payments tied to achieving research, development, and commercial milestones across two potential programs.

Mammoth is also eligible for tiered royalties from Boston-based Vertex on future net sales on any products that may result from the collaboration, the first one announced by Mammoth for the development of gene-edited therapies.

“Vertex and Mammoth share the same commitment to developing therapies that have the potential to be transformative for people with serious diseases,” stated David Altshuler, MD, PhD, Vertex’s CSO. “We look forward to expanding our cell and genetic therapies capabilities with the addition of Mammoth’s ultra-small CRISPR systems for in vivo genome editing, which will provide us with another set of tools to tackle many of the diseases we’re interested in.”

CRISPR-based diagnostics

Mammoth is also developing CRISPR-based diagnostics, having applied Cas12 in its COVID-19 diagnostic effort which culminated in the SARS-CoV-2 RNA DETECTR Assay, a COVID-19 diagnostic for which UCSF Health Clinical Laboratories was granted an FDA Emergency Use Authorization (EUA) in August 2020.

The 45-minute test is designed to detect nucleic acid from SARS-CoV-2 in upper respiratory specimens. The test extracts, isolates, and purifies SARS-CoV-2 nucleic acid for simultaneous reverse transcription into cDNA, followed by amplification using loop-mediated amplification (RT-LAMP).

The SARS-CoV-2 RNA DETECTR Assay was co-developed by Mammoth through its partnership with UCSF professor Charles Chiu, MD, PhD, who is also director of the UCSF-Abbott Viral Diagnostics and Discovery Center, and a member of the company’s Scientific Advisory Board. Mammoth in 2019 exclusively licensed two U.S. patents granted to the regents of the University of California that cover CRISPR collateral cleavage diagnostic systems.

In July 2020, Mammoth won funding for its development of a scalable COVID-19 test, when the company was awarded $23.1 million of $248.7 million in contracts to the first seven lab-based and point-of-care tests diagnostics developers funded through the NIH’s Rapid Acceleration of Diagnostics (RADx) initiative. The testing system can be adapted to detect for other viruses, though Mammoth has not made public which ones.

Two months earlier in May 2020, Mammoth launched a collaboration with GlaxoSmithKline’s GSK Consumer Healthcare to develop a handheld test designed to apply the DETECTR platform at point of need. Mammoth has disclosed few details since the initial announcement, with Martin saying last month: “I can’t say too much about it, but definitely we’ve made huge strides.”