A growing landscape for sickle cell disease (SCD) treatments, a growing relationship between the companies, and the potential for a lower-cost alternative to an ex vivo SCD therapy now under FDA review have prompted Sanofi and Scribe Therapeutics to launch an up-to-$1.2 billion-plus collaboration to develop an in vivo genome editing therapy for the genetic disorder.
“Sickle cell is a very well understood genetic disease. There are decades of research outlining some of the better ways to treat sickle cell patients, and we’re seeing great success in many of the therapeutics that have emerged for sickle cell patients with genome editing today,” Benjamin L. Oakes, PhD, Scribe’s co-founder, president, and CEO, told GEN.
The partnership is the second one to emerge between Sanofi and Scribe, whose co-founders include Nobel laureate and CRISPR pioneer Jennifer Doudna, PhD. Last year, the companies launched an up to $1 billion partnership to develop CRISPR-based cell therapies to fight cancer. That partnership has made progress, Oakes said, referring questions about details to Sanofi.
If Scribe and Sanofi achieve success in SCD, Oakes said, the companies plan to expand their latest collaboration to developing therapies for other genomic diseases, though the companies are also not specifying how many that could be.
Headquartered in Alameda, CA, Scribe develops CRISPR-based treatments through genetic modification platforms designed to build and apply the company’s suite of CRISPR technologies in hematopoietic disorders and other therapeutic areas. These areas include neurodegenerative diseases, ophthalmological diseases; and multi-system, muscle, and metabolic disorders.
Scribe’s X-Editing (XE) platform applies a proprietary genome editing approach, called CRISPR by Design™, which is intended to transform bacterial immune systems into therapeutically relevant technologies. Scribe’s in vivo genome editing tools directly modify genes within the body—an approach that according to the company delivers important safety, efficacy, and delivery benefits over existing methods.
Sanofi and Scribe are, however, expressing optimism that combining Scribe’s CRISPR XE technologies with Sanofi’s targeted non-viral delivery technologies could lead to a new and possibly less costly in vivo therapy for SCD compared with ex vivo therapies.
One ex vivo SCD therapy could be approved by year’s end—exagamglogene autotemcel (exa-cel), the autologous, ex vivo CRISPR/Cas9 gene‑edited therapy developed by CRISPR Therapeutics and Vertex Pharmaceuticals to treat the disease. Exa-cel is also being developed to treat transfusion-dependent beta-thalassemia (TDT).
Exa-cel is now under FDA Priority Review for SCD and standard review for TDT. The FDA has set target decision dates of December 8, 2023, in SCD and March 30, 2024, in TDT. In exa-cel, a patient’s own hematopoietic stem cells are edited ex vivo using CRISPR-Cas9 to produce high levels of fetal hemoglobin (HbF) in red blood cells. If approved, exa-cell will further reshape an SCD treatment landscape that has grown to more than two dozen new therapies in development and a market that could exceed $6 billion by 2028 (See New Therapies Reshape SCD Treatment Landscape, below)
CRISPR Therapeutics and Vertex reason that the elevation of HbF by exa-cel could reduce painful and debilitating sickle crises for patients with SCD. Oakes, however, cites several potential drawbacks to ex vivo treatment—from the time and steps needed to prepare cells for treatment outside the body, to the potential for complications as treated hematopoietic stem cells are put back into a patient’s body.
“By treating this disease in vivo, I don’t want to call it a shortcut, but we essentially leapfrog all of those challenges and can provide ideally the same or similar therapeutic benefit without all of the risks associated with ex vivo-based therapies,” Oakes said. “Therefore, we believe that the greatest advantage in this field in treating sickle would be to bring these therapies in vivo, and that will be really transformative for patients as much as, if not even more so than, the ability to modify the genome itself.”
Yet in vivo treatment isn’t free from potential drawbacks either—such as the need for precise delivery of a therapy to a given area of the body, and thus avoid a potential immune response to treatment.
In a statement, Sanofi said its technology is designed to avoid that problem through effective targeting.
“We’re encouraged by what we’ve accomplished to date with Scribe in creating ex vivo NK cell therapies and now look forward to accelerating our ability to effectively leverage genome editing in vivo through Sanofi’s innovative research work in targeted lipid nanoparticles (LNPs), for in vivo therapies with the potential to dramatically improve treatment outcomes and ultimately to change patients’ lives,” stated Christian Mueller, global head of Sanofi’s Genomic Medicine Unit.
LNPs, CRISPR, and mRNA
At the recent American Society of Gene and Cell Therapy (ASGCT) 26th Annual Meeting, held in Los Angeles, a team of Sanofi researchers presented research showing how they had developed a non-viral gene therapy strategy that applies LNPs along with CRISPR editing technology and messenger RNA (mRNA).
“This strategy will enable CRISPR nuclease mRNA and an associated guide RNA (gRNA) to be encapsulated by an LNP as cargo. The LNP will then be intravenously injected into a patient, where a targeting moiety will enable specific transfection of HSCs in vivo,” the Sanofi researchers reported in an abstract presented at ASGCT. Leading the team was Christopher Borges, PhD, Sanofi’s head of non-viral gene therapy and genome engineering.
“Once the mRNA cargo is released into the HSCs, the translated CRISPR effector will complex with the gRNA to genetically modify the target resulting in a concomitant increase in the expression of HbF.”
The researchers said they engineered LNPs to effectively encapsulate nuclease mRNA and associated gRNA specific to their therapeutic genetic target or the hematopoietic cell-surface markers CD45 or B2M. LNPs were then conjugated with antibodies targeting cell-surface proteins on HSCs, and were screened for binding and transfection on primary human HSCs ex vivo. From that screen, one antibody was identified and characterized to optimally transfect HSCs, called FabGMU101.
“By incorporating our strategy to enable LNP binding and transfection of nuclease-mRNA, we demonstrate successful disruption of multiple loci in primary human HSCs in vitro. This success provides the foundation for a non-viral gene therapy for SCD that will be effective, economically viable, and safe,” the researchers concluded.
Sanofi has obtained an exclusive license to use Scribe’s XE genome editing technologies for the development of in vivo therapies for SCD and other genomic diseases. In return, the pharma giant agreed to pay Scribe $40 million upfront, and up-to-$1.2-billion-plus in payments tied to achieving development and sales milestones. Sanofi also agreed to pay Scribe tiered royalties ranging from high single digits to low double digits on net future sales of any products developed through the collaboration.
Scribe has a right to opt into sharing the cost of development, as well as sharing co-promotion, profit, and loss with Sanofi on one future program.
In addition to Sanofi, Scribe is pursuing genome editing collaborations with two other biopharma giants. In May, Scribe and Eli Lilly subsidiary Prevail Therapeutics launched an up-to-$1.575 billion-plus partnership to develop in vivo CRISPR-based therapies for “serious” neurological and neuromuscular diseases.
Also, in 2020, Scribe and Biogen launched a collaboration to treat neurodegenerative disorders, which aligns with Biogen’s core growth area of neuromuscular disorders. The up-to-$415-million-plus partnership started with a first target focused on a genetic cause of amyotrophic lateral sclerosis (ALS), and an option held by Biogen for a second “neurological disease target with high unmet need.”
Last year, Biogen expanded its collaboration with Scribe by exercising an option for a second, unnamed target through which they aim to treat disease. Also undisclosed was how much more Biogen will pay Scribe if the second target leads to a successful therapy.