Michael Amoroso, Precision BioSciences CEO and president

Maximizing opportunities for its proprietary ARCUS genome editing platform was among the priorities Precision BioSciences articulated last fall when it named veteran biotech executive Michael Amoroso as president and CEO.

Precision and Amoroso have begun to deliver on that commitment—and satisfy Novartis’ growing interest in gene editing therapies—by inking an approximately up-to-$1.5 billion in vivo gene editing R&D collaboration and license agreement with the pharma giant aimed at helping it develop one-time treatments for blood disorders that include sickle-cell disease (SCD) and beta thalassemia.

To that end, Precision has agreed to develop for Novartis a single custom ARCUS sequence-specific DNA-cutting enzyme, or nuclease, designed to insert in vivo, a therapeutic transgene at an undisclosed “safe harbor” location in the genome where a new gene can be added without otherwise affecting the patient’s DNA of gene expression patterns. Precision has agreed to issue an exclusive license for the custom ARCUS nuclease to Novartis for further development.

“We identify here a collaborative opportunity to imagine a unique therapeutic option for patients with hemoglobinopathies, such as sickle-cell disease and β-thalassemia—a potential one-time treatment administered directly to the patient that would overcome many of the hurdles present today with other therapeutic technologies,” Jay Bradner, president of the Novartis Institutes for Biomedical Research (NIBR), said in a statement.

Novartis is Precision’s seventh collaboration partner, and the second biopharma giant applying ARCUS to develop treatments; the first is Eli Lilly. The two giants alone could generate more than $4 billion for Precision.

“People have started to understand why it is why we believe that ARCUS is the best in vivo gene editing platform in the world,” Amoroso told GEN Edge. Precision has not disclosed a development timeline for the custom nuclease.

For all the excitement galvanized by CRISPR over the past decade as a powerful and flexible new approach for precision genome editing, Precision Bio believes that its own proprietary platform holds some key advantages. ARCUS uses nucleases designed to insert (“knock in”) or remove (“knock out”) or repair DNA of living cells. ARCUS is derived from a natural genome-editing enzyme called I-CreI, a homing endonuclease that can be optimized to control for potency and specificity. I-CreI evolved in the algae Chlamydomonas reinhardtii to make highly specific cuts in cellular DNA. Precision’s platform and products are protected by a portfolio of nearly 100 patents.

Precision can use an ARCUS nuclease to insert or add its payload—typically a healthy version of a gene—at a designated site within the genome to enable healthy gene expression. The mutated copy of the gene is still there but the healthy copy overcomes the negative effects of the mutated copy.

In the collaboration with Novartis, an ARCUS nuclease will be used to insert a healthy copy of the gene at the safe harbor site, a location in the genome other than where the gene is found—and a location which can be used to insert a healthy copy of the gene replacing the mutated or disease-causing copy, in order to enable production of the healthy gene product without otherwise affecting the patient’s DNA of gene expression patterns.

“We do know where the safe harbor locus is. We have not disclosed where the safe harbor locus is,” said Derek Jantz, PhD, Precision’s chief science officer and co-founder.

Separating from the pack

“Several of our therapeutic programs are focused on gene deletion or knockout. But really, where we think ARCUS really separates from the pack in the gene editing field is for targeted gene addition,” he added. “Part of the allure of a gene addition type of project, like what we’re pursuing with Novartis, is to some extent, the approach that we’re using could be universal or applicable to a wide range of genetic disorders.”

Precision BioSciences has agreed to develop for Novartis a single custom ARCUS sequence-specific DNA-cutting enzyme, or nuclease, designed to insert in vivo, a therapeutic transgene at an undisclosed “safe harbor” location in the genome. [Precision Biosciences]
The safe harbor is where DNA ‘cargo’ could be expressed consistently over time, without having any impact on the surrounding chromosomal sequence, he said.

“You can imagine if this approach is successful, we wouldn’t be limited to simply inserting an anti-sickling gene, which is what we’re doing with the Novartis collaboration to treat SCD. We could introduce other genes into that same location in the genome or use that same type of approach, where we’re inserting genes into a different safe harbor locus in the genome,” Jantz explained. “Because that process is somewhat independent of what gene you are adding to the genome, there is the potential to use that same approach for the treatment for a pretty wide spectrum of genetic disorders.”

Precision’s in vivo gene editing approach will better enable the company to treat patients in developing countries where stem cell transplant is not a realistic option

In the Novartis partnership, the same ARCUS enzyme and transgene could be inserted into the genome potentially to treat both SCD and β-thalassemia.

Maury Raycroft, PhD, equity analyst with Jefferies, estimates that Precision’s development process for the custom nuclease will take 1.5–2 years.

“[The Novartis] deal provides [additional] validation to [Precision’s] ARCUS editing technology, which should be a long-term source of value” for the company, Raycroft wrote in a June 26 research note.

Crowded Field

Novartis looks to grow a presence in SCD beyond that of its approved drug Adakveo, as well as an ex vivo SCD program being studied in a Phase I/II trial (NCT04443907) that is expected to enroll 30 participants. The trial is assessing the genome-edited, hematopoietic stem cell therapy OTQ923/HIX763, developed through a five-year research collaboration with Intellia Therapeutics that ended in 2019.

Novartis is among several drug developers pursue gene-based therapies for SCD and beta thalassemia. For example, Vertex Pharmaceuticals and CRISPR Therapeutics plan regulatory submissions later this year for their CTX001, being developed for SCD and β-thalassemia through a multi-billion-dollar partnership, with Vertex committing $900 million upfront.

By the end of this year, Editas Medicine expects to report topline data for its ex vivo CRISPR-Cas12a gene-editing cell therapy, EDIT-301, in SCD, from the Phase 1/2 RUBY trial (NCT04853576), which is currently recruiting patients. Also this year, Editas plans to dose the first patient in a study of EDIT-301 for β-thalassemia later this year.

Earlier this month, Bluebird Bio won a positive recommendation from an FDA advisory committee for its lentiviral vector (LVV) gene therapy candidate betibeglogene autotemcel (beti-cel) for people with beta-thalassemia who require regular red blood cell (RBC) transfusions. Bluebird’s LVV candidate for SCD, lovotibeglogene autotemcel (lovo-cel), is on track for a BLA submission to the FDA in Q1 2023. Bluebird has spent years developing lentiviral vector-based gene therapies for beta thalassemia and SCD despite numerous challenges.

Also, Global Blood Therapeutics recently launched a version of its SCD drug Oxbryta (voxelotor) for children ages 4–11 and won marketing authorization from the European Commission for Oxbryta, thus making it the first EU-approved therapy that directly inhibits the molecular basis of sickling and destruction of red blood cells in SCD.

Beam Therapeutics has two SCD treatments in development, BEAM-101 and BEAM-102, using its base editing technology. During the second half of this year, Beam has told investors, Beam expects to enroll the first patient in its Phase I/II BEACON-101 trial assessing BEAM-101, as well as submit an IND application for BEAM-102 to the FDA.

Three clinic-bound candidates

Precision’s in vivo gene editing pipeline is anchored by three wholly owned programs projected to enter the clinic over the next three years.

Derek Jantz, PhD, Chief Scientific Officer and co-founder, Precision BioSciences

The first clinical candidate is expected to be PBGENE-PCSK9, a familial hypercholesterolemia (FH) treatment that applies ARCUS to knockout the PCSK9 gene using adeno-associated virus (AAV) delivery. A clinical trial application (CTA) is expected later this year. PBGENE-PCSK9 will be advanced through Phase I studies by iECURE, an in vivo gene editing company that has licensed access to Precision’s PCSK9-directed ARCUS nuclease in order to develop additional gene editing therapies for genetic diseases, initially targeting liver diseases.

The second clinical candidate is expected to be PBGENE-PH1, a treatment for primary hyperoxaluria type 1 that uses ARCUS to knockout the HAO1 gene to prevent the production of oxalate, which causes extremely severe and potentially fatal kidney stone accumulation in patients. Precision expects to submit an IND application for PBGENE-PH1 in 2023 using lipid nanoparticle (LNP) delivery.

The third wholly owned candidate, PBGENE-HBV for chronic hepatitis B virus (HBV), applies ARCUS to knockout covalently closed circular DNA (cccDNA) and integrated HBV genomes that enable the virus to persist. Precision expects to submit an IND in 2024 for PBGENE-HBV, which also uses LNP delivery.

At the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting, held last month in Washington, DC, Precision presented data showing that LNP delivery of messenger RNA (mRNA) via ARCUS in vivo gene editing represented a promising approach and potential functional cure for chronic HBV.

Precision showed that ARCUS efficiently targeted and degraded HBV cccDNA by 85% and reduced expression of Hepatitis B surface antigen (HBsAg) by 77% in HBV-infected primary human hepatocytes (PHHs). The data included a 96% reduction of HBsAg in a mouse model, plus high on-target editing and a 70% decrease in the cccDNA surrogate in both mouse and non-human primate models. The data was published on May 16 in Molecular Therapy by researchers from Precision, Gilead Sciences and Acuitas Therapeutics.

In 2020, Gilead terminated an HBV in vivo genome editing collaboration that was launched in 2018, in which it committed to paying Precision up to $445 million tied to achieving milestones. The HBV program is now wholly owned by Precision, which has non-exclusive rights to evaluate Acuity’s LNP technology for delivery of ARCUS—plus an option to develop and commercialize ARCUS products delivered through Acuitas’ LNP.

Also at ASGCT, Precision presented data showing the preclinical feasibility of using ARCUS’ gene insertion approach for treating ornithine transcarbamylase (OTC) deficiency—one of two programs Precision has partnered with iECURE. Precision showed therapeutically meaningful and stable levels of OTC expression in non-human primates (NHPs), with no evidence of transaminase elevations or liver histopathology in any animals treated with iECURE-OTC, now in an IND-enabling phase.

The other iECUIRE-partnered program, iECURE-PKU, is a phenylketonuria treatment using gene addition and AAV delivery to target the PAH gene.

Positive preclinical data

Amoroso and Jantz, who co-developed ARCUS, said Novartis approached Precision after it published positive preclinical data on ARCUS’ genome editing technology. Among data studied by Novartis were researchers at Precision and the University of Pennsylvania’s Gene Therapy Program led by gene therapy pioneer James M. Wilson, MD, PhD, iECURE’s Chief Scientific Advisor and a co-founder of the company.

James M. Wilson MD, PhD, Director, Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania

Wilson and Lili Wang, PhD, Research Director, Translational Research and Gene Editing for Penn’s Gene Therapy Program, led the study, in which non-human primates showed stable reduction of low-density lipoprotein (LDL) cholesterol levels three years after in vivo gene editing of the PCSK9 gene with ARCUS in 2017. NHPs treated with ARCUS experienced stable reductions of up to 85% in PCSK9 protein levels and a 56% reduction of LDL cholesterol levels. The study was published February 2021 in Molecular Therapy.

Jantz called the study “a very compelling demonstration of ARCUS in a large animal model, both from the standpoint of demonstrating that the gene edits made by ARCUS are permanent, but then also that the gene edits made by ARCUS and expression of an ARCUS enzyme is safe over the long term.

“Maybe the most valuable aspect of those studies,” Jantz added, “is demonstrating that we can express an ARCUS nuclease from an AAV vector in the liver of a primate for a very long period of time—weeks, months, years—and we don’t see any safety side effects in the animals, even five years later.”

Amoroso said another reason Novartis was drawn to ARCUS was Precision’s ongoing up-to-$2.7 billion collaboration with Lilly launched in 2020. Lilly paid Precision $135 million upfront, including $35 million in equity, and agreed to pay Precision up to $420 million per target in development and commercialization milestone payments, plus tiered royalties ranging from mid-single digits to low teens.

Precision has applied ARCUS to generate nucleases for three initial gene targets selected by Lilly—the collaboration’s lead program targeting Duchenne muscular dystrophy in muscle (PBGENE-DMD), an undisclosed target directed to the liver (PBGENE-LLY2) and another undisclosed target directed to the central nervous system (PBGENE-LLY3). Lilly has rights to nominate up to three additional gene targets for genetic disorders.

Precision has not furnished updates on its progress with Lilly. According to a Precision investor presentation last year, ARCUS genome editing has led to increased expression of a shortened version of dystrophin in cultured myoblasts from a DMD patient, using two ARCUS nucleases delivered by a single AAV to simultaneously cut and delete a large segment of the dystrophin gene that encodes exons 45 through 55 of dystrophin. That region of the gene accounts for more than half of DMD-causing mutations.

Drawing attention

“[Novartis] had done their homework for a while and I think, certainly the collaboration with Lilly drew a lot of their attention to our platform,” Jantz said.

Novartis has agreed to pay Precision $75 million upfront, consisting of $50 million cash and $25 million in equity, at a 20% premium to Precision’s 10-day volume weighted average price (VWAP) ending June 13—amounting to $2.01492 a share, based on the VWAP of $1.6791.

The upfront payment multiplies Precision’s 2022 revenue to date, which was $3.317 million in Q1 after generating $115.53 million last year. Nearly half of Precision’s 2021 revenue consisted of $54.8 million recognized after its performance obligation was deemed fully satisfied under an agreement to reacquire all global development and commercialization rights for all CAR T programs previously partnered with Servier. Precision also recognized $21 million from Lilly, $17.9 million from iECURE, and $2.9 million from an agricultural partnering collaboration.

As of March 31, Precision reported $116.11 million in cash and cash equivalents (down 19% from December 31, 2021), and $104.94 million in working capital (down 16.5%).

Novartis also agreed to pay Precision up to about $1.4 billion in payments tied to achieving milestones. Novartis has also agreed to pay Precision toward research, as well as tiered royalties on product sales ranging from the mid-single digits to low-double digits, should the companies commercialize a therapy through their collaboration.

ARCUS is Precision’s genome editing platform used to develop therapeutic gene editing approaches for treating hematologic malignancies (ex vivo CAR T therapies) and genetic diseases (in vivo gene editing).

Precision is also developing therapies using an ex vivo single-gene edit platform it has developed for allogeneic chimeric antigen receptor T-cell (CAR-T) immunotherapies based on single-dose, donor-derived off the shelf CAR-T cells.

Earlier this month, Precision announced data from its Phase I/IIa study (NCT03666000) of its lead ex vivo candidate, the CD19-targeting PBCAR0191 for CAR T relapsed patients with non-Hodgkin’s lymphoma (NHL). The company reported that CAR T relapsed patients who received a median of five prior lines of therapy showed an overall response rate of 100% (all 11 evaluable patients), a complete response rate of 73% (8 of 11), and a 50% (3 of 6 evaluable patients) “durable” response rate of greater than six months.

Precision also announced it was progressing with two other clinical ex vivo allogeneic CAR T therapy candidates—PBCAR19B, a second generation, anti-CD19 targeting allogeneic CAR T candidate for relapsed/refractory (R/R) patients with NHL; and PBCAR269A for R/R multiple myeloma.

PBCAR269A is in a Phase I/IIa study (NCT04171843) with and without nirogacestat, a gamma secretase inhibitor developed by SpringWorks Therapeutics as an alternative to autologous CAR T therapies targeting B-cell maturation antigen (BCMA) for R/R multiple myeloma.

A fourth ex vivo CAR T candidate program is in preclinical predevelopment—a CD-19 targeting cancer-fighting combination of Tiziana Life Sciences’ fully human anti-CD3 monoclonal antibody foralumab with allogeneic CAR T candidates.

Amoroso took Precision’s helm in October 2021, succeeding company co-founder Matt Kane, who is now CEO of epigenomic control platform developer Tune Therapeutics. Amoroso was previously President and CEO of gene and cell therapy developer Abeona Therapeutics, and earlier held executive positions there and at Kite Pharma (acquired by Gilead in 2017 for $11.9 billion), Eisai, Celgene (acquired by Bristol Myers Squibb for $74 billion in 2019) and Aventis (now Sanofi), where his biopharma career began.

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