Three weeks ago, on January 5, Graphite Bio announced a voluntary pause of their Phase I/II CEDAR clinical trial of nulabeglogene autogedtemcel (nula-cel) for sickle cell disease (SCD) after observing complications in the first dosed patient—prolonged low blood cell counts (pancytopenia) requiring ongoing transfusion and growth factor support. While the event did not meet the requirements to halt the study, based on evolving clinical data, Graphite Bio decided to pause the CEDAR study voluntarily and reported the event to the FDA.

This event raises several important questions: Why did the company stop the trial on its own instead of waiting for the FDA to step in? How are investors reacting? And how is the competition affected?

Voluntary pause 

The CEDAR study was designed to enroll up to 15 patients. “Multiple patients were moving through the enrollment and treatment process at the time we decided to voluntarily pause the study,” a Graphite Bio spokesperson told GEN Edge.

“However, only one patient has been dosed with nula-cel. The patient remains enrolled in the CEDAR study and continues to receive care and close monitoring from the clinical investigator and study staff. We are in close contact with the clinical site and are monitoring the patient’s status. Out of consideration for this patient’s privacy, additional details about the patient cannot be disclosed at this time.”

The decision to pause the trial came down to the health of the patient affected and the other participants. As Fyodor Urnov, PhD, director of technology and translation at the Innovative Genomics Institute (IGI), pointed out on Twitter, “The patient’s welfare is at this point the only thing that matters. Understanding the cause of this will take time and data that we currently don’t have.”

Geulah Livshits, a senior research analyst at Chardan, who covers biotech companies with a focus on gene editing and oncology, told GEN Edge that it is difficult to discern the impact Graphite’s trial pause will have for the rest of the space.

“It’s a little bit premature to think about the ultimate extent of read-across in the space in general,” said Livshits. “People do become cautious around the extent of read-across when it is something that is fundamental to gene editing itself, but, at this point, we don’t know. As is typical with some of the adverse events seen in the broader genetic medicine space, there is initially little insight into the underlying biology of what caused it.”

From a scientific standpoint, there are several differences between Graphite Bio’s program and the other gene editing programs for SCD that are in the clinic.

Graphite Bio’s nula-cel, formerly known as GPH-101, is the first investigational therapy to use a gene correction approach to correct the SCD point mutation in the beta-globin gene, resulting in decreased sickle hemoglobin (HbS) production and restored adult hemoglobin (HbA) expression.

Graphite’s gene correction strategy differs from that of competitors Editas Medicine and CRISPR Therapeutics (in collaboration with Vertex Pharmaceuticals), both of which use gene editing to target regulatory regions that lead to activation of the gamma-globin gene—a component of fetal hemoglobin (HbF)—to compensate for the mutation in HbS.

CTX001—now called exa-cel—from Vertex Pharmaceuticals and CRISPR Therapeutics uses CRISPR-Cas9 to disrupt the binding of BCL11A, a transcriptional repressor, to the erythroid-specific enhancer region for the gamma-globin gene. Having launched the clinical trial in 2019, the two companies are preparing to seek approval from the FDA for exa-cel to treat SCD and beta-thalassemia. Initial results from these ongoing trials were published in the New England Journal of Medicine in January 2021 and updated results on 31 SCD patients were shared at the annual American Society of Hematology conference in December 2022. Most if not all patients so far report significantly improved symptoms thanks to restoration of HbF expression.

Meanwhile, EDIT-301 from Editas uses AsCas12a—a novel, proprietary, efficient, and specific nuclease—to edit the promoter regions of the gamma-globin gene to increase the expression of HbF, to mimic the natural mechanism of hereditary persistence of fetal hemoglobin to treat SCD. The RUBY trial of EDIT-301 for treating severe SCD is the first time AsCas12a has been used to edit human cells in a clinical trial. It was reportedly well tolerated and safe in two patients.

Then there’s the base editing approach to SCD, notably from Beam Therapeutics. BEAM-101 incorporates base edits that are designed to mimic single nucleotide polymorphisms seen in individuals with hereditary persistence of HbF. In November 2022, Beam enrolled the first patient in its BEACON clinical trial evaluating BEAM-101 as a treatment for SCD. Beam expects to complete enrollment in the sentinel cohort and initiate enrollment in the expansion cohort of BEACON in 2023, with plans to report data from multiple patients from one or both cohorts in 2024.

21 days

News of Graphite’s decision to pause the CEDAR trial sank the company’s share price by almost 40% from $3.06 to $1.85. (This marks a 90% drop from the company’s first day of trading as a public company in June 2021.) Since the trial pause, Graphite Bio’s share price has not risen above $2.19 and opened at $1.92 on January 25, 2023.

Following the pause, Graphite announced that it will no longer be asking the FDA for approval to test its other experimental therapy, GPH102, on humans by mid-2024. GPH102 is designed to replace the mutated beta-globin gene in patients with beta-thalassemia with a functional gene and restore HbA expression to levels similar to individuals who do not have the disease. The company stated that it was also looking for ways to increase its cash position beyond the previously stated cash runway of the fourth quarter of 2024, to at least 2026.

The announcement hasn’t had a major impact on the other competitors. The stock price of Editas has fluctuated but is slightly down, while that of CRISPR Therapeutics and Beam Therapeutics has trended upward over the past few weeks.

While there are clear variations in the CRISPR editing strategy between these three approaches, other factors also warrant scrutiny. For example, the viability, parameters in the processing and isolation, and dosing of the edited stem cells back into patients can play major roles in both the safety and efficacy outcomes of cell-based therapy.

Looking back

In an exclusive interview with GEN Edge last September, Graphite Bio CEO Josh Lehrer, who previously worked in small molecules and biologics, said that the difference with gene editing is that there’s no target risk and that the challenges lie in the manufacturing—the CMC (chemistry, manufacturing, and controls).

“Where things can be slower, because the steps are not as efficient and the standards are still evolving, is going from that to the clinical material and then commercial supply,” said Lehrer. “This requires strict controls and analytics. And this is a new field, so to some extent, the testing required by the FDA is a moving target. Regarding manufacturing, there’s a lot of experimentation, continued investigation, and learning that has to happen in tandem with your clinical experience. That isn’t true if you make an antibody or a small molecule.”

The company still believes that harnessing the power of homology directed repair (HDR) has great potential to cure many genetic diseases and is trying to hone in on specifics in their editing process.

“We know achieving gene correction is the ideal approach to cure sickle cell and many other genetic diseases, but we also know that this is more technically challenging than indirect approaches (e.g., using CRISPR technology just to cut),” said the Graphite Bio spokesperson on January 18, 2023.

“We are focusing our assessment on the differences in our process, which include using AAV6 to deliver the DNA template that contains the correct DNA sequence. The impact of AAV6 on stem cells, or the way that using AAV6 interacts with other components of our editing process, is a hypothesis as we consider potential manufacturing process improvements.”

In our 2022 interview, Lehrer pointed to the importance of another variable in their procedure: the conditioning treatment, or how a patient’s bone marrow is treated to make room for the gene-edited stem cell therapies.

“The conditioning treatment—how a patient’s bone marrow is treated to make room for the gene-edited stem cell therapies—is as critical as the editing technology,” Lehrer told GEN Edge. “We have used our experience in stem cell biology and immunology to begin research on a new approach to conditioning. We are now developing what we hope will become a best-in-class, nontoxic antibody-targeting approach, ultimately enabling a one-time cure that wouldn’t require a hospital stay or have chemotherapeutic conditioning risk—a very different paradigm than what we can currently offer patients.”

But Graphite has revealed few details about how those parameters might have been affected in their program, whether that’s typical of their manufacturing process or there was something about this specific patient that they had dosed that made them more susceptible to this type of outcome. “We are conducting a comprehensive assessment of the safety event, associated risk factors, and possible mitigation strategies, including potential modifications to our manufacturing process,” said the Graphite Bio spokesperson.

Livshits reiterated that it’s hard to get a sense of how this will be viewed throughout the gene therapy space. “I think people tend to extrapolate a little bit more if there’s a safety signal or something concerning in the first program in a space when there are no additional data that can serve as a frame of reference,” said Livshits.

In this case, there’s an existing database from the CRISPR Therapeutics (which Livshits covers at Chardan) and Vertex study as well as some early-stage data from Editas that, Livshits said, provides some context that there’s not universally a serious problem in this direction. “We’ll have to see the details for the product, the patient, and then how those interplay,” said Livshits.

GEN Edge reached out to Graphite co-founder and gene editing pioneer Matthew Porteus, MD, PhD—the first to show that engineered nucleases could be used to precisely modify human cells by homologous recombination as well as a co-founder of CRISPR Therapeutics—but he declined to comment. A spokesperson for Graphite Bio told GEN Edge that there are no further updates to share at this time but the company has committed to providing a business update by the end of March.



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