DUBLIN – Crispr Therapeutics AG has delivered what appears, so far at least, to be a safe, functional cure for the first patient enrolled in each of its phase I/II trials of lead CRISPR/Cas9 gene editing therapy CTX-001, in beta-thalassemia and in sickle cell disease.

The data constitute the first clinical evidence that the great promise of CRISPR/Cas9 can be realized in patients with severe genetic disease, although the interim read-out represents just a preliminary safety and efficacy peek at the autologous ex vivo engineered cell therapy.

Sam Kulkarni, CEO, Crispr

Each study is due to enroll up to 45 patients, who will be followed for 24 months. Given the scale of the initial effects seen in each patient, Crispr is already starting to think in terms of a registrational filing based on a much smaller number, in order to get the therapy to patients in a “responsible but expeditious fashion,” Sam Kulkarni, CEO of Zug, Switzerland-based Crispr, told BioWorld.

Bluebird Bio Inc., of Cambridge, Mass., provides the relevant precedent. It gained European approval for Zynteglo (lentiglobin; autologous CD34+ cells encoding betaA-T87Q-globin gene) in beta-thalassemia earlier this year on the basis of efficacy data from just 10 patients. “It all depends on effect size,” Kulkarni said. For that reason, it is still too early to talk about numbers in the case of Crispr. In each study, the company is treating the first two patients sequentially. After successful and safe engraftment of those, it can then start treating patients in parallel, which would accelerate its rate of data acquisition. It hopes to get to that point shortly.

The patient with beta-thalassemia was dosed in the first quarter of this year, and the data represent nine months of follow-up. For the patient with sickle cell disease, the data cut-off was made after just four months of follow-up.

Although each patient experienced a number of serious adverse events, they proved manageable, and none, moreover, was considered to be due to the therapy itself. The patient with transfusion-dependent beta-thalassemia developed pneumonia, presumed to be due to neutropenia, and veno-occlusive liver disease, an obstruction of blood vessels in the liver which is a common complication of the myeloablative conditioning administered in advance of hematopoietic stem cell therapy. Both resolved. The patient with sickle cell disease developed sepsis, presumed to be associated with neutropenia, gallstones and abdominal pain, all of which resolved as well.

“Overall, the safety profile that was observed in both the thalassemia and sickle cell studies has been consistent for what you would expect for an autologous stem cell transplant, and none of the serious adverse events were considered related to CTX-001,” Kulkarni told a conference call audience Tuesday.

Dramatic improvements

CTX-001 comprises patients’ own CD34+ hematopoietic stem and progenitor cells that are modified to produce fetal hemoglobin by disrupting the locus for BCL11A, a transcriptional repressor of fetal hemoglobin production. BCL11A normally becomes active shortly after birth, when infants switch production to adult hemoglobin. The therapeutic strategy compensates for the loss of adult hemoglobin that is characteristic of both beta-thalassemia and of sickle cell disease, both of which are caused by mutations that disrupt hemoglobin production. It mimics a small number of healthy individuals who continue to produce fetal hemoglobin as adults even though they also carry mutations that would otherwise cause them to develop a hemoglobinopathy.

On the efficacy side, each patient experienced a dramatic improvement. “The patient with beta-thalassemia required frequent transfusion prior to treatment and has now been transfusion-free for approximately eight months,” Crispr’s head of R&D, Tony Ho, said on the call. The patient had a severe heterozygous phenotype (beta0/IVS-I-110) and had previously needed an average of 16.5 transfusions per year. Neutrophil engraftment and platelet engraftment occurred 33 days and 37 days, respectively, after the patient received a single dose of CTX-001. She also exhibited sustained production of fetal hemoglobin, defined as >10 grams/deciliter of blood.

In sickle cell disease, the therapeutic goal is to reduce the number of vaso-occlusive crises (VOCs), which are intermittent episodes of severe pain due to blockage of the blood vessels by aggregation of misshaped or “sickled” red blood cells. The picture here, too, is also dramatic if less developed. At baseline, the patient experienced an average of seven VOC episodes per year and had 7.2g/dL of total hemoglobin, of which 74.1% was the disease-associated hemoglobin S species and just 9.1% of which was fetal hemoglobin. After therapy, total hemoglobin rose to 11.3g/dL, of which 46.6% comprises fetal hemoglobin and 41.2% comprised hemoglobin S. That shift led to a substantial clinical improvement.

“Similarly, the patient with sickle cell disease has experienced no VOCs in the first four months after treatment compared to a baseline rate of seven per year,” said Ho. “This is likely due to the 46.6 percent fetal hemoglobin being produced due to CTX-001 treatment, which is far more than our primary endpoint target of 20 percent.” Neutrophil engraftment and platelet engraftment both occurred 30 days after the patient received a single dose of CTX-001.

Analyst response was positive, if guarded, given the preliminary nature of the data. “We consider these initial results quite promising. Clearly data from more patients, with a variety of genotypes, and longer duration follow-up will be necessary to better understand CTX-001's place in treatment, particularly in light of the variety of gene and cell therapies in development,” wrote Cowen analyst Phil Nadeau in a research brief. Cory Kasimov at JP Morgan was similarly circumspect: “There remain lots of unknowns, including the dose being used, long-term durability, and whether results will be replicated in more patients and with other genotypes. We look forward to seeing more updates from the program next year,” he wrote.

Shares in Crispr Therapeutics (NASDAQ:CRSP) gained as much as 26% during trading Tuesday before ending the day at $68.46 up $9.93, or 17%, on the previous close. Shares in its development partner, Vertex Pharmaceuticals Inc. (NASDAQ:VRTX), edged up by about 2.4% to close at $215.

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