CRISPR Therapy Turns a Corner With First Cures In Sight

Latest Trial Data Shows That CTX001 Is Efficacous and Safe

CLIMB-Thal-111 and CLIMB-SCD-121 are both open-label Phase 1/2 trials designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with TDT or severe SCD, respectively.

In June 2020, Vertex and CRISPR Therapeutics released preliminary, mainly positive safety and efficacy data from the first two patients enrolled in these trials, and we covered these updates in a previous article. Since then, a total of 13 TDT patients and 6 SCD patients have been dosed CTX001 and the latest results demonstrate potential efficacy and durability among a larger population of patients with these diseases.

The New Data - Efficacy, Durability and Safety

At the ASH meeting, 7 TBT patients were reported to be transfusion-independent with follow-up ranging from 3 to 18 months after a single CTX001 infusion. All 7 patients had normal to near normal total haemoglobin levels at the last checkup, including total haemoglobin from 9.7 to 14.1 g/dL and foetal haemoglobin from 40.9% to 97.7%.

Data was presented for 3 SCD patients who had reached at least 3 months of follow-up after CTX001 adminstration. These patients showed similar response patterns, with rapid and sustained increases in total haemoglobin and foetal haemoglobin, as well as elimination of vaso-occlusive crisis (VOCs), a serious complication of SCD that results when sickled red blood cells obstruct the blood vessels, at the last analysis.

For both trials, bone marrow allelic editing data, which is a measure of the success rate of gene editing, was collected from a selection of patients with 6 or 12 months of follow-up after CTX001 infusion demonstrated a durable effect.

In the peer-reviewed article in NEJM, the authors write: »These findings, which indicate that CRISPR-Cas9–edited HSPCs underwent engraftment that was durably maintained, are consistent with an expected survival advantage of erythrocytes with a high level of fetal hemoglobin«. The authors also point out that: »The clinical course of both patients supports our conclusion that CTX001 mimics the phenotype of hereditary persistence of fetal hemoglobin levels.«

In general, the safety data from all 7 TBT and 3 SCD patients was consistent with an autologous stem cell transplant and the prior chemotherapy to removed diseased cells. Four serious adverse events considered related or possibly related to CTX001 were reported in 1 patient, but which later resolved, and the majority of non-serious adverse events were considered mild to moderate. There were no SAEs considered related to CTX001, and the majority of non-serious adverse events were considered mild to moderate.

A Milestone For CRISPR Medicine Field

The CTX001 trials, which are still ongoing, were originally designed to enroll a total of 45 patients each, but according to an interview covered elsewhere, David Altshuler, Chief Scientific Officer at Vertex Pharmaceuticals is quoted as having said: »I think we could move very quickly here. More patients want to get the therapy and we don’t think we need that many patients for approval. With this kind of effect, we likely need fewer people.«

In a press release about the new data, Reshma Kewalramani, M.D., Chief Executive Officer and President at Vertex said: »These are the first published results from CRISPR/Cas9 therapy in people with a genetic disease and represent an important milestone in medicine and for our collaboration with CRISPR Therapeutics. Most importantly, these data represent a critical step in our effort to bring transformative and potentially curative therapies to patients. With clinical proof-of-concept for both beta thalassemia and sickle cell disease and 19 patients dosed, we look forward to continued efforts to bring our investigational treatment to patients living with TDT and SCD as quickly as we can.«