Vertex and CRISPR’s Ongoing Trial for Sickle Cell Disease Gene Therapy Seeks to Gather Patient Reported Outcomes


Exa-cel was recently approved for the treatment of SCD in the US, but data from the pivotal clinical trial continues to be collected.

On December 8, 2023, the FDA approved Vertex Pharmaceuticals' and CRISPR Therapeutics’ CRISPR-Cas9-edited autologous CD34+ gene-edited cell therapy exagamglogen eautotemcel (exa-cel), marketed under the name Casgevy, for the treatment of severe sickle cell disease (SCD) in patients aged 12 years and older with recurrent vaso-occlusive crises.1 The agency’s decision was largely based on data from the phase 1/2/3 CLIMB-121 clinical trial (NCT03745287) and the phase 3 long-term follow-up study CLIMB-131 (NCT04208529), with reference being specifically made to the ability of therapy to bring about freedom from vaso-occlusive crises (VOCs), which formed the basis of a primary end point in CLIMB-121.

Although exa-cel has already been approved, the CLIMB-121 study, which was originally initiated on November 27, 2018, remains ongoing. Although the primary end point, which related to freedom from VOCs, was key in the FDA’s decision, an important aspect of the ongoing data collection is patient reported outcomes (PROs).

The trial, which is taking place at 17 study sites in countries including the United States, Belgium, Canada, France, Germany, Italy, and the United Kingdom, has an estimated completion date of October 2024. It has a single-arm, single-dose, open-label study design in which patients receive a one-time administration of exa-cel through a central venous catheter. Patients undergo myeloablative conditioning with busulfan before receiving exa-cel through intravenous infusion. According to the page, which was last updated on December 11, 2023, the trial is active, but no longer recruiting new patients.

“As you know, SCD is a debilitating disease. It's a chronic disorder of hemoglobin production, wherein patients who have the genetic mutation suffer from painful crises throughout their life...” Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital, who presented on PRO data from CLIMB-121 at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California, told CGTLive shortly before the conference started.2

“Because of these painful crises and progressive organ damage, individuals with SCD have tremendous disadvantage in their life, not only because they have to be admitted and be seen in a hospital frequently, but also because these painful crises and organ dysfunction affects their ability to earn: their ability to be productive members socially and economically,” Sharma continued. “As such, it really is a comprehensive chronic disease where it affects all aspects of an individual's life. Many studies are ongoing right now which are developing potentially curative therapies for patients with SCD. The primary outcome measure that most of these studies have is looking at reduction in painful crises—which makes sense—it's a disease that causes painful crises, so if we can objectively measure how much decrease in painful crises has happened that's a good outcome measure.”

In addition to the aforementioned primary end point, which measured freedom from VOCs for at least 12 consecutive months during a 24-month follow-up period, additional primary end points in CLIMB-121 include the proportion of patients who achieved engraftment; time to engraftment; the frequency and severity of collected adverse events; the incidence of transplant-related mortality (TRM) in 100 days posttreatment; the incidence of TRM in 1 year posttreatment; and all-cause mortality. Among the secondary end points for the trial were the proportion of patients free from inpatient hospitalization for severe VOCs sustained for at least 12 months; the proportion of patients who have not experienced any severe VOC for at least 9 consecutive months any time posttreatment; the proportion of patients with a 90%, 80%, 75%, or 50% reduction in annualized rate of severe VOCs; the relative change from baseline in the annualized rate of severe VOCs; the duration of severe VOC freedom in patients who have achieved the first primary end point; the relative change from baseline in the rate of inpatient hospitalization for severe VOCs; and the relative change from baseline in annualized duration of hospitalization for severe VOCs.

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Additional end points included a number of laboratory measures and PRO outcomes. For the latter, the change in PRO over time was assessed with instruments including weekly pain-scale; EuroQol quality of life scale; EQ-5D-Youth; functional assessment of cancer therapy-bone marrow transplant questionnaire; adult sickle cell quality of life measurement system; pediatric quality of life inventory (PedsQL); and PedsQL sickle cell disease module.

“...Beyond measuring a reduction in painful crises, I think the most important thing that affects a patient is how the disease affects their life,” Sharma added. “That's an aspect that gets captured by asking the patients questions about their quality of life and how the disease has affected their day to day activities. This is what's captured in PROs... I really commend the study team and the investigators for actually capturing that data and reporting it at this meeting to show that not only these therapies are clinically effective, but they're also effective in improving a patient's life—which I think is the overall goal of any treatment that we undertake for a chronic disease, such as SCD.”

CLIMB-121 was open to patients aged 12 years to 35 years who have a diagnosis of severe SCD defined by genotype, a history of at least 2 severe VOCs per year for the 2 years prior to enrollment, and eligibility for autologous stem cell transplant as per investigator judgment. Patients with an available 10/10 human leukocyte antigen-matched related donor; those who had previously received hematopoietic stem cell transplant; and those with clinically significant and active bacterial, viral, fungal, or parasitic infections were excluded from participation. According to the page, additional protocol defined criteria may have applied.

1. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. News release. FDA. December 7, 2023. Accessed January 8, 2024. 2. Taysha Gene Therapies reports third quarter 2023 financial results and provides corporate and clinical updates. News release. Taysha Gene Therapies, Inc.. November 14, 2023. Accessed December 7, 2023.
2. Sharma A, Frangoul H, Mapara M, et al. Improvements in health-related quality of life after exagamglogeneautotemcel in patients with severe sickle cell disease. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #4999
3. A safety and efficacy study evaluating CTX001 in subjects with severe sickle cell disease. Website. Accessed January 8, 2024.

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