Patient Reported Outcomes May Help Give a Better Picture of Exa-cel's Impact

Akshay Sharma, MBBS

On December 8, 2023, Vertex Pharmaceuticals and CRISPR Therapeutics’ autologous gene-edited cell therapy exagamglogene autotemcel (exa-cel; marketed as Casgevy and formerly referred to as CTX001) was approved by the FDA for the treatment of sickle cell disease (SCD) in patients aged 12 years and older with recurrent vaso-occlusive crises (VOCs).¹ The agency’s decision was based largely on results from the primary end point of the phase 1/2/3 CLIMB-121 clinical trial (NCT03745287): the proportion of patients who achieved freedom from severe VOCs for at least 12 consecutive months.

Although, patient reported outcomes (PRO) data was also collected in the trial.² An analysis of this data was presented by Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital, at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California. In an interview with CGTLive™ held shortly before the conference, Sharma discussed the importance of this data in informing the true impact of the new therapy on patients’ lives.

CGTLive: Can you give some background info on the presentation you are giving at ASH?

Akshay Sharma, MBBS: The data that I'm presenting is from the CLIMB-121 clinical trial, which is the clinical trial led by CRISPR Therapeutics and Vertex Pharmaceuticals for exa-cel. It's a CRISPR-Cas9-edited autologous CD34+ stem cell therapy for treatment of patients with SCD. Specifically, the poster that we are presenting is describing the PRO data from this clinical trial. 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. These crises generally begin early in infancy and they continue to progress with progressive organ damage for the rest of the life of these individuals.

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. 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.

But beyond measuring a reduction in painful crises, I think the most important thing that affects a patient is how the disease affects their life. 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. The data from this particular study, as far as the clinical outcomes are concerned, have been presented previously, and will be presented again, at the 2023 ASH Meeting by Dr. Haider Frankel [MD, medical director, Sarah Cannon Pediatric Hematology/Oncology & Cellular Therapy at TriStar Centennial]. But I will be talking specifically about the PROs in the participants of this study.

Can you give an overview of the key results that you are presenting?

As I just mentioned, PRO measures measure the global scenario of how the patients are feeling following a treatment. For this particular study, there were a number of different instruments that were used to assess patient functioning after undergoing gene therapy. Many of these instruments also have subinstruments or subsections within them, which look at different aspects of a patient's life.

One of the instruments that was used was the Functional Assessment of Cancer Therapy–Bone Marrow Transplant, and other one was a comprehensive Functional Assessment of Cancer Therapy - Genera score. These 2 are standard instruments that are used following transplantation. In addition to that, there were instruments specifically looking at SCD quality of life. In all of these instruments, without going into too much detail, but to just describe the overall outcome measure: we saw improvement across all the domains and across all the instruments in patients after undergoing gene therapy. These improvements were seen as early as 6 months after undergoing gene therapy and they would continue to be seen as much as 24 months after undergoing gene therapy, signifying that not only do the changes in the quality of life of these patients happen pretty early, but they are sustained over a long period of time.

What are the main implications that the healthcare community should take away from these findings?

I think the main takeaway from this is not only that these therapies (especially exa-cel) are successful in reducing the medical complications of disease—which obviously is the primary objective of this and other similar studies that are going on in the field—but beyond that the PRO data that we have generated and are presenting at the conference clearly show that that reduction in the incidence of painful crises actually reflects an improvement in quality of life of these individuals, which I think is usually missed out in such analysis. 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.

This transcript has been edited for clarity.

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REFERENCES
1. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. News release. FDA. December 7, 2023. Accessed December 7, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease 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. https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-reports-third-quarter-2023-financial
2. Sharma A, Frangoul H, Mapara M, et al. Improvements in health-related quality of life after exagamglogene autotemcel in patients with severe sickle cell disease. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #4999