Exagamglogene autotemcel

Why is it a drug to watch?

Inherited blood disorders, SCD and beta-thalassemia cause severe pain, organ damage and shortened life span. With only a one-time administration, these therapies aim to treat the underlying cause of SDC and transfusion-dependent beta-thalassemia and result in patients being transfusion-independent or vaso-occlusive crises (VOC)-free, with significant improvement in quality of life and physical performance. The enthusiasm for gene therapies in this space is based not only on the potential curative effect but also concerns about the effectiveness of other current treatments, their accessibility and their side effects. In its recent evaluation of SCD treatments, the Institute for Clinical and Economic Review (ICER) considered both treatments to potentially provide a substantial net health benefit compared with standard of care, given the severity of disease and the rate of treatment success and despite uncertainties around durability and harms.

Exagamglogene autotemcel is the first treatment to emerge from the joint research program between Vertex and CRISPR Therapeutics that started in 2015 to focus on using CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. ICER rated exagamglogene autotemcel, compared with standard of care, as “Comparable or Better.”

The MHRA CMA, U.S. FDA approval and other submissions to regulatory agencies were based on data from two pivotal phase 1/2/3 studies, which showed the following:

1. CLIMB-111:

• Patients aged 12 years to 35 years with transfusion-dependent beta-thalassemia characterized by recurrent VOCs 
• 88.9% with independence from transfusion for at least 12 consecutive months
• 20.5-month mean duration of independence from transfusion (maximum 40.7 months)  
• 9 g/dL mean weighted hemoglobin
• Increase in total hemoglobin from an average of 8.9 g/dL to an average of 16.9 g/dL  
• Increase in fetal hemoglobin (HbF) from an average of 67.4% to an average of 99.6%

2. CLIMB-121:

• Patients aged 12 years to 35 years with SDC characterized by recurrent VOCs 
• 94.1% VOC-free for at least 12 consecutive months
• 18.7-month mean duration of being VOC-free (maximum 36.5 months)  
• 100% with no VOC-related hospitalizations for at least 12 consecutive months
• Increase in total hemoglobin from an average of 11 g/dL to an average of 15.9 g/dL  
• Increase in fetal hemoglobin (HbF) from an average of 39.6% to an average of 49.6%
• Minimum clinically important difference (MCID) met for the mean change in baseline EuroQoL Visual Analog Scale (EQ VAS), the functional assessment of cancer therapy – general (FACT-G), and the bone marrow transplantation subscale of the FACT scale (BMT) scores at month six, which were sustained throughout 18 months of follow-up

The safety profile in both trials has been generally consistent with myeloablative conditioning with busulfan and HSCT, and potential off-target effects have not been detected,

In addition, the following phase 3 trials are ongoing:

1. CLIMB-141: patients aged 2 years to 11 years with transfusion-dependent beta-thalassemia characterized by recurrent VOCs
2. CLIMB-151: patients aged 2 years to 11 years with SCD characterized by recurrent VOCs
3. CLIMB-161: to support expansion of the company’s manufacturing footprint after initial potential approval and launch; patients aged 12 years to 35 years with either transfusion-dependent beta-thalassemia or SCD characterized by recurrent VOCs

Participants in the CLIMB-111, 121, 151 and 161 trials have also been asked to continue in CLIMB-131, a long-term follow-up trial of up to 15 years for continued safety and efficacy evaluations.