Role of Clinical Trial Endpoints and Metrics in SCD Therapies

Biree Andemariam, MD: Let’s talk about future directions, keeping in mind the unmet needs in sickle cell disease therapeutic management. Elna, there are dozens of clinical trials ongoing in various stages of development for sickle cell disease. This is an exciting time, with lots of new pathways, targets, and mechanisms of actions that we’re only beginning to consider. They’re super-exciting, including potentially curative gene therapy. As you think about the clinical trials underway and novel agents that may be ready for prime time for prescribing in the near future, I want to ask you about 2 things. In terms of clinical trial data, how important is longevity of data when thinking about new and emerging therapies? What are the clinical trial end points that you think are most important to be investigated?

Elna Saah, MD: When you’re looking at disease-modifying agents, the longevity of the data is a little different, and the end points that matter will also be different. The disease-modifying agents aren’t curative. We’re kicking the can down the road. We’re trying to not only increase longevity of the patients but also improve the longevity of their end organs. Adding end points [can help] assess end-organ damage: renal, microalbuminuria, cardiac, pulmonary hypertension, neurological pain. The FDA had papers in the past couple of years looking at clinical end points of trials and also biomarkers validating those. They have to incorporate the longevity of the data. We saw this with the voxelotor studies, in which the end point was no longer the number of VOCs [vaso-occlusive crises] or pain. The BABY HUG hydroxyurea study also showed that we were looking at splenic function and the validating effect of modifying the disease. In the voxelotor studies, they looked at rising hemoglobin as an end point. Beyond that, when patients feel better, and you get the hemoglobin [level], you’re not treating a number while looking at a patient. Are there organs that we can follow like they did in the BABY HUG hydroxyurea study. Are we looking at renal function? … Are we looking at circulation markers? Are we looking at oxygenation? How do we incorporate these other biomarkers? Are we going to follow them?

Part of what the studies are incorporating—the FDA is mandating them because most of them are fast-tracked to approval—is a lot of real-world evidence and long-term follow-up. In some of these patients, it takes 5, 6, 7 years to monitor their organ function and see if there’s any difference. If there’s any preservation, we won’t be able to do it because it’s not a randomized study. The longevity is important. How long are we able follow these patients and report on their organ function over time? Five years, 10 years, decades? Once we add the combination, does that make a difference?

When it comes to curative therapies, we had the recent report last February of secondary-malignant neoplasms in patients treated with gene therapy who had sickle cell disease but not thalassemia. How long does the FDA require them to be followed? I think it’s 13 years…. Ten to 13 years makes sense because from oncology treatments for solid tumors with secondary-malignant neoplasms, we know that you have those that occur within the first 5 years and others that tend to be a little later. The accumulating agents will show up at 10 years.

Declaring victory will not be possible until you follow these long patients. If you did gene therapy on a patient at 5 years, you’d follow them for 10 years, until it’s 15 years. Also, from the front end, we’re doing biological studies to understand the propensity for people with sickle cell disease. Do they have increased malignancy risk? Are they hematopoietic clonal proliferation in term of significance? How much of these clones are bystanders? How many are significant? If you add chemotherapy, does that increase the conversion rate? Adding all this, we need long-term data 5 to 15 years to analyze the risk better.

Transcript edited for clarity