Increasing Confidence in Emerging Therapies

Biree Andemariam, MD: I want to open this question to the panel a bit more. This is worth a discussion in terms of longevity of the data we have in front of us when making clinical decisions with patients on new agents or even recommending clinical trials. I wonder what your feelings are, Nirmish and Matt, about longevity of data and the end points in clinical trials that Elna [Saah] outlined so well for us.

Matthew M. Heeney, MD: That’s always a question. We need brave participants in trials to help us move the field forward. There’s no promise of good longevity of efficacy, but our hope is that there will be. As Nirmish spoke about earlier, we need to use the medications that have recently been approved and use them in different settings to balance the incredible pressure—because of the unmet need—to approve drugs early. But we want to make sure they’re effective. We still need ongoing investigations of current drugs.

In the terms of the curative approaches, Elna is correct. For some of these experimental approaches, like gene therapy, there are requirements for decades of follow-up in patients. That’s appropriate too because we don’t know the long-standing effects of genetic modification. I find it very important to have end points that are relevant to patients.

One of the biggest challenges with oxygen dissociation curve-shifting agents is that by increasing your hemoglobin by 1 g/dL, you may improve mortality years from now. It’s extremely difficult to explain to a 14-year-old that taking this medicine every day makes you different from everyone else, but it makes you live a little longer. Every 14-year-old thinks they’re going to live forever. It’s hard to explain to persuade them to be adherent to their medication when they don’t see any meaningful symptom reduction. We have to have some mix of immediate benefit that the patient can hopefully recognize—even that’s challenging in my age group —but also some promise of future benefit in terms of the protection from end-organ damage we described.

In case of curative, what does cure really mean? The cessation of that accumulation of end-organ damage and the cessation of acute complication. It’s a tough balance to get effective medicines to people quickly and safely, not only immediately but also in the long term.

Nirmish Shah, MD: We need to be real with patients about the data. To Matt’s point, we have a certain amount of data, and this is all I can speak to. Patients are coming to us and asking about gene therapy. They want a cure, and rightfully so. But even if there’s approval the end of this year or next year for sickle cell disease, as Elna brought up, we have only 2 years of data for about 20 patients. Based on the California registry and the UK registry, patients with sickle cell disease have an increased risk of hematologic malignancy at baseline.

If you look at data coming out of the University of Illinois Chicago, patients with sickle cell disease who get chemotherapy for any reason have an increased risk for complications. It’s not surprising that you give chemotherapy to a hyperplastic marrow and sickle cell disease. As a comparator, patients with β-thalassemia aren’t having this. They’re being transfused their whole life. Their marrow is in a very healthy state. We need to be very clear with patients that this is what we know. Then [we need to] make that decision with the patient, based on the data, about what we recommend as the next step. We’re having a great conversation there are many research studies going on right now. We’re thankful that our patients are trying to push this ahead. We’re starting to get to the point that I have almost too many studies and I have to triage the next best thing to evaluate in a research study for my patients.

Biree Andemariam MD: That’s where the ongoing post approval setting studies are important, because they look at the real-world evidence of approved agents. And this is very much so in gene therapy. We don’t know what the long-term durability of gene therapy is going to be beyond first patient on study. It depends on how long it’s been that they’ve received treatment. Those are going to be key to watch and support to get data for the long term.

Transcript edited for clarity