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Novel Biologic Therapies for Sickle Cell Disease Management


Neil B. Minkoff, MD: There’s a biologic also in development. What can we say about that?

Ahmar U. Zaidi, MD: The biologic right now that’s in development is a medication called crizanlizumab, which is being made by Novartis. Crizanlizumab is just starting phase 3 trials now, but the phase 2 trials showed quite a significant reduction in vaso-occlusive episodes. And the way that crizanlizumab works basically is that it targets adhesion molecules, which we call selectins, in particular P-selectin, which is almost like a scaffold on endothelium. It’s like a magnet on endothelium that attracts white blood cells, and it also is expressed on platelets. And as we discussed earlier, the vaso-occlusion is very multifaceted in the players that contribute to the occlusion.

So this monoclonal antibody was developed, and as we were discussing, in the phase 2 trial showed tremendous reduction in just under 100 patients, again randomized-controlled trial, placebo-controlled. They showed that not only did they reduce the amount of pain, they also significantly reduced the time to the first pain crisis and the time to the second pain crisis. So it’s quite exciting.

Neil B. Minkoff, MD: Was that in addition to the standard of care they were already on?

Ahmar U. Zaidi, MD: Correct. Again, about two-thirds of those patients were on hydroxyurea.

Neil B. Minkoff, MD: And where would you anticipate the use of this in a practice setting?

Ahmar U. Zaidi, MD: This is a molecule that is being explored as a prophylaxis, so this is an infusion patients would get once a month for several doses to prevent pain from coming. I think that that is a very interesting component because it puts the adherence issue off the table. Because this is something that patients have to come into the clinic to receive an infusion or to an infusion center. And that takes away the daily need to have to open a bottle and take a pill.

Neil B. Minkoff, MD: Also in our discussion here looking at what’s coming down, there was the recent RESET trial.

Ahmar U. Zaidi, MD: That’s right.

Neil B. Minkoff, MD: Could you talk a little bit about what was involved in that?

Ahmar U. Zaidi, MD: Sure. The RESET trial explored the efficacy of a molecule called rivipansel, which was a pan-selectin inhibitor, again focusing on the adhesion molecules that work as magnets to pull together these components of vaso-occlusion. And that molecule was being trialed in patients who were having pain, inpatient. So it was an infusion for patients who were admitted in the setting of pain who were getting opioids. In the phase 2 trial, what they looked at was the time it took for readiness to discharge, and they also looked at the cumulative opioid use. The phase 2 trial showed trends that looked favorable but not necessarily statistically significant. They tried to address that in the phase 3 trial, and just recently we found out that they were unable to meet their primary endpoint in the phase 3 trial. Hopefully, we’ll get more information about where we went wrong with rivipansel.

Neil B. Minkoff, MD: My understanding is there’s 1 other drug in the pipeline that’s getting a little bit of attention.

Ahmar U. Zaidi, MD: Yes, absolutely. We discussed a little bit about the role that platelets may play in vaso-occlusion. People started investigating the role of antiplatelet therapy. The medication being examined by AstraZeneca is called ticagrelor. This is a medication often used in patients with coronary artery disease and works by essentially inhibiting ADP [adenosine diphosphate]-mediated platelet aggregation. This trial is also going now into a phase 3 with some promising phase 2 results. We have had an antiplatelet agent that was assessed in what we called the DOVE trial, and this was called prasugrel. And prasugrel was unable to achieve the meeting of endpoints in its trial. We hope we have a different result with ticagrelor.

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