Rapid Approvals & Innovative Approaches, But Which Sickle Cell Therapies Will Offer Real Benefits?

Sickle cell disease (SCD) currently effects 100,000 patients in the US and about 1 in every 365 Black or African-American births; historically unmet need has been incredibly high with only a narrow selection of largely ineffective therapies available. November 2019 however sees a changing of the tide for sickle cell patients with FDA approvals of Novartis’ Adakveo and GBT’s Oxbryta, both of which were granted heavily expedited review processes in acknowledgement of the necessity of new treatments.

Vasco-occlusive crises (VOCs) are amongst the most severe manifestations of sickle cell disease - these acute episodes in which sickled red blood cells obstruct blood vessels are incredibly painful for patients and result in hospitalization and irreversible organ damage. Whilst by no means the only issue at hand, VOCs are highly feared by both patients and payers alike.

Novartis score clear win against VOCs
It is these VOCs which Novartis look to target with its anti-adhesion antibody approach. Adakveo (crizanlizumab), the first of the assets approved this November, demonstrated in the Ph2 SUSTAIN study, a reduction in VOCs leading to health care visits by 45.3%. Significantly for payers, a 42% reduction in hospitalisation visits was also demonstrated. In light of the unmet need, this Ph2 data was deemed sufficient to support US regulatory filing.

Whilst the monthly IV dosing regimen may appear as a significant increase in treatment burden (aside from for those minority of patients receiving chronic transfusion), payers can be expected to look favourably on Adakveo, given its demonstrated ability to reduce number of costly SCD associated hospitalization days. Similarly, adoption of Adakveo has potential to reduce the use of chronic blood transfusion as VOC prophylaxis in more severe patients: This would be seen favourably in health economics analyses, not only in terms of transfusion clinic hours, but also by removing reliance on therapies addressing iron-overload issues associated with chronic transfusion. From a patient’s perspective, in addition to preventing organ damage, the promise of avoiding traumatic VOCs will be a significant draw that has been long awaited.

Is the true benefit of GBT’s Oxbryta yet to become clear?
GBT’s once daily oral agent Oxbryta (voxelotor) has been shown to bind to hemoglobin, increasing its affinity for oxygen and preventing sickling of red blood cells. The agent was granted subpart H accelerated approval based on its ability to raise hemoglobin levels (51% of patients in the Ph3 HOPE study high dose arm, achieved a >1 g/dL increase) and on the understanding that the company would subsequently provide confirmatory transcranial doppler data demonstrating reduced risk of stroke, in order to get the final stamp of full approval.

The oral dosing profile is the asset’s clear win within the current space. SCD patients will typically have direct experience of QD oral medication via hydroxyurea therapy, therefore Oxbryta requires little change of habit. As it stands, the oral convenience of Oxbryta is where the clearly demonstrated benefits end.

Whilst its ability to increase on hemoglobin levels is clear, it is difficult to directly correlate this with real clinical or quality of life benefits to SCD patients, with GBT showing no statistically significant effect on VOC rate in the Ph3 HOPE study. Whilst the company claim the study was not powered to show such a result, the in-licensing by GBT of for P-selectin inhibitor inclacumab, (loosely comparable to Adakveo) from Roche, indicates a lack of confidence in Oxbryta ever scoring against VOCs.

It is important to acknowledge that the increased hemoglobin will be sickled globin, potentially with a reduced ability to release its oxygen payload due to the drugs action. This has therefore raised questions about the suitability of transcranial doppler as a confirmatory endpoint – yes the blood is flowing, but is it doing what it needs to do? From a payer perspective, it may therefore be difficult to justify the increased cost of Oxbryta over Adakveo ($125k vs $85k-113k annually), especially in light of GBTs lack of efficacy against costly VOCs.

It therefore appears that there may more work to be done, beyond the confirmatory study, before GBT can fully convert its effort. Whether this be through organised post-marketing studies or through real world use demonstrating benefit beyond the currently available figures, it will ultimately be this which determines if Oxbryta can get close to generating the lofty $1.5bn in 2024 as forecast by Evaluate, or if GBT will be left hoping.

The performance of front runners will impact appetite for gene therapies
Whilst both these treatments have the potential to be very significant to many patients, they fall short of the promises made by the gene therapies (GTs), which look to enter the space in the coming years. A broad selection of GT approaches are currently under investigation, including from Bluebird who look to transfer lentiviral success from beta thalassemia into SCD, and Vertex who recently reported data from the first human Crispr/Cas9 trial. Dispute this innovation, these more conventional therapies may still have a hand to play in determining the uptake of their one-time administration successors.

For the first time, the two recent approvals may enabled patients and stakeholders to have a degree of choice of treatment options. The diversification of available therapies can be expected to sway individual risk reward analysis of undergoing gene therapy, (which currently convey appreciable risks associated with the myeloablative conditioning required), by conveying differing strengths and weaknesses to patients and stakeholders. Whilst the search for a sickle cell panacea goes on, movement towards a situation where different therapy options can be selected from, to suit different patients’ lives, will represent a real sea change from the therapeutic doldrums gone by.