Approved SCD Therapies Too Costly, ICER Watchdog Group Says

The Institute for Clinical and Economic Review (ICER) says three recently approved therapies for managing sickle cell disease (SCD) are too costly based on early assessments of their effectiveness, and is recommending their prices be lowered.

In a new evidence report, the independent watchdog agency on drug pricing focused on the clinical benefits and cost-effectiveness of Novartis’ Adakveo (crizanlizumab) and Global Blood Therapeutics’ Oxbryta (voxelotor), while also considering Emmaus Life Sciences’ Endari (L-glutamine).

The three “new” therapies — Adakveo and Oxbryta were both approved in 2019, and Endari in 2017 — are the first in many years to provide new alternatives for treating the inherited blood disorder and improving patients outcomes, ICER noted.

Previously, treatments for SCD were limited, primarily to hydroxyurea, a cancer medicine that reduces the frequency of pain crises and the need for blood transfusions. Transfusions and stem cell transplants were used to fight anemia and ease painful vaso-occlusive crises (VOCs), but they did not treat the causes of the disease. Now, the new therapies offer “important options for patients,” ICER said.

Endari, the first to win U.S. Food and Drug Administration approval, reduces oxidative damage in red blood cells (RBC), increasing their flexibility and ability to transport oxygen.

Adakveo is a monoclonal antibody against P-selectin, an adhesion protein found in platelets and endothelial cells, which line the inner surface of blood vessels. Blocking this protein helps reduce the adhesion of sickle-shaped RBCs and prevents them from blocking small blood vessels. Meanwhile, Oxbryta binds to hemoglobin and increases its ability to bind to oxygen, thereby reducing the clumping of hemoglobin molecules that ultimately lead to the sickling of RBCs.

“Patients and families in the sickle cell community have been without new treatment options for decades, so it is a welcome challenge to be reviewing three new drugs for this condition,” Pamela Bradt, chief scientific officer of ICER, said in a press release.

“Our report analyzes the evidence, which remains relatively short-term and presents difficulties for estimating how much clinical benefit will be realized by patients in real-world practice,” she said.

The research organization’s findings were encouraging for the three therapies’ clinical benefits, but called for cost-cutting on the prices of the two newer treatments. A budget impact analysis was not done on Endari as it already has been on the market for several years.

“Even under favorable modeling assumptions, however, and benefitting from new data from patients and a curated real-world evidence database, the list prices set for crizanlizumab and voxelotor appear too high to align fairly with clinical benefits,” ICER said in the release.

ICER’s evidence report explored and rated the outcomes of clinical trials that tested each one of these three therapeutic options for people with SCD.

Data on Adakveo from the Phase 2 SUSTAIN trial (NCT01895361) showed that acute pain crises dropped from a median annual rate of 2.98 to 1.63, compared with a placebo. This decrease suggests that Adakveo reduces the risk of acute crises by 50%, ICER said.

Despite this improvement, no statistically significant changes were detected for the annual hospitalization duration.

“The difficulty in estimating the amount of longer-term organ system benefit conveyed by the absolute reduction in acute pain crises, coupled with uncertainty about long-term safety, gives us only moderate certainty overall in the magnitude of net health benefit, which seems likely to range from small to substantial,” ICER’s report stated, giving the therapy a B+ rating.

Oxbryta was tested in the Phase 3 HOPE trial (NCT03036813). The results showed that Oxbryta increased hemoglobin levels and reduced hemolysis (RCB destruction), compared with a placebo. However, no reductions in the incidence of acute pain crises were reported. Overall, experts believe more data on Oxbryta is needed.

“Given that we cannot determine the magnitude of the clinical benefits but feel they are likely to be somewhat greater than usual care, we have assigned a rating of ‘Promising but Inconclusive’ to the comparative clinical effectiveness of voxelotor at this time,” the experts said in the ICER report.

Data from a Phase 3 trial (NCT01179217) testing Endari showed there was a reduction in the median number of acute pain crises compared with a placebo (3.0 versus 4.0). However, in that particular study, a large portion of the patients withdrew from the trial. As such, ICER found the comparative clinical effectiveness of L-glutamine to also be “Promising but Inconclusive.”

Moreover, ICER experts noted that neither Adakveo nor Oxbryta showed improvements on patients’ quality of life and that the trial on Endari did not study that outcome. At this point, ICER said, it was not able to assess the long-term safety profile of the three treatments.

Taking into consideration the clinical outcomes of these trials, along with real-world evidence provided by patients and the health sector, ICER modeled the cost-effectiveness of the three  treatments. Its conclusion was that, in general, the prices were too high for all three.

“At current prices, only 21% of patients could be eligible for Adakveo and 16% to Oxbryta,” the report specifically noted.

To ensure that the costs match the clinical benefits for patients, ICER recommends that prices be lowered.

“The aggregate benchmark range for crizanlizumab of $16,900-$52,000 would require a 61-89% discount off the treatment’s $132,000 annual list price,” the report said. “The aggregate benchmark range for voxelotor of $8,300-$36,500 would require a 71-93% discount off the treatment’s $127,000 annual list price. Finally, the aggregate benchmark range for L-glutamine of $9,900-$33,400 would require an 18-76% discount off the treatment’s $40,540 annual list price.”

“Our report takes an objective look at the evidence while highlighting that insurers and other policymakers must be fully aware of the broader clinical and social perspectives when developing prior authorization coverage criteria and negotiating prices with drug makers,” Bradt said.

ICER’s evidence report, released on March 12 can be found at its website. Additionally, ICER also made available public comments from patient groups, clinicians, pharmaceutical companies, and other stakeholders.

The report’s conclusions has been slated for review at an upcoming meeting of the New England Comparative Effectiveness Public Advisory Council (New England CEPAC). However, due to the COVID-19 pandemic, all ICER Public Meetings have been postponed. An updated tentative timeline will be available on the ICER website in the coming days.