ICER Publishes Evidence Report on Therapies for Hemophilia A

— Emicizumab assessed as providing comparable or better clinical benefits when compared to common current dosing levels of prophylactic factor VIII; it is also cost-saving but only because factor VIII prices are extremely high and have not moderated with competition —

— Review of valoctocogene roxaparvovec based on data available prior to FDA decision to request longer-term outcomes; preliminary analyses suggest that at a price of $2.5 million, valoctocogene roxaparvovec would also be cost-saving compared to the high costs of current factor VIII dosing levels; next week, ICER will add to this report supplementary analyses exploring scenarios where single-time therapies could be priced lower to share a portion of their savings with the health system —

— Expert roundtable will discuss implications of comparative effectiveness, non-clinical benefits, and long-term economic value at October 30 virtual New England CEPAC meeting —

BOSTON, October 16, 2020 – The Institute for Clinical and Economic Review (ICER) today released an Evidence Report assessing the comparative clinical effectiveness and value of valoctocogene roxaparvovec (Roctavian™, BioMarin Pharmaceutical) and emicizumab (Hemlibra®, Genentech) for the treatment of hemophilia A. In August 2020, BioMarin received a Complete Response Letter from the FDA requesting an additional two years of follow-up safety and efficacy data on valoctocogene roxaparvovec, and that process may delay the gene therapy’s US approval decision until at least 2022. ICER previously assessed emicizumab when the treatment was approved by the FDA in 2017 with an indication of treating the subset of individuals with hemophilia A who have inhibitors to the clotting protein factor VIII; reflecting emicizumab’s expanded indication in 2018, this year’s report assesses the value of the treatment in individuals who do not have those inhibitors.

“Treatments to reduce the risk of bleeds for patients with hemophilia have profoundly improved the lives of patients and caregivers,” said David Rind, MD, ICER’s Chief Medical Officer. “Recently, exciting new strategies for prophylaxis like emicizumab have become available, and gene therapies have even raised the possibility of a cure on the not-too-distant horizon. Our analysis of the evidence suggests that emicizumab is comparable to or better than factor VIII prophylaxis and does save money overall. But our report notes that this is because the prices for factor VIII, despite recombinant technologies and apparent competition in the marketplace, have not decreased, making prophylaxis with factor VIII an extremely expensive treatment required for a lifetime.

“Patients and patient groups have fought to get access to higher doses and multiple preparations of factor VIII so as to reduce the time each week that they are at increased risk for bleeding. We look forward to our public meeting at which all stakeholders can discuss the tensions created by the pricing of factor VIII options, and the extent to which the high costs for prophylaxis should drive considerations of fair pricing for treatments like emicizumab and the gene therapies that will hopefully soon be available.”

This Evidence Report will be reviewed at a virtual public meeting of the New England Comparative Effectiveness Public Advisory Council (New England CEPAC) on October 30, 2020. The New England CEPAC meeting is one of ICER’s three independent evidence appraisal committees comprising medical evidence experts, practicing clinicians, methodologists, and leaders in patient engagement and advocacy.

Register here to watch the live webcast of the virtual meeting.

A draft version of this report was previously open for a two-month public comment period. The updated Evidence Report and voting questions reflect changes made based on comments received from patient groups, clinicians, drug manufacturers, and other stakeholders. Detailed responses to public comments can be found here. Both clinical and cost-effectiveness findings for valoctocogene roxaparvovec are preliminary, due to the FDA’s initial rejection of BioMarin’s licensing application.

Key Clinical Findings

The evidence provides high certainty that emicizumab provides at least a comparable net health benefit compared with factor VIII prophylaxis at the doses now typically used in the US, but limitations in long-term outcome data provide only moderate certainty regarding whether it provides a small or substantial net health benefit. As such, in patients with severe hemophilia A without inhibitors, ICER rates emicizumab as “comparable or better” (C++) to factor VIII prophylaxis.

For valoctocogene roxaparvovec, with the data available at this time, while it provides clear clinical benefits for many patients, the durability of these benefits, the implications for disqualification from treatment with other adeno-associated virus type 5 (AAV5) therapies, and potential long-term harms such as liver disease are all uncertain. In total, therefore, we have judged that the current evidence does provide moderate certainty of a small or substantial benefit of valoctocogene roxaparvovec compared with factor VIII prophylaxis, but a small likelihood remains that further evidence will demonstrate net harm over a longer time frame. As such, in adults with severe hemophilia A without inhibitors, ICER rates valoctocogene roxaparvovec as “promising but inconclusive” (P/I) when compared to factor VIII prophylaxis.

Given the lack of head-to-head trials, along with the uncertainties about valoctocogene roxaparvovec described above, the evidence is currently “insufficient” (I) to compare valoctocogene roxaparvovec to emicizumab as treatments for adults with hemophilia A without inhibitors.

Key Cost-Effectiveness Findings

The cost-effectiveness of emicizumab in patients without inhibitors is highly dependent on which level of treatment is being considered as the most appropriate comparator. In our cost-effectiveness modeling, emicizumab was found to be equivalent in reducing bleeds when compared to factor VIII prophylaxis at the doses now typically used in the US. At this level of factor VIII use, emicizumab is cost-saving despite its own high cost because it reduces the need for even more expensive factor VIII. However, when compared instead to the effectiveness and costs of lower doses of factor VIII from earlier clinical trials, emicizumab is found to be much more effective than prophylactic factor VIII but would no longer save costs, nor would it come close to meeting common thresholds for cost-effectiveness.

Valoctocogene roxaparvovec was modeled using a placeholder price of $2.5 million and the preliminary data available at this time. At this price, when compared to factor VIII prophylaxis at the doses now typically used in the US, valoctocogene roxaparvovec would be both more effective and less expensive for adult patients with hemophilia A without inhibitors.

Given that valoctocogene roxaparvovec meets ICER’s criteria to be evaluated under our adapted methods for a high-impact single and short-term therapy, we plan to issue an updated version of this report in the next week that will contain two additional scenario analyses. In one of these scenarios, 50% of the modeled cost savings from treatment are “retained” by the health system instead of being ascribed to the therapy; in the other, cost savings from treatment beyond $150,000 per patient per year are retained by the health system.

ICER has not calculated health-benefit price benchmarks for either treatment because this preliminary analysis of valoctocogene roxaparvovec will need to be updated when the company reports longer-term safety and efficacy data requested by the FDA, and because the results for emicizumab suggest that any price lower than that of factor VIII would make it a preferred strategy.

About ICER

The Institute for Clinical and Economic Review (ICER) is an independent non-profit research institute that produces reports analyzing the evidence on the effectiveness and value of drugs and other medical services. ICER’s reports include evidence-based calculations of prices for new drugs that accurately reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall health care system.

ICER’s reports incorporate extensive input from all stakeholders and are the subject of public hearings through three core programs: the California Technology Assessment Forum (CTAF), the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC), and the New England Comparative Effectiveness Public Advisory Council (New England CEPAC). These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of health care. For more information about ICER, please visit ICER’s website.