Zolgensma’s “Day One” programme—an intriguing new venture for managed entry in Europe

Managed entry in Europe has taken a fascinating new turn with the launch of the “Day One” patient access programme for Zolgensma, a high-profile new gene therapy for spinal muscular atrophy (SMA). The drug, marketed by AveXis (a subsidiary of Novartis), received conditional approval in the EU on 19th May 2020.

The “Day One” access programme has been designed to align the cost of treating patients before national pricing and reimbursement agreements have been negotiated with value-based prices based on HTA. The programme includes a range of customisable options:

• Retroactive rebates
• Deferred payments and instalment options to manage initial budget impact
• Outcomes-based rebates that can be backdated to patients treated during the early access period
• Training for healthcare professionals on the administration of the therapy and follow-up care
• Access to a global registry of SMA patients that is linked to national registries

AveXis has reportedly met with more than 100 stakeholder organisations across Europe to ensure the "Day One" programme is compatible with payers’ pricing and reimbursement frameworks and can be tailored to individual markets.

The company has not disclosed its targeted pricing in Europe. Zolgensma made headlines in 2019 for its US list price of $2.1 million, and the treatment costs approximately $1.55 million in Japan, where it was approved in March 2020.

By way of shaping the pricing debate in Europe, AveXis has publicly stated that the estimated cumulative healthcare costs of managing SMA in just the first ten years of a child’s life are in the range €2.5-4 million per patient. The company has also indicated that Zolgensma has a value of €1,945,000.

Encouraging prospects in France, Germany and the UK

Zolgensma is already available in France under an autorisation temporaire d’utilisation (ATU) cohorte (cohort temporary authorisation for use) that took effect on 25th May 2020. The ATU system is one of the most highly structured early access programmes in Europe and offers manufacturers the significant benefit of covering therapy costs (up to a maximum of €10,000 per patient per year and overall expenditure of €30 million).

In Germany, Zolgensma will be available from 1st July 2020. A statement issued by AveXis in Germany reveals that “several contracts have been concluded for success-based reimbursement models that take into account the special features of gene therapy for one-time application. These models take into account various outcome parameters relevant to the patient. AveXis assumes the risk of paying back up to 100% of the drug costs on a staggered basis.” These contracts are presumably with Krankenkassen (health insurance funds), either individually or in groups.

It should be noted, however, that the Krankenkassen, the Gemeinsamer Bundesausschuss (GBA; Joint Federal Commission) and the Verband der Universit?tsklinika Deutschlands (VUD; Association of University Hospitals of Germany) have previously criticised Novartis for what they described as an “unprecedented media campaign” on physicians and payers to use Zolgensma. In a letter sent to Jens Spahn in November 2019, they expressed concern that recent experiences with Zolgensma could be a “blueprint” for marketing other high-priced drugs in Germany before they are licensed in the country. The writers warned that such a development would risk compromising the GBA’s early benefit assessment process, as well as pricing negotiations with manufacturers.

In the UK, AveXis began discussions in 2018 regarding Zolgensma’s eligibility for NICE’s highly specialised technology appraisal programme. Being evaluated by this method, instead of the standard technology appraisal process, would have a number of advantages—not least, that the drug would potentially benefit from an incremental cost-effectiveness ceiling of ￡100,000-300,000 per quality-adjusted life year (QALY) gained, instead of the usual threshold of ￡20,000-30,000.

AveXis will likely have high hopes of striking a deal with the NHS for rapid access to Zolgensma. In September 2018, Novartis concluded a commercial access agreement with the NHS for its CAR-T-cell therapy Kymriah (tisagenlecleucel) less than 10 days after the drug received marketing authorisation—described by NHS England as “one of the fastest funding approvals in the 70-year history of the NHS.” The company will also be encouraged by the knowledge that the NHS negotiated a managed access agreement with Biogen for Spinraza (nusinersen), another treatment for SMA, in May 2019.

Implications for managed entry in Europe

AveXis’s strategy is particularly fascinating when seen against the backdrop of a high-profile product launch in the midst of the current COVID-19 pandemic. Given the risk of significant delays to HTA and pricing and reimbursement negotiations, the promise of a programme that can be implemented on “Day One” may prove appealing.

It will certainly be interesting to see if AveXis’s proactive approach—taking the initiative to offer retroactive rebates, instalment payments, outcomes-based rebates and a global product registry—will stimulate greater interest in managed entry agreements (MEAs) among payers. Historically, the picture has varied enormously across Europe in recent years.

Italy has long been in the vanguard of managed entry, thanks in large measure to its network of online registries. Interestingly, however, the use of “payment by results” has declined sharply recently, as have the savings that the health service derives from such agreements. Instead, Italy has focused increasingly on appropriate prescribing agreements and caps on expenditure.

The UK began experimenting with outcomes-based agreements (OBAs) as long ago as 2002, when the Department of Health negotiated a risk-sharing scheme with four manufacturers of disease-modifying multiple sclerosis therapies, followed by several more high-profile OBAs in the following years. However, the cost and burden of administering OBAs prompted a decisive swing away from such deals to simple discounts for many years. More recently, however, the NHS has expressed interest in negotiating a broader range of MEAs, including OBAs and coverage with evidence development.

In Germany, the industry is accustomed to negotiating voluntary rebate contracts with Krankenkassen but has limited experience of OBAs. However, there has been a spate of activity in the last couple of years, including pay-for-performance agreements for Merck KGaA’s Mavenclad (cladribine), Novartis’s Kymriah and Kite Pharma’s Yescarta (axicabtagen-ciloleucel). In January 2020, Bluebird Bio launched Zynteglo (autologous CD34+ cells encoding βA-T87Q-globin gene) in Germany, the first market in the world for this gene therapy. The drug is a one-time treatment for transfusion-dependent β-thalassaemia (TDT). The company has negotiated value-based payment agreements with multiple Krankenkassen: an initial payment will be made at the time of infusion, with the four additional annual payments due only if the patient subsequently requires no transfusions for TDT.

Notwithstanding these deals, Wolf-Dieter Ludwig, the Chairman of the influential Arzneimittelkommission der deutschen ?rzteschaft (Akd?; Drug Commission of the German Medical Association), believes pay-for-performance deals make sense only for very expensive drugs that have limited evidence at launch on account of accelerated marketing authorisation—principally, orphan drugs, cancer therapies and biologics. Antje Haas, the head of the medicines and therapies department at the GKV-Spitzenverband (National Association of Statutory Health Insurance Funds), predicts “we won’t have P4P contracts for every drug. We will focus on the particularly important medicines whose effects can be measured relatively easily and unambiguously. We cannot push the complexity of measuring and classifying success, or data transfer, into the realms of the unquantifiable. We are feeling our way in this world.”

Spain was a relative latecomer to managed entry, with much of its early activity at the regional, or even local, level. In recent years, however, there has been an increase in risk-sharing agreements. For example, in February 2018, Biogen concluded a risk-sharing deal for Spinraza with the Spanish Ministry of Health. Spain intends to use its Sistema de Información para determinar el Valor Terapéutico en la Práctica Clínica Real de los Medicamentos de Alto Impacto Sanitario y Económico en el SNS (VALTERMED; Information System for Determining the Therapeutic Value in Real-World Clinical Practice of Medicines of High Health-Related and Economic Impact in the NHS), an online registry system for the collection of real-world data, to gather outcomes data to support at least seven new OBAs.

If initiatives such as AveXis’s “Day One” programme can secure earlier access to high-priced advanced therapy medicinal products, other companies are sure to take note. Of course, OBAs are not suitable for all new drugs, but they could offer hope—particularly when combined with instalment payments—of overcoming the formidable obstacles to reimbursement for the growing number of curative therapies that will reach the market in the coming months and years.