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"Escaping" the European market, the commercialization of gene therapy

 Last Update: 2022-11-05
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In the past two months, Bluebird Biologics has launched two gene therapies in the United States, and the price has been rising all the way, reaching a maximum of $3 million
.
Affected by this, the sluggish stock price of Bluebird Bio has finally improved
a little.

However, it is worth noting that both Skysona and Zynteglo have previously been approved in the European market, but commercialization is not ideal
.
Last year, due to the failure of negotiations with the payer and other factors, Bluebird Bio decided to withdraw from the European market and switch to the United States
.
Bluebird's plight is not unique, and the data shows that many gene therapy manufacturers have also suffered setbacks
in the EU.

In this article, Research The Partnership reviews why the commercialization of six approved gene therapies in Europe over the past few years has not been smooth and shares feedback
gathered from its payment network on the outlook for market access for gene therapies in Europe.

2022 is a record year?

In January, the State of the Cell and Gene Industry Brief, from the Alliance for Regenerative Medicine (ARM), designated 2022 as a record year
for gene therapy approvals for rare diseases.
But that didn't happen
.
As of September, only three gene therapies on the ARM list have been approved by the EMA, three of which are expected to hit the market
in 2023.

、

Gene therapies are complex and expensive
to develop, manufacture, and deliver to patients.
Gene therapy is associated with high material costs, so a price
that reflects the value of its treatment is required.
For ultra-rare diseases, the small number of patients benefiting means that high prices are required to ensure profitability, and achieving this has proven challenging
.

While the industry is still actively developing advanced therapies (including gene therapies) in the field of rare diseases, including blood and eye diseases, there is a growing trend towards a shift away from the entire advanced therapy sector towards more general diseases
.

According to ARM, of the 2405 clinical trials of advanced therapeutics, including industry and academic/government-funded studies, only 59 percent of the subjects studied were diseases
defined by ARM as "common.
"

Gene therapy "bumps" on the road

The latest positive news about gene therapy is interspersed with a series of "again" moments
.

In July 2022, the decision of the Italian non-profit Telethon Foundation Strimvelis for adenosine deaminase severe combined immunodeficiency (ADA-SCID) once again highlighted the economic challenges
of commercializing gene therapies for an ultra-rare disease.
Current licensee Orchard After Therapeutics opted out of the project due to lack of economic viability, the Foundation decided to take sole responsibility for the commercialization
of Strimvelis.

The chart below shows the tortuous history
of cell and gene therapy in the European market.

Prior to the development of Strimvelis, U.
S.
Bluebird Biologics made a high-profile decision to halt operations in Europe due to the company's failed
two-year negotiations with reimbursement authorities over its β-thalassaemia gene therapy Zynteglo.

Zynteglo's failure to obtain proper value recognition and the inability to identify a commercial partner led the company to withdraw its marketing regulatory license
for Skysona, a brain and adrenaline leukodystrophy (ALD) gene therapy in Europe.
Skysona is the only gene therapy
approved by the EMA in 2021.

When the Telethon Foundation stepped in to save Strimvelis, it echoed the thoughts of many developers, saying that given the uniqueness of gene therapies compared to traditional drugs, scientific advances have not yet matched
the full development of the regulatory, market access process for gene therapies.

Gene therapy faces a range of evidence generation challenges, including uncertainty about the size and duration of treatment effects, poorly defined patient populations, limitations on trial duration and size, and reliance on
single-arm trials and surrogate endpoints.

The challenges associated with the value of representation make Research The Partnership is curious
about the readiness of health technology assessment (HTA) agencies and payers to respond to the impending influx of gene therapies with inherently high list prices.
From Research Across Partnership's global network, researchers contacted seven payers with gene therapy expertise from the UK, France, Germany, Spain and Italy to solicit their views
.

When asked about the readiness of their country's pricing and compensation (P&R) system, most payers believe they are prepared
to some extent.
This level of preparedness, in part, has to do with its awareness of the importance of collecting real-world evidence (RWE), which can resolve uncertainty
of evidence at launch.

Respondents generally felt that RWE had a certain importance
.
However, a French payer stressed that it depends on the target and context
.
Haute Autorité de santé's, a French health consultancy The latest evaluation of gene therapies (HAS's) requires RWE to collect as part of the re-evaluation, including monitoring data as part of an
early access program.

German payers noted that the German Federal Joint Commission (G-BA) selects certain EMA conditionally approved products and orphan drugs, i.
e.
products
that must be part of mandatory RWE data collection registration.
While only selected products are expected, the registration requirements are intended to help overcome the uncertainty caused by insufficient evidence at the
time of listing.
After the first test case, Zolgensma, which treats spinal muscular atrophy, and Roctavian, which treats hemophilia A, are the next gene therapies
to receive registration.

The impact of Zynteglo's exit from Europe

Most payers interviewed expect Zynteglo's challenge to have a moderate to high negative impact
on future P&R evaluations of other gene therapies.

Only three respondents, two of them from France, don't see the move as having an impact
.
A French payer stressed that HAS is granted to Zynteglo for patients over 12 years of age to under 35 years of age Grade III Clinical Improvement (ASMR) rating
.
This means it is well positioned to obtain a high price from the French Council for the Economy of Sanitary Products (CEPS) until negotiations cease
due to the withdrawal of marketing authorization.

German payers believe that Zynteglo's list price is 1.
575 million euros, which is one of
the main reasons for the company's commercial failure.
During the proceedings before the arbitration committee of the German Pharmaceutical Market Reform Act (AMNOG), this price was unreasonable
considering that the cost of blood transfusion per year was very low.

The arbitration committee met after Bluebird Biotech was unable to agree with the German National Association of Statutory Health Insurance Funds (GKV-SV) on the final compensation price
.
According to the European Federation of Pharmaceutical Entrepreneurs (EUCOPE), it is not G-BA's fault, but the GKV-SV's hard line
in not recognizing performance-based guarantees.

Annuity payments have landed in some areas

There has been quite a bit of discussion about innovative payment models to better reflect the value of gene therapy, but the amount of discussion has not matched
implementation.
Finding a way to truly realize their value and overcome uncertainty remains challenging
.

With the influx of more gene therapies, compared to the other models listed in the table below, Research Payers surveyed by the Partnership are more open to the following models, including outcome-based payments (non-annuities), annuity payments (results-based), and price-quantity agreements
.

The outcome-based pay-out (non-annuity) model has been used in Germany by the Individual Disease Fund for gene therapies
commercialized to date.
At the GKV-SV level, it is more common to use one-time payments
for products developed for evidence through mandatory registry data collection.

In Germany and France, annuity payment (outcome-based) models are becoming possible, which will allow the high upfront costs of gene therapy to be spread over
many years.

As of March 2022, there was a debate
in Germany over the revision of the GKV-FKG Act 2021 for the high-cost treatment risk pooling mechanism (the incentive to remove installment contracts).
In France, the CEPS-LEEM framework agreement, introduced in March 2021, includes contract amendments, which may achieve assessed payments within a few years, but these amendments have not yet been implemented into
legislation.

The importance of developing cross-border corridors

In addition to national market access challenges, especially in ultra-rare areas, manufacturers must also go through the EU's cross-border reimbursement route
.
Under this pathway, EU citizens are entitled to access health care in any EU country and be reimbursed for medical expenses
by their home country.

Due to the complexity of patient management and the clinical expertise required, this pathway is becoming a key market access route for products treating serious genetic and ultra-rare diseases, for which quality centers
of expertise are often required.
Despite Brexit, in February 2022, Orchard announced that patients would be able to access their gene therapy Libmeldy
from centres in the UK, one of five in Europe, using a cross-border route.

Although pharmaceutical companies like Orchard are using this framework, the industry believes it is not suitable
.
The key hurdle is the complexity and opaque discretionary approval process, especially for products
that do not have good P&R results in the patient's home country.

The industry seems to need better planning
.
In Research Only two of the seven payers in the Partnership's study (Germany and France) said their countries were well prepared
to manage the pathway.

Interestingly, the EU's new joint clinical evaluation is scheduled to begin evaluating advanced therapies in 2025, but payers interviewed do not expect this to help cross-border pathways reach their full potential
.
One French payer said this was because P&R decisions would continue to be made
nationwide.

A mindset shift that requires a policy response

In terms of cross-border considerations, the pharmaceutical industry needs to continue lobbying for greater transparency and understanding in order to streamline guidance on gene therapies for rare diseases as an alternative market access route
.
While preparing for the 2025 EU HTA advanced therapy milestone is critical, national P&R decisions will continue to dictate the commercial fortunes
of gene therapies.

Strimvelis' case also highlights the need for a policy environment to support progress
in gene therapy for rare diseases.
This is inseparable from an awareness of the economic challenges in the sector, which have an impact
on pricing.
Importantly, the promise of gene therapy can be met in rare disease indications, although the ultimate value may depend more on indications
for common diseases.

In the pursuit of these indications, the commercialization of gene therapy represents an "extreme storm" as the issue of economic sustainability becomes acute
.
Research In addition to the potentially high budget impact, the unmet need for diseases such as β-thalassemia and hemophilia is no higher
than spinal muscular atrophy treated with the "sky-high drug" Zolgensma.
In addition, in this case, the price of the control drug is usually much
lower.

This means that HTA agencies and payers will continue to demand more data to justify reimbursement for such gene therapies
.
Therefore, as highlighted by a survey in the UK, it is important
for pharmaceutical companies to seek early feedback on data requirements and expectations from these stakeholders.
This feedback should cover a range of areas, including clinical trial design, economic modeling programs, additional data collection requirements, and appropriate payment models
.

To improve HTA/P&R results at startup, it is critical to strengthen the evidence generation program to show potential lifetime durability and capture additional value elements
.
A commitment to the long-term and continuous submission of post-marketing data, follow-up pivotal clinical trial data, and RWE collection can support this effort
.
Direct measures of health-related quality of life in clinical trials also help demonstrate improvements
in quality of life.

Ongoing education on HTA institutions and payers is necessary to change mindsets, especially when
it comes to the treatment of common ailments.
This will help increase willingness and support to pay, driving greater HTA/P&R process adjustments while reducing concerns
about budget implications, health system sustainability and administrative burdens.

Innovative payment models, such as outcome- and annuity-based models, are potential solutions to ensure that relevant data is collected to reduce long-term uncertainty about the effectiveness of these therapies on payers while providing a reasonable return on investment
.
However, the development and implementation of such a model is complex
.
Payers can also address affordability/budget impact issues by spreading their costs over several years associated with the presentation of results, but this depends on greater flexibility and legislative reform.

After receiving conditional approval from the EMA, all eyes are on how Roctavian succeeds
in the EU P&R space.

References:

References: References:

1.
Priced at $3 million! Will the world's most expensive gene therapy make Bluebird Bio take off again?

2.
Take-off: Will the price of gene therapy get higher and higher?

3.
Freehand discussion | the future path of gene therapy drug development

41.
Gene therapies for prevalent diseases in Europe – the perfect storm of economic sustainability?； pharmaphorum

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