Near-term challenges of
advanced therapy medicinal products:
a maturing product class

Regulatory Rapporteur

 

May 2024  |  Volume 21  |  No.5

 

Abstract

Advanced therapy medicinal products (ATMPs) have already played a transformational role in the lives of patients with rare diseases. However, questions do remain with regards to longevity of product effect, repeatability of dosing and manufacturing scalability. An additional challenge is the high upfront cost of ATMPs and how conventional reimbursement schemes affect ability to pay. There is a need to focus on solutions to these challenges, through ongoing studies, new gene therapy platforms, technology advances to support ATMPs manufacturing at scale, as well as alternative drug pricing models. At the end of the day, ATMPs have saved and changed lives. Taking positive steps must remain a priority so that greater numbers of innovative products can reach more patients.

Since the introduction of orphan pharmaceutical legislation which was designed to incentivise innovators to develop medicinal products for rare diseases, there has been a significant increase in the number of advanced therapeutic medicinal products (ATMPs) such as cell and gene therapies. Today, novel ATMPs are well-established for orphan indications and are gradually moving into larger indications.

As this class of therapies continues to mature, challenges are inevitably coming to the fore. And with the expansion of cell and gene therapies into therapeutic categories such as auto immune and metabolic diseases, these issues are set to become increasingly acute.

Exploring ATMPs longevity

While claims of one-and-done ATMPs to potentially cure disease are often made, the duration of therapeutic effect remains uncertain.^[1] As researchers have highlighted, repeatability of dosing is important, particularly for diseases that change over time such as in oncology where tumours can evolve to evade destruction by the immune system.^[2]

Several factors need to be considered regarding the longevity of ATMPs:

Stability of gene modification

The longevity of gene therapies will often depend on the stability of the introduced genetic modifications. Integrating vectors like lentiviruses into the host genome can provide long-term expression, particularly in long-lived cell types such as stem cells or memory T cells, while non-integrating vectors like adeno-associated virus (AAV) vectors might offer more transient expression.

A study into recombinant AAV (rAAV) vectors found a 50% decline in transgene protein expression from peak expression at 12 to 24 weeks through to 57 weeks.^[3] This suggests an associated epigenetic regulation of the transgenes.

Conversely, ongoing and long-term follow-up studies into the CRISPR-Cas9 gene editing technology exagamglogene autotemcel (Casgevy) to treat sickle cell disease show lasting effects. One study found that 28 of the 29 subjects being followed reached the primary endpoint of remaining free from vaso-occlusive crisis for a mean duration of 22.3 months.^[4]

Cell persistence

With cell therapies, the longevity of the therapeutic effect often depends on the persistence and functionality of the infused or edited cells. In chimeric antigen receptor (CAR)-T cell therapy for instance, low-level persistence of the modified T cells has been demonstrated. Nonetheless, the length and degree of persistence necessary for a durable response are unclear from the available data and could vary with different CAR constructs and malignancies. Other factors consistently associated with durable long-term remissions are depth of initial response, type of malignancy, receipt of lymphocyte depleting chemotherapy and CAR-T cell levels following infusion.^[5]

Immune responses

Key determinants of the efficacy of ATMPs are immune responses to the product. Potentially, the immune system may eliminate cells producing the therapeutic protein, causing loss of therapeutic effect and potentially leading to immunotoxicities.^[6] Since viral delivery vectors and allogenic cell therapies can limit the longevity of ATMPs, several strategies are being explored to address immune response and extend therapy longevity. In AAV-based gene therapies for example, the following strategies are either already implemented or explored:

• capsid modifications
• use of alternative AAV serotypes (with low prevalence in human populations)
• pre-existing immunity screening
• transient pharmacological immunosuppression
• plasmapheresis to remove harmful anti-vector antibodies or incorporate immune-evasion genes in the vector ^[7]
  

Broader barriers to gene therapy longevity

Over time, the promoters driving the expression of therapeutic genes may be silenced through epigenetic modifications, or transgene silencing, leading to a loss of therapeutic efficacy.^[8]

Additionally, vector dilution due to cell division can lead to a decrease in therapeutic gene expression over time, particularly in rapidly dividing cells or growing tissues. Studies have found that gradual decline of vector dilution may impact durability of recombinant AAV gene therapies, with significant variability depending on disease indication, dose, serotypes and the patient.^[9]

The ability to re-administer gene therapies is an important aspect for maintaining therapeutic efficacy over time. However, immune responses to the vector can hinder or prevent re-administration…

Therapeutic longevity can also be affected by the initial dose, route of administration and the possibility of dose titration. If the dose is insufficient but cannot be repeated, patients may be left with few other treatment options. One example is sickle cell disease where the clinical threshold is estimated to be at least 20% correction. However, if the dose falls short, the gene therapy would be ineffective through not being able to the repeat treatment.^[2]

The ability to re-administer gene therapies is an important aspect for maintaining therapeutic efficacy over time. However, immune responses to the vector can hinder or prevent re-administration.^[10]

Addressing longevity challenges

Long-term follow up studies will be key to understanding the longevity of ATMPs. These studies can provide insights into the durability of therapeutic effects and the long-term safety of these therapies. Indeed, as other researchers have noted, these studies are crucial, not only for patients and their caregivers, but also for payers and regulators.^[11]

The Food and Drug Administration (FDA) recommends follow-up of up to 15 years for gene therapy in its 2020 guidance.^[12] Specifically, the agency recommends a five-year follow-up period for AAV vectors and 15 years for integrating vectors and genome editing products.^[13] This is reinforced in new guidance on Human Gene Therapy Products Incorporating Human Genome Editing. Both guidances provide a framework to assess the risk of gene therapy-related delayed adverse events, and introduces gene product characteristics, patient-related factors and recommendations on patient monitoring for licensed gene therapy products.

For its part, the European Medicines Agency (EMA) issued its guidelines on patient follow-up in 2009.^[14] The agency’s guidelines take into account the risk profile of a gene therapy based on delivery systems used and in 4.3 of the guideline issues recommendations for each delivery system.

Given the likely ongoing challenges longevity will present, the emphasis should be on developing new gene therapy platforms that are compatible with repeat dosing.^[2]

ATMPs at scale – manufacturing challenges

While the ATMPs focus has largely been on rare diseases, there is growing interest in their potential to treat more common conditions. These include metabolic disorders such as obesity and inherited high cholesterol.^[15],[16] By way of example, Fractyl Health is developing a local AAV-delivered pancreatic gene therapy expressing glucagon-like peptide 1 receptor agonist (GLP-1RA) for the treatment of both type 2 diabetes and obesity. Both studies are expected to go into phase I clinical trials in 2024.^[17]

However, developing ATMPs for these larger disease areas poses challenges for manufacturing scalability, since these require both higher yield and lower cost of goods to make them practicable.^[18]

While autologous products such CAR-T therapies that have been successful in treating many relapsed/refractory B-cell and plasma cell malignancies, manufacturing is costly and complex.^[19] Even manufacturing of simpler in vivo treatments is multifaceted. Yet, as Peter Marks MD, head of the FDA’s Center for Biologics Evaluation and Research (CBER), has noted, gene therapies could remain inaccessible to patients if these manufacturing challenges cannot be overcome.^[20]

Viral vectors such as AAV are a major area of cell and gene therapy research and development, with several approvals by both the FDA and European Commission…

With demand for manufacturing facilities soaring, some attention has turned to point-of-care or decentralised, in-house production methods. Increasingly, academic institutions and biotechnology companies are looking to technology advances to support point-of-care manufacturing and address potential quality challenges.^[4] Technologies being trialled to scale up and scale out manufacturing of CAR- and T-cell receptor (TCR)-engineered T cells in the clinic include cell purification, transduction/transfection, expansion and harvest.^[21]

(Note: ‘Scale out’ refers to running many smaller units in parallel, and ‘scale up’ means increasing the size of the process).^[22]

Scaling in vivo gene therapies

Viral vectors such as AAV are a major area of cell and gene therapy research and development, with several approvals by both the FDA and European Commission.^[23] However, large-scale manufacturing of products such as these remains untested. According to a McKinsey report, the priority will be to carefully consider the production system, optimise downstream processing and develop standardised chemistry, manufacturing and control (CMC) methods, and quality assays.^[4]

AAV gene therapy is a relatively mature field and in a recent edition of the Cell & Gene Therapy Insights podcast, industry experts reported that there is now wider use of more efficient and scalable manufacturing platforms for these therapies.^[24]

Tackling scalability will be key to bringing widespread availability to patients as these therapies being developed move into more prevalent disease categories such as metabolic, autoimmune and neurodegenerative disorders, and the requirement for delivering high doses.

ATMPs and reimbursement in the EU

ATMPs have the long-term potential to save money in health systems by reducing ongoing costs and eliminating the need for life-long treatments. However, their high upfront costs represent a major challenge, as most conventional reimbursement schemes are designed to cover chronic conditions, or in the case of specialist treatments, those that require continuous administration over time.^[25]

In addition, these novel therapies can lack the robust, long-term evidence that more established drug classes enjoy.^[26]

For its part, the European Federation of Pharmaceutical Industries and Associations (EFPIA) has developed recommendations aimed at increasing patient access to ATMPs while supporting payer decision-making and ensuring a sustainable approach for healthcare systems and patients.^[27] Among the key proposals put forward are:

• Using outcomes-based innovative payment models for ATMPs.
• Harmonising evidence requirements across regulators and health technology assessment (HTA) agencies.
• Ensuring an inclusive, multi-stakeholder approach to ATMPs value assessments to include patients and healthcare professionals.

To address ongoing challenges, several alternative drug pricing models have been proposed or implemented in different countries and settings.^[28] Two that are most relevant for ATMPs include:

• FINANCIAL-BASED AGREEMENTS: portfolio-based agreements, free initiation or indication-based pricing, payment schedules for one-time therapies with milestone payments.
• OUTCOMES-BASED AGREEMENTS: conditional treatment continuation, coverage with evidence development and outcomes guarantee models – this includes Risk Share Schemes.

Alternative drug pricing models should not be considered to be mutually exclusive and can be combined or adapted to suit different contexts and objectives. However, they also entail some challenges and limitations, such as data availability and quality, measurement and verification of outcomes, administrative complexity and feasibility, as well as stakeholder acceptance and alignment.^[29] Therefore, it is recommended to carefully consider design, implementation and evaluation of these models and related key performance indicators (KPI) measures to support their effectiveness and sustainability. It is also advisable to engage early on with payers to discuss these models.

However, the increased use of innovative contracts indicates a generally positive trend in attitudes towards ATMPs from European payers and policymakers.^[30] Policy changes or proposals have been seen in several countries, increasing the potential for innovative contracting. In Sweden for example, the Dental and Pharmaceutical Benefit Authority (TLV) in 2023 proposed the application of a higher price level to orphan drugs covered by the Swedish national benefits system.^[31] And in the UK, the government is proposing new controls on drug pricing aimed at giving patients access to new medicines while balancing NHS spending.^[32] Other countries in Europe have also adopted new pricing policies aimed at supporting the use of innovative therapies.

Streamlining EU decisions

Under the EU’s Health Technology Assessment Regulation (HTAR) adopted in 2021, Joint Clinical Assessments (JCAs) will become mandatory for new technology.^[33] One objective of the JCA process is to have a more consistent HTA evaluation across the EU. This would reduce the redundancy of having the same clinical trial submissions for different EU countries as well as seek to address inconsistent patient access and process duplication.

The JCA will come into force from January 2025 for ATMPs and oncology medicines. Engaging in the JCA process, which is anticipated at the time of EMA regulatory dossier filing, offers health technology developers parallel scientific advice from both the regulators and national HTA bodies through a procedure termed Parallel EMA/HTA body (HTAb) Scientific Advice.^[34] While pricing and reimbursement are distinct from the JCA process and will remain under full individual member state control, having aligned clinical assessments should allow health technology developers and local authorities to more quickly agree well-informed pricing and reimbursement processes.

Tackling issues of longevity and dosing repeatability of ATMPs will remain a priority for researchers…

Going forward, a priority should be to establish co-creation and collaboration between payers, regulators, and industry to develop agreements that ensure all stakeholder perspectives are considered. It is our recommendation that co-creation begins at the point of initial contact, to consider questions over budgetary impact, clinical value or even long-term outcomes. Furthermore, to identify potential innovative payment schemes, including any infrastructure requirements to address them and to share learnings and best practice.

Conclusion: a patient-first perspective

Tackling issues of longevity and dosing repeatability of ATMPs will remain a priority for researchers and innovator companies. Equally, more will need to be done to tackle manufacturing scalability if innovative ATMPs are to reach more patients and at cost levels that healthcare systems can sustain. However, it’s crucial that we don’t lose sight of the overarching objective: to transform the lives of patients. The experience of the parent of a child with Duchenne muscular dystrophy, who has seen her son’s life transformed by an experimental gene therapy, as well as testimonials from patients who have received Casgevy, were heard during the FDA’s 76^th Meeting of the Cellular, Tissue and Gene Therapies Advisory Committee, made this point: it is vital that barriers aren’t put in the way of enabling patients to receive these pioneering treatments.^[35],[36]

References

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^[2] Cell&Gene. Why Repeatability of Dosing Matters for Gene Delivery. Accessed 20 February 2024

^[3] Handyside B, Ismail AM, Zhang L, et al. Vector genome loss and epigenetic modifications mediate decline in transgene expression of AAV5 vectors produced in mammalian and insect cells, Molecular Therapy, Dec 2022. Volume 30, Issue 12, 7 December 2022, Pages 3570-3586

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