Realising the Potential of Advanced Therapies for Patients Conference Report

Transcription

1 Realising the Potential of Advanced Therapies for Patients Conference Report Both the remarkable opportunities that cell and gene medicinal products can offer, and the challenges to their wide application, were presented to a full audience in London s Canary Wharf on December 5th, This was the sixth annual regulatory conference organised by the European Biopharmaceutical Enterprises, with the participation of the European Medicines Agency, the European Commission, industry, patient representatives, and many other healthcare stakeholders. This annual event is a rare opportunity to meet and discuss making new therapeutic approaches available in Europe that can effectively treat unmet medical needs. In an effort to support the development of next-generation medicines including cell and gene therapy products such as stem cells and T-cells, and tissue-engineered products, the EU established a specific legal framework for Advanced Therapy Medicinal Products (ATMP) in The EMA's Committee for Advanced Therapies (CAT) provides scientific advice and recommendations on the development of ATMPs and the evaluation of applications for marketing authorisations. In addition the CAT issues ATMP s classification and ATMP s certification. Once centrally authorised, in theory, these products can be marketed and used in all EU Member States. However, pricing and reimbursement remain a national competence, with reimbursement decisions taken in each Member State. This year s conference showed that despite promising new ATMP pipelines and an increase of ATMP Marketing Authorisations over the past few years, direct patient access in the Member States remains an important challenge. Understanding the challenges of ATMP development and to bringing ATMPs to patients Enrica Alteri, Head of EMA s Human Medicines Research & Development Support Division, began the conference by stating that there is excellent quality of research and innovation in Europe, but regarding ATMPs, Will anybody fund it? Will the therapies be reimbursed? This sentiment was echoed by Maria Pascual, Chair of the Joint EBE EFPIA Advanced Therapies working group, who said, It s an exciting time for the sector, and an intense period for industry and regulators, but we re facing challenges in translating EU marketing authorisations into patient access in the Member States. She concluded by highlighting that, Events like today are vital as we need to continue engaging in order to discuss these key challenges together. Ana Hidalgo-Simon, the EMA s Head of Specialised Scientific Disciplines, began the first session addressing the development of ATMPs and patient access. Her data showed that broadly, from an EMA regulatory perspective, the ATMP framework had been a success, with 500 clinical trials started, 270 ATMP classifications granted, 19 marketing authorisation applications (MAAs) received, and finally, nine ATMPs approved since the legislation came into force at the end of According to data from PSURs presented by the EMA, centrally approved ATMPs have however only been used to treat a relatively small number of patients. Furthermore, Of the nine products approved since entry into force of the ATMP Regulation in 2008, three have been withdrawn, and one has been suspended, leaving only five authorised ATMPs in the EU market. Regarding current research trends, the EMA noted an overall increase in the use of Scientific Advice, a process whereby a developer of medicines can prospectively discuss the evidence requirements for a planned clinical trial or marketing authorisation application. It was further noted that there had been a

2 particular increase in requests for advice for gene therapy products. The fact that ATMPs are innovative products addressing high unmet medical need is reflected by the high proportion of ATMPs versus non-atmps (13/28) that have been assessed to be eligible for the PRIME scheme. Of the 487 ATMP trials registered since 2008, 302 (roughly 62 per cent) have been sponsored by nonprofit or academic institutions. The fact that so much of this development is being driven by academics has far-reaching implications, given the research results presented by the Escher platform in the subsequent presentation highlighting development challenges linked to academic spinouts. Renske ten Ham of Utrecht University gave an introductory presentation on the results of research into factors associated with successful development of ATMPs. The study, carried out via the Escher platform from the Netherlands and supported in part by a grant from EBE, examined the factors associated with successful ATMP development and commercialisation in Europe. The research was based on a survey supplemented with interviews, and covering a broad and representative cross-section of commercial developers in the sector, with 38 per cent of the 271 identified companies working in ATMPs in the EU responding. The data show that 65 per cent of the companies are SMEs, with almost 40 per cent focused on gene therapy, and the rest working on cell therapy. The percentage of companies focusing on gene therapy has increased over the past ten years and is expected to continue to increase. Regarding the challenges of ATMP commercial successes in Europe, ten Ham said that, The survey showed clearly that the major hurdle to bringing ATMPs to patients is the divergence of Member States in interpreting and implementing legal or regulatory requirements, for example of the GMO legislation and clinical trial authorisation. Commercial developers find EU efforts have helped ATMP development in general in the past years. However, local interpretation and implementation of the regulations in practice lead to many additional information requests, delays, and increased costs. The research also provides insights into how national authorities have different interpretations and requirements for clinical trial applications, as well as divergent approaches to the hospital exemption and the implementation of good manufacturing practice requirements. Renske ten Ham noted that, Not all small companies have the resources to address country-specific requirements, high data requests burden the SMEs and create uncertainty to maintain the promise of growing the EU ATMP market. The data further showed that ATMP development is much more complex than traditional drug development. Companies that start without high-quality in-house or contracted regulatory knowledge, manufacturing expertise, and well-defined business goals, are mostly unable to catch up. This is especially true for academic spin-outs and SMEs, said ten Ham. European efforts through the EMA s CAT and the European Commission were very well received by developers. However, survey participants highlighted the need to foster common interpretation and implementation across the Member States to avoid competitive disadvantage for EU ATMP developers when compared to other international markets. Rocío Salvador-Roldan, the European Commission s policy officer for ATMPs at DG Santé, gave the final

3 presentation of the opening session, providing an overview of how the European Commission is working to optimise the application of the current ATMP legal framework. Of specific interest is the desire of the EU to align current good manufacturing practices requirements to ATMPs through the recently published Guidelines on GMP for ATMPs. Among others, it was also highlighted that the Commission and EMA are working on developing a specific framework for risk management plans and post-marketing studies. It was finally noted that the Commission is aware that the application of GMO requirements to investigational gene therapy products is challenging for developers. Work is ongoing with the national pharmaceutical authorities and the GMO authorities to improve the current situation, said Salvador-Roldan. After the formal presentations, the panel was joined by Chris Sotirelis of the orphan drug patient group EURORDIS, and Rimma Berenstein of the German Federal Joint Committee (G-BA), who each gave an opening statement before an open question and answer session, moderated by Martina Schüssler- Lenz, Chair of the CAT. Sotirelis gave his view on the need for multiple stakeholders to have an input into the evaluation of new ATMPs, saying, In terms of the regulatory pathway, as we progress to an earlier approval, we also need to consider what happens downstream relative to patient s access and payers. These additional stakeholders have often not been involved in the discussions regarding the implementation of a new access paradigm. We need to develop better ways to keep them involved and engaged in the process. Speaking for Germany, Berenstein stated, we have limited experience with these advanced medicines as few have reached the market. ATMPs given to patients through a complex administration procedure are under the authority of the method evaluation department rather than the pharmaceuticals department of the G-BA. At the moment we don t have the infrastructure to collect and use real world evidence (RWE) in a standardised way to ensure that the data quality fulfils the requirements for the evaluation of ATMPs within the G-BA. For a comprehensive view we will have to collect further practical experience in the handling of the challenges associated with ATMPs in upcoming assessments and learn from them for future decisions. Schüssler-Lenz began the open Q&A session by asking rhetorically, Is there a disconnect between the national level and EMA and CAT? Member State representatives are members of the CAT, and they are the link to the national competent authorities. What exactly is it that makes the developer s life difficult? Margareth Jorvid of Methra responded: For an SME, the questions we receive from a national authority versus what we need to address from the EMA are really different. That s challenging. One point of discussion involved the use of the voluntary harmonisation procedure (VHP), which is a coordinated and simplified procedure for clinical trial applications with joint assessment by multiple EU Member States. Schüssler-Lenz asked, In terms of complaints about the divergence in clinical trial assessment between Member States, wouldn t a solution be to use the VHP more frequently? Some companies and CROs in the audience, which had used the VHP, commented that the process had resulted in added administrative complexity, and more importantly, added costs to clinical trial

4 development. More problems were encountered with ATMPs consisting of genetically modified organisms (GMO), due to disparities across Member States. The session ended on a comment from Renske ten Ham, who pointed out, You can create excellent legislation in the EU, but the reality is, it s up to local people to use and implement them. Challenges for ATMP development and supply to patients Christina Basford, from the Cell Characterisation Team within GlaxoSmithKline s (GSK s) Cell & Gene Therapy group, began the following session with an overview of the evolution of GSK s comparability strategy in the cell and gene therapy space. She pointed out that, GSK s focus, originally, has been in ultra-rare genetic diseases since our development of Strimvelis and that GSK are now moving into the oncology space. She highlighted the key challenges that both of these approaches created. When trying to manage manufacturing, low volume in ultra-rare and acute diseases puts severe pressures on the system to manage variability and process robustness. Ultimately, GSK decided that a simple strategy was needed. We had to do something, but not change everything, to reduce variability and increase scalability, said Basford. The majority of the ATMPs developed so far have been autologous, meaning that the patients own material is reformulated or manipulated in some way to become a medicinal product. Due to this, autologous products are a bespoke process, and maintaining comparability of product quality and performance when scaling up from the clinical product to the commercial product is key to successful development. We are looking for markers that are subject to process changes but robust enough not to be affected by donor variability, said Basford. With the excitement around its groundbreaking development of the first successful commercial CAR-T product, and its approval, Daniel Stark, Novartis Global Head of External Supply Management for the Cell and Gene Therapy Unit, gave an overview of the challenges of moving from a single-site university setting to a global supply chain. Novartis CAR-T therapy Kymriah is a customization of the individual patients T-cells through genetic modification, so the product is both ex vivo and autologous. The cells are taken from the patient, and six stages of production are required to transform the T-cells into an immunocellular product. With the cell material being taken from the patients themselves, Stark stressed that The heterogeneity of the starting material is a huge challenge; automation only works as well as the control. The overall control strategy is based on understanding of several critical quality attributes (CQA) that we ve developed to ensure the response is equal across all our production sites. He highlighted that Novartis current approach to manufacturing is to prove any new processes or changes at its centre of excellence in Morristown, New Jersey, where all process development is managed. Any new approach or alteration to manufacturing is always checked against the centre of excellence, to identify any performance drift. He summarized the Novartis experience with the following key findings from the expansion of its CAR-T

5 supply chain: Manufacturing and supply of autologous products need to address the chain of identity through all steps, and use automation to facilitate scale-out of manufacturing and logistics. Compliant change control management and sound comparability practices are vital to perform development and life cycle activities. Understanding CQAs is the key to the successful development and commercialization of ATMPs. Finally, autologous cell therapy products require a novel integrated approach with end-to-end data management and analysis. This goes from the material drawn ex vivo from patients through to the clinical response, in order to ensure the quality of commercial CAR-T products over their entire life cycle. Given the evolution in treatments with the new class of CAR-T cell therapy, Ilona Reischl, the CAT Vice Chair and a member of the Federal Office for Safety in Health Care for the Austrian Agency for Health and Food Safety, presented on the EMA s status regarding the new guideline on requirements for ATMPs in clinical trials. Whilst the EMA s intention had been to have a draft of this guideline ready in 2017, this timeline could not be kept. Independently, the practical application of the Clinical Trials Regulation has been delayed to Q She highlighted that the enhanced efforts that had been dedicated to developing the guidelines in good manufacturing practice (GMP) had drained resources from other guideline development. In addition, since a number of ATMP related guidelines are being developed in parallel, alignment of content is an issue to be taken into consideration, i.e. which content should be included in which specific guidance document. With the publication of the GMP guideline for ATMPs in November 2017, the work plan for 2018 now focuses on the further development of the guideline on investigational ATMPs. A stakeholder meeting is planned for Q2 2018, distribution of the draft guideline for external consultation in Q4 2018, and after completion of external consultations, publication of the guideline by Q3 of Patrick Celis, Scientific Administrator for the CAT Secretariat, began the open discussion by highlighting that, From the perspective of the CAT, there will be a reticence to develop any new guidance for newly innovative ATMP processes, since ATMP science innovation evolves ever so quickly nowadays. This is why the ATMP drafting process has been so challenging. This position was expanded upon by Margarida Menezes Ferreira, CAT alternate member for Portugal, who pointed out in relation to innovative characterisation tools We always struggle with any innovation in analytical methods. When you get too many signals, how can we as the regulator deal with the validation of those signals in terms of which ones are meaningful, and which ones are signal noise? It s a very important field, but in the end, we often don t know how to deal with the data generated. If developers can identify a good, sound marker, it s a very important approach to finding a process that works and can be verified. Alexis Cockroft of GSK, the session s moderator, highlighted that The concern of product quality doesn t stop when you manufacture it. The risks of handling will also factor into your global strategy. You see different organisations take different approaches. Patrick Celis responded to that by pointing out, Ultimately, the burden of evidence and proof is on the producer. Your responsibility is to convince us of the safety and comparability of the product.

6 How to translate gene editing from the laboratory to the clinic The conference continued with a session dedicated to the utilisation and commercialisation of gene editing technologies such as CRISPR/Cas9. Put simply, gene editing acts like molecular scissors, where DNA is inserted, deleted or replaced in the genome of a living organism. It holds huge promise for the ability to correct genetically inherited diseases such as Duchene s muscular dystrophy, but it is still highly experimental, and not yet used commercially for human treatment. Mick Fellows, Principal Scientist at AstraZeneca (AZ), gave a presentation of the current status of what his firm calls precise genome editing (PGE). Recently, there is increasing debate regarding the tools still needed in order to accurately predict gene edits that occur off target, or are not what was intended. There are currently only limited informatics or tools available to understand how sensitive patient will be to any off-target edits. It was pointed out by Fellows that there is no safe dose of a DNA reactive mutagen, but several research studies, particularly a study by George Church of Harvard Medical School, show that CRISPR in its current form seems capable of less than one error (off target) per 300 trillion base pairs. It was shown that this equated to less than one off-target hit per 100,000 cells, while humans naturally have more than 100 DNA strand breaks (the equivalent of an off-target edit) per day. In order to begin to understand the implications, both commercial and of treatments through gene editing, the EMA in 2017 held a meeting of invited experts to discuss next steps for developing a regulatory framework. Nearly all the major industry partners attended, and most disclosed that they are following ex vivo approaches in blood disorders or liver-specific targets. There was a general consensus at the meeting amongst industry and regulators that, with an appropriate benefit-risk analysis, PGE holds great promise, but early regulatory interactions, such as scientific advice, will be key to the development of a fully functioning framework. There are still significant challenges for translating an animal model to humans, and a need to define what the actual product is. Fellows concluded by saying, The move to the clinic for ex vivo gene editing is being established. Given the potential benefits and the willingness of researchers and regulators to establish safety testing paradigms, it is very much hoped that the promise will be realised. Continuing the discussion on the regulatory challenges of gene editing, Paolo Gasparini, CAT member for Italy and Vice-Director of the Department of Medical Sciences as well as Head of the Medical Genetics Service of the University of Trieste, gave his overview of the expert meeting held in October. He said, We tried to have different examples related to the various current applications of genome editing. There are lots of challenges, and some are related to the tools. But, by far, the major challenge is determining the impact of off-target effects. We have no gold standard for evaluation, and whilst we can try to use in silico techniques, they still need to be validated. He opined, It could take years to fully understand off-target significance. Regarding the EMA s next steps to facilitate gene editing, Gasparini said that the publication of the expert meeting s outcomes was envisaged in early The CAT and CHMP will publish a revision of

7 the guideline on genetically modified cells (ex vivo). There will be a preliminary reflection on other possible guidance dealing with in vivo gene-editing applications, and continuing efforts to harmonise the environmental risk assessment (ERA) and genetically modified organism (GMO) requirements. Gasparini also made the point that, There are currently no clinical trials using CRISPR/Cas9 based products in Europe or the US, but he also stated that there are several pre-clinical programmes taking place, mainly in the US, by academic sponsors and SMEs. There is a great pipeline and many challenges, he said. The conference also had the virtual participation of Anna Kwilas of the US Food and Drug Administration (FDA), who presented the US position on the current state of regulation for CRISPR/Cas9 to the attendees. The FDA places the regulation of gene editing under its Center for Biologics Evaluation and Research (CBER), which has been regulating gene therapy since Much like EMA, the discussions at FDA regarding CRISPR are related to the safety concerns of the emerging technology, and Kwilas stated that any gene editing application will require a 15-year followup. The FDA further states that one of the challenges to understanding the safety of human genome editing products is the use of the multiple methods for predicting and identifying off-target genomic modifications, as not all genomic modifications lead to adverse biological consequences. Further, animal models may currently be of limited value for discerning these biological consequences. Marcos Timón of Spain s Agency for Medicines and Health Products (AEMPS), a CAT alternate member, gave the final presentation of the session on the revision of the guideline for quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. On the reason for the revision, he stated, The guideline was published five years ago, and needs to be updated to address current innovation challenges. Not specific to gene editing, the guideline is broadly applicable for ex vivo genetically modified cells, irrespective of intention, origin, or type. Timón outlined that the update was needed to reflect the experience gained with products that have sought marketing authorisation, as well as Scientific Advice and PRIME. There is also a need to consider developments and the continuing evolution of the tools used in the genetic modification of cells, as well as to reflect the clinical experience with CAR-T cells and related products. Highlighting the need for coordination between the EMA and Member States on ATMPs, Timón presented data taken from ClinicalTrials.gov in November 2017 showing where CAR-T cell trials were being carried out. While Europe was home to 68 CAR-T trials, the US was running 153, with China was running 145. The implication is that Europe risks falling behind the rest of the world in the development of this next generation of advanced therapies. The concept paper to revise guidance on genetically modified cells was published at the end of July 2017, and the plan is to publish the draft guidance in the first quarter of The panel discussion was then joined by Falk Ehmann, Science and Innovation Support Manager at EMA. He began by saying, New technologies always come with new challenges and questions. As regulators, we are asked to make a decision on benefits and risks of new products. From this perspective, we re looking at a very promising technology, and I think it s very important that we strike

8 the right balance. We don t want to over-regulate, but we also want to ensure safety. A question was asked from the audience about where the panel thought CRISPR would be in 5 10 years. Paolo Gasparini responded, We have experience with this in animals, we know it is working very well in knockout models, my feeling is that in five years we ll have several examples using new gene editing techniques. Ehmann also said The technology will definitely not only survive, but flourish, be refined, optimised and exceedingly be used in research and drug development. While every technology has its risks, we will start to gain experience in life-threatening indications and we ll move on from there. The session ended with Anna Kwilas saying, CRISPR is definitely going to get into the clinic, simply because of the number of people working on it. Where will it be in five years? That will depend on what we see. We ll go after the most serious diseases first, and then it will depend on the results. Ensuring safety for patients throughout the lifecycle of an ATMP The final session of the day was a discussion of safety issues that had become apparent in recent CAR-T clinical trials. Miriam Fuchs, Global Drug Development, Regulatory Affairs at Novartis, highlighted in the first presentation of the session how Novartis had managed to maintain the safety profile of its CAR-T product whilst scaling up its development from a single centre innovation into a global program in two indications including more than 50 clinical sites in 12 countries across North America, Europe, Australia, and Asia and manufacturing from a central Novartis facility. The new CAR-T therapy product CTL019 (tisagenleucel) was developed in partnership with the University of Pennsylvania (Penn). Penn and the Children s Hospital of Philadelphia (CHOP) pioneered CTL019 in patients with relapsed or refractory B-cell malignancies with early promising efficacy and a manageable safety profile. The challenge was the global and safe expansion of the CAR-T cell product after the technology was transferred from Penn to the newly acquired manufacturing site for cellular products based in Morris Plains, NJ. Establishment of a global supply chain and maintenance of chain of identity for the autologous product were key aspects. Based on the experience gained at Penn and the CHOP, Novartis had established a rigorous safety protocol to manage and control its global studies of CTL019 in its clinical trial sites. These included a comprehensive site training program for leukapheresis (the harvesting of the patients own leukocyte cells) in the stem-cell laboratory and training for the management of the CTL019 safety profile in clinical centres, as well as the staggered enrolment of the first three patients at each clinical site, accompanied by regular information exchanges between the investigators and sponsor. Education for patients and families was an important aspect and patients were requested to remain in proximity to the clinical site for 3-4 weeks to ensure immediate attention by the treating physician in case of symptoms of adverse events. In addition, there was a panel of tests and checks before the infusion, including influenza testing, a check for laboratory abnormalities, and testing the patient for active infections.

9 Novartis used its clinical trial experience with CTL019, which has been approved under the name of Kymriah by the FDA in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse, to establish the training regime for the commercial centres of excellence, and its approach to safety was broadly successful. The safety profile of CTL019 was similar between indications but differed in respect to frequency and severity of adverse events. Different CAR-T developers use different grading and management systems for adverse events like cytokine release syndrome and harmonization should be considered for the benefit of treating physicians. Many of the activities and recommendations that were implemented in the clinical studies to ensure safe use are now included in the prescribing information and training material. Nick Trede of Juno Therapeutics presented a summary of the root cause investigation into severe neurotoxicity, including fatal cerebral oedema in the Phase 2 Rocket trial of its CAR-T product JCAR015. While JCAR015 had shown great promise in the Phase 1 trial at Memorial Sloan Kettering, in the Phase 2 ROCKET trial five patients developed fatal cerebral oedema. Trede pointed out that, The cause of cerebral oedema is multifactorial, including the presence of at least one of four specific patient risk factors, high levels of pre-infusion IL-15 and rapid CAR-T cell expansion. These clinical and additional manufacturing factors impacted dose and function of the CAR-T cell product and resulted in an increased incidence of severe neurotoxicity and cerebral oedema. Juno, under its partnership with Celgene, worked towards a defined composition, flat-dose CAR-T product in the manufacturing platform for their following clinical trials of JCAR017. Jens Hasskarl of Celgene outlined that this has also been accompanied by a comprehensive safety monitoring protocol for their current EU clinical trials, including a 14-day period of evaluation after treatment, continuous safety monitoring, and weekly investigator calls. Additionally, Celgene and Juno have put substantial effort into monitoring procedures and training, as well as the implementation of predictive algorithms for cytokine release syndrome and neurotoxicity, so as to quickly identify risk factors and adverse events in their JCAR017 CAR-T trials. According to Hasskarl, On the ground CAR-T clinical expertise is needed to support clinical sites and patients. Trede added, JCAR017 has much better control. Preliminary data from the continuing TRANSCEND trial of Juno and Celgene shows that patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were treated with JCAR017 achieved a three-month complete remission (CR) rate of nearly 75 percent. Caroline Voltz-Girolt, EMA product lead in the Oncology, Haematology and Diagnostics Office at the EMA gave the session s final presentation with an overview of the ATMP guideline for safety and efficacy follow-up and risk management, which is currently under revision and expected to be shortly published for consultation. She began by mentioning that every effort should be made during the ATMP development to generate quality, safety, and efficacy data in order to define safety and efficacy of the product, which will be the basis for the evaluation and granting of a marketing authorisation based on a positive benefit risk balance. She highlighted the fact that ATMP developers should ensure

10 that they receive necessary data from the different parties (e.g. hospitals, blood and tissue establishment, registry owners, raw material or starting material manufacturers, and patients) they have agreements with, to be able to adequately define the safety of the ATMP. Voltz-Girolt highlighted that it was vital, early in development, to start defining the potential risks and gaps in knowledge related to the quality characteristics, storage, distribution, patient associated conditions, concomitant treatments, reconstitution and administration procedures and the persistence of the product in patients, amongst other things. Going into specifics for CAR-T cells, she highlighted the risks of cytokine release syndrome, the neurological events, the risk of hypersensitivity, the potential risk of developing a secondary malignancy. All risks should be minimised at the time of marketing authorisation, for example by way of introducing contraindications, warnings and precautions, additional monitoring, restricted prescriptions, controlled access programmes as well as educational programmes. She concluded by highlighting that it is an exciting time for the ATMP field, which requires collaborative effort to deliver safe and effective treatments. The EMA will be holding a workshop on 9 February 2018, to address the need of CAR-T cell products for robust post-authorisation data collection in registries, said Voltz-Girolt. Martina Schüssler-Lenz, Chair of the CAT, made the closing address, saying, I think the meeting today was rightfully focused on the challenges related to the development of ATMPs towards marketing authorisation and the efforts made by EMA and European Commission to further support the development of these products. It is very good to see the increasing research and development activities in the field, as well as the increasing number of marketing authorisation applications. But what we have not been able to discuss today in more depth are the reimbursement issues. EMA is offering parallel consultation and advice with regulators and HTAs, which we encourage to use. Reimbursement is not in the EMAs and CATs remit, but certainly more efforts need to be made to foster patient access to these innovative products. Barbara Freischem, the Executive Director of EBE, concluded the meeting by reminding everyone, We have our marching orders, and we will continue to address reimbursement. As well, we must continue to focus on patients and their needs, as they, ultimately, are why we re trying to bring ATMPs to the market.