The Advanced Therapies Europe 2022 conference focused on exploring the commercialization of advanced therapy medicinal products (ATMPs), with talks on patient access, the manufacturing chain, and clinical case studies of cell and gene therapies. The event targeted Europeans looking for global growth as well as the global audience aiming to expand into the European market. Sessions were run by over 100 leading experts from top companies in their fields, who gave presentations, presented case studies, and conducted Q&A panels. This blog will summarize some of the most insightful sessions held at the Advanced Therapies Europe conference.
31/08/2022 | Day 1, Session 1
Day 1 began with a presentation on the importance of patient engagement and its relationship to personalized medicine. The session was chaired by Karin Blumer from Novartis, who provided an interesting thought to kick off the first session.
“While we are hopefully at the tail end of a pandemic,
I think it is a fascinating time to talk about patient engagement.
Never before did we have families sitting on the couch, talking about phase one, two and three clinical trials.
Never before was the whole world a potential patient.”
11:05 – 11:20 | Case Study: Strategic Approach to International Harmonization of Gene Therapy Products
Focusing on the effective international delivery of cell and gene therapies, Katherine Donigan from BIO began by talking about the current challenges, which range from regulatory policies to practical concerns.
Cell and gene therapy products (CGTPs) often target patients with rare diseases. Small patient populations highlight the need for large multinational clinical trials, which can be challenging to design and organize. Regulatory challenges arise from the personalized nature of CGTPs. The reliance on patient derived materials can create a concern in terms of proximity to manufacturing. In cases where the patient is outside of the manufacturing country, the export of materials may be complicated. In addition, the product may require import testing on return to the patient. These difficulties mean that it is near to impossible for innovative startups to navigate regulatory hurdles and this is ultimately causing a delay in the development of potentially curative medicines.
In order to tackle the problem, BIO is actively working with the International Council for Harmonisation (ICH) to bring in new and holistic guidelines that are aligned, but not necessarily uniform. This will mean that there is coherence between all companies working in the cell and gene therapy field. Back in 2019, when BIO expressed its concerns regarding a lack of guidelines, the ICH noted that it was too early to process guidelines for cell and gene therapies. The ICH wanted time to monitor the field. Since then, one of the biggest advances have been WHO’s white paper, which discusses WHO’s position on CGTPs. In response, BIO has formally submitted its comments and suggested amendments. BIO is also working on a reflection paper that proposes an ongoing discussion group for CGTPs in the ICH.
In summary, BIO believes that the time for focus on regulatory guidelines for CGTPs is now. There are many potential cures and treatments being delayed due to regulatory challenges. These treatments could be life-changing for patients with debilitating or fatal conditions. Many of these patients cannot wait much longer, and so BIO is making every effort to accelerate CGTP guidelines.
11:35 – 11:50 | Case Study: The Value of Early Patient Engagement to Build Credibility and Support for Clinical Development of a First in Class Cell Therapy for Hearing Loss
Hearing loss is shockingly common, especially in the UK where there is an aging population. Despite this, patients have limited options and most likely use a hearing device that is not suitable for everyone. Rinri Therapeutics presents a novel cell therapy solution for hearing loss. By extracting and administering progenitor cells from human embryos, Rinri Therapeutics hopes to replace damaged auditory cells. Currently in the advanced pre-clinical stage, Rinri Therapeutics looked back at their journey to clinical trials.
For Rinri Therapeutics, clinical trials present many challenges. Being the only cell therapy for hearing loss, there was no reference or proof of concept to follow. Rinri Therapeutics was unsure of how patients would react to the prospect of a cell therapy, rather than the devices that they are
accustomed to. Patients may also question the ethics of a therapy that involves the use of human embryos. In addition, the condition itself introduced new complexities. These include the fact that any clinical trial into hearing loss will need to rely on subjective real-world measures. As a result, it is difficult to prove efficacy while maintaining safety. Also, currently, the research is not translating well from animal to human models. These concerns were noticed by crucial investors, from which Rinri Therapeutics needed money and support. With all these challenges, Rinri Therapeutics needed a novel clinical strategy with a new delivery and data collection method.
Rinri Therapeutics used patient engagement to fill in their knowledge gaps and address any risks in strategy. Adaptations like online focus groups, text translators and one-to-one interviews allowed for valuable conversations with the hearing loss community. Rinri Therapeutics received positive responses to the three main questions that they posed.
- Is there a demand for a cell therapy over other available therapies?
Patients wanted new solutions. They understood the unique benefits of cell therapies and agreed that it would increase their quality of life.
- Do patients think it is unethical to use cells from a human embryo?
Rinri Therapeutics saw very little pushback from patients when asked about ethics.
- Are patients willing to take part in clinical trials?
Patients were excited to take part in clinical trials that may benefit them.
With realigned assumptions, Rinri Therapeutics returned to regulators and investors. Both were impressed with the early PPE and the board of investors now had confidence in the company’s potential. Vital patient conversations have allowed Rinri Therapeutics to continue in their journey to providing a cell therapy solution to hearing loss.
31/08/22 | Day 1, Session 2
13:50 – 14:05 | Case Study: Use of CTL019 In Paediatric ALL: A 17 Year Old With Refractory ALL Completes 10 Years of CAR-T Follow Up
In this case study, Dr Stephan Grupp spoke about the first ever paediatric CAR-T cell therapy, which was given to Emily Whitehead, a patient who was diagnosed with acute lymphoblastic leukaemia (ALL) at the age of five in 2010. As the paediatric oncologist who delivered the CAR-T cell therapy to Emily Whitehead, Dr Grupp speaks from a truly unique perspective. The session is even more special, with Emily Whitehead’s father being in the audience, ten years on from the successful therapy.
While patients have a 85-90% chance of being cured by the therapy, Emily had relapsed twice following her treatments. At that time, CAR-T cell therapy was in the stage of Phase I clinical trials. CAR-T cell therapy is a treatment that modifies a patient’s T cells to allow them to target cancer. Emily’s parents decided to participate in the clinical trial.
Being the first ever patient to receive this treatment, Emily faced significant risks. Dr Grupp describes the fact that doctors and scientists, including himself, could not answer Emily’s parents’ questions with certainty despite years of research and clinical experiments. The fact was that although the therapy had been shown to be effective in animal models, the efficacy in humans was completely unknown. There was enormous hope, but no real-world evidence was available.
Following the therapy, Emily developed a life-threatening complication of CAR-T called cytokine release syndrome (CRS). She was admitted to the ICU and by protocol, was given a steroid medication which unfortunately had little effect. Unexpected results from laboratory tests showed increased levels of the interleukin-6 cytokine and led to the use of tocilizumab, a drug that is normally used to treat rheumatoid arthritis. Administration of this drug led to a vast improvement over the next two hours and was released from the ICU support in the next few days. With effective management and innovative research, Emily was saved from a critical state. The drug used for Emily’s CRS is now the only drug that is implicated for the treatment of CRS, allowing for safe CAR-T cell therapy.
The standard approach used following successful remission from leukemia is to carry out a bone marrow transplant (BMT) for definitive control of disease. However, there can be serious complications following a bone marrow transplant, which include severe pain, a 10% chance of mortality from toxicity and almost certain infertility. Younger patients also tend to have difficulties in school following this procedure. In Emily’s case, her parents decided not to proceed with a BMT. Scientists and doctors following the case found that it was not necessary for patients to undergo a BMT in order to remain in remission. As a result, 80% of the CAR-T therapy patients in Stephan Grupp’s clinic decide to opt out of a BMT.
Longterm follow up of the Emily Whitehead case showed good rehabilitation following her time in the ICU, with a quick recovery as a child and she soon returns to school. Research follow-up continued for a year, and after this time, only physical exams and lab tests were performed. As CAR-T cell therapy does destroy B cells, it affects antibody production. Due to this, it is necessary for Emily to take antibiotics. In the past ten years, she has been hospitalized twice due to infections. However, her hospital stays were short. Overall, Emily Whitehead’s case is an example of where CAR-T cell therapy has provided significant improvement in quality of life.
Ten years on from the case of Emily Whitehead, enormous advances have been made as a result of ongoing research. In 2014, CAR-T cell therapy for leukaemia had an 80% hospitalization rate with 40% of patients being admitted to the ICU. In 2022, hospitalizations have decreased significantly to 50%, with approximately 12% of patients admitted into the ICU. There is 82-97% complete remission seen in approximately 60% of patients who remain relapse-free for two years. Therefore, although CAR-T therapy can have extraordinary patient burden, there are also extraordinary results as seen in this case study. Currently, there are seven FDA approved CAR-T cell therapies. The Emily Whitehead Foundation, set up by Emily´s parents, aims to share her experience of CAR-T cell therapy and spread awareness of paediatric cancer research with the public.
Stephan Grupp speaking about the journey to obtaining approval for CAR-T therapy
01/09/2022 | Day 2, Session 1
11:05 – 11:20 | Case Study: Gene & Cell Therapies for Rare Respiratory Diseases
Day 2 began with a presentation by Uta Griesenbach, a professor from Imperial College London, who discussed the advances made in the development of cell and gene therapies for cystic fibrosis in the past 20-30 years. As a rare autosomal recessive genetic disorder, cystic fibrosis was one of the first disorders to be targeted by gene therapy. Over time, the mechanism of therapy has been refined for cystic fibrosis and has also been applied to other disorders such as β-thalassemia and Wiskott Aldrich Syndrome.
Delivering gene therapies into the lung is particularly difficult due to the need for deep delivery into small airways. The procedure is further complicated by a layer of mucous that sits on top of the target cells. Around twenty years ago, research into gene therapy for cystic fibrosis began experimenting with the Sendai virus method for DNA transfer. The short duration and strong immune response demonstrated that the Sendai virus was unfortunately unsuitable for chronic treatments. The results of the Sendai virus were similar to that of the standard lentiviral vector which also found to be ineffective in the lung. Use of the two viral vectors in combination, however, proved to be incredibly effective. The new vector was named F/HN pseudotyped lentivirus. It has many “unique selling points” including being single dose, long lasting, and stable. This vector simultaneously solved many issues and was found to be effective in a variety of animal models including mice, sheep, and non-human primates. While there is some expressed concern about the safety of lentiviral vectors, Uta’s research showed no worrying hotspots. In mice, only a mild acute inflammation which subsided after a few days, was noted. Data from mouse models have shown no evidence of the shedding viral particles (for example, by sneezing).
Based on the success of lentiviral vectors in cystic fibrosis trials, similar approaches have been employed to target other types of disorders including pulmonary alveolar proteinosis and alpha I antitrypsin deficiency. The aim of these approaches is to use the lentiviral vector to achieve long-term therapeutic effects.
Looking into pulmonary alveolar proteinosis (PAP) more closely, it is easy to see why a gene therapy would benefit patients with this condition. PAP is a syndrome in which lung surfactant accumulates over time and prevents gaseous exchange. This is due to a lack of the GM-CSF antibodies that are needed for the growth of macrophages. These macrophages clear excess lung surfactant. Current management procedures are both highly invasive and risky. In a lentiviral gene therapy for patients with PAP, the lentiviral vector would be pseudotyped with the GM-CSF antibodies and subsequently, will increase the number of GM-CSF antibodies. Lentiviral based gene therapy is more patient-friendly as less frequent doses are required and it also offers a better long-term prognosis. It is the translational ability of lentiviral vectors that shows its real clinical potential across a number of conditions.