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Medicines Development in Children: Principles Applied to Gene Therapy for a Rare and Fatal Paediatric Disease

Lead author: Suyash Prasad, MBBS MSc MRCP MRCPCH FFPM, SVP and Chief Medical Officer
Co-author: Emma James, DPhil MFPM (Hon), Senior Director Medical Affairs and Health Outcomes

Drug development is a complex, time-consuming, and rapidly evolving discipline. This is particularly true for gene therapies, which have the potential to dramatically alter the lives of patients and their families, but for which little precedent exists. Further, many severe, rare, genetic diseases are diagnosed in infancy or the first years of life, and working with children adds additional medical, ethical, regulatory, and operational complexities to the study of novel therapeutics.

This article examines the ways in which the general principles of medicines development in children differ from those principles applied to adults, particularly within the context of gene therapy development for rare and fatal congenital diseases. It specifically assesses a systemic adeno-associated virus serotype 8 (AAV8) for X-linked Myotubular Myopathy (XLMTM), currently being developed by Audentes Therapeutics. Consideration is given to the practical and ethical aspects of studying medicines in children in this highly innovative and evolving field, where, with no currently approved alternative therapies, the opportunity to transform the lives and well-being of children and their families is apparent.

X-Linked Myotubular Myopathy: An Ideal Target for Gene Therapy
XLMTM is a severe, rare centronuclear myopathy caused by pathogenic variants in the MTM1 gene, which result in a lack or dysfunction of the protein myotubularin. Infants present with severe hypotonia, weakness, and respiratory distress, and nearly half die of respiratory failure in the first year of life1. Children who survive infancy require extensive supportive care. Most never achieve independent ambulation, require respiratory support, and die prematurely.

Currently, there are no approved disease-modifying treatments for XLMTM. Clinical management focuses on maximising functional abilities and minimising medical complications through multidisciplinary supportive care1. Early work, however, indicates that delivering a functional copy of the MTM1 gene using an AAV8 vector ameliorates symptoms of the disease in animal models2, 3, 4 and clinical trials are ongoing with promising early results5.

Appreciating the Differences Between Children and Adults
Children are not small adults. They differ physiologically, which may affect a drug’s pharmacokinetics and pharmacodynamics. For example, studies on hepatic drug metabolism show that a person’s enzyme activity changes over his or her lifetime, which affects how drugs are metabolised. Physiological differences may also affect a drug's safety profile. For example, the heart rate of a new-born baby is normally approximately 120–140 beats per minute (bpm) and decreases to approximately 70 bpm in adulthood. Therefore, if a drug has a known effect on cardiac parameters such as heart rate, the difference between new-born and adult heart rate bpm should be taken into consideration. Similarly, if a drug is renally excreted, differing glomerular filtration rates between children and adults may produce considerably different safety and toxicity profiles. Inadequate consideration of physiological differences can expose children to a direct risk of under or overdosing and a delayed risk of long-term adverse effects.

In the field of AAV gene therapy, an adverse effect that may be seen in some patients is elevation of liver function tests (LFTs) several weeks after dosing, reflecting a T-cell-mediated inflammatory reaction of hepatocytes. Normal ranges for children’s LFTs differ from those seen in adults. Therefore, to accurately assess the degree and clinical relevance of such elevations and implement appropriate medical management, a full understanding of appropriate LFT values across the paediatric age range is necessary.

Understanding the Natural History of Disease
When developing new therapies, understanding the natural history of the disease is extremely important. Heterogeneity within the same disease may exist between children and adults, and this is an important factor to consider to better understand a disease’s natural history. For example, certain types of epileptic seizures, such as Benign Rolandic Epilepsy or Petit Mal epilepsy (absence seizures), or malignancies, such as acute lympohoblastic leukaemia, Wilms tumour and certain central nervous system (CNS) tumours, occur in children more frequently than adults. Other diseases that are common in adulthood, such as ischaemic heart disease or essential hypertension, are extremely rare in children.

Another challenge in understanding the natural history of a rare disease is there is frequently a lack of published information in the literature for rare diseases6. Identifying rare disease experts can also be difficult. Often specialists are few and far between, and many of them have only cared for a small number of children among a specific rare disease population. These factors have an impact on how we design, set up, and operationalise clinical trials.

In the Audentes XLMTM clinical programme, the RECENSUS study was conducted to help us form a deep understanding of the natural history of XLMTM. The study confirmed the high level of mortality and morbidity for XLMTM that had been discussed in the literature, highlighting that 90 percent of patients required respiratory support at birth, and approximately 50 percent of patients died within the first 18 months of life1. Further, RECENSUS added new findings regarding the considerable disease burden and degree of health care utilisation among these children. In their first year of life, patients underwent an average of 3.7 surgeries and spent 35 percent of their time in the hospital1. Following RECENSUS, we initiated INCEPTUS, a prospective natural history run-in study. These natural history studies provide important comparator data for our subsequent ongoing Phase 1/2 study, ASPIRO.

The marrying of a retrospective chart review and a prospective natural history study with an interventional trial enable us to demonstrate efficacy and safety in a small patient population. For example, we will be able to compare the retrospective chart review data in RECENSUS to the results of the ASPIRO interventional study, and also plan to use the INCEPTUS study as a longitudinal within patient control for the ASPIRO study participants.

The Impact of Developmental Progression
It is important to appreciate the developmental difference between children and adults. Children are growing physically with respect to weight and height, while their organs are maturing in size and capability. Cognitive functioning, social skills, and neurological development are also progressing, and they are maturing in terms of reproductive physiology. Caution must be applied to ensure a medicine given to a child does not affect aspects of their development.

The photo shows Suyash at a patient meeting, spending time with a young boy with XLMTM. As you can see, the boy is profoundly hypotonic and needs ventilatory support due to respiratory muscle insufficiency.

To investigate the potential ways a drug may impact children’s development, preclinical studies in immature animals should be included as part of the clinical program. Our XLMTM gene therapy programme explored dose selection, pharmacology, and toxicology in juvenile animal models to assess toxicity, growth, organ maturation, reproductive development, and neuro-behavioural development as these animals matured through adolescence into adulthood.

A topical issue in the field is whether a gene therapy’s effect gets ‘diluted’ as the target organ increases in size. However, in a pre-clinical dog model, our investigational gene therapy for the treatment of XLMTM demonstrated dose dependent improvements, including protein expression levels, muscle and respiratory function, and survival, and the results have proven to be durable. In the study, dogs were dosed at eight weeks of age when the dogs weighed approximately five kg. Six years later they weighed 27–28 kg and have maintained an excellent response to their single dose of therapy consistently through this period2, 3, 4.

In addition to pre-clinical work, there are numerous requirements to ensure an appropriate safety evaluation of the effects of medications on the development of children and adolescents in clinical trials. Short-term clinical trials, however, cannot determine the effects on their development, for which longer-term studies are needed. The ASPIRO interventional trial will monitor patients for five years, after which the intent is to continue to monitor the children in a long-term safety study or a registry. Importantly for a gene therapy, this would also inform durability of efficacy and understanding of long-term safety. These extension studies allow further exploration of developmental parameters such as growth and pubertal status and are increasingly expected by regulators.

Addressing Family Matters, and Social and Emotional Development Needs
In addition to growing physically, it is important to appreciate that children progress in terms of social and emotional development. Specifically, they develop autonomy and adapt to functioning within society. Information about treatment plans, including the risks and benefits of treatments, should be conveyed to children and their parents or guardians in an appropriate manner. Communication between children and clinicians should be meaningful (i.e. age appropriate and empathetic) when treatments are explained or feedback is solicited. Notably, ethics committees are increasingly sensitive to ensuring that appropriate communication is addressed in clinical trial materials.

Children and families affected by XLMTM are our partners, collaborators, and teachers. We believe that their perspectives should be considered throughout the drug development process, from initiation of a clinical program to its completion and beyond. We accomplish this through activities such as patient focus groups, attendance at patient advocacy meetings, and one-on-one meetings with patient advocacy leaders.

Importantly, our conversations with the XLMTM patient groups had a direct impact on the clinical trial designs. For example, based on conversations with parents and caregivers, we learned that respiratory aspects of the disease are the most worrisome to them. As a result, we elevated the importance of respiratory outcomes measures in our ASPIRO study. Additionally, we added assessments for a variety of functional measures, including, for example, the ability of a child to vocalise and generate sound, as we heard from families that the ability to communicate would be an exceptionally important skill to attain. Ventilators prevent patients with XLMTM from being able to speak, and from a social and emotional perspective, families want to connect with their loved ones affected by XLMTM through speech. In short, we strive to weave the patient and family perspectives into all aspects of our programme.

Understanding the Child-Focused Health Care Professional
Those who work closely with treating clinicians, investigators, and key opinion leaders (KOLs) appreciate the importance of understanding the motivations and drivers of these groups. Health care professionals (HCPs) working with children must possess a few unique attributes. To be successful, paediatricians and child-focussed HCPs need to be adept communicators, leveraging an age-appropriate communication style. They should embody kind, gentle, and empathetic qualities, demonstrating a high degree of emotional intelligence and sensitivity. Additionally, they should appreciate a holistic approach to caring for patients while taking children’s behaviours and feelings into close consideration.

The Balance of Benefits and Risks
It is critical to evaluate the potential benefits and acceptable risks of a drug or therapy before development. Every treatment is associated with both of these factors: the key issue is to what degree one outweighs the other. Such deliberations take on greater complexity when children are being considered for inclusion and treatment in a clinical trial. It is particularly important to consider children’s rights, experiences, and well-being as well as parental expectations of HCPs, and the 'emotional urgency' that tends to exist when working with young children.

Before initiating a clinical programme, it is important to consider the unmet medical need. For XLMTM, the unmet need is clear: there is no available treatment and mortality is high. Regulators usually take these factors into consideration when assessing potential therapies for diseases, and they are often willing to expedite discussions that may facilitate an earlier assessment under these conditions. The XLMTM gene therapy program has received both PRIME (Priority Medicines Review) designation in Europe, and RMAT (Regenerative Medicine Advanced Therapy) designation in the United States. These designations demonstrate that regulators recognise the unmet need of XLMTM, appreciate the promising early clinical data, and are willing to collaborate closely to rapidly advance the program toward global regulatory approvals.

Preliminary Data from the AAV8 Gene Therapy Study for XLMTM
In August 2018, we reported promising interim safety, efficacy, and muscle biopsy data at the 24-week timepoint from the first dose cohort of ASPIRO.

Data from the first dose cohort demonstrate significant improvements in neuromuscular function as assessed by the CHOP-INTEND scale and increased respiratory function as demonstrated by gains in maximal inspiratory pressure (MIP), a measure of respiratory muscle strength. Perhaps most importantly, we have seen dramatic reductions in ventilator dependence with two of six patients coming off the ventilator completely – something that is nearly unheard of in children with a congenital myopathy who have been ventilated from birth. In addition to these functional outcome measures, muscle biopsy results from the first three patients treated in the study at the six-month timepoint demonstrate highly efficient tissue transduction as indicated by vector copy number, robust myotubularin protein expression as assessed by western blot, and significant improvement in histology as assessed by an independent panel of histopathologists who are reading and interpreting the samples in a blinded manner.

AT132 has been generally well tolerated in patients to date. The few events we have seen have all been without clinical sequelae and manageable with treatment. The ASPIRO study is ongoing.

Concluding Remarks
The area of paediatric medicines development continues to evolve, particularly as society increases its focus on children’s rights. The United Nations' Convention on the Rights of the Child (UNCRC) is a treaty that contains four core principles including, non-discrimination; devotion to the best interests of the child; the right to life, survival and development; and respect for the views of the child. Those of us involved in paediatric health, including those working on drug development programs that focus on children, have a responsibility to help carry out this treaty. To accomplish this, I advocate for pharmaceutical and biotech companies to build competencies in paediatric medicine, either by setting up a paediatric department, establishing an internal or external cross-functional expert group, or employing appropriate consultants.

Importantly, physicians within the industry need to ensure that that the perspectives of the patient and the family are considered in medical decision-making. Nowhere is this more important than in innovative and rapidly evolving environments that have the potential to make a long-term transformational change, such as gene therapy.

This article was first published in the third edition of the Journal of the Faculty of Pharmaceutical Medicine

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