Conducting gene therapy clinical trials based on natural history studies for inherited retinal diseases in Chinese population

A breakthrough in the treatments of patients with inherited retinal diseases (IRDs) have been achieved with the development of gene sequencing and gene editing technologies. Luxturna, the world's first IRD gene therapy drug for the treatment of Leber's Congenital Amaurosis (LCA) was launched in 2017.¹ It indicates that IRD gene therapy had entered the new stage of clinical application. The new era of gene therapy is coming. However, IRD has a low prevalence and a high degree of genetic and clinical heterogeneity. Most of the existing gene therapy-related researches and drugs were based on the genetic backgrounds of western people. The researches and drug developments related to IRDs gene therapies in China are currently in the initial stage. The few natural history studies (NHSs) of IRDs that have been conducted, the lack of professional knowledge about the characteristics of IRD lesions, and low early diagnosis rate of IRD patients remain problems and challenges for further basic research and clinical practice related to gene therapy in China.² Conducting studies on the natural history of IRDs based on the genetic background of Chinese people is an important prerequisite for the development of gene therapy. A deep understanding about the progressions of IRDs is not only crucial for the diagnoses of the diseases, but also a major consideration for the design of relevant research protocols and drug developments.

1. The natural history of IRD is an important prerequisite for gene therapy

Natural history of disease refers to the progression of a disease process in an individual over time, in the absence of treatment. Many diseases have a characteristic natural history, although the time frame and specific manifestations of disease may vary from individual to individual and are influenced by preventive and therapeutic measures.³ NHSs can be divided into retrospective and prospective studies. It includes studies reported in the literature, treatment experiences, and data recorded by patients themselves. NHSs focus on both published reports of relevant NHSs in the literature, both domestically and internationally, as well as well-designed cross-sectional studies, retrospective studies, or prospective cohort studies that address the natural history of the disease early in development. In contrast to traditional disease progression studies conducted without intervention, NHSs document the progression of disease in patients undergoing medical care interventions such as treatment or emergency care as a means of understanding the demographic, genetic, environmental, and other factors associated with disease progression and outcome.⁴

The natural history of disease helps in drug development for many diseases and disorders. For rare disease, natural history information is often incomplete. Therefore, NHSs are particularly needed for these diseases. IRDs are a group of rare diseases with low incidence, small number and scattered distribution. For example, retinitis pigmentosa is the most common type of IRDs, but its prevalence is only 1 in 4000–1 in 3000, and the patients are scattered.⁵ On the one hand, it makes professionals less knowledgeable and less aware of IRDs. On the other hand, IRD clinical studies were difficult and time-consuming to recruit patients, making it costly for companies to develop drugs. The atypical clinical phenotypes and high phenotypic heterogeneity of patients with IRDs in the early stages greatly affect the diagnoses and treatments of IRDs. The clinical heterogeneity of IRD is high, and patients have a wide variety of clinical manifestations that vary greatly in terms of age of onset, degree of visual impairment, rate of progression, and fundus changes. Specialized systematic studies are needed to understand the universality and specificity of the progression of a disease in different individuals, and which indicators or clinical outcomes can be used to evaluate the changes in treatment modalities for patients.

Most of the existing large-scale systematic natural histories of IRDs were based on European and American populations.^6,7 However, it has shown that the hotspot genes, lesion characteristics and disease spectrum of IRDs in Chinese populations are significantly different from those in Western populations.^2,8 It is necessary to establish a database of genetically related diseases in Chinese populations, which will help the discovery and mechanism of pathogenic genes of IRDs, reshape the disease classification and diagnosis system, and develop precise treatment and drug screening methods for IRDs.

In the past, researches on IRDs in China had been limited to a very small number of cross-sectional studies.² Chinese researchers had conducted the first prospective natural history of IRDs in China (ClinicalTrials.gov, NCT03691168) in 2018. However, there is still an urgent need to conduct a natural history based on the genetic background of our population to provide an in-depth and systematic observation of the clinical features and natural course patterns of IRDs in the Chinese population. To lay the foundation for gene therapy as well as clinically applicable therapeutic manipulation and efficacy evaluation.

2. Natural history of IRDs is the basis for accurate diagnosis of patients

Genetic variation is an important pathogenic factor in IRDs. The genes and mutations that cause IRDs are very complex and heterogeneous. Approximately 270 genes had been identified for IRDs.⁹ Most cases of IRDs are monogenic. However, only a fraction of IRDs cases had been able to identify the causative gene, and in many cases the causative variant in the coding region remains unidentified. It must be clarified that even for very clear pathogenic genes, some mutation types in their different regions may not be pathogenic. In addition, some genes have been poorly reported and the relationship between their mutations and IRDs needs to be confirmed by more NHSs.

Currently, the NHSs of IRDs in China is mostly cross-sectional studies. The discovery of new pathogenic genes and new mutation types of IRDs still need to be further improved. The ophthalmology professionals need to carry out more studies about the genetic pattern and pathogenesis of the IRDs deeply enough. The solution of these problems depends on the establishment of large-scale disease-specific cohorts and large population reference databases. It was important to fully utilize our abundant clinical resources in China to carry out prospective natural history based on the genetic background of the Chinese population. This will lead to the establishment of a national disease-specific cohort (including pedigree study and high-quality cohorts) and a biobank. To establish a large-scale population-based database of IRDs genotypes in China for the discovery of novel pathogenic genes and novel variants of IRDs specific to the Chinese population. Mapping the genetic map and genetic information transfer network of IRDs in the Chinese population. It will provide a basis for the precise diagnosis of IRDs and the development of downstream gene therapies that are more suitable for the Chinese population.

3. Natural history is an important basis for drug administration departments to make scientific evaluation decisions

Drugs for rare diseases had always been a weak link in pharmacy development due to low prevalence, relatively little medical research, and low economic benefit from research inputs and outputs. Several countries have issued a series of laws, regulations and preferential policies, which have greatly promoted the development of rare disease drugs. In 2018, China released the catalogue of rare diseases for the first time, and several ministries and commissions issued policies, which greatly accelerated the approval of rare disease treatment and drug development. As one of the rare diseases, the research on precise diagnosis and treatment of IRDs is at the right time. Many of the national drug regulatory authorities have emphasized the importance of natural history in the guidelines issued.

The U.S. Food and Drug Administration (FDA) has announced a draft guidance for industry entitled “Rare Diseases: Natural History Studies for Drug Development".¹⁰ The draft guidance is intended to help inform the design and implementation of NHSs that can be used to support the development of safe and effective drugs and biologics for rare diseases. It mentioned that NHSs collect information about the natural history of a disease without intervention, from the beginning of the disease to its resolution or the death of the individual. Understanding the natural history of a disease can help in drug development for many diseases and conditions, but for most rare diseases, natural history information is often unavailable or incomplete. Therefore, natural history information is particularly needed for these rare diseases.

At the end of last year, the Center for Drug Evaluation (CDE) of the National medical Products Administration (NMPA) of China released the “Guidelines for Clinical Development of Drugs for Rare Diseases” and the “Statistical Guidelines for Clinical Studies of Drugs for Rare Diseases",^4,11 which considered NHSs as important elements for clinical development programs. NHSs may provide creative solutions to overcome the outstanding difficulties in drug development for rare diseases. For patients, natural history could bring direct benefits to the rare disease community, including understanding and evaluating current treatments and care practices, improving patient care practices, facilitating subject recruitment by sponsors, and facilitating patient voice listening by regulators; from a commercial development perspective, high-quality NHSs can optimize trial protocol design and promote efficient study conduct, thereby reducing enrollment, as well as shortening study periods. From a commercial development perspective, high-quality NHSs can optimize trial protocol design and facilitate efficient study conduct, thereby reducing enrollment, shortening study duration, and saving R&D investment.

4. Natural history provided important guidance for relevant drug R&D and post-marketing using

A prominent feature of IRDs is the early age of onset and the younger age distribution of patients, who are mostly of labor force age. If these patients could be effectively treated, they can significantly improve the quality of life and reduce the burden on society. However, most patients of IRDs had no therapeutic drugs available globally. Although some drugs of IRDs were available outside of China. In addition, most of the drugs marketed abroad have been developed based on data from Western populations only. Considering the differences between Chinese and Western populations, there is a need to study the efficacy and safety of existing drugs for the treatment of IRDs in Chinese populations. On the other hand, there is an urgent need to develop drugs for IRDs based on data from the Chinese population. Several research groups and companies in China have already developed relevant gene therapy drugs for IRDs and realized original strategies for IRDs intervention (http://www.chinadrugtrials.org.cn, CTR20211179), which is expected to establish a new paradigm for the development of new drugs for IRDs intervention.

The clinical development of IRDs-related gene therapy drugs has its own uniqueness due to the low incidence. Moreover, the difficulty of drug development was much more than that of age-related macular degeneration (AMD) and other common diseases. Due to the wide variation in the length of disease, severity of clinical manifestations and age of onset in IRDs patients, it is difficult to define the optimal window for gene therapy. Clinical trial endpoints for gene therapies for IRDs might not be designed exactly with reference to common eye diseases. Last year, Biogen announced the failure of its Phase II/III clinical study, codenamed XIRIUS (ClinicalTrials.gov, NCT03116113), due to failure to meet the primary clinical endpoint. The study was designed to evaluate the efficacy of the gene therapy cotoretigene toliparvovec (BIIB112) in the one-time treatment of patients with X-linked retinitis pigmentosa (XLRP). The results of this study did not demonstrate a statistically significant improvement in the proportion of treated study eyes with clinically meaningful improvement assessed by Macular Integrity Assessment (MAIA) microperimetry, and thus failed to meet its primary endpoint. But positive trends were observed in several clinically relevant pre-defined secondary endpoints. Therefore, the drug development and efficacy evaluation of IRDs should follow the general drug development rules, in addition to closely integrating its own disease characteristics.¹² This includes patient population identification, efficacy threshold determination, study endpoint selection, biomarker development, control selection, etc. The combination of data from early clinical studies and data from the natural history of the disease can scientifically constitute a sound and logically adequate chain of evidence to support the later development of drugs.

5. Natural history could help expand the indications for gene therapy

Gene therapy researches are currently focused on rare monogenic genetic diseases and oncology.¹³ Several gene therapy clinical trials of AMD targeting the key causative factor, vascular endothelial growth factor (VEGF), have yielded encouraging results. In one clinical trial AMD patients achieved significant improvements in visual acuity after subretinal injections with AAV8 delivering anti-hVEGF antibody (ClinicalTrials.gov, NCT03066258). It suggested that gene therapy was not used only for rare diseases. The development of orphan drugs was favored by many innovative companies because they are more targeted, have fewer enrolled cases and are less difficult to obtain approval than common diseases. These companies typically obtain approval for orphan drugs first and then extend them to general diseases (i.e., new indications) before developing them into general drugs. With the increasing understanding of diseases and the emergence of new technologies and theories, the future promises the expansion of gene therapy to common eye diseases such as diabetic retinopathy and viral keratitis. Gene therapy can provide a new way of drug delivery for diseases that require continuous drug administration.

In summary, gene therapy for IRDs is different from conventional therapies and poses higher requirements for related clinical study design and drug development. Research and drug development related to gene therapy for IRDs in China is currently in its infancy. A few natural histories of IRDs have been conducted in China, and there is an urgent need to conduct more NHSs of IRDs on the genetic background of Chinese people. Gene therapy brings hope for the treatments of rare eye diseases. And it is an inevitable trend for the development of gene therapy from rare diseases to common diseases. We should seize the opportunity to carry out the NHSs of IRDs and drug developments based on the genetic background of Chinese population. To explore the clinical characteristics and pathogenic gene network of IRDs in the Chinese population, and develop original gene therapies.

Study Approval

Not Applicable.

Author contributions

The authors confirm contribution to the paper as follows: Conception and design of study: XS; Data collection: TL, JC; Analysis and interpretation of results: WL, JC; Drafting the manuscript: WL, TL, XS; All authors reviewed the results and approved the final version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (82171076, 82101168), the Science and Technology Commission of Shanghai Municipality (20Z11900400), and the Shanghai Hospital Development Center (SHDC2020CR2040B, SHDC2020CR5014).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.