Advanced therapies (Advanced therapy medicinal product or Atmp) represent a major medical innovation and include a multiplicity of medicinal products defined by Regulation 1394/2007 of the European Parliament and Council on advanced therapy medicinal products containing the amendments to Directive 83 of 2001 and Regulation 726 of 2004. These particular medicines are innovative biological products, divided into four categories:
- Gene therapy – Contain or consist of a recombinant nucleic acid capable of inducing a therapeutic, prophylactic or diagnostic effect in individuals with genetic diseases in which a gene is defective or absent;
- Somatic cell therapy – Contain or consist of cells or tissues manipulated in a way that changes their biological characteristics, physiological functions, or structural properties. The cells or tissues can be of autologous origin (derived from the patient himself), allogeneic (obtained from a donor) or xenogenic (derived from a donor of an animal species other than humans);
- Tissue engineering – Contain cells or tissues that have been subjected to significant manipulation or are not intended to be used for the same original functions in the body, with the aim of repairing, regenerating or replacing human tissue;
- Combination therapy – Contain cells or tissues that have been subjected to significant manipulation or are not intended to be used for the same original functions in the body, with the aim of repairing, regenerating or replacing human tissue
Advanced therapies are considered the new frontier for the treatment of various rare genetic and oncological diseases, which have no therapeutic alternatives after the failure of classic treatments.
What impact from advanced therapies?
The clinical use of these medicines, some of which have already been approved by the European Medicines Agency (EMA), is revolutionizing the evolution of many diseases such as:
- Spinal muscular atrophy (SMA), a serious neuromuscular disease with no cure prospects, in which gene therapy has demonstrated significant improvements in survival and motor function in patients, especially in children treated early;
- β-thalassemia, in which the use of patients’ hematopoietic stem cells modified with Crispr/Cas9 gene editing technology, allows the production of increased levels of fetal hemoglobin, compensates for the deficiency of adult hemoglobin and consequently reduces the dependence on transfusions and improving the quality of life of patients;
- Mantle cell lymphoma, acute lymphoblastic leukemia and Hodgkin lymphoma, in which treatment with genetically modified T lymphocytes (Car-T) has brought excellent results, with complete disease remission of 62, 81 and 54 percent respectively one hundred and one long-term survival;
- Melanoma, where patients with metastatic disease treated in a phase 2 trial with tumor-infiltrating lymphocytes (TILs) showed an overall response rate of 36 percent and in some cases durable remission (as described on subsequent pages) .
Furthermore, very encouraging and promising results have recently been obtained in the treatment with Car-T cells of some autoimmune diseases such as systemic lupus erythematosus, idiopathic inflammatory myositis and systemic sclerosis.
Compared to what is recorded in the field of genetic and oncological diseases, the development of advanced therapies is further behind in the field of neurodegenerative diseases. Clinical trials are currently evaluating the efficacy and safety of various approaches, with encouraging preliminary results (in multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis). However, studies are still needed to fully understand the mechanisms of these diseases and to develop effective and long-lasting therapies.
The numbers of research on advanced therapies in the world
Based on this scientific evidence, it is estimated that over 500 thousand patients worldwide will be treated with advanced therapies by 2030 worldwide and that the compound annual growth rate for the cell therapy industry will be over 17 percent in five-year period 2024-2029.
There are currently 4,565 cell therapy trials registered and over forty percent of them are planned or ongoing. Up to sixty new gene and cell therapies could be brought to market globally in the near future.
At the end of 2020, there were over 1,200 clinical trials on gene, cell or tissue therapies underway around the world, of which approximately 150 were already in phase 3. Planned and ongoing clinical trials are predominantly in the early testing phases.
Advanced therapies: what role for Italy?
In Italy, although there are fifteen academic/hospital workshops authorized for the production of advanced therapies and four private production sites. However, the entire journey still encounters many problems: from the pre-clinical and clinical phase to that of access and sustainability. Obstacles that create difficulties in ensuring that these therapies bring about a concrete benefit for the patient. One of the most complex challenges is to make these medicines sustainable for the Italian healthcare system. This game can only be won by acting with a multidimensional approach: involving different strategies at the level of research, development, production, regulation and distribution. It is essential that in our country research in the field of advanced therapies – which often begins in academic laboratories – continues to grow. But to pursue this goal, changes and incentives are needed. A key factor for the development and sustainability of advanced therapies is represented by the manufacturing (production) of these medicines, which requires complex and multi-step production processes (cell manipulations, genetic modifications, tissue cultures). Without forgetting that a batch of product almost always corresponds to just one specific treatment. Manufacturing must meet strict regulatory requirements that vary from country to country, further complicating the process and distribution. Going from small (for clinical trials) to large scale (for market) is another significant challenge. The production complexity, together with that of logistics and the supply chain, significantly affects the (high) costs of these therapies. Another fundamental element for the development of this sector is the need for highly qualified personnel capable of managing complex processes and ensuring product quality.
Five moves to become protagonists in the advanced therapies market
The future, therefore, cannot ignore these advances:
- implementation and adoption of automation systems and closed systems that will increase the efficiency and reproducibility of production processes, also improving product quality while reducing costs;
- use of development and adoption of standardized production protocols;
- collaboration between academic bodies, research institutes and biotech companies to share knowledge, infrastructure and resources;
- investment in the continuous training of staff to ensure they are updated on the latest technologies and production practices, as well as in the creation of specific training paths through university courses, masters and doctoral programmes;
- use of flexible production platforms that can be quickly adapted to production needs, allowing various types of therapies to be managed without the need for substantial structural changes. These platforms will thus be able to facilitate scalability, standardization and speed of response to market needs.
Decentralize advanced therapies
Another aspect of fundamental importance, which could impact sustainability, is the decentralization of the production of advanced therapies. The European regulatory authority is working to identify the appropriate regulatory tools to guarantee the reproducibility and safety of the processes. This step could represent an interesting possibility for academic/hospital workshops, which could form alliances with private companies in order to make these advanced therapies accessible to an ever-increasing number of patients (also guaranteeing proximity to treatment). Italy will be able to play a leading role in the production and treatment in this area only if it manages to implement strategies that involve investments in innovation and biotechnological research, support policies, collaboration between public and private and development of infrastructure. The streamlining of regulatory pathways by the Italian Medicines Agency (Aifa) and the European Medicines Agency (EMA) will also be fundamental to speed up the approval of advanced therapies. Far from being the future, the challenge of advanced therapies is already our present: the sooner we face it, the more chance we will have of improving the lives of patients and the scientific authority of our country.
* Massimiliano Petrinicell factory manager of the Romagna Institute for the Study of Tumors (IRST) Dino Amadori of Meldola
