Advanced Therapy Medicinal Products (ATMPs)

Overview

Advanced Therapy Medicinal Products (ATMPs) are medicines for human use based on genes, tissues, or cells.
They offer new opportunities for treating diseases and injuries.

Types of ATMPs

1. Gene Therapy Medicines

Contain genes that lead to a therapeutic, prophylactic, or diagnostic effect.
Work by inserting recombinant genes into the body to treat genetic disorders, cancer, and long-term diseases.
A recombinant gene is a stretch of DNA created in the lab from different sources.

2. Somatic-Cell Therapy Medicines

Contain cells or tissues that have been manipulated to change their biological characteristics.
Include cells or tissues not intended for the same essential functions in the body.
Used to cure, diagnose, or prevent diseases.

3. Tissue-Engineered Medicines

Contain cells or tissues modified to repair, regenerate, or replace human tissue.
Some ATMPs may contain one or more medical devices as an integral part (combined ATMPs), e.g., cells embedded in a biodegradable matrix or scaffold.

Regulatory Compliance

Good Manufacturing Practice (GMP): Required during manufacturing and storage to ensure product stability, reproducibility, and patient safety.
Good Distribution Practice (GDP): Required during transport to the clinical site.
Good Laboratory Practice (GLP): Required for pre-/non-clinical animal testing.
Good Clinical Practice (GCP): Required for clinical trials to ensure patient safety and clinical efficacy.
Combined ATMPs are regulated by the Medical Devices Regulation ((EU) 2017/745) and ATMP regulation.
ATMPs are regulated by the Medicinal Products Directive 2001/83/EC and Regulation (EC) No 726/2004.
The first ATMP was launched in the EU market in 2009; to date, a total of 24 ATMPs have been approved.

ATMP Classification

Gene-Based Therapeutic Medicinal Products

Definition: Gene transfer-based approaches leading to a therapeutic, prophylactic, or diagnostic effect.
Applications: Inherited diseases, cancer therapy, tissue regeneration (e.g., eyesight).

Somatic Cell Therapeutic Medicinal Products

Definition: Cell-based approaches including in vitro manipulation of cells or tissues with therapeutic, prophylactic, or diagnostic effect.
Manipulation: Cells from a donor behave differently in the patient due to “substantial manipulation” steps outside the body and/or due to a different essential function in the patient compared to their original role in the donor.
Applications: Products against immune diseases, Parkinson’s, Alzheimer’s, ALS, cartilage, cardiac repair, skin, cancer immunotherapy.

Tissue-Engineered Medicinal Products

Definition: Tissue engineered-based approaches applied to repair, regenerate, or replace human tissues or organs.
Applications: Small diameter vascular grafts, trachea replacement, liver and kidney implantation, nerve repair.

Goals and Characteristics of ATMPs

Main Goal: Treat incurable, orphan, and chronic diseases that traditional drugs cannot treat.
Application Fields: Genetic and metabolic diseases, degenerative neurological diseases, malignancies and hematological diseases, serious cardiological and orthopedic cases.
Regenerative Medicine: Action for the regeneration of damaged tissues is responsible for the rapid development of regenerative medicine.
Development Origin: Result of extensive work of academic and research centers without pharmaceutical company involvement.
Early Implementation: Applied in small-scale clinical trials or as consolation therapy due to the lack of a comprehensive regulatory framework.
Heterogeneity: Characterized by great heterogeneity related to the origin of raw material (human biological material).
Variation: Great variation in methods of isolation, culturing, and processing/modification of tissues and cells.
Administration Methods: Cover the spectrum from a single intravenous injection to surgical placement.

Gene Therapy in Detail

Gene Therapy Medicinal Products (GTPs)

Design: Designed to introduce a nucleic acid sequence into cells to replace or compensate for abnormal gene expression and to express a therapeutic protein.
Techniques:
- Gene Therapy: Adds a functional version of the defective gene inside the cells.
- Gene Editing: Corrects or edits the defective gene by making a local modification in the genome to restore its function.
Ideal Genetic Therapy: Should fix defective genes without activating oncogenes or causing off-target effects or immune or inflammatory reactions.
Proto-oncogenes: Genes responsible for cell growth and proliferation; mutation can turn them into oncogenes, promoting uncontrolled cell growth.

Adverse Effects of Genetic Therapies

Development of acute T cell lymphoblastic leukemia has been reported.
Off-Target Effects: Unintended modifications in the DNA that occur when gene editing unintentionally modifies a non-target area.
Genotoxicity Risks: Include disruptive insertions and deletions, loss of chromosomal material, bystander edits, and off-target editing.
Immune Reactions: Most common adverse effects; occur when the body recognizes an exogenous substance as harmful and responds with an inflammatory reaction.

Gene Therapy Requirements

Requires knowing the genetic defect causing the disease.
Requires providing the cell with a functional copy of the missing or defective gene.
Requires genetic engineering manipulations.
Promoter: A short DNA sequence which regulates the expression of the gene; added to the gene if specific types of cells are desired to express the protein.
Vector: Transports the gene-drug to the nucleus.

Gene Therapy Delivery Methods

Ex Vivo: Cells are taken from the body, modified in a lab, and put back into the body.
In Vivo: Viruses or other methods deliver genes directly into the cells.

Types of Gene Therapy

Somatic Gene Therapy:
- Occurs in the somatic cells of the human body.
- Therapeutic genes are transferred into the somatic cells or the stem cells.
- Considered the best and safest method.
Germline Gene Therapy:
- Occurs in the germline cells of the human body.
- Used to treat genetic, disease-causing variations of genes passed from parents to children.
- Involves introducing a healthy DNA into the cells responsible for producing reproductive cells.
- Not legal in many places due to risks outweighing the rewards.

Somatic Cell Therapy in Detail

Characteristics

Heterogeneity and Complexity: Resulting from different source tissues of the cells, the original differentiating stage of the starting material (stem cells or somatic cells), the varying differentiation capacity of the cells and multiple differentiation stages, the manipulation method(s) performed on the cells, the variability of the exogenous genetic sequences expressed into the cells and the different delivery systems used.
Combined ATMPs: May contain medical devices (e.g., biodegradable matrix or scaffold).
Cell Isolation:
- Autologous Cell Therapy: Cells isolated from the same patient to be treated.
- Allogeneic Setting: Cells arise from a donor; can be manipulated to obtain the same function of tissue of origin (homologous clinical use) or used for non-homologous use if they are applied in the recipient to exert a different function.
Stem Cell Therapy: Exploits the self-renewal property and multilineage, differentiating capacity of embryonic or adult stem/progenitor cells to regenerate damaged cells and tissues when transplanted in the recipient or to replace compromised cells with fully functional cells.
Non-Stem Cells: Terminally differentiated cells (fibroblasts, chondrocytes, keratinocytes, hepatocytes, pancreatic cells) with reduced proliferating activity; mainly related to repairing a compromised function in the recipient cells.
Immune System Cells: Mainly used with the purpose of immunotherapy.
CAR-T Cell Therapy: Classified as cell-based gene therapy; entails genetic modification of patient’s T-cells to express a gene for a receptor (chimeric antigen receptor, or CAR) specific for a tumor antigen, followed by ex vivo cell expansion and re-infusion back to the patient.
Pharmacotherapeutic Groups: Key groups include antineoplastic agents, immunosuppressants, ophthalmologicals, and disorders of the musculoskeletal system.

Clinical Trials and Approved Products

To date, 142 clinical trials using cell therapies (27 of phase 3) have been conducted in the EU; however, conditional marketing authorization has been granted only for five products.
Alofisel (darvadstrocel):
- Approved in 2018 as an orphan drug.
- Based on expanded mesenchymal adult stem cells isolated from adipose tissue.
- Indicated for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn’s disease when fistulas have shown an inadequate response to at least one conventional or biologic therapy.
- Exerts immunomodulatory and anti-inflammatory effects at inflammation sites by impairing proliferation of activated lymphocytes and reducing the release of pro-inflammatory cytokines.
Ebvallo (tabelecleucel):
- Approved in 2022 as an orphan drug.
- Based on Epstein-Barr virus (EBV)-specific T-cell immunotherapy.
- Indicated for the treatment of adult and pediatric patients ≥2 years of age with relapsed or refractory (r/r) EBV positive post-transplant lymphoproliferative disease who have received at least one prior therapy.
- The T-cell receptor recognizes an EBV peptide, exerting cytotoxic activity against the EBV-infected cells.

Conditional Approval and Monitoring

Alofisel and Ebvallo have been authorized with conditional approval and are under additional monitoring.
The marketing company is required to carry out additional studies for long-term effectiveness and safety data.
Alofisel Trial Results:
- Statistically significant difference in combined remission at 6 months in the active (52%) and placebo (35%) groups.
- Common adverse events included infections and gastrointestinal disorders.
- Real-world study (INSPIRE) showed clinical remission at 6 months in 65% of patients.
Ebvallo Results:
- Objective response rate of 56% in patients with previous solid organ transplant and 50% in those with previous hematopoietic cell transplant.
- Special warnings include tumor flare reaction, transplant rejection, cytokine release syndrome, neurotoxicity syndrome, and infusion-related reactions.

Hematopoietic Stem Cell Transplant (HPSCT)

Involves administering healthy hematopoietic stem cells to patients with dysfunctional or depleted bone marrow.
Benefits:
- Augments bone marrow function.
- Destroys malignant tumor cells.
- Generates functional cells to replace dysfunctional ones.
Used to treat malignant and non-malignant conditions like immune deficiency syndromes and hemoglobinopathies.
Survival rates are increasing, but morbidity due to complications continues.
Serves as a platform for cell therapies.

Approved Cell Therapy Products in the EU

ChondroCelect (viable autologous cartilage cells):
- Approved for repair of single symptomatic cartilage defects of the femoral condyle of the knee.
- Histological examination showed superior structural repair; clinical outcome measure KOOS improved.
Provenge (sipuleucel-T):
- Approved for treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer.
- Statistically significant improvement in overall survival.
Zalmoxis (nalotimagene carmaleucel):
- Approved as adjunctive treatment in haploidentical hematopoietic stem cell transplantation.
- Immune reconstitution was found in 77% of patients.
Alofisel (darvadstrocel):
- Approved for treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease.
- Phase 3 study showed combined remission (52% vs. 35%).
Ebvallo (tabelecleucel):
- Approved for the treatment of adult and paediatric patients ≥2 years of age with relapsed or refractory Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD) who have received at least one prior therapy.
- Phase 3 single-arm study showed an objective response rate.

CAR-T Cell Products Approved in the EU

Kymriah (tisagenlecleucel):
- Treatment of paediatric and young adult patients up to and including 25 years of age with B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse
Yescarta (axicabtagene ciloleucel):
- Treatment of adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy
Tecartus (brexucabtagene autoleucel):
- Treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy
Breyanzi (lisocabtagene maraleucel):
- Treatment of adult patients with DLBCL and high-grade B-cell lymphoma (HGBL) that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy
Abecma (idecabtagene vicleucel):
- Treatment of adult patients with relapsed and refractory multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and have demonstrated disease progression on the last therapy
Carvykti (ciltacabtagene autoleucel):
- Treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and have demonstrated disease progression on the last therapy

Comparison of Autologous and Allogeneic CAR-T Therapies

Autologous:
- High compatibility with the patient's immune system.
- Strong efficacy in clinical trials.
- Challenges include on-demand manufacturing, high cost, and poor manufacturing reliability.
- Future direction involves centralized commercial cell therapy manufacturing centers and closed-system, automated manufacturing.
Allogeneic:
- Universal,