Biologics and advanced formulations II

what is the current ATMP landscape

• as of october 2024 19 regulatory approvals in the UK

• december 2023 175 ATMP clinical trials ongoing

• majority of ATMP clinical trials were GT products followed by SC and TE products

• majority of the cell therapies were autologous 74% compared to 26% allogenic

what is the definition of gene therapy medicinal product

• it contains an active substance which contains or consists of a recombinant nucleic acid use in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence

• therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains or to the product of genetic expression of this sequence

what is the definition of somatic cell therapy medicinal product

• contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used or the same essential function in the recipient and the donor and

• is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues

what is the definition of a tissue engineered product

• contains or consists or engineered cells or tissues and

• is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing human tissue

what are gene modified cell therapies

• extract cells from a patient/ donor

• look under a microscope

• mrna virus to modify them

• new cells produced are then grown and administered to a patient

what is the definition of autologous therapies (SC therapies)

• they are cells from the patient

• cells are then modified, grown and injected back into the patient

what is the definition of allogenic (sc therapies)

• cells from a healthy donor

• then injected into a patient

what are 4 examples of viral vectors

• adenovirus (non integrating)

• AAV (non integrating)

• y- Retrovirus (integrating)

• Lentivirus (integrating)

what is in vivo modification

• modify the virus and inject it directly into the patient

• do not want it to integrate into the host genome

• transient expression

what is ex vivo modification

• remove cells from the host

• modify them with viruses containing the therapeutic gene

• engineered cells contain the therapeutic gene

• integration into the genome

• stable transfection

what is the process of producing CART cells

• remove blood from patient to get T cells

• mix t cells with virus, transfect T cells with virus

• virus carries genetic instruction to grow the CAR receptor

• Make CAR t cells in the lab by inserting the gene for CAR (chimeric antigen receptor)

• grow millions of car T cells

• (IV) infuse CAR T cells into the patient

• CAR T cells bind to cancer cells and kill them

what are CAR T cells

• genetically modified T cells that are designed to target and destroy specific cancer cells

• chimeric antigen receptor T cells

what are examples of approved CAR T cell therapies

• Kymriah (Novartis) relapsed or refractory B cell acute lymphoblastic leukaemia in people aged up to 25 years old.

• relapsed or refractory B-cell lymphoma in adults after 2 or more systemic therapies

Yescarta (Gilead)

• diffuse large B-cell lymphoma and primary mediastinal large B cell lymphoma after 2 or more systemic therapies

Zolgensma

• spinal muscular atrophy

what is Kymirah

• genetically modified autologous cell based product containing T cells

• transduced ex vivo using a lentiviral vector expressing an anti-CD19 chimeric antigen receptor

• medicinal product is packaged in one or more infusion bags

how must Kymirah be stored

• it must be stored and transported at <120 degrees in a container for cryogenic storage in the vapour phase of liquid nitrogen

• must remain frozen until the patient is ready for treatment to ensure viable cells are available for patient administration

what are potential toxicities of CAR-T therapy

• CAR-T cell therapies lead to the release of IL-6 cytokines

• leads to cytokine release syndrome

• neurotoxicity (delirium, aphasia, seizured, cerebral oedema)

• Hemodynamic instability (tachycardia, hypotension, capillary leak syndrome)

• organ dysfunction ( AST and ALT elevation, hyperbillirinemia, respiratory failure)

• increased vascular permeability

• altered blood brain barrier

• first line of treatment is a mAb - dose in clinical trial range from 4-8mg/kg

what cells does somatic cell therapy use

• adult cells autologous or allogenic

• adult stem cells (multipotent) ChondroCELECT

• differentiated cells: dendritic cells, cancer immunotherapy

• embryonic stem cells (pluripotent), blindness, spinal injury

• Induced pluripotent stem cells (iPS cells)

• xenogenic cells

what is ChondroCelect

• vial contains 4 million autologous Hu cartilage cells suspended in 0.4ml DMEM media

• 48 hour shelf life

• store 15-25 degrees, do not refrigerate

• prior to implantation match patients name to the patient/ donor

• if vial is damaged or its sterility has been compromised return to the company

tissue engineering products may contain

• cells or tissues of human or animal origin or both

• the cells or tissues may be viable or non viable

• additional substances such as scaffolds or matrices

what are examples of tissue engineered products

• in vitro cultured skin ( repair for burns of chronic wounds)

• beo-organs (corneal, blood vessel, liver, cartilage or bone tissue)

• tissue engineered trachea

what are implications for pharmacy

• regulation MHRA, HTA, GTAC, HSE, DEFRA, HFEA

• clear tracability from manufacture to recipient

• contracts with clear responsibilities between manufacture/ tissue establishment

• records to be kept for 30 years

• patient alert card

• Handling cryopreserved -160

• shelf life

• biosafety class/ containment level

• spillages

• decontamination/ inactivation

• waste management

• shedding

• temperature monitoring

• Toxicity/ pharmacovigilance

• cytokine release syndrome

• safety reporting

• long term follow up/ unknown risks

what are the three types of ATMPS

• gene therapy

• somatic cell therapy

• tissue engineered products