Drug development for rare and orphan diseases
The drug development process for rare diseases
Orphan diseases do not benefit from viable treatments for their patients. Primarily linked to genetics, rare diseases are often called orphan diseases as a result of the economic difficulties to create new treatments that very few patients will benefit from. Therapeutic care of rare diseases often consists in managing symptoms and limiting the disease’s progression in order to improve the patient’s quality of life. However, progress in gene therapy now allows patients to benefit from biopharmaceuticals.
The production of biodrugs is complex, since it involves manipulation of weak living agents (cells, proteins, DNA…). It globally includes a first phase of cell culture derived from a unique cell line, then a phase of isolation and purification of the wanted therapeutic agents, and finally a phase where the pharmaceutical form is produced.
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Saving time in the experimentation phase
Access to the best in vivo and in vitro models to develop your project
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In vivo models
In vivo model tests are performed on animals. They may be part of the proof-of-concept validation or may be performed for the regulatory dossier. Typically, in vivo tests will study the physiological and behavioral aspects, as well as the toxicity of the molecules being studied.
In vitro models
Tests on in vitro models are generally part of the pre-clinical study phase of drug development. They are used to test compounds by studying their effects on defined targets and functions. The robustness of in vitro tests is a determining factor for their use in R&D projects.
HCS & HTS screening
High throughput screening (HTS) or high content screening (HCS) are techniques that aims at studying and identifying, within chemical and target libraries, molecules with novel and biologically active properties. Screening consists of using a large number of molecules in a biochemical or cellular test, which must be particularly robust, reproducible, and if possible inexpensive.
The biochemical model is used in the discovery of candidates. The advantage of this type of model is to limit the number of molecular actors, and thus validate a target or mechanism of action. FRET and HTRF techniques applied to biochemical models are particularly effective in studying the phosphorylation and signalling pathways of molecules.
In silico studies
In silico studies correspond to the modelling of biological phenomena, such as the interaction between several molecules or a change in the structural conformation of an active domain. This analysis is relevant upstream of more expensive studies, or when classical chemical methods have reached their limits.
Tools for innovative therapies
ATMPs (Advanced Therapy Medicinal Products) are medicines based on genes, tissues or cells for human use. They offer revolutionary new possibilities for the treatment of diseases and injuries.
Molecules synthesis and optimization
The development of a "small molecule" drug candidate requires tools directly derived from chemistry. In this case, the de novo synthesis of the molecule, the search for candidates in chemical libraries, and the possibility of modifying these molecules by labelling techniques.
Formulation and galenic
Formulation is a critical step in drug development and partly determines the success of a drug's market entry. The aim is to propose the solution best suited to the nature of the pharmaceutical ingredient candidates, their therapeutic target and the route of administration envisaged.
Regulatory studies and assays
Pharmacokinetics studies the fate of an active substance of a drug after its administration in an organism. It consists of four phases: absorption, distribution, metabolism and excretion of the active ingredient (ADME). Different tests, in vitro and in vivo, exist to answer these pharmacokinetic questions.
The different stages of drug development
Chemical drugs are often used to manage and relieve the symptoms of rare and orphan diseases. Each drug development follows a unique process, in terms of drug candidate identification, validation and optimization, pre-clinical and clinical protocols and marketing. There are, however, some broad outlines in the drug development phases, which are described here.
Discovery - 2-4 years
Pre-clinical - 1-2 years
Measurement of ADME(Absorption, Distribution, Metabolism, and Elimination): potency tests, solubility, LogD, Caco-2 permeability, CYP inhibition, etc.
Measurement of pharmacokinetics and pharmacodynamics PK/PD
Structural optimization and synthesis (chemical or bioproduction)
Selection of candidates
The different types of providers
The different drug development phases involve a large number of actors with different capacities.
Academic structures are involved in the development of drugs, particularly at the level of the in vitro and in vivo studies they can propose.
Some very expensive equipment may also be required (e.g. for mass spectrometry or robots for HTS screening) - in this case, academic platforms may be asked by private companies to support them.
Service companies for experimentation
Many service companies produce tools in drug discovery or development. This concerns in vitro tests for example, or formulation optimization. Other companies are specialized in regulatory testing, such as PK/PD and toxicity experiments.
These companies are often required to work under Good Laboratory Practice (GLP) conditions.
Service companies for production
Anticipating the drug production during its development is an early process: a marketed molecule has to be manufactured in very particular conditions (good manufacturing practice, GMP). The GPM production is not necessary for research use and preclinical studies, but commercial and clinical batches have to meet the GMP conditions.
What defines a cell model?
Cell models, if appropriately designed, can be used to rapidly identify the molecular mechanisms of human diseases and develop new therapies.
The design of a robust, reproducible, relatively easy-to-read test (it should use quantifiable molecular markers) is particularly appropriate when using a molecule library for high-throughput screening.
As soon as the model is designed, the experimenter raises the question of how to quantify the expected effect: either by molecular markers or by phenotypic observation.
A molecular marker that is well identified and characterized in a pathology or cellular process has the great advantage of limiting observations linked to an indirect effect.
The FRET technique typically proves to be relevant when studying conformational changes (e.g. intracellular nuclear receptors), aggregation (especially in neurodegeneration), or measurement of receptor-ligand interactions. FRET is based on the transfer of energy between two fluorophores, possible when the two molecules are physically close. Other methods for measuring molecular markers, such as qPCR or dPCR for modulation of gene expression, ELISA or Western Blot for protein quantification, etc., are also available.
Microscopy and imaging in general are useful in phenotypic studies.
The technologies used in drug development
Cell culture & in vitro tests
Imaging on organisms
HTS and HCS screening
Prediction in silico
Cloning, sequencing, recombinant expression
Estimated rates for this type of services
A few hundred to a few thousand euros for a non-regulatory in vitro test.
An in vivo test can be between € 8,000 and € 100,000.
Outsourced HTS screening can cost between € 50,000 and € 100,000, an HCS screening can cost up to double, depending on the number of molecules tested.
Formulation optimization can cost several tens of thousands of Euros for in silico studies, and several hundreds of thousands of Euros for optimization by synthesis and validation.
Regulatory toxicity studies are very expensive and vary considerably depending on the test required.