November 2018 Newsletter

The Drug Development Pathway

TAT-CF project is focused in the discovery and development of a novel potential therapy (drug) for Cystic Fibrosis treatment. This means a great challenge, as any future drug has to follow a  rigorous development pathway before being approved to reach the markets and be used by the patients, and sometimes is not well known/understood by society and patients. In the case of small molecules based drugs, like those addressed by TAT-CF the full development may last for between 10 and 15 years, to cover all the subsequent phases from idea to clinical practice. Moreover, around nine out of every ten drug candidates fail to win approval. In any case, these failures may give also valuable knowledge for other developments, other indications for the drug, etc. During early clinical trials of sildenafil, a drug candidate originally intended for angina, male volunteers taking the pills consistently reported unprovoked, long-lasting erections. At the end this candidate is now better known by its trade name Viagra. The main steps of this challenging pathway are the following:

The generation of an idea. The importance of basic research
Long before a new drug can even be imagined, scientists are working to gain a basic understanding of chemistry, biology, disease mechanisms and how to connect all these pieces to solve the puzzle. In the case of TAT-CF, after relating ionic transport of ionophores and CF as a disease, hundreds of compounds have been synthesized, tested, and prioritized depending on their results. This idea has to be validated, as a firsts proof of concept, in the case of TAT-CF this includes the use of models mimicking the cellular behavior (i.e. vesicles). Computer models also help at this stage, these approaches also known as “in silico” trials are gaining importance to reduce
experiments and costs.

Preclinical Research
Once one chemical compound or a reduced number of them have proven their potential, the development pathway enters the next step, the preclinical research. Some research may be performed in vitro, using, for example, cell cultures. TATCF has applied this approach, complemented with a more innovative one, the use of 3D cell models, also known as organoids, which allow getting better, more representative results. Compounds which offer promising results in in vitro will be tested using animal models (in vivo tests). Researchers can use healthy, wild type animals to determine drug candidate safety, potential toxicity, tolerated dose, absorption, distribution, metabolism and excretion. More recently, genetically modified animal can be used to test efficacy, reproducing disease models in those mutant animals. In the case of TATCF, we have tried to rationalize and reduce the use of animals as much as possible, while obtaining valuable biodistribution, toxicity (using different routes of administration) and efficacy in mutant CF mice.

Formulation & Manufacturing
In parallel to preclinical research, it is necessary to get a formulation suitable to be administered through the selected route. Thismay include the use of excipients or even more sophisticated approaches, like the use of micro/nanoparticles that have been explored in TAT-CF to maintain/improve efficacy while reducing toxicity.

Clinical Research
Once a solid preclinical evidence exists, the drug candidate will be tested in humans. This step includes subsequent phases, Phase I clinical trials aim to determine safety, Phase II confirm safety and get efficacy data in a limited amount of patients, and, finally, Ohase III clinical trials involve a bigger number of patients. Once the drug is in the market, Phase IV clinical trials and pharmacovigilance monitors adverse events which may appear when the drug is applied to the overall patients population.

Regulatory approval of TAT-CF like compounds

The United States Food and Drug Administration is a federal agency of the United States Department of Health and Human Services. FDA is responsible for preserving and fostering public health by regulating and controlling products pertaining to different categories: foods, drugs, biologics, medical and electronic devices, cosmetics, and veterinary and tobacco products. Concerning drugs, FDA follows a thorough and strict protocol to approve their commercialisation. This article is focused on the drugs approved by FDA in 2017 and the features they have in common with the compounds that have been prepared within the frame of our European Commission-funded project.
The whole drug development process can take between 15 and 20 years, and from the beginning to the end of it the number of candidates decreases dramatically. As commented previously, it is common to start the process with thousands of compounds and to finish it with only one. Every year the agency approves a small number of drugs for medical treatment; for instance, in 2017 FDA approved 46 new formulations, representing a 20-year peak in industry productivity. More than 25% of them find their application in cancer therapy, whereas around 40% of them are aimed at treating diseases that affect fewer than 200,000 people.[2] Interestingly, almost two thirds of the active ingredients of the drugs approved last year are small molecules. This trend fits very well with our project, as our goal is to develop a therapy to treat cystic fibrosis, a rare disease, based on small-molecules.
The compounds synthesised within the frame of our project, although pertaining to different families, have something in common: they possess hydrogen-bond donor groups that may interact with a hydrogen-bond acceptor, e. g., an anion. Some of them are charged (tambjamine- and prodiginine-like compounds) and some of them are neutral (thioureas and squaramides), but all of them contain N-H fragments able to establish hydrogen-bonding interactions with anions such as chloride and bicarbonate. Cystic fibrosis comes from the defective transport of those anions through the cell membrane due to the malfunction of CFTR (cystic fibrosis transmembrane conductance regulator), a transmembrane protein,[3] hence the necessity for the drugs designed to fight against this disease to bear groups that can interact with anions.
Among the 46 drugs approved by FDA in 2017 there are charged and neutral compounds. In Figure 2 three examples are shown, the names of their active ingredients highlighted in bold. Xadago and Macrilen are indicated to treat Parkinson’s disease and adult growth hormone deficiency, respectively, while Benznidazole is indicated for Chagas disease.[2] These compounds share some features with those displayed in Figure 2: they are small molecules, either charged (Xadago and Macrilen) or neutral (Benznidazole), possess hydrogen-bond donor groups (N-H fragments) and incorporate aromatic and/or heterocyclic (indole in Macrilen and imidazole in Benznidazole) residues.

Figure 1: Three examples of drugs approved by FDA in 2017 (the names correspond to the drug’s active pharmaceutical ingredient).

There are more complex structures, and sometimes the drug is a combination of several active ingredients. For more information, the reader is referred to the corresponding webpage,[2] where in addition to the structures of most of the active ingredients the approved drugs are made of, the applicant company and the disease they are indicated for and their mechanism of action is disclosed.

3.- Hernando, E.; Capurro, V.; Cossu, C.; Fiore, M.; García-Valverde, M.; Soto-Cerrato, V.; Pérez-Tomás, R.; Moran, O.; Zegarra-Moran, O.; Quesada, R. Sci. Reports 2018, 8, 2608-2617.

Reimbusement in rare diseases

Together with the R&D&I efforts to develop a new drug or therapy and the regulatory approval, reimbursement is the other important request to make a treatment available to patients. While regulatory approval may be a centralized process (European Medicines Agency and are harmonized in any case), pricing and reimbursement are national competence of the member states. At this point the critical issue is cost-effectiveness. The crucial step at this point is the right performance of Health Technology Assessments (HTA). According to WHO, “HTA is a multidisciplinary process that summarises information about the medical, social, economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased, robust manner“. The overall process is shown in the next figure:

Reimbursement is becoming a big challenge in rare diseases, as they are affected by two critical factors: the small amount of patients and the higher costs for some of the novel therapies. This situation collides with a scenario where the payers (public and/or private systems) are fighting to reduce high burden of spent due to ageing of population and chronicity. On the other hand, drugs for minoritary diseases benefit from orphan drug status, which eases the development and market uptake. Going back to reimbursement, new approaches are being developed for rare diseases as Cystic Fibrosis. One of the most advanced systems is the UK National Institute for Health and Care Excellence (NICE). NICE considers the following aspects to admit reimbursement:

  • Cost to the NHS and personal social services: to cover budget impact and robustness of the costing and budget impact estimates, and patient access agreements (discounts).

  • Impact of the new technology: to cover clinical effectiveness, health benefits to patients and carers, heterogeneity of health benefits within the population, robustness of the evidence and treatment continuation rules.

  • Nature of the condition: to cover both the impact on the patient (in terms of morbidity and clinical disability) but also the impact on the carers’ quality of life and the range of current treatment options.

  • Value for money: to cover incremental benefit vs current treatment, other resources needed (e.g. tests etc) and the impact on the budget available for specialised commissioning (NHS spend on treating rare conditions).

  • Impact of the technology beyond direct health benefits: to cover a wider benefit such as whether costs or savings might fall outside of the health system and the potential for long-term benefits to the NHS of research and innovation.
  • Impact of the technology of the delivery of the service: to cover staffing and infrastructure requirements.

This evaluation has negatively impacted recent innovations in CF developed by Vertex (Orkambi), which is not currently admitted to be reimbursed and has already provoked a considerable conflict between the company, NICE and the UK government. Lower cost approaches as those proposed by TAT-CF would allow lower pricing and easier reimbursement.

TAT-CF Final Conference: “Research and new treatments in Cystic Fibrosis”

The University of Burgos (UBU), in collaboration with the National Reference Centre for People with Rare Diseases (CREER), will hold the TAT-CF final conference on 4th December in Burgos. This conference is aimed at associations and patients, as well as professionals in the sector and the objectives are to present the main results obtained within the TAT-CF project and establish a debate on the therapeutic advances that are currently being made in the field of Cystic Fibrosis. We will have the pleasure of hosting several renowned experts in the area, which will give an overview of new research and treatments related to this disease.

The event will be broadcast live to allow a wider participation. For more information and register, please visit:

This conference will be organized along with the final TAT-CF workshop (Monday, 3rd December) and the Steering Committee meeting (Wednesday, 5th December).