Challenges for the treatment of achondroplasia: from drug development to drug delivery, part 1.

When talking with parents and other people about drug research, often I am asked why we don’t see new treatments for so many rare disorders, taking in account that the technology is so advanced now, with stem cells and everything else. As achondroplasia is one of these many conditions, I thought it would worth to talk about drug development.

FGFR3 is a good target for therapy

Achondroplasia is not a complex genetic condition. On the contrary, it is caused by an already identified single point mutation in a protein that is produced by one single type of cell, the chondrocyte. This makes the fibroblast growth factor receptor type 3 (FGFR3) a very interesting target. So, why is there no therapy for achondroplasia available yet?

In the next two articles, we will be looking at challenges for the development of a new drug. In the first, we will talk a bit about the design, research and the development steps of the potential drug. In the second, we will talk about the delivery of the drug to the target site, specially of the new generation of drugs that someday in the near future might be used in achondroplasia as they are already starting to be applied for other conditions.

Drug development is not easy

Researchers have been working in several initiatives to find therapies for disorders that were untreatable in the past, such as conditions like achondroplasia. This is becoming possible because they have been successful in identifying:

• The molecular mechanisms that lead to the condition, beginning by learning about the assembly error (yes, we can say that in achondroplasia the amino acid switch in FGFR3 is an assembly error in the gene structure);
• The natural role of the altered protein and how it exerts its functions;
• The molecular consequences of those actions in the body.

Today, drugs are no more designed just to combat a symptom, like fever. In our days, developers of the centenary aspirin would have to show precisely how the drug works in fever, something unreachable 70, 80 years ago. Now, we need to understand where, in a given enzyme, that experimental compound would cause the desired effect. That´s why learning about FGFR3 and how its structure is (see it here) allows the scientists to look for parts of the molecule adequate for targeting. 

As you may remember FGFR3 is an enzyme with several spots bearing negative and positive electric charges. In a gross comparison, you could say that an enzyme is like a complex piece of magnet, with different electric charges distributed across the molecule, each of them with particular properties, made for a specific purpose. These enzymes' sites are made to attract other specific molecules - their targets - and to not respond to others, just like a magnet, which attracts a piece of iron or another magnet with the opposite charge, but will have no action in aluminum or will repeal another magnet with the same charge. Drug developers must find the correct site where a potential drug will bind to produce an effect. In other words, drugs are developed aiming some specific spots of the target to which they would bind, causing the planned effect.

There is a potential drug. Now, how to make it find the way?

When a new potential therapy for a disease is under development, many questions arise about the way that drug will be given to a patient to treat that condition. Think about it: will it be an oral or an intravenous drug? How many times should it be given daily? Will it be given before or after the meal? During the morning or at night? Swallowed with water or milk? Can it be given at the same time with other drugs? Is there any risk to stop it suddenly? The question list is long, much longer than these examples. Many considerations must be taken in account to answer these and other questions.

The nature of the experimental compound is of upmost importance. In some of the previous articles, we have seen that electric charges influence how a protein reacts with others inside our body. Again here, the electric charges distributed in the structure of the experimental medicine will determine if it will request an intravenous injection or could be packed as a pill.

In the case of an oral drug, the researchers will need to find out where, in the digestive tract, it will be absorbed. Does the gastric acid affect its stability? Does this drug need a protection to cross the stomach? Some drugs can be delivered as soft capsules while others will demand a hard pill to reach the right part of the intestine to be absorbed.

It´s a long way

And then? The drug will enter the blood stream where other challenges must be solved. Will the drug enter the target tissues readily or will keep circulating longer? Are there any body neutralizing enzymes, like janitors, ready to chase and destroy the drug? Here, imagine the case of the CNP analogue (an analogue is a compound similar to an existing molecule), which is the first potential drug therapy for achondroplasia, now being tested in a phase 1 clinical trial. It is a small peptide, a molecule made of an amino acid chain. This is the kind of molecule for which there are several hunter enzymes circulating in the blood (they are called peptidases). When one of these enzymes reaches a peptide, good bye peptide.

If the experimental compound is an antibody, it won’t be given orally, since protein derived compounds normally can’t survive the gastric acid. So, it will need to be injected in the patient. What will happen to it after the injection? Being a kind of protein antibodies may, like any foreign protein, cause reactions by the body. Our immune system is built to identify strange molecules to provide efficient defense against an invader germ. So, we have to ask, how will the body react to the antibody? This is one of the major challenges for the development of new antibody-based therapies.

Drug researchers will need also to study if the compound will cause effects in targets other than of the aimed one, a phenomenon named ‘off target effect’. One of the major hurdles facing the development of new drugs like the so called small molecules tyrosine kinase inhibitors (TKIs), is that often they affect proteins other than the one they were designed for (reviewed here). 

How do they answer all of these questions?

The pre-clinical development

Before any experiment in humans, a potential drug must follow a very strict process, regulated by health regulatory agencies across the planet. Laws and regulations are intended to provide due protection to the society, ensuring that all efforts were made to prevent an inadequate drug to enter the market and reach drugstores. To learn more about the development of a drug you could visit the related Food and Drug Administration (FDA) website. You will find a vast source of information there.

In summary, before studying how a drug will work in the human body, researchers must test it adequately in a multi-step approach. This may include:

•  Creating computer simulations about the expected interactions between the compound and its target;

• Testing the drug in cell cultures This is the in vitro part of the research. The expression in vitro describes tests made in glass tubes, wells or plaques (vitro, Latin for glass);

• Testing the drug in fragments of living organs and tissues outside the body (ex vivo);

• Testing the drug in an appropriate animal model, the in vivo part of the research. Today, for a vast number of the human disorders where the cause is known it is possible to create similar animal models. Mice are the most adequate of them for several reasons (not discussed here because it is not in the scope of the article). Tests are performed to let the researchers learn about the path the drug takes in the body, its expected and unexpected effects and toxicity;

• Testing the drug in larger animals, one of them necessarily a primate, to confirm efficacy and safety.

     The clinical development
     
     Only after pre-clinical tests showed that the potential drug is safe and efficient in the tested model (s), regulatory agencies will authorize the first tests in humans. This is what is called the clinical part of the drug development, which is divided in four phases:
          
                Phase 1

In the majority of cases tests are performed in a small group of healthy volunteers. Here, the researchers want to see how the drug will be absorbed, metabolized and eliminated, analyses called pharmacokinetics and pharmacodynamics. They will also pay attention to any unexpected toxic effects. For diseases like cancer, tests are generally performed in real patients. Phase 1 usually lasts about 1 to 3 months, depending on the drug.

Phase 2

Tests in phase 2 are performed in affected individuals. Depending on the prevalence of the disease, tests in this phase may need from a few tenths to a couple of hundred patients.  Here, the researchers are looking for the right dose of the drug. They will also look for more pharmacokinetics information. But the more important part of the tests in this phase is about the efficacy of the drug to achieve the results it is intended for. And also, the safety in short term. In this phase, tests usually last up to six months, depending on the disease in scope.

Phase 3

Once the best dose of the potential new medicine is found and there is proof of its efficacy and safety in the short term, it comes the hour to test it in a larger group of patients. Depending on the kind of the disorder being tested, tests in this phase may take one year or more to be finished. For instance, for an acute disease like a myocardial infarction, if the experimental drug is intended to reduce the damage or prevent an early recurrence, a test in this phase will last around one month, according to the outcome researchers want to measure. For chronic conditions like diabetes, it may take a couple of years and thousands of patients to study the drug effects in a longer term. In compliance with the current legislation, any new potential drug will need to be tested in these settings before gaining the approval for registry and market. One of the main goals of the tests in phase 3 is to look for additional unexpected uncommon adverse effects of the drug.

If the drug proves to be safe and efficient for the clinical indication it was applied for in the phase 3 trial (s), then the authorities will grant a registry for it and the developer will have the right to sell it as a new medicine. This new medicine will have exclusivity (no copies allowed) in the market for a determined amount of time (the patent’s rights). 

However, the development of the new medicine will not stop here. It is very common that a drug studied for a specific disease is found to be potentially useful for other conditions. Depending on the new purpose of the drug, it will require new phase 3 studies for the new indication. In other cases, the drug developer will conduct additional post-marketing studies, aiming to study the drug efficacy and safety in the long term. These are the phase 4 studies. You can consult more about this topic in the ClinicalTrials.gov FAQ page.

It may take more than ten years for a conceptual compound to become a new therapeutic tool. Looking at the development process from a (personal) pragmatic perspective, it becomes clear that some of the drivers which help expedite the research are:

      ·      Prevalence of the disease. The commonest the disease, the more likely there will be research for it. The client population is large and revenues are more easily foreseen. This is the case of diabetes, hypertension, COPD etc.

     

      ·      Appeal of the disease. The more the disorder call attention of the society (and the willing to pay for a treatment), more likely is the chance that investments will be done to tackle it. This is the case of AIDS. Of course, HIV infection is severe as the consequences of it are too, but HIV drug research is the best example of how a strong social interest drives the research. In less than 20 years a previously unknown disease has its causative agent identified and drugs developed to treat it successfully. Compare it to sarcoidosis, which continues to be a mystery, or to the common malaria and tuberculosis, both still major global health problems for which there are no really fast, efficient treatments. For instance, therapy for tuberculosis beats the disease, but takes a minimum of six months.

     ·      Severity of disease. The more devastating the disease the better the chance there will be research for it. Here again, developers expect more willing from the society to pay for the new drug. This is the case of cancer. In fact, currently cancer is the most investigated clinical condition (Mak HC, 2011)

Nevertheless, rare or orphan diseases have been receiving more attention from the society and regulators in the last years. Laws and incentives, such as the Orphan Drug Act, have been created to facilitate or stimulate the research in these disorders. Broad reviews of this topic have also been published in the specialized literature (Tambuyzer, Melnikova, complete references below) and help raising the debate about rare diseases. Recently, the National Institutes of Health (NIH) published a major study on the need for developing therapies for rare diseases, Rare Diseases and Orphan Products: Accelerating Research and Development, available for free, which discusses the issue of access to research and developing strategies to accelerate the discovery of new therapies for this group of clinical conditions.

However, this is not enough. Greater risk of losing money prevents many investors to put resources in this therapeutic area. If parents and interested people really want to see drug development for new therapies for the many rare conditions, they will have to get organized and push for it, even including funding the research. There are many examples of these initiatives for a significant number of rare conditions, such as for cystic fibrosis, alkaptonuria and others. 

In summary, we have briefly reviewed the path a new potential drug needs to pass to become a new medicine to treat a disease. The subject is complex and I was far from having covered all its aspects. 

In the next article we will look for other challenges for drug development in achondroplasia. This time, we will focus on the strategies to make the new potential therapies, especially aptamers and other nucleic acid based approaches, to find their way to the growth plate and the chondrocytes.

References        

• Tambuyzer E. Rare diseases, orphan drugs and their regulation: questions and misconceptions. Nature Reviews Drug Discovery 9, 921-929 (December 2010) | doi:10.1038/nrd3275

• Melnikova I. Rare diseases and orphan drugs. Nature Reviews Drug Discovery 11, 267-268 (April 2012) | doi:10.1038/nrd3654