Wednesday, October 17, 2018

Treating achondroplasia: VI Fundación Alpe Congress

Gijón is a charming town in the northern coast of Asturias, in Spain. The town is also the home of Fundación Alpe (, one of the most active patient advocacy organizations for achondroplasia and skeletal dysplasias in the world. Alpe's mission has been clear from the beginning: 
  • "The satisfaction of the educational needs, early attention, school follow-up, social, cultural, and labour integration of persons affected by the alteration known as achondroplasia, and other common forms of dwarfism. Likewise, the Foundation will aim to solve health problems and promote physical and psychic development, create a legal and social framework that facilitates the development of the aforementioned objectives, promote research programs and methods of prevention, diagnose and treat said alteration known as achondroplasia” (
In fact, since its inception in 2000, Alpe has been not only a strong voice against social and political prejudice but also has been providing advice, care and support to an ever growing community of families not limited to Spain but to many countries in the world.

Just last week, Fundación Alpe held the sixth edition of the Congreso Internacional en torno a la Acondroplasia (International Congress of Achondroplasia; What makes this event distinct of those maintained by other groups is that Alpe organizes a comprehensive program where most aspects related to achondroplasia and skeletal dysplasias are approached, from topics such as social inclusion, education and civil rights to medical and healthcare related aspects, including the research over new pharmacological therapies. Alpe has also been working to support dwarfism associations in other countries.

Talking about therapies, during the meeting last week, experts from all over the world have presented their insights about current treatments in development for achondroplasia, such as vosoritide, TransCon-CNP, TA-46 and infigratinib, and also challenges to be overcome ahead. I was invited to talk about potential therapies that are not being due explored right now. This was a rich experience and a privilege for me and I want to share my presentation with you. Please, note that almost all potential therapies presented there have already been reviewed here in the blog. You just need to visit the index page in your preferred language to find them.

I recommend you to visit Fundación Alpe homepage and learn more about them and what they do for achondroplasia:

Slide 2: In this slide there is a list of the investigational drugs that are already being tested in clinical trials. Although infigratinib has not yet been tested in achondroplasia, it has been used in several clinical trials for cancer.

The right column showing "estimated launch" lists what is the current assumptions for the respective drugs, based in published information about their current development stage and in my knowledge of regulatory processes and some standards of the pharma industry strategy to launch new medicines. Both the predictions for vosoritide and TA-46 were in line with what their developers presented later during the congress.

Let see the estimates for vosoritide (you can extrapolate these assumptions for all other investigational drugs):

The developer is conducting the phase 3 study with vosoritide now, and they say the results will be available by the end of the next year (2019). With the results of that study in hands (provided the study is successful), they will be able to work with FDA towards the drug's approval. This usually may take 3 to 6 months, so well during 2020. I think approval in Europe will come short after FDA's, so still in 2020, followed by other relevant markets (UK, Australia, Canada, Switzerland, maybe others, too, such as Japan).

I predict that approvals in South America and other non-central countries will come during 2021 or later, but these are all just estimates, since the regulatory submission strategy is owned by the developer! 

I don't think there will be any major problem to get access to the drug once it is approved in the main markets, provided the country health system adopts it. This might turn to be a challenge in some EU countries, though, as we can predict that the drug cost will be high (this is also based in published information). The big fight will be between the developer and the payers (country health systems most of the time). The developer will need to show that the cost of the drug is worth given the benefit it can potentially deliver.

In each country the local advocacy group association can be fundamental to have the treatment available sooner than later, as they could be a strong voice advocating for families, but we see that in several of them there is still internal struggles about defining if they are pro- or against therapies. Compare the way Alpe (Spain) embraces the idea of providing solutions for the new generations with some concepts still defended by other associations. 

More than the associations, families are of utmost importance. If the local association can't or won't help, than the families should gather and push for the therapies.

There is another aspect to consider, which is that the first potential approval for vosoritide will be only for children 6 years old or more. This is the way the regulatory systems work. The potential approval for younger kids will be granted only after the end of the phase 2 study that has just started, so later, in 2022-23.

Slides 4 and 5: Statins are drugs that have been used for a long time to reduce cholesterol in individuals at high risk of cardiovascular diseases, since high cholesterol has been implicated as a causal or adjuvant mechanism for the development of these diseases. Recently, some statins have been tested in a murine model of achondroplasia with very positive results in the rescue of bone growth.

However, there is great concern about the use of statins in children because cholesterol is an important molecule for the synthesis of hormones and other substances produced by the body which are fundamental for the normal development of the growing body. Thus, there is a relevant question about exposing children to medication that could be harmful:

Are statins safe in children?

To answer this question, let's review what is there in the literature. Statins have been used in children and adolescents with familial hypercholesterolemia. There are medium-term studies (a few years) showing that the statins used did not cause any relevant harmful effect. The same has been observed  in several other studies with statins in n children and adolescents with genetic disorders  (as listed on slide 5) and even in pregnant women. Some of the listed disorders, such as neurofibromatosis and Noonan Syndrome, share bone metabolic features similar to those found in achondroplasia.Considering the sum of all safety data reported by these studies, it can be inferred that there is sufficient evidence to authorize a clinical study with statins in children with achondroplasia, since they have demonstrated safety in this population. To learn more about statins, visit this blog article.

Slide 6: RBM-007 is a small molecule designed to specifically bind to fibroblast growth factor 2 (FGF2) and block its activity. FGF2 is one of the activating factors of FGFRs most widely distributed throughout the body and is an important activator of FGFR3 after FGF18 and FGF9. The anti-FGF2 developer, Ribomic, lists achondroplasia among the clinical indications being explored. An important question is about the risk of undesirable effects that could arise due to prolonged use of a medication that could inhibit FGF2 activities beyond those expected in relation to bone growth.

Slide 7: The process that drives bone growth in children is very complex, and governed by the interaction of dozens of molecules. One such molecule is called PTH-related protein (or peptide) (PTHrP). PTH is the parathyroid hormone and regulates calcium metabolism in bones. PTHrP is one of the main stimulators of chondrocyte proliferation in the growth plate.In achondroplasia, the overactivity of FGFR3 causes a reduction of PTHrP, with clear consequences on chondrocyte capacity to proliferate, one of the hallmarks of achondroplasia.PTH and PTHrP are similar molecules and use the same receptors to exert their functions in cartilage and bone. Thus, it seems to make sense to explore PTH in the context of achondroplasia.  

In fact, PTH has already been explored in some studies such as in the example shown on slide 6. The use of an analog of PTH in a model of achondroplasia resulted in an evident rescue of the bone growth.  

An important issue regarding the use of PTH for long periods is the risk of development of bone cancer due to the prolonged stimulation of cell proliferation. This concern arose during the approval process of teriparatide, an analog of PTH, for the treatment of osteoporosis in adults. Tests on animals at doses that are much higher than the doses approved for treatment have resulted in the development of bone cancer. Since the approval of teriparatide, a surveillance system has followed users around the world and until recently, no case of bone cancer that could be related to teriparatide had been reported. 

Another question is whether the use of PTH to treat achondroplasia would be enough to rescue and guarantee near-normal bone growth, since PTH would only interfere in one of the developmental  phases (proliferation) of the chondrocytes in the growth plate, and would not have action on the other important stage by which these cells drive bone growth, the phase of hypertrophy (or maturation).

Slide 8: Out of the molecules presented so far, the peptide P3 is the only one that was designed to specifically block the activity of FGFR3. We could say that it is the one that would potentially be the most effective and safe among those we have reviewed so far here.  

Achondroplasia is caused by the excessive activity of a single enzyme, FGFR3, in the growth plate cartilage, so it makes sense to seek solutions that may block or inhibit that overactivity to allow the bone to follow the normal bone growth program. The study presented on slide 8 shows how this peptide caused significant growth recovery in the animal model used in the study. 

There are at least two relevant questions to be answered about the peptide P3. The first one is about the risk of undesirable effects associated with FGFR3 blockade in tissues other than the growth plate.  

The second is about ensuring that peptide P3 reaches the growth plate before it is neutralized by the body's natural "janitor" systems. Peptides are targets of neutralizing enzymes and usually do not withstand much time when in their free state. Thus, to ensure that it can circulate for a reasonable time to allow it to exert its effects, peptide P3 will probably need a transport system to protect it from those enzymes. One of these transports could be the one being developed by Ascendis, with its TransCon-CNP. Remember, CNP is also a peptide.

Slide 9: Osteocrin is a natural peptide that has the ability to bind to one of three natriuretic peptide (ANP, BNP and CNP) receptors, the NPRC. Just to remind you, CNP is the base molecule for vosoritide, the most advanced medicine in clinical trials now. NPRC has a regulatory function in the natriuretic peptide system, preventing, for example, CNP from exerting its effects for an extended period of time. If, on the contrary, some other molecule occupies the NPRC, then CNP has more time to perform its functions in the chondrocyte and to stimulate bone growth. 

Japanese scientists tested exactly this concept in their study shown on slide 9. By keeping osteocrin levels high in their animal model, the researchers found an increase in bone growth rate. This is a study that demonstrates another potential therapeutic solution for achondroplasia and other bone dysplasias. 

There are some questions to be answered about the use of osteocrin in achondroplasia. First, what would be the consequence of blocking the NPRC with osteocrin in relation to the action of the other natriuretic peptides, ANP and BNP? As with the peptide P3  (above), how do you ensure that osteocrin will survive the body's "janitor" systems. And finally, osteocrin has its own actions in the body. What are the consequences of using it as a therapy for achondroplasia?

Slides 10 and 11: MK-4 is one of the vitamin K2 sub-types. Vitamin K2 is important in the activation of various proteins involved in the regulation of calcium in bones and blood vessels. MK-4 has been routinely used in Japan for the treatment of osteoporosis. MK-4 also appears to exert some particular functions in processes associated with cell proliferation and therefore has been tested in liver cancer cells. In this model (slide 10), MK-4 has been shown to inhibit cell proliferation by inhibiting FGFR3. 

Shortly after this article on cancer, a new study was published on the long-term effects of MK-4 on normal young animals (slide 11). What is relevant to our subject here is that in this study mice receiving MK-4 grew more than those given placebo or vitamin K1. I wrote to the authors of this study to see if they would have also examined the growth plates of those animals, but unfortunately this was not explored. 

We can imagine how interesting it would be to find a low-cost molecule whose safety is firmly established, with the ability to block exactly the enzyme that is overactive in achondroplasia, FGFR3. But to use MK-4, we first need to know if it actually works. It needs to be tested on a model of achondroplasia.

Slide 13: Kaempferol is a flavonoid just like resveratrol, a molecule well known and researched in the context of the aging process. Kaempferol is present in many plants and fruits. 

Like other flavonoids, Kaempferol has anti-oxidant and anti-inflammatory activities and in this context was tested in a model of rheumatoid arthritis (RA) (slide). RA is an autoimmune disease, in which the body produces antibodies against its own structures, generating a chronic inflammatory process. In RA, continued inflammation leads to destruction of joints among other clinical complications.

In the study shown on slide 13, kaempferol was used in a model of RA, which demonstrated its ability to inhibit FGFR3. We can not extrapolate the results of this study to achondroplasia without first testing this flavonoid in an appropriate model. Here is another open opportunity for research and development of a solution for achondroplasia.

Slide 14: CRISPR-Cas9 means: CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; Cas9: CRISPR associated protein 9. Do not worry about this complex name! 

What is important to know is that this is a new method that has been used to modify how a gene manifests itself (or is expressed, as how we say in scientific jargon). With CRISPR-Cas9, one can introduce, modify or eliminate gene expression. There is much hope that this method could be used in the treatment of many diseases that afflict man, animals and plants. Given its immense potential, this genetic editing system also provokes relevant discussions in ethical grounds.

In any case, CRISPR-Cas9 can be used to regulate gene expression that, when deregulated, cause clinical problems, as is the case of achondroplasia. In fact, this system was explored in the study listed on slide 14, where the researchers succeeded in eliminating the expression of mutant FGFR3 in cells of an adult individual with achondroplasia. 

This study is just a proof of concept. There are many questions that need to be answered before a CRISPR-Cas9 based achondroplasia therapy could be considered viable. However, here is another avenue to be explored. If it is possible to prevent the mutant gene from manifesting itself, it can be expected that affected children could develop normally and would not present or would have a much lower risk of presenting the frequent clinical complications that accompany achondroplasia.

Slide 15: No matter the chosen therapy, drug developers need to be aware of a fundamental concept:
  • TIME
 Achondroplasia is a genetic disorder of growth and growth occurs during a limited period of time of an individual's life. 
  • Growth has an expiration date.  
The earlier a medication is given for achondroplasia, the better the potential outcome. In this way, any clinical research directed to achondroplasia or other genetic disorders with similar characteristics needs to be directed to three RIGHTS:

1. The RIGHT clinical study design. 

Regulators have called for studies proving the efficacy of drugs for achondroplasia using designs that include the use of placebo as a comparator aiming to reduce the risk of interpretation bias. Although the use of placebo in clinical studies is an appropriate method for high-prevalence diseases, its use in the context of rare diseases, and especially in those situations where the potential medication may only offer clinical benefits for a limited period of time, as is the case of achondroplasia, raises ethical issues (already discussed in this blog). 

There are alternative clinical study designs that, while protecting participants, reduce the risk of bias in interpreting results. They are listed in the basic document guiding current clinical research in the world (ICH). Among them is the use of historical data to compare a certain marker before the intervention (the use of study drug) with after the intervention.  

Interestingly, regulatory agencies have asked developers of achondroplasia medications to conduct such studies before beginning the study with their drugs. These studies are called "natural history" studies. However, as a recent example, in defining the requirements for the design of the phase 3 study of vosoritide, the FDA requested that the study should be controlled with placebo (May 2018). The same design was applied in the phase 2 study with infants and children under 5, also in progress. Hence, in fact, the natural history study that precedes the study with drug loses much of its value as a comparator, increases the emotional burden on participants and families, raises the costs of and slows down drug development.

2. The RIGHT population to study. 

Testing medications for growth in older children or adolescents is to risk that any results could be less than accurate. Regulators have called for studies to begin in older children before infants could be tested. Two arguments are used here and they interrelate: safety and ethics. The safety of the study drug needs first to be tested on older children before being given to younger ones because it would not be ethical to do so in reverse order.

To this argument, I ask: from the ethical point of view, what is the difference between a one year old child and a five year old one? In which situation is one more vulnerable than the other? For me, both need the same protection in the context of a clinical trial. 

With years of growth already elapsed, one can expect a much higher risk that a potential drug for achondroplasia will fail to achieve its intended endpoints when tested in older children to verify its safety and efficacy, because the drug has been tested in a population that from the outset might not respond optimally to the study treatment. There are examples in the recent literature on this type of situation (search for Duchenne Muscular Dystrophy and drisapersen and eteplirsen).

3. The RIGHT endpoints.

Clinical studies are performed as part of a plan to develop a potential new medication for a disease or clinical condition. Drug development undergoes a lot of pressure from a variety of sources, from the patent expiration date of the new potential drug to competition with other molecules in research, to issues that are sometimes inherent to the clinical indication being studied. Therefore, it is important that the design of a clinical study contemplates outcomes that can be verified and confirmed within a limited period of time, in a way that at the same time allows to determine that the medication is safe and effective. Choosing the right endpoints is critical to increasing the chance of success of a new drug.

In the case of achondroplasia, there are several outcomes that can be investigated, however a significant number of them can only be verified after many years of follow-up of individuals exposed to a given drug. As an example, sleep apnea is a frequent complication in children with achondroplasia. However, how to verify, within a reasonable period of time, that a medication may improve this clinical complication? Thus, it seems reasonable that growth velocity, total growth, changes in limb disproportion and other similar outcomes are more appropriate choices as clinical efficacy goals than others that can only be verified in the long run.

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