Beyond Achondroplasia

Growing together with Clara

June 9, 2018
by inesp.alves

A way to contribute to the knowledge on achondroplasia

An ongoing study on pediatric achondroplasia conducted by the Brod Group is still enroling participants

Call for participation – USA residents

  • Parents of children with achondroplasia under 18 years-old
  • children and adolescents with ACH, with ages between 9 to 14 years-old

You can get more information about this study in this post.

Honorarium for spent time

$125 honorarium for participating in a focus group and a $75 honorarium for participating in a telephone interview


If you are interested in participating, please contact Jane Beck, Senior Research Associate with The Brod Group:


telephone: (415) 317-3987

June 5, 2018
by inesp.alves

A documentary on the lengthening process

The documentary  “The Lucas´s Journey“, by the film director Juan Enis, was produced by the mother of Lucas in 2015 and tells about the lengthening process of a boy with achondroplasia with 15 years-old, that had a total height of 1.25 meters. He decided to undergo this process, facing a long and painful postoperative time. Some images can be harsh to sensitive people.

The documentary wan now the Personal category of the 2018 ALPE Awards.


May 12, 2018
by inesp.alves

TransCon CNP for achondroplasia starts Phase 1 clinical trial

Ascendis Pharma announced on the 8th May it has dosed the first volunteers in a first-in-human phase 1 trial of TransCon CNP. (2)

Image 1: The TransCon technology. Credits: Ascendis Pharma Company Presentation. 8th May 2018 (1)

Ascendis TransCon technology includes the TransCon CNP that is a long-acting prodrug of a C-type natriuretic peptide (CNP) in development as a therapeutic option for achondroplasia and potentially for other fibroblast growth factor receptor (FGFR)-related skeletal disorders.

Phase 1 is taking place in Australia with healthy volunteers and is a double-blind, randomized and placebo-controlled phase 1 trial will evaluate single ascending doses of TransCon CNP in healthy adult subjects to assess 1. safety, 2. tolerability and 3. pharmacokinetics.

Understanding clinical trials

What is a phase 1?

Phase 1 is the first stage and usually involves small groups of healthy people, or sometimes patients. Phase 1 trials are mainly aimed at finding out how safe a drug is. (3)

Image 2: Medicines development process. Credits: EUPATI (5)

What is a double-blind trial?

In a blind trial, the people taking part are not told which group they are in. This is because if they knew which treatment they
were getting, it might influence how they felt or how they reported their symptoms. Some trials are ‘double blind’, which
means that the people taking part and the doctors treating them do not know who is getting the new treatment. (3)

What is a randomized trial?

When people are put in the trials treatment groups at random, usually by using a computer programme. This is done so that each group has a similar mix of people of different ages, sexes, and states of health.(3)

What is a placebo-controlled trial?

Controlled trials are designed to compare different treatments. Most controlled trials compare a new treatment with the standard
or usual treatment by setting up two groups of people. One group, known as the trial group or intervention group, are given the new
treatment. The other group known as the control group is given the standard treatment and in situations where there is no standard
treatment (as in achondroplasia), the control group may not be given any treatment at all or may be given a ‘placebo’ (a dummy drug). A placebo is designed to look very similar to the treatment being tested. So, in a drug trial the placebo looks exactly like the real drug, but does not do anything. By comparing people’s responses to the placebo and to the treatment being tested, researchers can tell whether the treatment is having any real benefit.(3)

What is pharmacokinetics?

The word is derived from the Greek words pharmakon (drug) and kinetikos (movement), is the study of the disposition of a drug after its delivery to an organism—in short, a study of “what the body does to a drug“. is used to describe the absorption, distribution, metabolism, and excretion of a compound. (4)

Figures 3-5: The TransCon technology. Credits: Ascendis Pharma Company Presentation. 8th May 2018 (1)

Expected timelines for the TransCon CNP clinical trial


Figure 6: adapted from Ascendis Pharma company presentation (1)

Jonathan Leff, M.D., Ascendis Pharma’s Chief Medical Officer. “TransCon CNP has been designed to provide continuous CNP exposure to optimize efficacy without cardiovascular risk in a convenient once-weekly dose. Data from this trial will help validate our target product profile, once again translating our promising preclinical results into clinical data.” (2)

TransCon CNP is the third product candidate in Ascendis Pharma’s rare disease endocrinology pipeline to advance into clinic, developed using its innovative TransCon technology platform. The company anticipates top-line data from the phase 1 trial to be available in the fourth quarter of 2018. (2)



  1. Ascendis Pharma Company Presentation
  2. Ascendis Pharma- Investors and News
  3. NHS”Understanding clinical trial booklet
  4. ScienceDirect “Pharmacokinetics
  5. EUPATI- Medicines development process

May 8, 2018
by inesp.alves

Study on achondroplasia – request for participation in the USA

The Brod Group, a health outcomes research, and consulting firm are currently conducting an international study of pediatric achondroplasia.

Purpose of the study

To get a better understanding of the experiences and daily life of children and adolescents with achondroplasia, as well as the experiences of parents who have children with achondroplasia.

The study findings

Will be used to help identify important outcomes to consider in future studies of achondroplasia and the results may also be a useful tool to address misconceptions of achondroplasia.

In this document, ACH Study Advertisement you can find additional study details.


This will be an international study and researchers are now looking for participants living in the U.S.A.

  • children and adolescents with achondroplasia with ages between 9 and 17 years old
  • parents of children with achondroplasia under 18 years of age  (one interview per family)

How will the study be conducted?

  • In a 1-hour telephone interview or a 2-hours focus group (location is to be determined but possibly in New York City)
  • All data will be kept confidential, and no individual will be identified in the study results
  • There is a $125 honorarium for participating in a focus group and a $75 honorarium for participating in a telephone interview

If you are interested in participating, adding value to this research with your personal real-life knowledge on achondroplasia, please contact Jane Beck, Senior Research Associate with The Brod Group:


telephone: (415) 317-3987

May 4, 2018
by inesp.alves

The soluble FGFR3, Therachon´s TA- 46, may prevent early onset of obesity in achondroplasia

Obesity and metabolism are important topics related to achondroplasia but rarely discussed.

Developed especially during childhood, obesity is a common complication associated with achondroplasia, affecting more than 50% of people with this condition. The extra weight exacerbates many other complications associated with achondroplasia, such as lumbar lordosis and obstructive sleep apnea, and may play a role in the increased cardiovascular-related death observed in people with achondroplasia, making it a relevant medical complication in the management of this disease [1].

This complication is generally accepted as a risk factor for a number of complications, such as cardiovascular disease, diabetes, and hypercholesterolemia (excess cholesterol in the blood) in the general population. Although cardiovascular disease is higher in people with achondroplasia than in the general population [2], a few case studies suggested that achondroplasia related obesity doesn’t cause alterations in insulin and cholesterol levels [3-5].
This study was firstly presented in the 2017 International Skeletal Dysplasia Society meeting (report of ISDS 2017 here) by Dr. Celine Saint-Laurent, from Elvire Gouze research team, and the team demonstrated the existence of metabolic alterations in achondroplastic mouse model and in children with achondroplasia. Also, they showed how that the soluble FGFR3 (sFGFR3) therapy could revert these metabolic alterations in this mouse model.

To understand what happens to children witachondroplasiaia, the research team performed a longitudinal retrospective study. So what is this? 

In a longitudinal study, subjects are followed over time with continuous or repeated monitoring of risk factors or health outcomes, or both [6]. And retrospective is when a study looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study [7].

They also evaluated anthropometric measures: body mass index – BMI, height, weight, etc, and blood parameter values were recorded and compared between children of 3 age groups: 0-3, 4-8 and 9-18 years old. After this, the researchers discovered that glucose (blood sugar) and insulin levels (a hormone made by the pancreas that allows your body to use glucose from carbohydrates in the food consumed for energy or to store glucose for future use. Insulin helps keeps your blood sugar level from getting too high (hyperglycemia) or too low (hypoglycemia) [8], were within normal, but these children had a tendency to have low cholesterol and triglyceride levels (fat), which is markedly different from what happens in obesity not associated with achondroplasia.

Key points:

1. The fact that obesity in achondroplasia is different at a metabolic level from obesity in the general population and that it is a relevant medical complication makes it a good indicator for the efficacy of a medication for achondroplasia.

2. Although sFGFR3 has already shown to increase body length and decrease mortality in an achondroplasia mouse model, the researchers also measured how this drug would affect these metabolic disturbances in the same mouse model and demonstrated that the soluble FGFR3 prevented the atypical abdominal obesity observed in untreated mice and that it normalized some of the blood parameters.


Image 2. Regions of interest (ROI) for obesity in children with achondroplasia and Android:gynoid fat ratio measurement in the three age groups. Credits: Saint-Laurent C, Garcia S et al., 2018. Android fat distribution describes the distribution of human adipose tissue in the trunk and upper body while Gynoid fat refers to the body fat that forms around the hips, breasts and thighs [10]

Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients and is associated with life-threatening complications including increased risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication.
Methods and findings:
To achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0±3], [4±8] and [9±18] years old. Our results show unexpected results with the development of an atypical obesity
with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholesterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during a high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to
D22), the development of these metabolic deregulations was prevented in adult animals(between 4 and 14 weeks of age). The lean-over-fat tissues ratio was restored and glucose metabolism showed normal levels. Treating Fgfr3ach/+ mice with soluble FGFR3 during the growth period, prevented the development of these metabolic deregulations in adult animals and restored lean-over-fat tissues ratio as well as glucose metabolism in adult animals.

Conclusions:This study demonstrates that

  1. achondroplasia patients develop an atypical obesity with preferential abdominal obesity not associated with classical complications.
  2. These results suggest that achondroplasia induces an uncommon metabolism of energy, directly linked to the FGFR3 mutation.
  3. These data strongly suggest that this common complication of achondroplasia should be included in the clinical management of patients.
  4. In this context, sFGFR3 proved to be a promising treatment for achondroplasia by normalizing the biology at different levels, not only restoring bone growth but also preventing the atypical visceral obesity and some metabolic deregulations.

We look forward in seeing how this compound, the soluble FGFR3 (the same as TA-46 from Therachon) will be effective in children with achondroplasia when the company presents phase 2 clinical trial results.

  1. Unger, S., L. Bonafé, and E. Gouze, Current Care and Investigational Therapies in Achondroplasia. Current Osteoporosis Reports, 2017. 15(2): p. 53-60. 
  2. Wynn, J., et al., Mortality in achondroplasia study: A 42-year follow-up. American Journal of Medical Genetics Part A, 2007. 143A(21): p. 2502-2511. 
  3. Collipp PJ, Sharma RK, Thomas J, Maddaiah VT, Chen SY. Abnormal glucose tolerance in children with achondroplasia. Am J Dis Child. 1972; 124(5):682±5.
  4. Pirgon O, Atabek ME, Sert A. Achondroplasia associated with metabolic syndrome: patient report. J Paediatr Child Health. 2008; 44(10):602±4.
  5. Alatzoglou KS, Hindmarsh PC, Brain C, Torpiano J, Dattani MT. Acanthosis nigricans and insulin sensitivity in patients with achondroplasia and hypochodroplasia due to FGFR3 mutations. J Clin Endocrinol Metab. 2009; 94(10):3959±63.
  9. Saint-Laurent C, Garcia S et al.Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia, PLos One, 2018 Apr 13;13(4):e0195876.

March 4, 2018
by inesp.alves

5th Nordic Skeletal Dysplasia Symposium – full session dedicated to achondroplasia

The 5th Nordic Skeletal Dysplasia Symposium will be held in Copenhagen, on March 8-9, 2018.

As stated in the Welcome note of this symposium “Skeletal dysplasias are rare diseases and the annual symposium is important to share medical knowledge with colleagues in different countries. We hope to attract all medical professionals who are working in – or are interested in – the field of skeletal dysplasias. This includes both caregivers, clinicians, scientist, and students“.

On the day 2 of the event, a full session will be dedicated to achondroplasia, on the following topics:

13.30-14.30 Management and follow-up of achondroplasia, Irwing M/Osmund D
14.30-15.00 Cervical spine compression/instability: diagnoses, signs and symptoms, Borbjerg T
15.00-15.15 Achondroplasia: mechanical axis considerations. Orthosis – true or false, Hindsø K
15.15-15.30 Finnish quiz with focus on achondroplasia three-five questions, Valta H

We will try to gather and share some information that will be presented at this symposium.


March 2, 2018
by inesp.alves
1 Comment

FDA Advisory Committee Meeting on Achondroplasia – Call for patients input

On March 22, 2018, FDA, the US Food & Drug Administration, will conduct a public advisory committee meeting on achondroplasia. The purpose of this meeting to discuss the major objectives of a phase 3 drug development program indicated for the treatment of children with achondroplasia.

FDA values patient perspective on the development of pharmaceutical treatments for achondroplasia and this meeting presents individuals with achondroplasia and their families a valuable opportunity to provide FDA with input on important topics. These topics include the types of clinical trial endpoints that would have a clinically meaningful impact on patients’ functional or psychological well-being and other considerations on the design of clinical trials involving people with achondroplasia.

The meeting’s open public session will take place on March 22, 2018, from 10:30 a.m. to 5:30 p.m. at our location in Silver Spring, MD, just outside of Washington, DC). Individuals, families, and others (patient organizations) may provide testimony in person at this meeting’s open public comment. Anyone interested in providing public comment at the meeting should register with by March 7.

There are a limited number of speaking slots. In addition, individuals, families, and others can submit a written comment on the topic of achondroplasia and development of potential treatments to the public docket. Additional details can be found in the federal register notice of the meeting.

FDA is seeking to collect a rich and diverse set of patient perspectives on this topic.  We have developed a flyer, attached, with information relevant to this meeting and encourage you to disseminate it to any individuals or groups who may be interested in this meeting.

Preview of the information flyer. To read the flyer in full, click on the following link: AchondroplasiaAC

FDA link to the announcement


Beyond achondroplasia will participate in this call for contribution by sending a written comment.

The information here provided was kindly shared by Blake Bannister, Decision Support and Analysis Team, Center for Drug Evaluation and Research, FDA     

February 14, 2018
by inesp.alves

Therachon starts phase 1 clinical trial with TA-46 for achondroplasia

Therachon announced today, 14 February 2018, the beginning of Phase 1 for the clinical trial with TA-46 for achondroplasia.

This trial will take place in The Netherlands, with 70 adult healthy volunteers and it will be:

  • randomized – A study in which the participants are divided by chance into separate groups that compare different treatments or other interventions. Using the chance to divide people into groups means that the groups will be similar and that the effects of the treatments they receive can be compared more fairly. At the time of the trial, it is not known which treatment is best. Pubmed health
  • placebo-controlled – Studies of new drugs often compare the effects of an investigational drug with the effects of a placebo. The reason for using a placebo control is that the benefits of taking medications are not always due to the drug itself. These benefits are called “placebo effects.” An example is when an investigator’s enthusiasm about a new medication sometimes influences the patient’s response. In a double-blind, placebo-controlled research design, the doctors, nurses working directly with patients, and participants themselves involved in the study, will not know which group patients are in. PsychCentral
  • double-blind trial – is a trial where neither the researchers or patients/participants know what they are getting (the drug or the placebo). The computer gives each patient a code number. And the code numbers are then allocated to the treatment groups. Cancer Research UK

The number of participants vary significantly, depending on the study and if teh new medicine is for a more common condition or a rare condition. Credits: Global Medical Institutes


The trial is designed to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses of TA-46.

Luca Santarelli, Therachon´s CEO said that this is “an important milestone for the company,”.

Beyond Achondroplasia has published more information about TA-46 previously (read the first article). The company has high expectations that Ta-46 may show significant therapeutic impact in achondroplasia as may improve anatomical proportions and prevent complications related to achondroplasia, that start to occur in early life phases.

Next steps

Is important to know the timelines for this phase 1 trial, namely the duration of this trial as also the results of safety, tolerability and mechanism of the drug in these healthy volunteers and then, after positive results, know the expected dates of the beginning of phase 2, with children with achondroplasia.

How is expected TA-46 to work?

TA-46 acts as a ligand trap can reduce the superactivation of the mutated receptor FGFR3 (that is overworking in achondroplasia, which reduces the multiplication and development of chondrocytes, that the cells that give origin at the growth plate level, to the bone formation).

TA-46 is being developed as a weekly subcutaneous drug for children and adolescents living with the disease.

And this investigational therapy has received Orphan Drug Designation from the European Medicines Agency (EMA) on the 27th March 2017 and the U.S. Food and Drug Administration (FDA).

You can check Therachon´s press release here

January 24, 2018
by inesp.alves

Short videos about the work of Medicines Regulators and the path of new medicines

This is a short videos series from EMA, the European Medicines Agency, about new medicines reaching the market and also about the works of regulators, EMA and FDA, which is focused on protecting patients and to approve the best possible new medicines.

December 31, 2017
by inesp.alves

The TransCon CNP for achondroplasia – Ascendis Pharma publications

Ascendis Pharma, a company funded in 2007, applies the TransCon technology which combines a prodrug with a sustained-release technology. This way, the company can offer products with a predictable and sustained release of an unmodified parent drug.

Before heading for the publications the company released in 2017 in selected events, is important to explain some concepts.

What is a prodrug?

A prodrug is an inactive medication or compound (the same as having no action), and after being administrated, it is converted within the body (metabolized) into a pharmacologic active drug.

Prodrugs undergo an enzymatic and/or chemical transformation in vivo (inside the body) to release the active drug: the parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving several properties of active agents: physicochemical, biopharmaceutical or pharmacokinetic.1

Example of a prodrug. Credits:

During 2017 Ascendis Pharma released relevant information on the TransCon CNP. Through selected publications, the company shows high expectations on the efficacy of TransCon CNP in improving the quality of life in achondroplasia and reducing complications. In the company website it can be read the following:

Our preclinical studies of TransCon CNP have been encouraging. Continuous exposure to TransCon CNP has been found in preclinical studies to be more efficacious at inducing skeletal growth compared to once-daily injections. In preclinical safety studies, a low Cmax due to slow release of CNP has been shown to improve hemodynamic tolerability. And, the half-life extension observed confirms the potential of convenient weekly dosing in patients with achondroplasia. Additionally, preclinical data suggest a trend toward bone growth associated with TransCon CNPBuilding on these positive results, Ascendis Pharma plans to submit an Investigational New Drug Application for TransCon CNP in the fourth quarter of 2017. Ascendis pharma

What is the Cmax?

Is the maximum concentration of the drug that is measured in the plasma after one dose administration. 2 The concentration of a drug is the abundance of a compound divided by the total volume of a mixture. The following image gives a simple example how to reach the concentration value of a mixture.


So, once the TransCon CNP shows a low Cmax, this avoids side effects in the body after the administration of CNP, namely the reduction of blood pressure and an increase of heart rate has shown by other CNP (as BMN-111).

And what is the plasma?

Is the clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma.3 Blood is composed of blood cells suspended in blood plasma, that can be separated by centrifugation (a process used to separate substances that as mixed together).


What is the half-life of a drug?

Is the time that takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. 4

So due to an increased half-life of the TransCon CNP, the company sees the potential of having one administration per week of the drug instead of a daily administration.


Structural Optimization of TransCon CNP – Development of a Sustained-Release Prodrug of CNP for Achondroplasia


The TransCon technology. Credits: Ascendis Pharma

The reduced drop in the blood pressure after Vosoritide and TransCon CNP administration. A preclinical study conducted in monkeys.  Credits: Ascendis Pharma

Main conclusions

  1. The TransCon CNP prodrug has minimal binding to the NPR-B and NPR-C receptors and improved NEP stability in vitro compared to unmodified CNP.
  2. In vivo TransCon CNP demonstrated the desired half-life extension without adverse hemodynamic effects.
  3. These data support clinical development for weekly dosing and suggest TransCon CNP may be a safe and efficacious option for children with ACH. Ascendis Pharma

TransCon CNP, a sustained-release prodrug of C-type natriuretic peptide, prevents premature synchondroses closure in an achondroplasia mouse model

The reduction of the ossification of the areas around the foramen magnum, the synchondroses (IOSA). Credits: Ascendis Pharma

Main conclusions:

  1. In a murine model of ACH, TransCon CNP prevented the closure of synchondroses and resulted in an improvement in foramen magnum and skull shape, suggesting normalization of the overall skull contour.
  2. These results suggest that the early administration of TransCon CNP may alleviate the risk of foramen magnum stenosis that leads to some of the most serious clinical complications of ACH. Ascendis Pharma

Pharmacokinetics and Cardiovascular Assessment of TransCon CNP, a Sustained-Release C-type Natriuretic Peptide Prodrug, for the Treatment of Achondroplasia

Main conclusion:

  1. Continuous exposure to CNP showed better efficacy and CV tolerability than intermittent, daily injections.
  2. TransCon CNP exhibited a substantially longer half-life in cynomolgus monkeys compared to daily CNP analogs, supporting once-weekly dosing in humans
  3. TransCon CNP showed no adverse hemodynamic effects in cynomolgus monkeys or mice at doses exceeding the expected therapeutic dose
  4. TransCon CNP may improve efficacy and safety over daily administered CNP. Ascendis Pharma

TransCon CNP, a Sustained-Release Prodrug of C-Type Natriuretic Peptide, exerts Positive Effects on Bone in Juvenile Cynomolgus Monkeys and in a Mouse Model of Achondroplasia

TransCon CNP administration to Fgfr3Y367C/+ mice from birth to day 15 increased the naso-anal length and bone length (femur; blue arrows, tibia; red arrows). Credits: Ascendis Pharma

Main conclusions:

  1. In young healthy monkeys, once weekly TransCon CNP increased long bone growth in a dose-dependent fashion.
  2. In a murine model of ACH, TransCon CNP improved growth plate architecture and improved phenotypical features.
  3. These data support further development of TransCon CNP as a potential therapy for ACH, providing efficacious CNP levels with weekly administration. Ascendis Pharma



1. Rautio J et al, 2008, Prodrugs: design and clinical applications.

2. Science Direct – Cmax (pharmacology)

3. Pubmed Health – Blood Plasma

4. UNIL-Université de Lausanne

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