Beyond Achondroplasia

Growing together with Clara

February 14, 2018
by inesp.alves
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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
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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
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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: www.clayton.edu

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.

Credits: www.fao.org

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

 

Bibliography

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

December 10, 2017
by inesp.alves
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Update on BioMarin´s Achondroplasia Clinical Development Program

BioMarin Pharmaceutical sent to patient organizations an update of the clinical development program for BMN-111. The current status of the achondroplasia clinical programme is described in the document below.
BioMarin’s investigational therapy for achondroplasia, BMN 111, is currently under investigation and has not been approved for use in any country.

Study 111-301

This trial is a phase 3 placebo-controlled trial with BMN-111, includes children from 5 to 17 years of age and approximately 110 participants globally. In this trial, participants are randomly selected to be included in the placebo group or in the drug group.

Outcomes of study 111-301

The primary outcome of the trial is to evaluate a change in the rate of growth or change in height. Secondary outcomes include measurements of health through evaluating health-related quality of life scores, other
associated symptoms, sleep quality as well as major illnesses and surgeries.

Duration

This trial lasts for 52 weeks and participants will have to have to complete a minimum of 6 months in the
observational trial (111-901) before they can be selected for the Phase 3 (111-301) trial.
Participants on placebo can receive the investigational therapy, or the BMN-111, after the 1 year trial period is
complete.

Study 111-501

BioMarin is preparing a new study, the 111-501, on the Lifetime Impact of Achondroplasia Study in Europe (LIAISE) is an observational study (so, no drug will be included) looking at the impact on quality of life, healthcare resource use, clinical, socioeconomic and psychosocial state of individuals living with achondroplasia.

This study is recruiting up to 300 participants between 5 and 70 years of age and will be opening in the following countries between now and early 2018: Germany, Spain, Italy, Sweden, and Denmark. Participation in the

study will include a 5-year review of historical clinical data as well as data obtained using questionnaires.

Read the full document here:

BioMarin ACH clinical development program Nov 2017

October 23, 2017
by inesp.alves
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The International Society of Skeletal Dysplasia 2017 meeting report

The International Skeletal Dysplasia Society meeting was held in Bruges between the 20th and 23rd September 2017, with the presence of world-renowned geneticists and clinicians with interest in skeletal dysplasias; also some pharmaceutical companies and patients representatives from all around the world were present.

The companies that were present and that are currently developing medicines for achondroplasia were, by alphabetic order: Ascendis Pharma, BioMarin, and Therachon.

ALPE Foundation has a report of this meeting, where the most relevant information is shared.

To add some clarification on the concepts regarding the Meclozine representation by Hiroshi Kitoh, that presented “Oral administration of meclozine for the treatment of short stature in achondroplasia”

 

His team observed that cutting-off the FGFR3 signaling in-vitro promoted (produced) longitudinal bone growth in transgenic ACH mice (mice that were genetically changed to be born with the ACH mutation). The team has been investigating which is the optimal dose of meclozine for the treatment of short stature in ACH for further clinical application in children.

In vitro - In vitro (Latin for "within the glass") refers to the technique
of performing a given procedure in a controlled environment outside of a 
living organism. Many experiments in cellular biology are conducted outside 
of organisms or cells. One of the weaknesses of in vitro experiments is 
that they fail to replicate the precise cellular conditions of an organism. 
In mpkb.org
FGFR3 ach mouse – Mouse models are currently available for genetic 
research and include thousands of unique inbred strains and genetically 
engineered mutants.  In Genome.gov.
FGFR3 ach mouse model is a mutant strain developed for mice to be born
with the achondroplasia mutation, to conduct scientific studies.

For this study, the team administered orally 1, 2 or 20 mg/kg/ day of meclozine to 7-day-old FGFR3 ach mice for 10 days. The body lengths were measured during the treatment periods and at the end of the treatment, the mice were subjected to micro-computed tomography (micro-CT) scans for calculating the bone length and bone volume.

The pharmacokinetic analyses demonstrated that peak drug concentration (Cmax) of 2 mg/kg of meclozine to mice was similar to those of 25 mg/body to human, which is a clinical usage for anti-motion-sickness. The body lengths of FGFR3 ach mice were increased by oral administration of 1 or 2 mg/kg/day of meclozine and the bone volume and trabecular bone quality were improved by meclozine treatment. Treatment of 20 mg/kg/day of meclozine, however, showed no positive effects on bone growth of mutant mice.

Pharmacokinetics: Pharmacokinetics is the study of drug absorption, 
distribution, metabolism, and excretion. A fundamental concept in 
pharmacokinetics is drug clearance, that is, elimination of drugs
from the body. In Principles of Pharmacokinetics
Micro-computed tomography: Enables a non-invasive inspection to 
screen anatomical changes in small animals. Once the dose received
by the small animal can be a critical concern in the research, the 
advantages of micro-CT include high resolution, high sensitivity 
to bone and lung, short scan time and cost-effectiveness. 
In Li H et al., 2008

Kitoh finished saying that they confirmed a preclinical proof of concept for applying meclozine for the treatment of short stature in ACH, although toxicity and adverse events associated with long-term administration of this drug should be examined. Also, the team is aiming to start a phase 1 clinical trial in Nagoya, Japan in children with ACH, between the end of 2017 and beginning of 2018. The study design is still not disclosed.

 

Metabolic studies on Achondroplasia

But one of the most relevant moments during ISDS was a study presented by Celine Saint-Laurent, a young researcher working in Elvire Gouze´s team in Nice, France (and in collaboration with Therachon). In her presentation, Celine showed that there is a link between the FGFR3 mutation and the metabolic complications related to achondroplasia.

Prior to this study in a mouse model with ACH, Celine firstly conducted a retrospective longitudinal study in children and adolescents with achondroplasia carrying the most frequent mutation of achondroplasia: the G380R FGFR3 mutation. Anthropometric, densitometric measures and several blood parameters were recorded from birth onward during follow up visits and compared between three age groups ranging from [0-3], [4-8] and [9-18] years old.

Celine’s study confirmed that there are metabolic disturbances in achondroplasia patients, that are unexpectedly not associated with classical obesity complications. Indeed, the data gathered showed that while patients with achondroplasia usually develop abdominal obesity, this does not correlate with an increase of typical risk factors of obesity such as high glucose, insulin or lipid levels and that they do not appear to develop diabetes.

In the mouse model study, Celine injected the mice with Flag-soluble FGFR3 (sFGFR3) during the mice growth period and could confirm that the bone growth was restored and the metabolic deregulations were corrected with the administration of soluble FGFR3. The researchers concluded that sFGFR3 proved to be a promising treatment for achondroplasia by restoring bone growth and also by preventing the metabolic deregulations and the development of obesity.

 

Anthropometric measurements: are used to assess the size, shape and 
composition of the human body. Some common methods used to gather 
these measurements are BMI, waist-to-hip ratio, skin-fold
test and bioelectrical impedance.

 

 

October 20, 2017
by inesp.alves
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Recruitment in clinical trials

The following document, shared by BioMarin in September 2017, is a clarification on the ongoing clinical trials for achondroplasia and was released for associations and families:

BioMarin Achondroplasia Programme Update 20Sept17

It is important to mention that families interested in having their children enrolled in BioMarin ongoing observational study (111-901) and interventional clinical trial (111-301), have to contact the centers that are conducting the clinical trial driectly, listed here.

Pharmaceutical companies DO NOT recruit patients for clinical trials. The companies, such as BioMarin, select the clinical centers (hospitals) in which their trial will take place and is the trial coordinator of that clinical center (usually a chief clinician), that recruits patients and who must be contacted for recruitment.

August 29, 2017
by inesp.alves
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13th International Skeletal Dysplasia Society meeting

From the 20th to the 23rd September 2017, it will take place in Bruges, Belgium, the ISDS meeting.

The ISDS is registered as a non-profit organization and the principal aim of the Society is to promote scientific progress in the field of skeletal dysplasias and dysostoses. To this aim, the society organizes meetings on a two-year basis.

The focus of the meeting will be on the clinical, radiographic and molecular aspects of rare and genetic disorders of the skeleton with special attention to the newest discoveries within this field.
Clinicians and researchers with interest in rare bone disorders will attend this meeting, as representatives from industry and patient groups.

The themes related to achondroplasia that will be presented during the course of the three days meeting will be:

  • Longitudinal bone growth velocity assessment by near-infrared imaging in a murine model of achondroplasia, by Florence Authier
  • Achondroplasia natural history: the power of a multi-center clinical study, by Julie Hoover-Fong
  • Disruptive, targeted emerging therapies in skeletal dysplasias, by Robin Forbes
  • Oral administration of meclozine for the treatment of short stature in achondroplasia, by  Hiroshi Kitoh
  • FLAG-sFGFR3 treatment prevents the metabolic deregulations in achondroplasia, by Celine Saint-Laurent

And also, in a specific session “Treatment: ready for patients?”, Adrian Quartel, from BioMarin Corporate, will present “Who we are, what we do”.

There will also be posters presentation, with more than 50 posters submitted. The most relevant titles by now for achondroplasia are:

  • How occupational therapy intervention within a multidisciplinary bone dysplasia clinic can promote functional independence for children with skeletal dysplasia, by Jennifer Robin
  • Patient and public involvement (PPI) in designing clinical trials for rare diseases – the achondroplasia experience, by Emma Glass.

Insights of the meeting will be presented here after.

 

August 25, 2017
by inesp.alves
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Research on ARQ 087, a Tyrosine kinase inhibitor

 

In 2016, the research team led by Dr. Pavel Krejci published the following article:

Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes. Gudernova I, Vesela I Balek L, Buchtova M, Dosedelova H, Kunova M, Pivnicka J, Jelinkova I, Roubalova L, Kozubik A, Krejci P.

Turning this title into something comprehensible, the researchers said that the 5 agents/products (SU5402, PD173074, AZD1480, AZD4547 and BGJ398), known as TKIs (Tyrosine kinase inhibitors) showed great results in blocking FGFRs tyrosine kinases in dish cells (plates where the researchers put specific cells into a culture to be tested). The image below is an example of a cell culture plate.

Tissue culture. Credits: Ferentis

There are 4 kinds of Fibroblast growth factor receptor (FGFRs): FGFR1, FGFR2, FGFR3 and FGFR4 and their actions (called signaling) are distinctive and involve diverse and multiple biological processes, including cell proliferation, survival, differentiation, migration, and apoptosis (means cell death) during embryonic development and adult tissue homeostasis. 5,7

FGFR 3 is the receptor where the mutation of achondroplasia is in chondrocytes and knowing that TKIs can block FGFR3, they can also block the other FGFRs. This means that TKIs target not just FGFR3 but all or almost all FGFRs.

FGFR3 is a major physiological negative regulator of bone growth, and therefore a safe and effective FGFR3 inhibitor would undoubtedly revolutionize the treatment of short-stature syndromes in general, possibly including many that are unrelated to FGFR3. 3

Credits: Khan Academy

So, in 2016, the team concluded that the 5 FGFR TKIs evaluated were poor candidates for therapy for achondroplasia, mainly because TKIs exhibited significant off-target activity. What does this mean? TKIs lack specificity for FGFR3, attack the other FGFRs, and show cell toxicity which would compromise TKIs’ use for treatment of achondroplasia. 3

Although Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, and these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. This occurs because tyrosine kinases are widely distributed with specific functional roles in different organs. 2

Recently, in August 2017, the same team published:

ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations, in FGFR1, FGFR2, and FGFR3.

ARQ 087 is a tyrosine kinase inhibitors that was tested in cultured chondrocytes (dish cells), and the team observed that ARQ 087 efficiently rescued all major effects of pathological FGFR3 activation as inhibition of chondrocyte proliferation, loss of extracellular matrix and induction of premature senescence. This means that in the cultured chondrocytes with the achondroplasia mutation and with ARQ 087, chondrocytes could grow and multiply as they do in a typical growth plate. Unfortunately, ARQ 087 has an off-target action too and blocks FGFR1, FGFR2 and FGFR3.

The main conclusion of the study is the following:

“The off-target effects of ATP-competitive TKIs represent a major obstacle compromising their use in the clinic, despite the fact that even serious side-effects may be tolerated in cancer, where the main objective is patient survival. In contrast, the side effects might not be acceptable in ACH or craniosynostoses, where the main treatment objectives are to increase stature height and correct disproportionate cranial development, respectively.” 4

This research proves that TKIs are not an appropriate selection to treat achondroplasia.

Developing new studies for achondroplasia can be very demanding and time-consuming, but patients trust that researchers do the best they can to deliver results that, ultimately, can be converted in a treatment and reduce the complications originated by achondroplasia: limbs and trunk disproportionality, neurologic, respiratory issues, orthopedic complications, negative social image, among others issues that are concerns and raise problems throughout life.

Not every study will originate a new medicine, but most studies will help researchers decide which way to go and which not to.

 

Author Comment: The title and text of this post was amended after reconsideration of previous content.

 

Bibliography

  1. http://www.tuftsctsi.org/about-us/what-is-translational-science/
  2. Shah DR, Shah RR, Morganroth J. Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy.Drug Saf. 2013 Jun;36(6):413-26.
  3. Gudernova I, Vesela I, Balek L, Buchtova M, Dosedelova H, Kunova M, Pivnicka J, Jelinkova I, Roubalova L, Kozubik A, Krejci P. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes.Hum Mol Genet. 2016 Jan 1;25(1):9-23.
  4. Balek L, Gudernova I, Vesela I, Hampl M, Oralova V, Bosakova MK, Varecha M, Nemec P, Hall T, Abbadessa G, Hatch N, Buchtova M, Krejci P. ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2, and FGFR3. Bone. 2017 Aug 18. pi: S8756-3282(17)30311-3.
  5. Kai Hung Tiong, Li Yen Mah, and Chee-Onn Leong. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis 2013; 18(12): 1447–1468
  6. http://www.the-scientist.com/?articles.view/articleNo/10487/title/The-Pressure-To-Publish-Promotes-Disreputable-Science/
  7. Ornitz D, Itoh N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015 May; 4(3): 215–266.

July 31, 2017
by inesp.alves
1 Comment

Exercises and postural education for children with achondroplasia – OSCAR 2016

In 2014, several Reference Centers in France dedicated to diseases involving the same organs, created OSCAR, the French network of rare diseases of bone, calcium, and cartilage.

Citing Dr. Geneviève Baujat (Necker-Enfants Malades hospital, Paris) “The aims are to expose various resources (people, hospitals, e-structures) and to make people working all together with “axes”: to develop concrete tools…such as the “Follow-up schedule” or video tutorials (on YouTube) for achondroplasia and some others rare conditions”.

Although all information is in French only, it is very valorous and must be shared worldwide.

Video tutorial

Child placement for the four exercises:

  1. Use a semi hard surface
  2. Do the exercises between meals
  3. The child wears little and comfortable clothes
  4. Distract the child during the exercises as like a playing moment
  5. Do soft massage during the exercise

Exercise 1: the child is placed stomach down

This exercise is to strengthen and reinforce the hip extensor muscles

 

Image credits: AQSpeed

Exercise 2: Lying on the side

While keeping the hips steady, work on the upper limb, producing a slight traction. And change limbs after. Repeat 10 times.

Exercise 3: Lying on the back

Produce gentle stimulation for the child to respond with active abdominal contractions. Repeat 10 times.

To remember:

  1. Do these exercises during 2 to 3 minutes every day.
  2. Encourage the child to do the exercises himself/herself
  3. Avoid extended sitting positions
  4. Keep doing the exercises throughout the child’s growth

Dr. Geneviève  Baujat ends saying:

These postural exercises are very important for children with achondroplasia and must be done in a very precise way. Also, the exercises should be done during all the child early development and more, this exercise time can be a very privileged moment between parent and child, done in a pleasant and playful way“.

All credits: OSCAR.

June 25, 2017
by inesp.alves
4 Comments

Therachon heading to Phase 1 clinical trial

Therachon’s medicine in development for achondroplasia, TA-46, was granted Orphan Drug designation by the medicine agencies FDA and EMA.

TA-46 is a type 3 fibroblast growth factor receptor antagonist addressing achondroplasia. This medicine is an inactive form of the receptor that binds to available fibroblast growth factors (FGFs) and with this stops the abnormal receptors from working. Through its action as a decoy, the medicine is expected to reduce the activity of these receptors, thereby helping to restore normal patterns of growth (EMA, 2017).

To understand the evolution of the process, these are the latest known timelines:

  • 27 Feb 2017 –  TA 46 received Orphan Drug status for Achondroplasia by the European Medicines Agency, EMA

Captured image – EMA documents library

 

  • 2 Jun 2017 TA 46 received Orphan Drug status for Achondroplasia by the US Food and Drug administration, FDA

Captured image in Access Data FDA

  • 15 Jun 2017 Therachon signed an agreement with Catalent Pharma Solutions, to support the preclinical and clinical development of TA-46, heading to plan of clinical trials in paediatric patients with Achondroplasia
  • 20 Jun 2017 Press release of Therachon receiving orphan drug designation for TA-46

About Orphan Designation

FDA: The Orphan Drug Act (ODA) provides for granting special status to a drug or biological product (“drug”) to treat a rare disease or condition upon request of a sponsor.

EMA: The European Medicines Agency is responsible for reviewing applications from companies /pharmaceutical industry, who intend to develop medicines for rare diseases, known as ‘orphan drugs'(EMA, 2017). When an Orphan Drug designation is granted, EMA provides incentives for the drug’s development as:

  1. Market exclusivity:  10 years with no competition by similar products,after  the drug is approved for sale
  2. Protocol assistance:  The agency provides scientific advice to optimize development and guidance on preparing a dossier that will meet European/US regulatory requirements
  3. Fee reductions
  4. EU-funded research

Designation as an orphan medicinal product does not indicate that the product has already satisfied the efficacy, safety and quality criteria necessary for the granting of a marketing authorization. As with any medicine, these criteria can only be assessed once the application for marketing authorization has been submitted.

Next steps – clinical trial Phase 1

At the time of submission of the application for orphan designation in EMA, the evaluation of the effects of the
medicine in experimental models was ongoing (EMA, 2017).

Phase I trial (short video)

Is the first in a series of four stages in testing new therapies in humans. The primary goal of these studies is to determine whether the therapy can be given safely, so one of the main evaluations is to watch for harmful side effects that may be caused by the treatment. The doctors who lead the clinical trial also will try to determine the best way to give an experimental drug (e.g., by mouth, IV drip, or injection) and how often and how much should be given, which is called dosing (John Hopkins Medicine, 2017).

Phase I clinical study for TA-46 is scheduled for the beginning of 2018

In further phases of the clinical trial, TA-46 will be evaluated in children that will receive 1 single subcutaneous (under the skin) injection per week to reduce the effects of achondroplasia.

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