Beyond Achondroplasia

Growing together with Clara

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

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.

June 3, 2017
by inesp.alves
1 Comment

BioMarin updates the Multicenter and Multinational Clinical Study 111-901

The “Multicenter, Multinational Clinical Assessment Study for Pediatric Patients With Achondroplasia” is a prospective observational study. This study’s code name is 111-901.

The aim of this study is to collect systematic growth measurements of the children in order to collect data to better understand the natural history of achondroplasia.

Children between 2 and 13 years old can be enrolled in the 111-901 study. The measurements take place every 3 months and can go for up to 60 months (or 5 years).

BMN-111 will not be administered in this study. Yet, only children that participate in the study 111-901 can be enrolled in the drug study afterwards, with the code 111-301, in which BMN-111 will be administrated to 50% of participants while the others will receive a placebo.

Credits: Brakefield R. Observational Studies and Experiments, 2015

The 111-901 study is now being conducted at 21 clinical centers around the globe, and new centers have been added in the USA and centers in Spain and Turkey have been included. All centers are currently recruiting patients.

United States,


Harbor-UCLA Medical Center
Los Angeles, California, United States, 90048
Contact: Nathalia Patritti Cressey, Study Coord    310-781-3682 ext Office
Contact    310-597-1960 ext Cell
Principal Investigator: Patti Dickson, MD
Children’s Hospital and Research Center Oakland
Oakland, California, United States, 94609
Contact: Jacqueline Madden, Study Coord    510-428-3885 ext 5745
Children’s Hospital Colorado
Aurora, Colorado, United States, 80045
Contact: Laurel Ware, BSN    720-777-5378

Principal Investigator: Gary Bellus
Nemours/Alfred I. duPont Hospital for Children
Wilmington, Delaware, United States, 19803
Contact: Cassie Brown, Study Coord    302-298-7930

Contact: Michael Bober, MD
Emory University
Decatur, Georgia, United States, 30033
Contact: Elizabeth Smith, Study Coord

Contact: William Wilcox, MD

Ann and Robert H Lurie Children’s Hospital of Chicago
Chicago, Illinois, United States, 60614
Contact: Victoria Sanders, Study Coord    312-227-6120
Indiana University, Riley Children’s Hospital
Indianapolis, Indiana, United States, 46202
Contact: Susan Romie    317-278-6650

Principal Investigator: David Weaver, MD
Johns Hopkins McKusick- Institute of Genetic Medicine
Baltimore, Maryland, United States, 21287
Contact: Adekemi Alade, Study Coord

Contact: Kira Lurman, Study Coord

University of Missouri
Columbia, Missouri, United States, 65201
Contact: Vicki L Jones, Study Coord    573-882-7583

Contact: Daniel G Hoernschemeyer, MD    573-882-1351
Principal Investigator: Daniel G Hoernschemeyer, MD
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Contact: Racheal Powers    800-647-4805
Principal Investigator: Howard Saal, MD
Vanderbilt University
Nashville, Tennessee, United States, 37232
Contact: LeeAnna Melton, Study Coord    615-343-6761

Baylor College of Medicine
Houston, Texas, United States, 77030
Contact: Catherine Loffredo, Study Coord

Seattle Children’s Hospital
Seattle, Washington, United States, 98105
Contact: Tressa Mattioli-Lewis

Contact: Klane White, MD

Principal Investigator: Klane White, MD
Medical College of Wisconsin, Children’s Hospital
Milwaukee, Wisconsin, United States, 53226
Contact: Paula Engelking    414-266-3289

Contact: Donald Basel, MD

Principal Investigator: Donald Basel, MD


Australia, Victoria
Murdoch Children’s Research Institute
Parkville, Victoria, Australia, 3052


Institut Necker
Paris, France, 75015
Contact: Kim-Hahn Le Quan Sang, MD    33 1 44 49 59 51

Principal Investigator: Valerie Cormier-Daire, MD


Institut Catala de Traumatologica I Medicina de l’Esport
Barcelona, Spain, 08028
Contact: Miriam Perez    +34 932 05 43 62 ext 21148

Contact: Ignacio Ginebreda    +34 619 21 35 77

Principal Investigator: Ignacio Ginebreda
Hospital Sant Joan de Deu Barcelona
Barcelona, Spain, 08950
Contact: Jose Maria de Bergua    +34 650 80 60 71
Contact: Rosendo Ullot    +34 650 80 60 71

Principal Investigator: Rosendo Ullot
Hospital Universitario Virgen de la Victoria
Málaga, Spain, 29010
Contact: Antonio Leiva    +34 646 56 87 89
Contact: Felipe Luna    +34 607 85 81 22
Principal Investigator: Felipe Luna


Acibadem University School of Medicine
Istanbul, Turkey, 34752
Contact: Beyzanur Gonenc    +90 532 300 09 13

Contact: Burcu Menderes    +90 555 313 40 86

Principal Investigator: Yesemin Alanay, MD
Sub-Investigator: Selda Karaayvaz


United Kingdom
Guy’s and St. Thomas NHS Foundation Trust Evelina Children’s Hospital
London, United Kingdom, SE1 9RT
Principal Investigator: Melita Irving, MD

Information available on

May 14, 2017
by inesp.alves

BioCentury published the article “Competing for growth”

BioCentury´s Senior writer Mike Leviten wrote a substantial article about the current medicines in research and development for achondroplasia. The article was published on the 7th April.

This competition between pharma companies is very positive since it stimulates industry to develop better medicines and at a faster pace. The investment in research and development of medicines is tremendous and the best possible outcomes for the companies in this race is when the company provides the most effective medicine in reducing achondroplasia associated medical complications, produces less side effects and substantially increases the quality of life of the patient and his/her family.

When a chef is creating a new recipe, the best product is discovered sometimes after countless attempts, but the chef will never achieve the goal without tasting what is being created. And in drug discovery, “tasting” is when pharma works in order to gather all efforts to know who the patient is and what the patient lives and needs.

The following excerpt is available on Biocentury page:

With little in the clinical pipeline for achondroplasia beyond BioMarin Pharmaceutical Inc.’s late-stage vosoritide, startups Therachon AG and BioClin Therapeutics Inc. are rethinking how to tackle the disease. By targeting FGFR3 directly, the two companies think they can block a signal vosoritide misses, and produce compounds that have better efficacy and require less frequent dosing.

The field appears poised for an uptick of activity, triggered by BioMarin’s positive Phase II data and recent publications that validate the FGFR3 biology underlying the disorder.

Achondroplasia is the most common form of short-limb dwarfism, and is caused by a single point mutation in FGFR3 that constitutively activates the receptor and inhibits bone growth. The treatment landscape involves either painful limb-lengthening surgery or, typically, a one-year course of human growth hormone, which has limited benefit.

BioMarin’s approach is to block a downstream mediator in the FGFR3 pathway that is responsible for chondrocyte growth. Its candidate, vosoritide, is a stable analog of the peptide agonist CNP that acts via the cell surface receptor NPR2 to inhibit a ras-driven cascade downstream of FGFR3. In December, BioMarin initiated a Phase III trial of vosoritide in patients aged 5-14.

Ascendis Pharma A/S is taking a similar approach with its TransCon CNP, a sustained-release prodrug of CNP. The company plans to submit an IND this year (apply for an “Investigational New Drug” at the FDA and EMA).

By contrast, Therachon and BioClin are targeting FGFR3 activity directly, which allows them to block chondrocyte proliferation as well as growth.”

May 12, 2017
by inesp.alves

Phase 3 trial for achondroplasia – BioMarin Study 111-301

The following information is fully available at the European Union Clinical Trials Register. Some sections will be here highlighted:


Full title of the trial
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of BMN 111 in Children with Achondroplasia

What does PlaceboRandomized, Double-Blind mean?

Placebo: an inert substance that has no action or effect, but can produce the placebo effect, that is the response that follows the administration of a placebo [1].

Randomized: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. In this particular case, a placebo will be compared with BMN-111 [2].

Double-Blind: when the patient and the investigator are blind in knowledge. This means that neither the patient nor the investigator know which patients are getting the drug and which are getting placebo [3].


Sponsor’s protocol code number 111-301

This is the designation of the phase 3


IMP Role Test

The goal is to test an Investigational medicinal product (IMP)


The IMP has been designated in this indication as an orphan drug in the Community Yes

Any medicinal product that aims to treat a rare disease is designated orphan drug


Description of the IMP
D.3.1 Product name modified recombinant human C-type natriuretic peptide- CNP
D.3.2 Product code BMN 111
D.3.4 Pharmaceutical form Lyophilisate for solution for injection
D.3.4.1 Specific paediatric formulation Yes
D.3.7 Routes of administration for this IMP Subcutaneous use

CNP, is expressed as a 126–amino acid protein precursor (preproCNP), and is then processed to an active 53–amino acid cyclic peptide and further processed to a 22–amino acid peptide.  Native CNP (CNP22) has a short half-life inside the body of less than 2 minutes in mice and humans. BioMarin modified this CNP for a 39–amino acid CNP variant (BMN 111) and is produced in the bacteria Escherichia coli [4].


D.8 Placebo
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo Lyophilisate and solvent for solution for injection
D.8.4 Route of administration of the placebo Subcutaneous use


E.2 Objective of the trial
E.2.1 Main objective of the trial
Evaluate change from baseline in mean annualized growth velocity at 52 weeks in subjects treated with BMN 111 compared with control subjects in the placebo group.
E.2.2 Secondary objectives of the trial
• Evaluate change from baseline in mean height Z-score in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
• Evaluate change from baseline in mean upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
• Evaluate safety and tolerability of BMN 111 in children with ACH
• Evaluate the pharmacokinetics of BMN 111

This study will take 1 year to produce results. Upper:lower segment body ratio will be evaluated.

Upper to lower body ratio

The lower body segment is the measurement of the length from the pubic symphysis (roughly the pubic bone) to the floor; the upper body segment is the height minus the lower body segment. The average U/L ratio (upper body segment : lower body segment) at birth is about 1.7; at age 3 years it is 1.3; at greater than 7 years, it is 1.0 with the upper body segment and lower body segment being about equal. Higher U/L ratios are noted in short-limb dwarfism.

So the ideal is a ratio near 1.

Vitruvian man – Leonardo Da Vinci


Principal inclusion criteria
1. Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, subjects under the age of 18 are willing and able to provide written assent (if required by local regulations or the IRB/EC) after the nature of the study has been explained and prior to performance of any research-related procedure.
2. 5 to < 15 years old at study entry
3. Have ACH, documented by clinical grounds and confirmed by genetic testing
4. Have at least a 6-month period of pretreatment growth assessment in Study 111-901 immediately before study entry, and has one documented standing height at least 6 months (+/- 10 days) prior to the screening visit for Study 111-301
5. Females ≥ 10 years old or who have begun menses must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study
6. If sexually active, willing to use a highly effective method of contraception while participating in the study
7. Are ambulatory and able to stand without assistance
8. Are willing and able to perform all study procedures as physically possible
9. Caregivers are willing to administer daily injections to the subjects and complete the required training

All children that participate in this phase 3 study (111-301) have to first take, the natural history/growth assessment study (111-901) for at least 6 months.


End points
E.5.1 Primary end point(s)
The primary efficacy endpoint is the change from baseline in annualized growth velocity (AGV) at Week 52 (12- month).
E.5.1.1 Timepoint(s) of evaluation of this end point
Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 29, Week 52
E.5.2 Secondary end point(s)
The secondary efficacy endpoints include the change from baseline in height Z-score and the change from baseline in upper:lower body segment ratio.

Safety will be evaluated by assessment of AEs, SAEs, laboratory test results (urinalysis, chemistry, hematology), changes in vital signs, physical examination, ECG, X-rays/DXA, clinical hip assessment, and anti-BMN 111 immunogenicity assessments.

PK sampling will be carried out over the 12-month study period in subjects randomized to BMN 111 or placebo.

E.5.2.1 Timepoint(s) of evaluation of this end point
Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 29, Week 52

Clinical labs (urinalysis, chemistry, hematology): Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54

Vital signs and AEs: Screen, Day 1, Day 2, Day 3, Day 10, Week 6, Week 26, Week 39, Week 52, Week 54 (follow-up)

Physical exam: Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

ECG: Screen, Day 1, Day 10, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

X-Ray/DXA: Screen, Week 26, Week 52

Clinical hip assessment: Screen, Week 26, Week 52

Anti-BMN 111 immunogenicity: Day 1, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

PK: Day 1 (full), Week 13 (partial), Week 26 (full), Week 39 (partial), Week 52 (full)

Endpoint: In clinical trials, it is an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives.

Anthropometric measurements:  systematic measurements of the size, shape and composition of the body

PK: Pharmacokinetics is the study of ‘what the body does to the drug’ and includes:
•    the rate and extent to which drugs are absorbed into the body and distributed to the body tissues
•    the rate and pathways by which drugs are eliminated from the body by metabolism and excretion
•    the relationship between time and plasma drug concentration [5].


E.8.5 The trial involves multiple Member States Yes
E.8.5.1 Number of sites anticipated in the EEA – Europe 10


E.8E.8.6 Trial involving sites outside the EEA.
United Kingdom
United States
E.8.7 Trial has a data monitoring committee – Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial – LVLS

LVLS – Last visit, last subject/patient


F. Population of Trial Subjects- Age Range
F.1.1 Trial has subjects under 18 Yes
F.1.1 Number of subjects for this age range (all world): 110
F.1.1.1 In Utero No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3 Newborns (0-27 days) No
F.1.1.4 Infants and toddlers (28 days-23 months) No
F.1.1.5 Children (2-11years) Yes
F. Number of subjects for this age range: 88
F.1.1.6 Adolescents (12-17 years) Yes
F. Number of subjects for this age range: 22
F.1.2 Adults (18-64 years) No
F.1.3 Elderly (>=65 years) No


F.4.2 For a multinational trial
F.4.2.1 In the EEA 24
F.4.2.2 In the whole clinical trial 110
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
Following completion of 52 weeks subjects in both treatment groups may be eligible to receive BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over a longer term.





  1. Gupta U, Verma M. Placebo in clinical trials. Perspect Clin Res. 2013 Jan-Mar; 4(1): 49–52
  2. National Cancer Institute dictionary
  3. Misra S. Randomized double blind placebo control studies, the “Gold Standard” in intervention based studies. Indian J Sex Transm Dis. 2012 Jul-Dec; 33(2): 131–134.
  4. US national library of medicine
  5. IUPHAR Pharmacology Education Project
  6. EU Clinical Trials Register


April 9, 2017
by inesp.alves
1 Comment

The TransCon CNP, a prodrug for achondroplasia



A company based in Denmark and is applying its innovative TransCon technology that combines the benefits of prodrug and sustained-release technologies and developing the TransCon CNP for achondroplasia.


Achondroplasia is caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). The increased activity of the FGFR3 reduces the growth of the long bones. The C-type natriuretic peptide (CNP) has the ability to antagonize the FGFR3 action inside the chondrocytes by inhibiting the MAPK chain reaction (mitogen-activated protein kinase). MAPK signals, which slow bone growth, are subject to downregulation by the signaling cascade activated by C-type natriuretic peptide (CNP), resulting in the stimulation of endochondral ossification in vivo. In “Achondroplasia: pathogenesis and implications for future treatment” Laederich M and Horton W, 2010.

In a simpler way: when the CNP connects with its receptor in the cell (NPR-B) it can block the FGFR3 cascade that takes place inside the chondrocyte, as if stopping a chain reaction of domino pieces falling. And by this action, CNP can produce a positive effect in restoring growth in achondroplasia.

Several approaches have shown promise in preclinical studies for achondroplasia and one of them uses CNP. BioMarin Pharmaceuticals developed the CNP analog, BMN 111, which retains the biologic properties of native CNP but has an extended half-life due to its resistance to neutral-endopeptidase digestion, allowing for once daily subcutaneous administration. In “Advances in treatment of achondroplasia and osteoarthritis“. Klag K and Horton W, 2016

After this, what is a prodrug?

A drug is a small organic molecule introduced into the body for cure, prevention, treatment or diagnosis of a disease generally binding to a specific site or organ/cell and activating or inhibiting the function of the desired biomolecule. But drug administration is associated with certain problems like distribution of the compound throughout the body and undesirable side-effects.

Prodrug is the masked form of active drug capable of increasing the efficiency of drugs and decreasing its associated toxicity. As in the following image, a prodrug is considered to be the combination of active drug and side chain/ligand (covalently linked), which helps in targeting the specific cell/tissue. The prodrug is then converted to the original drug once it reaches the site of action, followed by rapid abolition of the released derivatizing group without causing side effects. In “Cutting Edge Approach on Prodrug: Contrivance for Target Drug Delivery“. Varsha Y et al., 2011

Cutting Edge Approach on Prodrug: Contrivance for Target Drug Delivery”. Varsha Y et al., 2011

What is a sustained release technology?

From all drug delivery systems, oral drug delivery remains the most preferred option for administration for various drugs. Sustained Release is also providing promising way to decrease the side effects of drugs by preventing the fluctuation of the therapeutic concentration of the drug in the bodyside-effects are reduced and cure of the disease is achieved. The principal goal of sustained release forms is the improvement of drug therapy… In “A review on sustained release technology“Gupta M and Brijesh U, 2012

The TransCon technology

It can be applied to previous therapeutic approaches to extend duration of a drug’s action in the body, and to enhance the overall benefit of a therapy.  This technology combines the benefits of conventional prodrug + sustained release technologies creating a platform technology that is broadly applicable to proteins, peptides and small molecules (Ascendis Pharma).

In sum, the TransCon is like a reservoir that holds the drug inside it. After this “reservoir” is injected into the body, it can release the drug at a predetermined frequency of time. So in the TransCon CNP case, the TransCon holds CNP inside

Image: Ascendis Pharma

The TransCon CNP

Ascendis Pharma stated that the TransCon CNP is a sustained-release prodrug of C-Type Natriuretic Peptide (CNP) for the treatment of achondroplasia and has shown the following relevant points:

  1. It is being investigated as a once-weekly prodrug to provide continuous exposure to CNP to potentially improve efficacy, safety and/or convenience over first-generation CNP analogues.
  2. It releases CNP via a non-enzymatic hydrolysis of the TransCon linker.
  3. It is designed to maintain the same mode of action and distribution as the continuous administration of CNP and could become an efficacious and safe therapy for patients with ACH, with a convenient subcutaneous weekly dosing profile.
  4. It minimizes binding of CNP to the NPR-C receptor to decrease clearance;
  5. Reduces binding of CNP to vascular NPR-B receptors to avoid hypotension caused by activation of this receptor. (There are receptors NPR-A, NPR-B and NPR-C being the B the specific receptor of CNP)
What is drug clearance?

Is the rate at which the active drug is removed from the body; and for most drugs at steady state, clearance remains constant so that drug input equals drug output. The university of Nothingham

Recent updates

Ascendis Pharma presented two posters at the ENDO 2017 (Endocrine Society Annual Meeting, 1-4 April 2017) on TransCon CNP, and the top conclusions were:

  1. Lack of adverse hemodynamic effects of TransCon CNP, allowing for the administration of high doses to facilitate optimal efficacy.
  2. Observation of a dose-dependent effect on tibia growth in juvenile monkeys with weekly TransCon CNP with results that demonstrated growth effects continued through six months.
  3. The effects of TransCon CNP in a mouse model of achondroplasia, included bone growth and the potential to ameliorate some of the more disabling achondroplasia traits, including stenosis of the foramen magnum.

So, with this, the bar stands higher for all the companies currently working on a potential treatment for achondroplasia. For patients, the key goal of receiving a drug that can reduce the complications directly related to achondroplasia, such as the stenosis of the foramen magnum, seems to be starting to catch the attention of the researchers, the industry and the investors.

“The encouraging TransCon CNP preclinical data support the hypothesis that a CNP analogue can be an effective treatment for achondroplasia without dose-limiting hypotension”

Kennett Sprogøe, Ph.D., Senior Vice President of Product Innovation

Transcript of interview to CEO and CMO of Ascendis Pharma, on the Earnings Conference Call- March 22, 2017

“Our long acting CNP pro-drug, TransCon CNP, is designed to optimize the therapeutic index by allowing a CNP level high enough to be therapeutic, but without achieving levels that result in hypotension, which has limited current investigational therapies.

In relevant animal models, we have shown no change in blood pressure following once weekly administration of TransCon CNP. In contrast a daily administered CNP which did lead to hypotension.”

Scott Smith – Senior Vice President, Chief Financial Officer

“We expect to submit an IND (Investigational New Drug application) or similar filing for TransCon CNP during the fourth quarter of 2017 and initiate clinical development in early 2018.”

Jan Mikkelsen – President and CEO

In conclusion, this is an enthusiastic time for patients with achondroplasia, their families, clinicians and the researchers community, by having several drugs in research and development: Vosoritide, TA-46, Meclizine, RMB-007, B-701 and TransCon CNP. We will keep a close look in all these drugs aiming to treat achondroplasia.

February 13, 2017
by inesp.alves

Foramen magnum growth in achondroplasia

What is the central nervous system (CNS)?

The nervous system has two parts: the central nervous system and the peripheral nervous system, due to their location in the body. The central nervous system (CNS) includes the nerves in the brain and spinal cord. It is safely contained within the skull and vertebral canal of the spine. All of the other nerves in the body are part of the peripheral nervous system (PNS). Pubmed Health

The central nervous system consists of two parts: the brain and the spinal cord.

The brain works like a central computer. It processes information that it receives from the senses and body, and sends messages back to the body. Brain tissue is made up of about 100 billion nerve cells (called neurons) and one trillion supporting cells which stabilize the tissue.

The spinal cord is the highway for communication between the body and the brain. When the spinal cord is injured, the exchange of information between the brain and other parts of the body is disrupted.

What is the foramen magnum?

Most anatomic designations originate from Ancient Greek and Latin. Both words in foramen magnum come from Latin: foramen means “hole” and magnum “great”.

The foramen magnum represents a large oval opening in the occipital bone that exists in the base of the skull. It is one of the several oval or circular openings (foramina is the plural of foramen) in the base of the skull. The spinal cord, an extension of the medulla, passes through the foramen magnum as it exits the cranial cavity a natural opening or passage, especially one into or through a bone. Radiopaedia

View from inside the skull, looking from above. Case courtesy of OpenStax College,, rID: 42751

Medulla oblongata and foramen magnum animation. Credits: Wikimedia commons. The medulla oblongata, or just medulla, is a transition between the lower part of the brain (the pons) and the spinal cord.

The foramen magnum is a fundamental component in the complex interaction of bony, ligamentous, and muscular structures composing the craniovertebral junction. Shape and size of the foramen are critical parameters for the manifestation of clinical signs and symptoms in craniocervical pathology.
Among developmental and acquired craniocervical junction disorders, achondroplasia is the most commonly reported. Tubbs R. et al., 2010

et al. – from Latin et alii, meaning “and others” (used to refer an article written by more than 3 authors).

Pathology – from the Greek pathos “suffering” and ology “the study of something

Achondroplasia results in abnormal endochondral bone formation at the cranial base resulting in a narrow cervical spinal canal, foramen magnum (Mukherjee D. et al., 2014) and jugular foramina which further leads to ventricular dilatation and prominence of the emissary veins. Some degree of ventriculomegaly (increased volume of the ventricles) is present in almost all children with achondroplasia. Bosemani et al., 2014
The presence of prominent emissary veins and meningeal veins (the veins visible in the forehead of many children with achondroplasia) supports the role of collateral vessel formation to compensate for intracranial venous hypertension and increased CSF pressures. Bosemani T. et al., 2014

Credits: Bosemani et al., 2014

Age controls are in this study, children of similar age without achondroplasia. Credits: Bosemani et al., 2014. The shape of the FM is variable and the size of the foramen magnum in patients with achondroplasia was small at all ages, particularly in those with serious neurological problems. Shepur M., et al., 2014

Babies with achondroplasia have significantly smaller foramen magnum diameters than unaffected babies, and this difference persists across the lifespan.  DelRosso L., Gonzalez-Toledo E., Hoque R., A Three-Month-Old Achondroplastic Baby with both Obstructive Apneas and Central Apneas, 2013

In the next image it is possible to see the size of the foramen magnum (dark cycle) in a baby with achondroplasia.

Clinical case: a 3 months old baby with achondroplasia. Mild foramen magnum narrowing without evidence of cervicomedullary junction stenosis. DelRosso L., Gonzalez-Toledo E., Hoque R., 2013

The CT scan of foramen magnum of 200 non achondroplastic children of all ages and 100 adults, showed an average foramen magnum length of 35 mm (1,38 in) in adults and that of children reached the adult foramen magnun size by 3-4 years of age. Shepur M., et al., 2014

What is cervicomedullary junction (CMJ) compression?

As the name implies, CMJ is the region where the brainstem (the medulla) continues as the spinal cord. A lesion located in this region affects either the brainstem or cervical cord or both depending on its extent and pathology. Involvement of brainstem is manifested as cranial nerve palsies, decreased respiratory drive, long tract signs: clonus (series of involuntary muscular contractions and relaxations), muscle spasticity (stiffness) or bladder involvement that usually indicate a lesion in the middle or upper parts of the spinal cord or in the brain and hydrocephalus if there is obstruction of the fourth ventricle. Nair A., et al. 2014

Hydrocephalus – a disturbance of cerebrospinal fluid (CSF) formation, flow, or absorption, leading to an increase in volume occupied by this fluid in the central nervous system (CNS). Animation here

Impaired venous drainage in achondroplasia has been shown to be caused by deformation of the skull base that in turn, results in stenosis of the foramen magnum and jugular foramina. Bosemani et al., 2014

The most serious neurological complication in patients with achondroplasia is cervicomedullary junction (CMJ) compression caused by a tight, deformed foramen magnum. Compression at the foramen magnum can result in cervical myelopathy manifested as clonus and hyperreflexia, hypotonia, sleep apnea, and even sudden death. Due to the potentially lethal complications associated with symptomatic disease, neurosurgical decompression has been used to widen the foramen magnum and relieve the pressure on the emerging cervical cord. Fortunately, most children with achondroplasia do not suffer neurological symptoms and achieve normal motor and intellectual development without surgical intervention (Mukherjee D. et al., 2014).


Monitoring the growth of the Foramen magnum in achondroplasia

The foramen magnum size increases slowly in achondroplasia, but does increase with age. Sudden infant death has been described in achondroplastic individuals, but this usually occurs when these individuals are awake and is associated to marked hypotonia, large head size and cranial vein dilatation. … Almost all children will gain significant muscle tone by age 2 or 3 years old and catch up on all motor milestones. This is probably due to the fact the foramen magnum size increases faster than cervical cord volume, thus relieving pressure on the cord. Thus the severe hypotonia on achondroplasia is self limited. Only those with significant neurological impairment and increased intraventricular pressure should require surgery. Nicoletti B., et al., Human Achondroplasia: A Multidisciplinary Approach, Volume 48 of Basic Life Sciences, Springer US, 2012

Taken from a very old paper:

The fitted nonachondroplastic foramen magnum growth curves demonstrate that the maximum growth occurs in the first 18 months and slows thereafter. Indeed, the sagittal dimension (lateral plane that divides the head into left and right halves) almost doubles within the first 2 years, while the transverse dimension (horizontal plane that divides the head into top and bottom parts) enlarges by half the original dimension. Growth of this area is essentially complete by 5 years of age. Hetch J., et al.,1989

Foramen magnum growth chart



The achondroplastic foramen magnum is small at birth and the curves demonstrate that in achondroplasia, during the first year of life, the transverse dimension (fig1a) is the most severely impaired and that growth throughout life is negligible. These curves suggest that foramen magnum growth is more severely impaired than can solely be attributed to abnormal endochondral growth. In the foramen magnum area, the early growth spurt (vertical line in fig 1, around 12 months of age) is absent in the transverse dimension, suggesting that other disruptive processes in achondroplasia contribute to the abnormal development of the foramen magnum. There is a premature fusion and aberrant development of the posterior synchondroses, that should normally occur by 7 years but in achondroplasia premature fusion has been observed as early as 1 year. Hetch J et al., 1989

The development of the skull base occurs mainly at the growth centers called synchondroses: intersphenoid, spheno-occipital and intraoccipital synchondroses. FGFR3 mutation accelerates ossification of cartilages in these synchondroses and causes early closure. This early closure can be the main reason of hypoplasia of the skull base in ACH. Hetch J et al., 1989

Left: view from beneath the skull. Right: view inside the skull base. Credits: Al-Zubair N., 2013

The anatomy of the skull base. There are some synchondroses of the intra- or inter-bones of the skull base. Credits: Nakai Y., et al., 2015

In conclusion mode:

1. Despite stenosis of foramen magnum and jugular foramina, only 10–15% of children develop progressive hydrocephalus, requiring neurosurgical treatment. Bosemani T. et al., 2014

2. The absence of correlation between degree of ventriculomegaly and severity of foramen magnum or jugular
foramina stenosis suggests that the decision for neurosurgical intervention cannot be taken on the basis of individual neuroimaging findings alone. Bosemani T. et al., 2014

3. It is unclear whether the absolute dimension of the foramen magnum is helpful in determining which patient will benefit from decompression. The American Academy of Pediatrics recommends an initial evaluation with a thorough neurological history, complete physical examination, neuroimaging, and polysomnography. DelRosso L. et al., 2013

4.”Only those with significant neurological impairment and increased intraventricular pressure should require surgery” Nicoletti B et al., 2012.” This conclusion is very important in the evaluation of young children with achondroplasia. Medicine and mathematics are not the same science and in medicine “1 plus 1 is not equal two”. This example was used to say that there are many factors involved in assessing a baby with achondroplasia as well the individual singularity, that has to be taken in account when deciding for a decompression surgery in a child with achondroplasia younger than 2 years-old. Many neurosurgeons without experience in achondroplasia cases, that face a baby with achondroplasia for the first time, with a MRI with a narrow foramen magnum, will encounter a huge challenge in evaluating the risk of cervical myelopathy and the exact need for decompression surgery.

5. Foramen magnum dimension should be regularly evaluated during early pediatric ages, and the data used to develop a better natural history guide for achondroplasia.

6. New medicines developed for achondroplasia should act directly at the foramen magnum area and reduce the synchondrosis’ early closure in achondroplasia.

January 26, 2017
by inesp.alves
1 Comment

Accelerating bone formation during limb lengthening

Currently, we stand in a great moment of drug development for achondroplasia with one drug in clinical trial, that just started phase 3 (Vosoritide) and another one, the TA-46, that maybe will start clinical trial phase 1 soon. And there is still another one, a repurposing drug (Meclizine) with chances of heading to phase 1 studies too.

In the next years there with be one or two medicines available for patients, but nevertheless, limb lengthening (LL) will keep being an approach for patients who wish to increase height and already have closed growth-plates or for those who don´t wish to take a drug treatment.

Limb lengthening process is based on the principle of distraction osteogenesis and until nowadays, it has improved significantly.

Distraction osteogenesis (DO)

“Is a surgical technique widely used in orthopedic surgery for the treatment of various pathological conditions such as leg length discrepancy, bone deformity or bone defects. The basic principle includes performing a transverse bone section before gradually distracting the two bone segments. New bone tissue is generated in the gap between the two segments. Bone regeneration during DO is believed to occur in response to the longitudinal mechanical strain applied to the callus during healing. One of the limitations of this technique is the long period of time required for the newly formed bone tissue to mineralize and consolidate. Various studies have reported that among growth factors, bone morphogenetic proteins (BMPs) may play a central role in the molecular signaling cascade leading to bone renegeration and remodeling in a DO procedure. ” Sailhan FBone lengthening (distraction osteogenesis): a literature review. Osteoporos Int. 2011 Jun

Limb Lengthening

The first case of limb lengthening was performed by Prof. G. A Ilizarov in 1972, in a person with achondroplasia on both legs. The first report on the principals and applications of distraction osteogenesis techniques was by Prof. Codivilla of Italy, in 1905.



Prof. Ilizarov Image credits – University of Jordan

Image credits: Al-Mohrej OA, Al-Ayedh NK, Al-Awlah AY, Al-Kenani NS. Current view of bone regeneration using mesenchymal stem cells. J Orthop Allied Sci 2016;4:1-4

Distraction osteogenesis is considered the best in vivo tissue engineering techniques as it has the ability to achieve spontaneous formation of de novo native bone without the need for bone grafts.

The Ilizarov device is still in use, but in 2011, appeared an innovative system was approved for the first time by FDA, the PRECICE system, “an intramedullary nail used for limb lengthening of the femur and tibia that utilizes an External Remote Controller (ERC) to non-invasively lengthen the implant. The key to the technology is the magnetic interaction between the PRECICE implant and the PRECICE ERC, a portable, hand-held unit that lengthens the PRECICE implant”. In 2013, the PRECICE 2 was approved and “improves on some of the characteristics of the original version, including allowing for a greater range of lengthening and a new narrower and longer nail that is compatible with more patient anatomies.

PRECICE Intramedullary Limb Lengthening System. (Image credits: Limb Lengthening and Reconstruction)

In 2014, PRECICE 2  system was presented and has improvements on some of the characteristics of the original version, including allowing for a greater range of lengthening and a new narrower and longer nail that is compatible with more patient anatomies.

Here you can read a presentation on application of the PRECICE system.

In the above image, are shown PRECICE 1 (P1) and PRECICE 2 (P2) tibial nails. The larger diameter part of the nail houses the mechanism. In the P1 there are welds at the upper and lower end of the mechanism (arrows). In the P2 there are no welds connecting the different parts of the larger diameter part of the nail.

How to accelerate the bone regeneration?

In the review article by Makhdom, Nayef, Tabrizian, Hamdy,” The potential roles of nanobiomaterials in distraction osteogenesis” Nanomedicine: Nanotechnology, Biology, and Medicine, 2014

“Distraction osteogenesis (DO) technique has been used worldwide to treat many orthopaedic conditions. Although successful, one limitation of this technique is the long time of fixator needs to be left in place until the bone is consolidated. The application of growth factors (GFs) is one promising approach to accelerate bone regeneration during DO. Despite the promising results from the animal data, its use still limited in the clinic. This is secondary to inherit limitations of these GFs. Therefore, a development of delivery systems that allow sustained sequential release is necessary. Nanoparticles and nanocomposites have prevailing properties that can overcome the limitations of the current delivery systems.”

Recently, Jauregui, et al. published a meta-analysis :”Regenerate bone stimulation following limb lengthening” present very relevant points related to Limb Lengthening:

Limb lengthening with external fixation is performed to treat patients with leg length discrepancy or short stature. Although the procedure has a high rate of success, one potential drawback from limb lengthening is the amount of time spent in the fixation device while regenerate bone consolidates”

In this article, the authors also approach different treatment modalities to increase bone regeneration velocity as low intensity pulsed ultrasound (LIPUS) or pulsed electromagnetic fields (PEMF), showing that these techniques have significant effects on regenerate bone growth.

“The LIPUS signal is transmitted through tissue to the bone, where cells translate this mechanical signal to a biochemical response via integrin mechano-receptors. The cells enhance the production of cyclo-oxygenese 2 (COX-2) which in turn stimulates molecules to enhance fracture repair. The aim of this review is to present the state of the art data related to LIPUS effects and mechanism”. Harrison et al., Mode & mechanism of low intensity pulsed ultrasound (LIPUS) in fracture repair, Ultrasonics, Volume 70, August 2016,

It was also proposed the use of pulsed electromagnetic fields (PEMF) and in the following article:  Erping Luo et al. “Pulsed electromagnetic fields promote osteogenesis and osseointegration of porous titanium implants in bone defect repair through a Wnt/β-catenin signaling-associated mechanism”Scientific Reports 6, 2016

Increase of osteoblast proliferation, or bone cells multiplication. Image credits: above article

Several modalities have been investigated to accelerate bone regeneration during DO including the
biophysical, mechanical, and biological methods, but the clinical use of most of these approachs is limited so far.

Future of limb lengthening

There is a finish company called SYNOSTE,  with a new approach in Limb Lengthening.

This new company is doing research on 3rd generation Limb Lengthening system, in order to make a quantum leap in performance and fulfill the newest trends in healthcare driven by Value-Based Healthcare and Personalized Medicine initiatives.

In the early 2000’s, expanding implantable nails using a procedure similar to intramedullary nailing were first used. The expense of these nails was offset by the reduced pain, less scarring, and less interruption to patient’s lives. The first generation nails promised a lot, but had their own set of problems. The second decade of the new millennium has introduced a second generation nail offering a degree of superiority over the fifteen year-old technologies.

The third generation needs to promise more than just an advancement in nail technology, it needs to be a complete package solution, offering a quantifiable improvement in outcomes and a new level of personal experience for both surgeons and patients.

January 5, 2017
by inesp.alves

Therachon protein for achondroplasia: TA-46

A press release from Business Wire stated that Therachon AG, a biotechnology company focused on rare genetic diseases, announced today it has appointed Luca Santarelli, M.D., as Chief Executive Officer and Director, and raised more $5 million for new medicines R&D (research a and development). The new financing will be used to advance the company’s emerging portfolio, including its lead program in achondroplasia, the most common form of short-limbed dwarfism.

I am excited to join Therachon and look forward to continuing to build a world-class pipeline and partnering with the achondroplasia community to develop a truly transformative therapeutic option,” said Dr. Santarelli.

Our lead pipeline candidate TA-46 has demonstrated exceptional preclinical efficacy and holds the promise of fully restoring normal growth and mitigating some of the devastating complications in children suffering from achondroplasia.”

TA-46 is the lab name of the Soluble FGFR3, a protein therapy in development for achondroplasia.

What is preclinical efficacy?

The development of new drugs and the application of drugs originally approved for a different disease almost always involves the need for the drug in question to be tested in animals that have been developed to model the human disease as closely as possible.

Usually it is only if the drug appears to have an effect on the animal model that it is considered worth taking it forward into clinical trial in humans. Such studies, the preclinical phase are key to assessing the efficacy of the drug and predicting success in humans with the disease.

Because the preclinical phase of research is so critical to the decisions made about a possible future therapy, it is very important that experiments done at this stage are based on best practice. This means essentially two things:

  1. Choose the most appropriate animal model.
  2. The experiments must be comparable and reproducible in different labs.

This minimizes the risk of discarding a useful therapy, or conversely, taking a compound into trial in humans that is then proven to have no effect.

Where several animal models exist for one disease, selecting the most appropriate one maximizes the value of the experiments performed. Then, to ensure comparability and reproducibility of results from different labs, as many variables as possible in terms of animal handling and testing need to be controlled for. The variability in phenotype of laboratory animals, which is influenced by housing conditions, litter size, food composition and many other factors, needs to be minimized by the acceptance of common rules in animal handling. Similarly, the use of the same core set of endpoints in all preclinical efficacy studies facilitates the comparison of results.

The soluble FGFR3  was tested in Fgfr3(ach/+) mouse model. There is another model, Fgfr3Y367C/+, in which the mice have a much more severe mutation, that mimics Thanatoforic dysplasia, a lethal form of  bone dysplasia. Even so,  Fgfr3Y367C/+ mice model is considered to present a phenotype between ACH and Thantophoric dysplasia.


About Therachon

Therachon is a global biotechnology company focused on developing treatments for rare, genetic diseases that currently have no available treatments. The company’s lead pipeline candidate, TA-46, is a novel protein therapy in development for achondroplasia, the most common form of short-limbed dwarfism. This rare genetic condition affects about one in 25,000 children and is caused by a genetic mutation of the FGFR3 receptor, which stunts child bone growth.

Therachon´ head researcher Elvire Gouze is committed to translate TA-46 into a new treatment option for patients with achondroplasia.

December 16, 2016
by inesp.alves

Partnership with “The Mighty”

Achondroplasia is much more than a rare condition. In specially, parents of a child that has achondroplasia live a totally new live and gain new life perspectives. They can be emotionally stable and recovered from the initial shock of the diagnosis and might have recovered from it, seeing achondroplasia as part of their child and working to offer their child the best life possible, or by the other side, can feel lost, afraid, hesitant on the future. By sharing social vision and experiences, people can see other sides of this life changing challenge.

For this reason, Beyond Achondroplasia has now a new partnership with The Mighty, and will have now a home page on The Mighty.

The Mighty is a story-based health community focused on improving the lives of people facing disease, disorder, mental illness and disability. More and more people want more than information. They want to be inspired.  And The Mighty publishes real stories about real people facing real challenges.
Beyond Achondroplasia focuses on updated information on achondroplasia, from biology, genetics, medicine, therapies and potential treatments under development, helping people with achondroplasia and their families in their lives. And this partnership will help parents, relatives and friends to speak out.

You can submit a story to The Mighty and, by sharing your thoughts, emotions and experiences related to achondroplasia, you will be help others also.

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