Beyond Achondroplasia

Growing together with Clara

December 10, 2017
by inesp.alves

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.


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

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

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. 
FGFR3 ach mouse – Mouse models are currently available for genetic 
research and include thousands of unique inbred strains and genetically 
engineered mutants.  In
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

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

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

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.



  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
  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

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


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