Beyond Achondroplasia

Growing together with Clara

July 17, 2014
by inesp.alves

Some moments of pure enchantment


BMN-111 protocol

July 14, 2014 by inesp.alves | 1 Comment

Data from the EU clinical trial registry

BMN-111 complete registry at Clinical Trials Register

EudraCT Number: 2013-004137-32
Sponsor’s Protocol Code Number: 111-202
National Competent Authority: UK – MHRA
Clinical Trial Type: EEA CTA
Trial Status: Ongoing
Date on which this record was first entered in the EudraCT database: 2014-02-17
Trial results
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A. Protocol Information
A.1 Member State Concerned UK – MHRA
A.2 EudraCT number 2013-004137-32
A.3 Full title of the trial
A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children with Achondroplasia
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language
A Study to Evaluate Safety, Tolerability, and Efficacy of BMN 111 in Children with Achondroplasia
A.4.1 Sponsor’s protocol code number 111-202
A.7 Trial is part of a Paediatric Investigation Plan No
A.8 EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1 Name of Sponsor BioMarin Pharmaceutical Inc.
B.1.3.4 Country United States
B.3.1 and B.3.2 Status of the sponsor Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support BioMarin Pharmaceutical Inc.
B.4.2 Country United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation BioMarin Pharmaceutical Inc.
B.5.2 Functional name of contact point Clinical Trials Information
B.5.3 Address:
B.5.3.1 Street Address 105 Digital Drive
B.5.3.2 Town/ city Novato
B.5.3.3 Post code 94949
B.5.3.4 Country United States
B.5.6 E-mail

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3 IMP Role Test
D.2 Status of the IMP to be used in the clinical trial
D.2.1 IMP to be used in the trial has a marketing authorisation No
D.2.5 The IMP has been designated in this indication as an orphan drug in the Community Yes
D.2.5.1 Orphan drug designation number EU/3/12/1094
D.3 Description of the IMP
D.3.1 Product name modified recombinant human C-type natriuretic peptide
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN – Proposed INN TBD
D.3.9.2 Current sponsor code BMN 111
D.3.9.3 Other descriptive name MODIFIED RHCNP
D.3.9.4 EV Substance Code SUB120857
D.3.10 Strength
D.3.10.1 Concentration unit mg/ml milligram(s)/millilitre
D.3.10.2 Concentration type range
D.3.10.3 Concentration number 0.2 to 10
D.3.11 The IMP contains an:
D.3.11.1 Active substance of chemical origin No
D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
The IMP is a:
D.3.11.3 Advanced Therapy IMP (ATIMP) No
D. Somatic cell therapy medicinal product No
D. Gene therapy medical product No
D. Tissue Engineered Product No
D. Combination ATIMP (i.e. one involving a medical device) No
D. Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5 Radiopharmaceutical medicinal product No
D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7 Plasma derived medicinal product No
D.3.11.8 Extractive medicinal product No
D.3.11.9 Recombinant medicinal product Yes
D.3.11.10 Medicinal product containing genetically modified organisms No
D.3.11.11 Herbal medicinal product No
D.3.11.12 Homeopathic medicinal product No
D.3.11.13 Another type of medicinal product No

D.8 Information on Placebo

E. General Information on the Trial

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18 Yes
F.1.1 Number of subjects for this age range: 24
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: 23
F.1.1.6 Adolescents (12-17 years) Yes
F. Number of subjects for this age range: 1
F.1.2 Adults (18-64 years) No
F.1.3 Elderly (>=65 years) No
F.2 Gender
F.2.1 Female Yes
F.2.2 Male Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers No
F.3.2 Patients Yes
F.3.3 Specific vulnerable populations Yes
F.3.3.1 Women of childbearing potential not using contraception No
F.3.3.2 Women of child-bearing potential using contraception Yes
F.3.3.3 Pregnant women No
F.3.3.4 Nursing women No
F.3.3.5 Emergency situation No
F.3.3.6 Subjects incapable of giving consent personally No
F.3.3.7 Others No
F.4 Planned number of subjects to be included
F.4.1 In the member state 5
F.4.2 For a multinational trial
F.4.2.1 In the EEA 10
F.4.2.2 In the whole clinical trial 24
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)
In order to assess safety and efficacy of BMN 111 over the longer term, subjects may be eligible to continue receiving BMN 111 in an open-label extension study after completing 6 months of treatment in the initial study.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned
N. Competent Authority Decision Authorised
N. Date of Competent Authority Decision 2014-02-14
N. Ethics Committee Opinion of the trial application Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion
N. Date of Ethics Committee Opinion 2014-04-03

P. End of Trial
P. End of Trial Status Ongoing

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July 14, 2014
by inesp.alves

One importante step forward on rare diseases registry

From now on, all sponsors of clinical trials have to share and publish relevant information about the trial on the EudraCT , the European Clinical Trials Database. Trials results information will be publicly available at the EU Clinical Trials Register including summary results from … Continue reading

July 12, 2014
by inesp.alves
1 Comment

Otitis media returns

The last few days have been hard for Clara. Last weekend, she had to deal with a high fever with gastritis for a couple of days. Two days later, her left ear (once again) released a large amount of effusion. … Continue reading

Rare diseases and orphan drugs market

July 11, 2014 by inesp.alves | 0 comments


July 4, 2014
by inesp.alves
1 Comment

A summary of achondroplasia´s potential treatments

I have been following for several months the search work of prof. Morrys Kaisermann around achondroplasia latest researchs. He keeps a blog about achondroplasia named “Acondroplasia-Achondroplasia” and his lastest post is a brilliant synopsis of the current achondroplasia potential treatments and … Continue reading

June 30, 2014
by inesp.alves

You can “unlock” a potential project to treat achondroplasia through the REACT community. I discovered this community several months ago and I only share it on facebook, but I share it now here, the right place to ask your support once just one person besides me decided to support this project.


The RE(ACT) Community is organized around four main axis dedicated to research on rare and orphan diseases: Learn, Meet, Share and Support. By supporting a research projects declared eligible for funding by the RE(ACT) and BLACKSWAN Foundation Scientific Advisory Board are associated to a Disease Dossier and are also visible on a specific section of the platform dedicated to crowdfunding (“Projects” page). Once the Scientific Advisory Board approves a project, another criterion is required to be entitled for funding: a minimum number of followers on the Disease Dossier. This additional criterion prevents the dispersion of small donations through a large variety of research projects.

And you can be a supporter by following achondroplasia and help open a new project.

Lets react!


June 24, 2014
by inesp.alves

Physical rehabilitation update

Yesterday, Clara had another appointment with her physiatrist. Four months after the last appointment, her physiatrist doctor found that Clara developed better protective reflexes and her whole locomotion structure was greatly improved. The doctor report had the following observations: -21 months-old baby -Slight … Continue reading

February 8, 2014
by inesp.alves

FGFR3, was many times mentioned here. But probably is an abstract concept to many. I will try to keep it understandable. FGFR3 is the short-term for fibroblast growth factor receptor 3. Is a very studied protein and there is an enormous amount of scientific papers written about it, specially related to cancer, once FGFR3 has intense action in some types of cancer growth.

FGFR3 exists in the wall of the chondrocytes, the cells where lays the genetic mutation for achondroplasia.

Well, imagine the FGFR3 as a wall power plug. Imagine that this wall plug is at the exterior of a garage wall. So, if for example, you need to trim the backyard lawn, you need to connect an electric lawn mower plug to this wall plug. And now, imagine this plug to be one FGF (fibroblast growth factor). And then something happens: an action-reaction. And the mower starts receiving energy and work.

Power plug type N Brazil power plug

So, FGFR3 will only start its action after some special particles, one FGF, connect with it.

Now, imagine the garage is a chondrocyte, that is the type of cell that exist in the growth plate in the long bones. The garage is surrounded by open space by all sides. In the biologic and microscopic vision, this open space is called extracellular matrix. Even if you observe a live tissue using a microscopic, you will see that each cell seems attached to others. But in a ultramicroscopic vision (a much powerful view), there is a free space between cells, filled with that matrix, and where particles like FGF exist.

FGFR3 exist in the chondrocytes membrane, that is the wall that separates the chondrocyte from the extracellular matrix. When a FGF connects with the FGFR3, it starts a few cascade reactions.

Falling Domino Pieces Arranged in a Line

Imagine these cascades as an amount of dominos falling over each other. Imagine the last piece of the domino falling and the result, for instance, is turning off something. So the last piece of FGFR3 cascades (with several factors evolved), end in the DNA of the chondrocyte with the information to the cell stop multiplying and to mature.

Don´t take FGFR3 wrong. It is needed! If not, we would growth too much. It a healthy person, while in a growing age, FGFR3 give signs to reduce growth in a controlled way.

Well, this is like cooking! To much salt and you can´t eat the food. To less, and it won´t taste good.

In achondroplasia, because FGFR3 has a mutation that produces an over expression of it cascades, it acts almost in a continuous way, giving too much signs to the chondrocyte DNA to shut down growth.

The most important FGFR3 cascade for achondroplasia fenotype is one that has a very strange name MAPK (after: Mitogen-activated protein kinase)


So science is in the way to break the FGFR3 effects in achondroplasia by shutting down pieces in the MAPK cascade (also called a pathway).

The particles (correctly they are enzymes)  involved in the MAPK cascade are RAS, RAF, MEK1/2 and ERK. Following ERK is the cell nucleus where the DNA is. And the DNA will produce the command given by this cascade: shut down growth.

Imagine them as domino pieces: RAS—>RAF—>MEK1/2—>ERK—>nucleus—>DNA—-> result


For instance, the action of BMN-111 is breaking the MAPK cascade between RAF and MEK. Like if it was a wrecking ball attacking that point. So the MAPK cascade will not reach the nucleus, and the information to stop growing won´t reach the DNA. And the chondrocyte will keep multiplying!


There are several compounds being studied or even in clinical trials for cancer, aiming for the MAPK cascade.

The FGFR3 exists in several types of cells and many types of cancer use the MAPK cascade to grow. And because cancer is such a relevant and frequent disease, the research around cancer pathways is a very studied subject.

There exist some drugs to treat cancer, named anti-RAF and anti-MEK, that will attack that particles of the MAPK cascade. Many are still being studied but others are already used for cancer.

So, the question arise: why aren´t we using those anti-RAF and anti-MEK already available to treat cancer in achondroplasia?

Well, most importantly, those drugs attack all types of cells that carry FGFR3 and that are naturally dividing. So it would be expected more damage that a positive result.

This month, it was published an article about a anti-Mek compound, Selumetinib, that as been tested in some pediatric cancers.

Modulation of endochondral ossification by MEK inhibitors PD0325901 and AZD6244 (Selumetinib), by El-Hoss.

One important observation in this study was that at the growth plate, they observed an increase in the height of the hypertrophic zone relative to the proliferative zone of +78% in PD0325901 treated mice.

If pharmaceuticals start to go forward studying deeper MAPK cascade in pediatric cancer, maybe we can have a shortcut to reach another treatment for achondroplasia besides BMN-111.

To know more, you can read the always updated and easily understandable written blog Tratando acondroplasia, by Prof. Morrys.

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