1. BMN-111

BMN-111 is a CPN analogue from BioMarin´s pharmaceutical, under evaluation in a clinical trial, now at Phase 2, that is open-label and a sequential cohort dose-escalation study.

Action

-CNP 22 (C-type natriuretic peptide) binds to NPR-B (natriuretic peptide receptor B) in chondrocytes, the cells at the growth plate.

-Induces elevation of intracellular cGMP levels

-Inhibit the Mapk kinase pathway at the level of Raf-1 BMN-111 properties

-Similar selectivity and potency as endogenous CNP22

-Neutral endopeptidases resistance

-CNP22 half-life is 2 minutes. BMN-111 has a longer half-life: 20 minutes.

– 1 daily subcutaneous administration BMN-111 in ex vivo tests

-Significantly reduces the growth deficit and rescues the size and architecture of the growth plate (rescues the columnar growth) and bone architecture

-Increase in the axial and appendicular skeleton lengths (spine, arms and legs)

-Growth and straightening of the long bones

-Modification in the size of the epiphyses of the femur (where the growth plate is located)

-Increase of the size of the proliferative zone of the growth plate (increase of chondrocytes) Tests in primates

-No cardiovascular effect

-Dose-related increase in body length BMN-111 phase 2 proof-of-concept

-26 children included (7,8 years old average)

-3 doses: 2,5 microg/kg, 7,5microg/kg, 15 microg/kg (higher growth observed)

-Drug well tolerated in all doses

-Still no improvement in proportionality

-No serious side effect

-Ancillary cohort starting in September: 30microg/kg

It was observed, after 6 months of drug administration, a mean increase of 50% in the annualized growth velocity compared to the annualized prior 6 months natural history line growth velocity (p<0,01).

2. Soluble FGFR3

Prof. Elvire Gouze is the researcher responsible for this study. The next step is the pre clinical studies with primates and then accelarating to a clinical trial

“Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice” Garcia et al. Sci Transl Med. 2013 Sep

– Recombinant protein therapeutic approach using a soluble form of human FGFR3 (sFGFR3)

– sFGFR3 acts as a decoy receptor and prevents FGF from binding to mutant FGFR3 – able to reach the growth plate.

– sFGFR3 soluble binds to FGF2, FGF9 and FGF18 (most frequently binding FGF´s to FGFR3)

– SC injection twice/week during 3 weeks in FGFR3ach/+ mice (mice genetically modified to have achondroplasia)

– Effective maturation of growth plate chondrocytes was restored in bones of treated mice

– Restoration of bone growth in FGFR3 ach/+ mice

- This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity

X-ray radiographs illustrating treatment effect on skeletal growth. Credit: Sci. Transl. Med. 5, 203ra124 (2013) DOI: 10.1126/scitranslmed.3006247

3. Meclizine

This is an antihistamine drug used to treat vertigo and motion sickness and also a drug with re-positioning purpose, under study for a new therapeutic indication for achondroplasia. Prof. Matsushita, head researcher from the Japanese team that is doing the study has to test if it will be safe and efficient in the tested doses.

Advantages: It is already available in the market worldwide, it´s cheap and it´s of oral administration.

Prof. Matsushita tested more than 1300 drugs for achondroplasia before finding meclizine.

“Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene” Matsushita et al.,Endocrinology. 2015 Feb

-Bone growth in FGFR3ach/+ mice

–Rescue of cranial synchondrosis (early closure of cranial sutures occur in achondroplasia, that increase the occurrence of cervico-medullar compression)

-Predicted annualized growth rate in mice: plus 4 cm/year