What are the potential treatments for achondroplasia?
This is a synopsis of the current potential treatments for achondroplasia. You will find that, at this point, there are four drugs that will potentially reduce, with expected significance, health complications in achondroplasia and its anatomic features produced by the aberrant FGFR3 activity.
- BMN-111
A CPN analogue from BioMarin pharmaceutical, under evaluation in a clinical trial, now in Phase 2, Open-label, Sequential Cohort Dose-escalation Study.
Action
- CNP 22 (C-type natriuretic peptide) binds to NPR-B (natriuretic peptide receptor B)
- Induces elevation of intracellular cGMP levels
- Inhibits the MAPK kinase pathway at the level of Raf-1
More information on it's mechanism of action here.
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
- Growth and straightening of the long bones
- Modification if the size of the epiphyses of the femur
- Increase of the size of the proliferative zone of the GP
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
- No improvement in proportionality
- No serious side effect
- Ancillary cohort: 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)
p<0,01 results are considered statistically significant
- Soluble FGFR3
Elvire Gouze is the researcher responsible for this study. The sFGFR3 has shown promising results. The next step is the preclinical study with primates.
"Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice"
- 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 FGF2, FGF9 and FGF18 (most frequently binding FGFs to FGFR3)
- Subcutaneous (SC) injection twice/week during 3 weeks in FGFR3ach/+ mice
- Effective maturation of growth plate chondrocytes was restored in bones of treated mice
- Restoration of bone growth in FGFR3ach/+ mice
-This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity
Learn more about how it works here.
- Meclizine
It is an anti-histamine 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. 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 worldwide, it's cheap and it's of oral administration.
Prof. Matstushita tested more than 1300 substances for achondroplasia before finding meclizine.
I met the Prof. at the ICCBH congress, last June, and he was willing to keep a close contact and to explain better the way meclizine works. His team is searching for support to take meclizine to next phase of study.
- Bone growth in FGFR3ach/+ mice
- Rescue of cranial synchondrosis (early closure of cranial sutures occur in ACH, that increase the occurrence of medullar compression)
- Predicted annualized growth rate in mice: plus 4 cm/year
- The team tested in a dog model too, but the dogs were a less sensitive species.
Although mentioned as a potential treatment for achondroplasia, Statins, a repositioning drug, can't be used in children with achondroplasia as they are now, since they interfere deeply with cholesterol biochemical chain production.
Statins are a class of drugs renowned for their action against cholesterol and investigated because they have anabolic and protective effects on chondrocytes.
Prof. Tsumaki team, a research group (also Japonese like the meclizine group) screened drugs using the induced pluripotent stem cells (iPSCs) technology, using skin cells samples from patients with achondroplasia and then, they vastly expanded the number of cells for study, by differentiating skin cells to chondrocytes ach+.
These researchers created, for the first time, patient-specific stem cell lines from three TD1 patients and three achondroplasia patients.
The exact mechanism by which statins stimulate proper cartilage production is unclear. Tsumaki's team found that FGFR3 protein levels (not FGFR3 mRNA levels), were decreased in statin-treated cells, indicating that the drug sped the degradation of the protein.
They tested an injection of 1 mg/kg of Rosuvastatin into the ACH mouse model, and they observed restored bone growth in the limbs and head. However, this dose exceeds limits allowed for this drug.
"Statins treatment rescues FGFr3 skeletal dysplasia phenotypes"
- Statins are lipid lowering agents
- Anabolic effect of statins on cartilage
- Bone elongation in FGFR3ach/+ mice
