Beyond Achondroplasia

Growing together with Clara

CNP resistance in achondroplasia

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Last month, while talking with Prof. Yayon (one of the world leaders in the research for a treatment for achondroplasia), I asked him about his opinion about the efficacy of BMN-111, and he answered: “Children with achondroplasia have lots of CNP”.

Well, this kept me thinking on this because it jeopardizes the efficacy of BMN-111, the drug under a clinical trial for the treatment of achondroplasia, that is a modified CNP.

Olney RC et al, from Nemours Children’s Clinic, Florida, published the following report:

C-type natriuretic peptide (CNP) plasma levels are elevated in subjects with achondroplasia, hypocondroplasia and thanatophoric dysplasia.

In vitro studies (in lab) have shown that activation of the MEK/ERK MAP kinase pathway (please see the image below) causes functional inhibition of NPR-B, the receptor for CNP (just like BMN-111).

Achondroplasia, hypochondroplasia, and thanatophoric dysplasia are syndromes of short-limbed dwarfism caused by activating mutations of fibroblast growth factor receptor-3, which result in over-activation of the MEK/ERK MAP kinase pathway.

The object of the report was to determine if these syndromes exhibited evidence of CNP resistance as reflected by increases of plasma CNP and its amino terminal propeptide (NTproCNP)


The research team concluded that in these skeletal dysplasias, elevated plasma levels of proCNP products suggest the presence of tissue resistance to CNP.

BMN-111 will act as the natural CNP, connecting with the NPR-B receptor. So this make me place a relevant question:

If the NPR-B has a function inhibition and there is data for CNP resistance in this skeletal dysplasias, might the expected efficacy of BIoMarin´s BMN-111 be not that significant?

We must wait for the phase 2 BMN-111 clinical trial results to answer this.

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