Ongoing research on achondroplasia

There is currently no cure or pharmacological treatment available for achondroplasia. Current care for achondroplasia manages the symptoms

and alleviates the consequences of complications (Unger S et al., 2017) (as seen above). However, there are potential drugs under development aiming to improve bone growth and decrease the rate of complications seen in achondroplasia (Ireland P et al., 2014).

The major goal in developing treatments for achondroplasia has been to safely reduce the output of FGFR3 signals close to normal. Strategies have ranged from blocking receptor activation, inhibiting FGFR3 tyrosine kinase activity, accelerating the degradation of the active receptor to antagonizing signals downstream of the receptor. These strategies are based on the understanding of relevant molecular events that lead to this skeletal dysplasia (Narayana J and Horton W, 2013).

 You can find this information in the section "Potential treatments for achondroplasia" on our "Medicine and Science" page (Last update -August 2018)

 

Innovative Medicines

BioMarin – Vosoritide / BMN-111

The strategy to treat achondroplasia that is currently in a more advanced stage of development is Vosoritide, a C-natriuretic peptide (CNP) analogue, developed by BioMarin Pharmaceutical. This CNP antagonizes the MAPK signals initiated by FGFR3. Vosoritide is being investigated in a Phase III clinical trial, a study in children with achondroplasia between 5 and 14 years old (Narayana J and Horton W, 2013). In June 2018, BioMarin started the BMN 111–206, a phase 2 study with Infants and Toddlers, that will evaluate the effect of BMN 111 in approximately 70 infants and toddlers between the ages of 0 to 5. (BioMarin press releases)

Ascedis Pharma - TransCon CNP

There is also a treatment approach from the company Ascendis Pharma, through their innovative TransCon technology with the TransCon CNP for achondroplasia. This technology combines the benefits of a prodrug and a sustained-release technology. A prodrug is a masked form of an active drug. In this case, the prodrug is capable to increase the efficiency of the CNP, decrease associated toxicity and reduce the frequency of administration. In May 2018, Ascendis announced the beginning of the phase 1 for TransCon CNP, Phase 1 is taking place in Australia with healthy volunteers that will evaluate single ascending doses of TransCon CNP, to assess safety, tolerability and  pharmacokinetics (Beyond Achondroplasia, 2018).

Therachon - TA-46

This potential treatment under development for achondroplasia is the  TA-46 from Therachon, a biotech company. TA-46 is a soluble form of human FGFR3 (sFGFR3), which acts as a trap for FGFs, the factors that bind to FGFR3, which prevents FGFR3 to be activated (Garcia S et al., 2013). In February 2018, the company announced the beginning of phase 1, a randomized, placebo-controlled, double-blind trial, designed to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses of TA-46 in approximately 70 healthy male and female volunteers. The trial is taking place in the Netherlands. (Therachon press releases)

Ribomic - RMB 007

There is also another approach from the company Ribomic, a Japonese biotechnology company working with aptamers for innovative therapeutics. In Ribomic pipeline there are several aptamers and among them is RBM 007, under investigation for 5 conditions including achondroplasia, that is about to enter the Toxicological Good Laboratory Practices (Beyond Achondroplasia, 2016).

QED Therapeutics - Infigratinib / BGJ398

The most recente company that started working in an inovative treatment for achondroplasia is QED Therapeutics, a biotechnology company focused on the development of infigratinib (compound BGJ398), an orally-administered FGFR selective tyrosine kinase inhibitor, for patients with FGFR-driven cancers and pediatric skeletal dysplasias.

Infigratinib has demonstrated potential in pediatric skeletal dysplasias, including achondroplasia. In the early work published in the Journal of Clinical Investigation (Komlra-Ebri D et al. JCO 2016), researchers demonstrated that low doses of infigratinib corrected pathological hallmarks of achondroplasia in mouse models. QED Therapeutics is currently completing a preclinical program in achondroplasia, including further efficacy studies and a robust safety program. Pending results from this program, the company intend to begin clinical studies with infigratinib in patients with achondroplasia in 2019(QED Press release for ALPE)

Repurposing drug

Nagoya University - Meclozine

Also under studies is Meclozine (also known by meclizine), an over-the-counter drug for motion sickness. In studies conducted by Matsushita M et al., 2015, meclozine inhibited the elevated FGFR3 signaling in chondrocytes, suggesting potential clinical utility of this drug for the improvement of short stature in achondroplasia. On the 30th July 2018, the research team led by Prof. Hiroshi Kitoh, conducted a phase 1 study with meclozine in 6 children with achondroplasia, in Nagoya Hospital, Japan. This study is entitled ”Safety and pharmacokinetics of meclozine hydrochloride for achondroplasia children” was conducted with the aim to evaluate safety as well as 24-hour pharmacokinetcs and accumulation at 1 week after single doce of meclozine. The study information is published at UMIN-CTR clinical trials page.