Treating achondroplasia: Ascendis releases outcomes of the phase 2 study with TransCon-CNP

The ACcomplisH trial

 On November 13th, Ascendis Pharma released top line results of the ongoing phase 2 study with TransCon-CNP, an analog of c-type natriuretic peptide (CNP) wrapped in a transport molecule to allow slow-release and extend the half-life of the analog. 

Let's pause here for a moment as in this first sentence there is a lot of information already. 

In other words, TransCon-CNP is a competitor of vosoritide. The main difference between them is that the CNP analog from Ascendis uses a kind of taxi: its CNP analog is covered by a molecule that serves as a protection against the body clearance systems, so it has an extended time to exert its actions. The taxi allows the Ascendis CNP analog to be given just once a week as opposed to vosoritide, which needs to be administered daily.

As typical of phase 2 studies, the ACcomplisH trial was designed to evaluate several different doses to TransCon-CNP in order to define which one would have the best safety/efficacy profile.

In summary, these are the headlines directly from Ascendis press release: 

• In the Phase 2 ACcomplisH Trial in children with achondroplasia aged 2-10, once-weekly TransCon CNP demonstrated the potential to meet patient and caregiver needs for a safe, effective, tolerable, and convenient treatment
  

• The primary endpoint, annualized height velocity (AHV) at Week 52, demonstrated superiority of TransCon CNP at 100 μg/kg/week compared to placebo (p=0.0218)

• TransCon CNP was generally well tolerated with low frequency of injection site reactions; all 57 randomized children continued, with the longest treatment duration beyond two years
  

• Data showed robust and consistent results in prespecified analyses across age groups and dose levels, supporting continued development at the selected dose of 100 μg/kg/week
  

 Efficacy

Three of the four doses tested lead to growth improvement but only the highest one was found to be significantly superior to placebo (Table 1).

It is important to learn that TransCon-CNP worked similarly in all age groups tested.

Table 1. Efficacy of TransCon-CNP weekly doses (from the AComplisH study presentation).

 

Safety

The press release informs us that TransCon-CNP was well tolerated. Most of the few adverse events reported were related to local injection site reactions.

Next steps

Based on the results of this study Ascendis informed that they are in conversations with regulators and also enrolling patients in their phase 2B study to further investigate the chosen dose for achondroplasia (100 µg/kg/week).

Context

As we can see in Table 1, children  the highest dose of TransCon-CNP on average grew 1.07cm (24.6%) more than those in placebo. This is lower than what was obtained with vosoritide in its phase 3 study (1,2), which you can see below (transcript from the original publication;(2)):

• In the placebo-controlled study, children randomized to treatment with vosoritide increased annualized growth velocity to 5.96 (1.51) cm/year at 26 weeks and 5.39 (1.87) cm/year at 52 weeks. In children randomized to placebo the annualized growth velocity was 4.08 (1.36) cm/year at 26 weeks and 3.81 (1.31) cm/year at 52 weeks.
  

Based on what we have already seen with vosoritide trials, one aspect to have in consideration is that there is a large variability of response to treatment (just look at the growth ranges among the treated groups in Table 1). This was also seen in vosoritide studies. 

The population treated in the phase 2 study with TransCon-CNP is considerably smaller than the one in the phase 3 vosoritide trial, but the results show the potential efficacy of the chosen dose that we would expect in the ongoing phase 2B study. It would be interesting to learn why the developer did not consider evaluating a higher dose of TransCon-CNP, as it is possible that its optimal dose (efficacy+safety) might not have been identified yet.

One relevant advantage of TransCon-CNP is its weekly dosing schedule, which would be likely considered more comfortable by parents and individuals than vosoritide's daily injection. 

Finally, if TransCon-CNP would be able to provide consistent growth in longer term (as we might see in the next step of its clinical development), and taking in account that it has been showing to work positively in younger kids, it might become a fair option to vosoritide in the future, even if the nominal growth increment was lower in the phase 2 study compared to the already approved treatment.

References

 1. Savarirayan R et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 2020; Oct 10;396(10257):1070. Free access.

2.  Savarirayan R et al. Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study. Genet Med 2021 Dec;23(12):2443-47. Free access.