Biotech Industry Liaison Committee Review

Current development:

Currently, there are 6 different drugs in clinical development (being studied in humans) for achondroplasia. Each targets the overactive FGFR3 pathway, which if successful would allow the bones to grow and develop more ordinarily. While the therapies have the potential to impact the symptoms and complications of achondroplasia, they will not impact any genetic factors. For the purpose of this review, we will focus on the 4 therapies and companies furthest in development (phase II and beyond).7

The 4 therapies and companies are:

  • Vosoritide (Biomarin)
  • TransCon CNP (Ascendis)
  • Recifercept (Theracon, acquired by Pfizer)
  • Infigratinib (QED Therapeutics).

Voxzogo (vosoritide) - Biomarin
Biomarin’s vosoritide is the furthest in development and is currently being reviewed by the FDA, with an approval decision expected in November 2021. Vosoritide is a c-type natriuretic peptide analog that binds to a receptor, which blocks one of the signaling mechanisms of the overactive FGFR3 pathway, allowing bones to grow.3,4,8 Given this mechanism of action, vosoritide will likely be indicated for achondroplastic children whose growth plates are still open, although the exact patient population that vosoritide is approved for will ultimately be decided by the FDA.

Vosoritide’s phase III trial studied children with achondroplasia aged 5 to 14 years. In this trial, vosoritide improved growth velocity or height by 1.39 inches over 2 years, a roughly 0.7-inch benefit per year versus placebo.9,10 While the trial met its primary endpoint (growth velocity), these studies are limited in their ability in determining whether improvements in growth will translate to benefits of functionality, quality of life, activities of daily living, and/or reducing any of the major complications associated with achondroplasia. Vosoritide was found to improve upper-to-lower body segment proportionality, a secondary endpoint of the trial, however key secondary endpoints such as the impact on quality of life, developmental status, and functional independence are inconclusive and are continuing to be assessed. More data and longer follow-up are needed to determine the exact impact vosoritide has on these endpoints. Additionally, the impact of vosoritide on other meaningful outcomes such as reduction in spinal stenosis, sleep apnea, and medical interventions is not known and is also continuing to be evaluated.9,10

Overall, vosoritide was well tolerated with the majority of adverse events or side effects being mild and no serious adverse events being reported. The most common side effects were injection site reactions such as redness and swelling of the skin.9,10

  • Phase in development: Phase III primary completion; submitted for FDA approval
  • Administration: Once daily subcutaneous shot under the skin and will likely be taken until the growth plates close (typically in the teenage years)
  • Cost: TBD, expected to be $250,000/year or more; patient costs will be influenced by the type of insurance & coverage
  • Ongoing studies:
    • Phase III extension: Continuing to follow the children from the phase III trial to assess the secondary endpoints
    • Phase II: Children at risk of life-threatening foramen magnum compression
    • Phase II: Infants and young children ages 0 to 5 years old

TransCon CNP - Ascendis Pharma
Similar to vosoritide, Ascendis Pharma’s TransCon CNP is also a c-type natriuretic peptide and works similarly. One difference is that it has a different formulation that allows the drug to stay in the body longer, leading to less frequent administrations. Overall, there is a lot of information still to be determined for TransCon CNP, which is to be expected since it is still only in phase II development.11

TransCon CNP is being studied in children 2 to 10 years of age. Currently, there is little data on the efficacy and safety of TransCon CNP, although the results from this phase II trial will provide an initial understanding.12

  • Phase in development: Phase II ongoing
  • Administration: Once weekly subcutaneous shot under the skin and will likely be taken until the growth plates close (typically in the teenage years)
  • Cost: TBD; patient costs will be influenced by the type of insurance & coverage
  • Ongoing studies: TBD

Truseltiq (Infigratinib) - QED Therapeutics
Infigratinib is already approved as a treatment for bile duct & bladder cancer and is in phase II development for achondroplasia with results expected in the second half of 2021. Infigratinib is a tyrosine kinase inhibitor that alters the FGFR3 receptor, reducing the ability of ligands or molecules from activating FGR3. This leads to a reduction in both of the overactive signaling mechanisms, allowing bones to grow.13

Similar to TransCon CNP, there is a lot of information to be determined for Infigratinib. What is known is that the phase II trial is being studied in children 3 to 11 years of age and is administered as oral tablets. Results from this study will provide an initial glimpse at the efficacy and safety of Infigratinib in achondroplasia.14

  • Phase in development: Phase II ongoing
  • Administration: TBD; Oral tablets
  • Cost: TBD; patient costs will be influenced by the type of insurance & coverage
  • Ongoing studies: TBD

Recifercept - Recifercept
Lastly, we have Pfizer’s recifercept, which is an FGFR3 decoy. It works by tricking the ligands or molecules that normally bind to FGR3 to bind to the drug instead. This reduces the FGFR3 activation and both overactive signaling mechanisms, leading to bone growth.15 The administration will likely be a subcutaneous injection, although the frequency is not known. Like TransCon CNP and Infigratinib, there is a lot to be determined with recifercept. What is known is that the phase II trial is being studied in 2 groups: children under the age of 2 years old and children 2 to 10 years old. The results from this study will provide an initial understanding of the safety & efficacy of recifercept.15,16

  • Phase in development: Phase II ongoing
  • Administration: TBD; likely subcutaneous injection under the skin
  • Cost: TBD; patient costs will be influenced by the type of insurance & coverage
  • Ongoing studies: TBD