Tag Archives: achondroplasia

Infigratinib is another potential FGFR3 inhibitor to increase height

Infigatinib is a potential alternative to Vosoritide to increase height during development. FGFR3 reduces growth in everyone it just does so in a greater manner in people with dwarfism as they have a mutation. CNP may have other beneficial effects on top of inhibiting FGFR3 but this just seems to be an FGFR3 inhibitor.

PMON30 Low-dose Infigratinib, an Oral Selective Fibroblast Growth Factor Receptor Tyrosine Kinase Inhibitor, Demonstrates Activity in a Preclinical Model of Hypochondroplasia 

Fibroblast growth factor receptor 3 (FGFR3) gain-of-function mutations play a crucial role in achondroplasia (ACH), thanatophoric dysplasia (TD), and hypochondroplasia (HCH).{But FGFR3 may decrease height in everyone during development just to a lesser degree if you have the mutation}. HCH is a less severe form of dwarfism than ACH, but similarly is caused by gain-of-function mutations in the FGFR3 gene. HCH is characterized by a disproportionate short stature and a growth deficit affecting both endochondral and intramembranous ossification. While multiple therapeutic strategies are being tested for ACH, currently there are no approved therapeutic options for individuals with HCH. We tested the hypothesis that the oral, selective FGFR tyrosine kinase inhibitor (TKI) infigratinib (BGJ398) could improve the HCH phenotype and improve endochondral and intramembranous ossification in a preclinical mouse model of HCH Fgfr3N534K/+.

The first Hch mouse model studied expresses the most frequent human mutation p.Asn540Lys (Fgfr3Asn534Lys/+), and exhibits a mild dwarfism and most of the hallmarks of the human pathology. Fgfr3N534K/+ mice received subcutaneous injections of infigratinib or vehicle control every 3 days (1 mg/kg) or daily (1 mg/kg) for 15 days (post-natal day [PND] 4–19) or 21 days (PND 3–24), respectively.

Fgfr3N534K/+ mice treated with 1 mg/kg infigratinib every 3 days did not show obvious and significant modification of the dwarf phenotype. In contrast, Fgfr3N534K/+ mice treated with 1 mg/kg infigratinib daily for a total of 21 days showed a statistically significant increase in appendicular and axial skeletal measures. Length of the long bones was statistically significantly increased in Fgfr3N534K/+ mice compared with Fgfr3+/+ mice (tibia +3.18%, femur +3.16%, humerus +3.04%, ulna +2.94%, radius +3.01%). Treatment also modified the skull shape (skull width, skull height, nasal bone length and naso-occipital length), the length of the mandible and skull base, as demonstrated by measurement of the foramen magnum (foramen magnum length +3.72%). Infigratinib treatment modified the cartilage growth plate organization, in particular the hypertrophic chondrocyte area. Finally, the high activation of the MAP kinase pathway due to the HCH missense FGFR3 mutation was reduced by treatment, as revealed by the immunolabelling of phosphorylated Erk1/2 proteins.

Treatment with daily 1 mg/kg infigratinib improved the length and weight of Fgfr3N534K/+ mice and significantly modified the skull and the axial and appendicular skeleton. We demonstrated in Fgfr3N534K/+ mice that infigratinib is able to counteract the constitutive activation of FGFR3 due to the heterozygous N540K mutation localized in the tyrosine kinase 1 domain of the protein. These results provide a rationale for targeting FGFR3 with a specific TKI for the treatment of children with HCH.”

So basically infigratinib works to increase height in people with dwarfism but given everyone has FGFR3 receptors it could help increase height in anyone with growth plates to a lesser degree.

bridgebio announces positive phase 2 cohort 5 results of infigratinib in achondroplasia demonstrating mean increase in annualized height velocity of 3.03 cm/year with no treatment-related adverse events

– In the highest dose level (Cohort 5, 0.25 mg/kg once daily), the mean change from baseline in annualized height velocity (AHV) at six months was +3.03 cm/yr (p = 0.0022) for the first 10 children with at least six months of follow-up in Cohort 5. The two remaining children who have not yet had six months of follow-up have a mean change from baseline in AHV of +8.8 cm/yr based on three months data“<-this is huge but again for normal children the gain will be smaller.

80% of children at six months were responders, as defined by an increase from baseline AHV of at least 25%. The mean change from baseline in AHV of responders was 3.81 cm/yr“<-but that does not mean the 20% who weren’t responders didn’t get additional height at all.

” Infigratinib is an oral small molecule designed to inhibit FGFR3 and target achondroplasia at its source”

“Combined with the previously reported Cohort 4 change from baseline in AHV value of +1.52 cm/yr, the Cohort 5 data demonstrate a strong dose response for infigratinib”<-meaning the more of it you take the better but there is usually a better of diminishing returns…

Tiffanie Didonato grew 14 inches with distraction osteogenesis

Tiffanie Didonato grew 14 inches with distraction osteogenesis but the limit for a normal person is about six inches. Why?

Looking at her instagram she seems to be doing fine.

According to Paley’s FAQ on limb lengthening surgery, “The total height gain with two lengthenings is up to 13cm (8cm in the femurs and 5 cm in the tibias. (8cm is not well tolerated in the lower leg (tibia) and
exceeding 5cm can lead to more serious complications such as equinus contracture [ballerina foot]). Most
patients will not tolerate more than 5cm in the tibias. Of course the cost of two lengthenings is nearly twice that of one lengthening. Although the Precice can lengthen up to 8cm, not every patient can safely achieve this much even in the femurs. We will only allow lengthening to the tolerance of the patient’s bone and soft tissues. SAFETY first. We will not risk a loss of function to gain one more cm. To get the full 8cm from both femurs and both tibias requires three lengthening surgeries (see option 5 below).”

Option five as mentioned is “Combined tibia (up to 4cm) and femur (up to 4cm) lengthening three
weeks apart: total 8cm followed by re-breaking femur and tibia with same nail in place and repeating up to 4cm femur and up to 4cm tibia lengthening one year or more later (up to total 16cm; 6.3 in.)”

So normal person can gain 6.3 inches but someone with achondroplasia can gain 14 inches. The answer may involve the ligaments.

According to the chandler project, “When we stretch the bones were also stretching the muscles, and the ligaments and the nerves in the blood vessels around it and some of those get tight, and when they get tight there can be other problems that come up” But for dwarfism, “[dwarves have] all the skin in the ligaments and everything like that to be average height, but her bones are shorter, and they just don’t get the signals to grow,” Lisa explained.”

So the reason that people with achondroplasia can grow taller with Limb Lengthening Surgery than people without it is because they have the ligaments etc of an average height person thus their muscles etc don’t stretch.

But why is the soft tissue such as problem in the first place with limb lengthening surgery?

Well the ligaments normally attach at the enthesis, and the enthesis is attached near the growth plate. It’s very likely that ligament and bone growth are connected in this way so that the ligaments can grow as needed to support longitudinal bone growth. ““Entheses are fibrocartilaginous organs that bridge ligament with bone at their interfaceMore info about the enthesis here.

So it’s likely that a superior option to limb lengthening surgery will develop that involves stimulating enthesis development as well.

Achondroplasia Treatment and Increase Height Using Meclozine aka Meclizine – Great News For Parents!

Achondroplasia Treatment and Increase Height Using Meclozine aka Meclizine – Great News For Parents!

MeclozineWe have already talked about the chemical BMN-111 by Biomarin which is supposed to be able to treat young children with open growth plate cartilage suffering from Achondroplasia. Achondroplasia is the most common type of skeletal disorder which causes people to end up with abnormally short stature, often below the dwarf/small people height of 4′ 10″.

Now there seems to be another chemical treatment that has been proven to have benefits to help treat achondroplasia by inhibiting the FGFR3 gene abnormality. This compound is called Meclozine or Meclizine.

Refer to the study…

Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia

From the abstract…

….We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias

We’ve seen already at least 1 Patent (by Nakao) filed which was used to treat idiopathic short stature using a type of C-natruretic peptide (CNP). This compound seems to work just as well for skeletal dysplasia as any of the CNP derivative types.

For more information on Meclozine/Meclizine, refer to its Wikipedia article here.

From the article, all these brand name pills have as the active ingredient meclizine inside…

  • Bonine
  • Bonamine
  • Antivert
  • Postafen
  • Sea Legs
  • Dramamine (Less Drowsy Formulation)
  • Emesafene

On its Wikipedia page, it says that this compound is supposed to be used for motion sickness, but has dementia enhancing effects on older people.

The conclusion made by that researchers are the following…

We found that meclozine dihydrochloride, a commonly used anti-emetic drug for its anti-histamine activity, efficiently suppresses FGFR3 signaling in three different chondrocytic cell lines and embryonic bone organ culture. We also identified that meclozine suppresses FGF2-mediated phosphorylation of ERK”

Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia.

“Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3). No effective FGFR3-targeted therapies for ACH are currently available. By drug repositioning strategies, we identified that meclozine, which has been used as an anti-motion-sickness, suppressed FGFR3 signaling in chondrocytes and rescued short-limbed phenotype in ACH mouse model. Here, we conducted various pharmacological tests for future clinical application in ACH. Pharmacokinetic analyses demonstrated that peak drug concentration (Cmax) and area under the concentration-time curve (AUC) of 2 mg/kg of meclozine to mice was lower than that of 25 mg/body to human, which is a clinical usage for anti-motion-sickness. Pharmacokinetic simulation studies showed that repeated dose of 2 mg/kg of meclozine showed no accumulation effects. Short stature phenotype in the transgenic mice was significantly rescued by twice-daily oral administration of 2 mg/kg/day of meclozine. In addition to stimulation of longitudinal bone growth, bone volume and metaphyseal trabecular bone quality were improved by meclozine treatment. We confirmed a preclinical proof of concept for applying meclozine for the treatment of short stature in ACH, although toxicity and adverse events associated with long-term administration of this drug should be examined.”

“Twice-daily oral administration of 1 and 2 mg/kg/day of meclozine reverses the dwarfed phenotype in Fgfr3 ach mice. (A) A representative image of the individual female littermates at the end of treatment demonstrated that an untreated Fgfr3 ach mouse reveled the dwarfed phenotype, which was rescued by oral administration of 2 mg/kg/day of meclozine treatment. (B) Relative body length of the wild-type mice and Fgfr3 ach mice was calculated based on the body length of untreated Fgfr3 ach mice at 0 day. The body length of 1 or 2 mg/kg/day of meclozine-treated Fgfr3 ach mice was larger than that of untreated Fgfr3 ach mice throughout the treatment period. On the other hand, 20 mg/kg/day of meclozine-treated Fgfr3 ach mice were not larger than untreated Fgfr3 ach mice at the end of treatment. Mean and SD are indicated. Statistical significance was analyzed by the unpaired t test for each dose of meclozine-treated Fgfr3 ach mice (n = 7, 5, and 4 for 1, 2, and 20 mg/kg/day of meclozine, respectively) or untreated wild-type mice (n = 16) versus untreated Fgfr3 ach mice (n = 15).”

Interesting that the higher dose did not help to increase length.  This could be why it’s so hard for meclizine to be effective in humans.  There’s an equilibrium dosage that’s hard to pinpoint.

Warning: We are not doctors or medical professionals. We would like to tell any parents of kids suffering from Achondroplasia/Short Stature to NOT just go down to the local drugstore and buying bucket-loads of Dramamine, the Less Drowsy Formulation, to try to treat/inhibit/suppress the FGFR3 abnormality. Please seek professional advice first before going off and try to make your children taller.