Beyond Achondroplasia

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The TransCon CNP, a prodrug for achondroplasia

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A company based in Denmark and is applying its innovative TransCon technology that combines the benefits of prodrug and sustained-release technologies and developing the TransCon CNP for achondroplasia.

FGFR3 and CNP

Achondroplasia is caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). The increased activity of the FGFR3 reduces the growth of the long bones. The C-type natriuretic peptide (CNP) has the ability to antagonize the FGFR3 action inside the chondrocytes by inhibiting the MAPK chain reaction (mitogen-activated protein kinase). MAPK signals, which slow bone growth, are subject to downregulation by the signaling cascade activated by C-type natriuretic peptide (CNP), resulting in the stimulation of endochondral ossification in vivo. In “Achondroplasia: pathogenesis and implications for future treatment” Laederich M and Horton W, 2010.

In a simpler way: when the CNP connects with its receptor in the cell (NPR-B) it can block the FGFR3 cascade that takes place inside the chondrocyte, as if stopping a chain reaction of domino pieces falling. And by this action, CNP can produce a positive effect in restoring growth in achondroplasia.

Several approaches have shown promise in preclinical studies for achondroplasia and one of them uses CNP. BioMarin Pharmaceuticals developed the CNP analog, BMN 111, which retains the biologic properties of native CNP but has an extended half-life due to its resistance to neutral-endopeptidase digestion, allowing for once daily subcutaneous administration. In “Advances in treatment of achondroplasia and osteoarthritis“. Klag K and Horton W, 2016

After this, what is a prodrug?

A drug is a small organic molecule introduced into the body for cure, prevention, treatment or diagnosis of a disease generally binding to a specific site or organ/cell and activating or inhibiting the function of the desired biomolecule. But drug administration is associated with certain problems like distribution of the compound throughout the body and undesirable side-effects.

Prodrug is the masked form of active drug capable of increasing the efficiency of drugs and decreasing its associated toxicity. As in the following image, a prodrug is considered to be the combination of active drug and side chain/ligand (covalently linked), which helps in targeting the specific cell/tissue. The prodrug is then converted to the original drug once it reaches the site of action, followed by rapid abolition of the released derivatizing group without causing side effects. In “Cutting Edge Approach on Prodrug: Contrivance for Target Drug Delivery“. Varsha Y et al., 2011

Cutting Edge Approach on Prodrug: Contrivance for Target Drug Delivery”. Varsha Y et al., 2011

What is a sustained release technology?

From all drug delivery systems, oral drug delivery remains the most preferred option for administration for various drugs. Sustained Release is also providing promising way to decrease the side effects of drugs by preventing the fluctuation of the therapeutic concentration of the drug in the bodyside-effects are reduced and cure of the disease is achieved. The principal goal of sustained release forms is the improvement of drug therapy… In “A review on sustained release technology“Gupta M and Brijesh U, 2012

The TransCon technology

It can be applied to previous therapeutic approaches to extend duration of a drug’s action in the body, and to enhance the overall benefit of a therapy.  This technology combines the benefits of conventional prodrug + sustained release technologies creating a platform technology that is broadly applicable to proteins, peptides and small molecules (Ascendis Pharma).

In sum, the TransCon is like a reservoir that holds the drug inside it. After this “reservoir” is injected into the body, it can release the drug at a predetermined frequency of time. So in the TransCon CNP case, the TransCon holds CNP inside

Image: Ascendis Pharma

The TransCon CNP

Ascendis Pharma stated that the TransCon CNP is a sustained-release prodrug of C-Type Natriuretic Peptide (CNP) for the treatment of achondroplasia and has shown the following relevant points:

  1. It is being investigated as a once-weekly prodrug to provide continuous exposure to CNP to potentially improve efficacy, safety and/or convenience over first-generation CNP analogues.
  2. It releases CNP via a non-enzymatic hydrolysis of the TransCon linker.
  3. It is designed to maintain the same mode of action and distribution as the continuous administration of CNP and could become an efficacious and safe therapy for patients with ACH, with a convenient subcutaneous weekly dosing profile.
  4. It minimizes binding of CNP to the NPR-C receptor to decrease clearance;
  5. Reduces binding of CNP to vascular NPR-B receptors to avoid hypotension caused by activation of this receptor. (There are receptors NPR-A, NPR-B and NPR-C being the B the specific receptor of CNP)
What is drug clearance?

Is the rate at which the active drug is removed from the body; and for most drugs at steady state, clearance remains constant so that drug input equals drug output. The university of Nothingham

Recent updates

Ascendis Pharma presented two posters at the ENDO 2017 (Endocrine Society Annual Meeting, 1-4 April 2017) on TransCon CNP, and the top conclusions were:

  1. Lack of adverse hemodynamic effects of TransCon CNP, allowing for the administration of high doses to facilitate optimal efficacy.
  2. Observation of a dose-dependent effect on tibia growth in juvenile monkeys with weekly TransCon CNP with results that demonstrated growth effects continued through six months.
  3. The effects of TransCon CNP in a mouse model of achondroplasia, included bone growth and the potential to ameliorate some of the more disabling achondroplasia traits, including stenosis of the foramen magnum.

So, with this, the bar stands higher for all the companies currently working on a potential treatment for achondroplasia. For patients, the key goal of receiving a drug that can reduce the complications directly related to achondroplasia, such as the stenosis of the foramen magnum, seems to be starting to catch the attention of the researchers, the industry and the investors.

“The encouraging TransCon CNP preclinical data support the hypothesis that a CNP analogue can be an effective treatment for achondroplasia without dose-limiting hypotension”

Kennett Sprogøe, Ph.D., Senior Vice President of Product Innovation

Transcript of interview to CEO and CMO of Ascendis Pharma, on the Earnings Conference Call- March 22, 2017

“Our long acting CNP pro-drug, TransCon CNP, is designed to optimize the therapeutic index by allowing a CNP level high enough to be therapeutic, but without achieving levels that result in hypotension, which has limited current investigational therapies.

In relevant animal models, we have shown no change in blood pressure following once weekly administration of TransCon CNP. In contrast a daily administered CNP which did lead to hypotension.”

Scott Smith – Senior Vice President, Chief Financial Officer

“We expect to submit an IND (Investigational New Drug application) or similar filing for TransCon CNP during the fourth quarter of 2017 and initiate clinical development in early 2018.”

Jan Mikkelsen – President and CEO


In conclusion, this is an enthusiastic time for patients with achondroplasia, their families, clinicians and the researchers community, by having several drugs in research and development: Vosoritide, TA-46, Meclizine, RMB-007, B-701 and TransCon CNP. We will keep a close look in all these drugs aiming to treat achondroplasia.

One Comment

  1. Hola
    gracias por su investigacion
    por favor me pueden estar enviando informacion, ya que soy padre de un niño con acondroplacia y me interesa saber los avances cientificos en esta enfermedad por su colaboracion
    gracias

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