Anniversary
Nine years ago, I was participating in a small online discussion group, in a time when blogs and social media were not yet as popular as now, and published a small summary of what I was reading about achondroplasia.
At that time, having already talked with a number of investigators in the field and with
a few representatives of advocacy groups I realized that the technical
information and advances I was seeing in the literature were difficult to
reach by the interested community. In that short article, my focus was perspective rather than reviewing what experts were doing already so well. I put together all potential strategies I found in the literature that could be used to treat achondroplasia in a few paragraphs. As most of the participants on that discussion group had no medical background I tried to use less heavy jargon and translate technical language to a more digestible vocabulary. I had hope.
That text received some positive feedback and was adopted by one of the advocacy groups. And was the seed for this blog.
That's it! Six years ago I started the Treating Achondroplasia blog to share what I was learning with all those interested in understanding achondroplasia and the ongoing work to beat the genetic mutation that leads to this skeletal dysplasia.
There are two kinds of articles published in the blog. The first type comprises reviews of the genetic disorder mechanisms and in the second there are those reviewing potential strategies. Nevertheless, I keep trying to mix both topics, to give a bit of background on the mechanisms involved in each strategy.
As of today, the blog has received more than 300K visits. When I review the statistics I can see that most visitors are more interested in the potential therapies and solutions for achondroplasia, so I think the blog is in the right track.
The blog has become a bit silent lately, as I mentioned in a previous article. And as I said then, this has more to do with my perception of a slight decrease in topics that may be interesting for the readers than for any other reason.
News, news, news
And, just to keep us on track and aware, I am happy to share with you that there is one more strategy that may become a strong option for the treatment of achondroplasia.
Just two days ago, a biotech venture called BridgeBio announced the establishment of QED Therapeutic, a new initiative to continue the research with BGJ398, a small molecule now called infigratinib, that was designed to block FGFRs, but which has more affinity with FGFR3. It was designed aiming to treat several kinds of cancer that use FGFRs to grow. To learn more about QED, visit their website here.
Infigratinib has been already tested in an animal model of achondroplasia and showed compelling promising results (1). This study leaded by Laurence Legeai-Mallet, a master in FGFR3-related dysplasias, was also reviewed here in the blog in 2016: Treating achondroplasia: NVP-BGJ398, a tyrosine kinase inhibitor, restores bone growth in a model of achondroplasia. This review starts with a tour through achondroplasia and the biology behind this skeletal dysplasia. It may help you to have a better view of the landscape (as I said, I mix topics...).
In short, infigratinib was given in doses lower than those intended for the treatment of cancer, and basically was able to rescue bone growth in the tested model. It is important to note that, having already reached clinical trials for cancer, infigratinib showed a balanced safety profile. Now, it must be tested in the context of the developing body and the reason is simple. Although the molecule shows more affinity to FGFR3, it can also block other FGFRs, so we need to understand whether there would be safety issues in the developing organism exposed to infigratinib before it reaches the clinical development in children. If proven to be safe, then the rationale for its use would be strong as it directly targets the protein that causes achondroplasia compared to others such as vosoritide, that works indirectly.
These are exciting times. Some years ago, I heard from a renowned investigator that "in the near future the problem won't be to treat or not achondroplasia. The problem will be to decide which drug we will use to treat it". This will be true for the new generations.
Thank you
Thanks for your interest in the Treating Achondroplasia blog. I hope it keeps being useful for you!
References
1. Komla-Ebri Det al.
Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related
dwarfism in mouse model. J Clin Invest 2016;126(5):1871-84. Free access.
Thursday, February 1, 2018
Thursday, January 11, 2018
Treating achondroplasia: TransCon CNP showed positive results in pre-clinical tests
Introduction
The seventeen readers of this blog may think this short article would not be hard to understand but there is a chance that newcomers might find this text a bit difficult to digest. No worries, we have been reviewing these topics for some time and there are introductory articles about everything written here that might make it easier for everyone to get onboard. :) So, for a friendly introduction to C-type natriuretic peptide (CNP), please visit this article!
CNP and bone growth
CNP has long been identified as an important regulator of bone growth (1). CNP exerts its actions by partially counteracting fibroblast growth factor receptor 3 (FGFR3) activities (1) (Figure 1). Evidence that points to the relevance of CNP on bone growth is given by studies showing that individuals bearing disabling mutations in both CNP or in its cell membrane receptor natriuretic peptide receptor B (NPRB) have severe impairment of bone development (2,3). Conversely, mutations that make NPRB hyperactive lead to bone overgrowth (4).
Overgrowth is also seen in mutations disabling another natriuretic receptor present in the cartilage chondrocytes, called NPRC. NPRC is thought to be responsible for capturing circulating CNP (a clearance mechanism, like a janitor), thus regulating CNP activity. When NPRC is not functional, more CNP is available to interact and activate NPRB, which in turn leads to overgrowth (4). This is the first time I mention NPRC in this context and I am not doing this without a reason. I recently learned that there is at least one group exploring if it is possible to block NPRC to "help" CNP analogues like vosoritide giving them more time to do their job in the growth plate (let's talk about this in another article, though).
Figure 1. FGFR3 and CNP signaling interaction.
So, CNP is an active peptide that works promoting bone growth by limiting the action of FGFR3. As mutations in FGFR3 are the cause of achondroplasia and other related bone dysplasias, it is natural to think that CNP could be used to treat achondroplasia. However, as with many natural active peptides produced by our body, CNP is allowed to work for just a very short time (~2 minutes!) and is readily cleared from the blood by neutralizing agents (enzymes) (1). Given this limitation, how could one show that CNP could be used as a therapy for bone growth restriction conditions like achondroplasia?
With this question in mind, the Japanese group leaded by Dr. Nakao created a model of achondroplasia in which they promoted continuous production of CNP, which not only rescued the bone growth arrest caused by the achondroplasia mutation but also some overgrowth (5). They also explored the use of continuous infusion of CNP, with similar results (6). The problem with their models is that they would not be reproducible in clinical settings. Therefore, as continuous delivery of CNP would not be feasible researchers started to look on how to give more time to CNP to reach the growth plate and work there.
Developing CNP analogues
CNP pertains to a family comprised by three main peptides and other closely related molecules. One of these peptides, brain natriuretic peptide (BNP), is naturally more resistant to those enzymes that easily neutralize CNP, so researchers created a CNP-like molecule now called vosoritide which contains the structure that allows BNP to resist more time to degradation (7). Vosoritide can be tracked in the blood for about 20 minutes, enough time for it to reach the growth plate and promote bone growth, as seen both in pre-clinical research (8) and in the ongoing clinical studies (9).
Other options
In Science, exploring different paths and asking more questions always lead to something new. Vosoritide needs to be given as a subcutaneous shot everyday to attain its effects, so what would happen if we could give CNP even more time to work in the growth plate?
This question was approached some years ago by the biotech Alexion, which developed NC-2 (you can visit the blog's article reviewing this molecule in 2014 here). This molecule is the fusion of the active part of CNP with the scaffold part of the structure of antibodies (take a look in the blog's article!), which confers striking resistance to the neutralizing enzymes. NC-2 was explored in an interesting study where the researchers used it to inhibit the exact same signaling cascade used by FGFR3 to exert its actions in the chondrocyte (10). However, this molecule seems to have been abandoned and no further research has been published (to my knowledge).
Ascendis pharma develops a drug transport system that allows fragile molecules to have longer action in the body. This is the case of this recently described new CNP analogue TransCon CNP. We don't have a full description of TransCon CNP (as published in a scientific journal) but the developer describes it as a molecule that involves CNP protecting it from enzymatic degradation. They have published a number of abstracts describing their pre-clinical studies, which we will summarize here. One important aspect of this new analogue is that it could be given once a week.
Pre-clinical results with TransCon CNP
In 2017, the developer presented a few number of abstracts/posters in scientific meetings, two of them which summarize the pre-clinical studies are accessible directly from their website here and here.
They describe the TransCon technology as a carrier (a taxi) for molecules that otherwise would be rapidly metabolized in the blood (Figure 2) before they could efficiently exert their actions. Based on their texts both in their website and in the published abstracts I think that the main secret about their molecule is not the carrier itself, but the bridge (the linker) between the carrier and the transported molecule (Figure 2). The carrier could be a layer of poliethylene glycol (PEG), a polymer largely used to prolong the half-life of many drugs, such as interferon (used for the treatment of hepatitis C) and several anti-cancer compounds.To those interested in more information about transporters or carriers, I have reviewed this topic back in 2012, in this article.
Figure 2. TransCon CNP concept.
Key results*:
Figure 3. Effects of TransCon CNP in a mouse model of achondroplasia.
Based on these results, the developer declared their intention to progress TransCon CNP to clinical settings soon, starting with asking authorization by Regulatory agencies.
Conclusion
Whether this new formulation of CNP will work is dependent on the results coming from clinical trials. The preliminary results so far are promising. If proven to be as effective as vosoritide has been showing to be, having a more sustained release and presence in the growth plate, less hemodynamic effects and more comfortable dosing, make this new CNP version a potential strong option in the therapeutic arsenal for achondroplasia and other skeletal dysplasias.
References
1. Pejchalova K et al. C-natriuretic peptide: An important regulator of cartilage. Mol Genet Metab 2007;92(3):210-5.
2. Hisado-Oliva A et al. Mutations in C-natriuretic peptide (NPPC): a novel cause of
autosomal dominant short stature. Genet Med 2018;20(1):91-97.
4. Matsukawa N et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc Natl Acad Sci USA 1999; 96: 7403–08. Free access.
5. Kake T et al. Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. Am J Physiol Endocrinol Metab 2009;297(6):E1339-48.
The seventeen readers of this blog may think this short article would not be hard to understand but there is a chance that newcomers might find this text a bit difficult to digest. No worries, we have been reviewing these topics for some time and there are introductory articles about everything written here that might make it easier for everyone to get onboard. :) So, for a friendly introduction to C-type natriuretic peptide (CNP), please visit this article!
CNP and bone growth
CNP has long been identified as an important regulator of bone growth (1). CNP exerts its actions by partially counteracting fibroblast growth factor receptor 3 (FGFR3) activities (1) (Figure 1). Evidence that points to the relevance of CNP on bone growth is given by studies showing that individuals bearing disabling mutations in both CNP or in its cell membrane receptor natriuretic peptide receptor B (NPRB) have severe impairment of bone development (2,3). Conversely, mutations that make NPRB hyperactive lead to bone overgrowth (4).
Overgrowth is also seen in mutations disabling another natriuretic receptor present in the cartilage chondrocytes, called NPRC. NPRC is thought to be responsible for capturing circulating CNP (a clearance mechanism, like a janitor), thus regulating CNP activity. When NPRC is not functional, more CNP is available to interact and activate NPRB, which in turn leads to overgrowth (4). This is the first time I mention NPRC in this context and I am not doing this without a reason. I recently learned that there is at least one group exploring if it is possible to block NPRC to "help" CNP analogues like vosoritide giving them more time to do their job in the growth plate (let's talk about this in another article, though).
Figure 1. FGFR3 and CNP signaling interaction.
So, CNP is an active peptide that works promoting bone growth by limiting the action of FGFR3. As mutations in FGFR3 are the cause of achondroplasia and other related bone dysplasias, it is natural to think that CNP could be used to treat achondroplasia. However, as with many natural active peptides produced by our body, CNP is allowed to work for just a very short time (~2 minutes!) and is readily cleared from the blood by neutralizing agents (enzymes) (1). Given this limitation, how could one show that CNP could be used as a therapy for bone growth restriction conditions like achondroplasia?
With this question in mind, the Japanese group leaded by Dr. Nakao created a model of achondroplasia in which they promoted continuous production of CNP, which not only rescued the bone growth arrest caused by the achondroplasia mutation but also some overgrowth (5). They also explored the use of continuous infusion of CNP, with similar results (6). The problem with their models is that they would not be reproducible in clinical settings. Therefore, as continuous delivery of CNP would not be feasible researchers started to look on how to give more time to CNP to reach the growth plate and work there.
Developing CNP analogues
CNP pertains to a family comprised by three main peptides and other closely related molecules. One of these peptides, brain natriuretic peptide (BNP), is naturally more resistant to those enzymes that easily neutralize CNP, so researchers created a CNP-like molecule now called vosoritide which contains the structure that allows BNP to resist more time to degradation (7). Vosoritide can be tracked in the blood for about 20 minutes, enough time for it to reach the growth plate and promote bone growth, as seen both in pre-clinical research (8) and in the ongoing clinical studies (9).
Other options
In Science, exploring different paths and asking more questions always lead to something new. Vosoritide needs to be given as a subcutaneous shot everyday to attain its effects, so what would happen if we could give CNP even more time to work in the growth plate?
This question was approached some years ago by the biotech Alexion, which developed NC-2 (you can visit the blog's article reviewing this molecule in 2014 here). This molecule is the fusion of the active part of CNP with the scaffold part of the structure of antibodies (take a look in the blog's article!), which confers striking resistance to the neutralizing enzymes. NC-2 was explored in an interesting study where the researchers used it to inhibit the exact same signaling cascade used by FGFR3 to exert its actions in the chondrocyte (10). However, this molecule seems to have been abandoned and no further research has been published (to my knowledge).
Ascendis pharma develops a drug transport system that allows fragile molecules to have longer action in the body. This is the case of this recently described new CNP analogue TransCon CNP. We don't have a full description of TransCon CNP (as published in a scientific journal) but the developer describes it as a molecule that involves CNP protecting it from enzymatic degradation. They have published a number of abstracts describing their pre-clinical studies, which we will summarize here. One important aspect of this new analogue is that it could be given once a week.
Pre-clinical results with TransCon CNP
In 2017, the developer presented a few number of abstracts/posters in scientific meetings, two of them which summarize the pre-clinical studies are accessible directly from their website here and here.
They describe the TransCon technology as a carrier (a taxi) for molecules that otherwise would be rapidly metabolized in the blood (Figure 2) before they could efficiently exert their actions. Based on their texts both in their website and in the published abstracts I think that the main secret about their molecule is not the carrier itself, but the bridge (the linker) between the carrier and the transported molecule (Figure 2). The carrier could be a layer of poliethylene glycol (PEG), a polymer largely used to prolong the half-life of many drugs, such as interferon (used for the treatment of hepatitis C) and several anti-cancer compounds.To those interested in more information about transporters or carriers, I have reviewed this topic back in 2012, in this article.
Figure 2. TransCon CNP concept.
 |
| from: Sprogøe K et al. Poster presented at the 67th Annual Meeting of The American Society of Human Genetics (ASHG), October 17-21, 2017 (Orlando, FL). Ascendis Pharma website. |
Key results*:
- TransCon CNP was tested in cynomolgus monkeys and confirmed to have a half-life of about 79hs (allowing a predicted weekly dose);
- TransCon CNP was compared with vosoritide and the original CNP molecule for circulatory effects and showed no decrease in blood pressure;
- TransCon CNP showed positive effects both in a mouse model of achondroplasia (Figure 3) and in normal cynomolgus monkeys.
Figure 3. Effects of TransCon CNP in a mouse model of achondroplasia.
 |
| from: Breinholt VM et al. Poster presented at the American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting, September 8-11 (Denver, CO). Ascendis Pharma website. |
Based on these results, the developer declared their intention to progress TransCon CNP to clinical settings soon, starting with asking authorization by Regulatory agencies.
Conclusion
Whether this new formulation of CNP will work is dependent on the results coming from clinical trials. The preliminary results so far are promising. If proven to be as effective as vosoritide has been showing to be, having a more sustained release and presence in the growth plate, less hemodynamic effects and more comfortable dosing, make this new CNP version a potential strong option in the therapeutic arsenal for achondroplasia and other skeletal dysplasias.
References
1. Pejchalova K et al. C-natriuretic peptide: An important regulator of cartilage. Mol Genet Metab 2007;92(3):210-5.
2. Hisado-Oliva A et al. Mutations in C-natriuretic peptide (NPPC): a novel cause of
autosomal dominant short stature. Genet Med 2018;20(1):91-97.
3. Wang W et al. Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports. Am J Med Genet A 2016;170A(2):426-34.
5. Kake T et al. Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. Am J Physiol Endocrinol Metab 2009;297(6):E1339-48.
6. Yasoda A et al. Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology 2009;150(7):3138-44. Free access.
7. Wendt DJ et al. Neutral
endopeptidase-resistant C-type natriuretic peptide variant represents a
new therapeutic approach for treatment of fibroblast growth factor
receptor 3-related dwarfism.J Pharmacol Exp Ther 2015;353(1):132-49. Free access.
8. Lorget F et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 2012;91(6):1108-14. Free access.
9. Hoover-Fong M et al.Vosoritide in children with achondroplasia: Updated results from an ongoing Phase 2, open-label, sequential cohort, dose-escalation study. Presented at the American Society of Human Genetics 2016 Meeting. Abstract Book p.1301: 2347W. Free access.
10. Ono K et al. The
ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR
signaling during endochondral bone formation. Hum Mol Genet
2013;22(15):3048-62.
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