Treating achondroplasia: from dream to reality

The future is at our door

We are now less than two weeks from Voxzogo's PDUFA* date, the day when the Food and Drug Administration (FDA) will release its response to vosoritide's application for commercialization. Vosoritide has been under clinical development for about ten years now, being investigated as a therapy for achondroplasia, the most common form of dwarfism. This long run has been taken with several humps and bumps throughout the way and, now that the drug is already approved in Europe, the expectations are all on how, and if, the decision by the FDA will truly open new doors for families interested in improving the health of their affected children. But let's see what these expectations are all about since the next steps may come with surprises.

As the 17 readers of this blog certainly know, achondroplasia is caused by a mutation on the gene that encodes an enzyme called fibroblast growth factor receptor 3 (FGFR3). I know, I know, I might become a little bit repetitive, but I think that the circle I will be doing here might help us to understand what we may expect on that vosoritide's breakthrough date (PDUFA). 

Causes and consequences

FGFR3, along with many other enzymes, plays a fundamental role during the phase scientists call development. Development starts with the fertilized egg and goes up until the end of puberty, and it is comprised by biological processes tightly regulated by hundreds of enzymes like FGFR3. You could call these processes standard operating procedures (SOPs). These enzymes work in concert to make the SOPs to run smoothly, but when one of them is modified (mutated) either working more than planned or not working at all, then the development process is deranged. 

FGFR3 is particularly important in bone development because it works by reducing the pace of bone growth, modulating the growth stimuli produced by several other enzymes. In a car, while those other enzymes would work as an accelerator, FGFR3 is a brake. If there was no FGFR3, bones would grow without control and cause several medical problems. In fact, mutations in FGFR3 that inactivate it do cause an overgrowth syndrome known as CATSHL syndrome  (camptodactyly, tall stature, scoliosis and hearing loss) (1).

A brake is important in a car, so its speed can be controlled. However, the mutation in FGFR3 that causes achondroplasia makes it to work too much, so the car can barely move (the brake rules over the accelerator). The result is that, in achondroplasia, bones, and especially the long bones and vertebrae, grow just a fraction of what they were supposed to, in contrast with all other body tissues. Individuals with achondroplasia have short adult stature but this is not the only key characteristic since restricted skeletal growth has consequences beyond height. 

The imbalance between shorter or narrow bones compared to all the other normal tissues will frequently lead to clinical complications that are listed in the published guidelines about achondroplasia. Due to their bone growth impairment, on average individuals with achondroplasia require more healthcare utilization, including surgical treatment to common orthopedic and neurological complications (e.g.: foramen magnum stenosis, spinal stenosis, joint problems, etc.) among others, while adults are also prone to obesity, higher incidence of cardiac disorders and have a shorter life span compared to the general population. (2)

As the knowledge about the natural history of achondroplasia improves it becomes clear that it is a genetic disorder affecting much more than the final height. 

Developing the first therapy for achondroplasia

The gene alteration that leads to achondroplasia was identified almost 30 years ago (3-5), but only more recently efforts have been directed to find ways to correct the bone growth defect caused by the overactive FGFR3 mutation. This became possible because the chemical networks regulated by FGFR3 have been identified (Figure 1) as well as of most of those pathways driven by the other agents involved in bone development and growth. This in turn allowed scientists to find out which of those pathways were impacted by mutations in FGFR3. (6)

Figure 1. FGFR3 relevant pathways in the chondrocyte.

One of those other bone development agents is an enzyme called natriuretic peptide receptor B (NPR-B). Both FGFR3 and NPR-B are located in the cell membrane of the chondrocytes, the cells that govern bone growth. They can be seen as power switches in our home walls that are turned on and off when we move them up and down. In the body, FGFR3 is turned on by FGFs while NPR-B is activated by the C-type natriuretic peptide (CNP). Scientists have discovered that CNP is a positive bone growth agent that works precisely reducing the activity of FGFR3 in the chondrocyte. (Figure 2). They have also seen that the FGFR3 pathway may downregulate the CNP+NPR-B axis. (7)

Figure 2. Crosstalk of FGFR3 and CNP pathways in the chondrocyte.

 

Having learned that CNP modulates FGFR3 activity and that it was working less than normal in achondroplasia, it was natural to check out if providing supplemental CNP would help reducing the effects of the mutated FGFR3. In fact, this was readily seen: adding CNP to cell cultures, bone explants and animal models of achondroplasia restored, at least partially, bone growth. (8) A first potential therapy for achondroplasia was at hand.

However, one problem that scientists faced when dealing with CNP is that this is a fragile molecule. Peptides like CNP are very active and must stay under control. When in the blood CNP will last less than three minutes circulating as it is an easy target for natural clearing systems we have. So, how to solve this problem? They learned that another natriuretic peptide called BNP is naturally more resistant to the clearing system due to having a slightly different structure. They adapted CNP to "look like" BNP and this change rendered the invention of vosoritide. (9) Therefore, vosoritide is a modified version of CNP, also called an analogue.

Vosoritide lasts about 20 minutes in the blood, enough time to reach the bone growth zones (the growth plates) and to exert its effects. So, what are these effects ? By reducing FGFR3 activity the NPR-B axis restores the chondrocyte capability to proliferate and enlarge (hypertrophy), which are the two key steps they need to take to make the bones grow. (8)

One hard challenge in the beginning of the clinical development of vosoritide must have been how to measure its efficacy. In humans, bone growth constitutes a long and slow process so changes are not identified in a day-to-day basis, but can only be seen when two distant time points are compared. This slow development makes it difficult to set objectives when someone is trying to correct a derangement in the bone growth process. Even harder would be to confirm whether the improved bone growth under the experimental drug would provide additional benefits in terms of reducing the frequent medical complications that result from the short and narrow bones, such as spinal stenosis. So, how can we measure those effects? After long discussions, as we can see described in the many public calls (mostly those financial conferences) throughout the years, the agreed endpoint between the developer and regulators that would allow determining if vosoritide was beneficial (efficacy) in the treatment of achondroplasia was bone growth velocity.

Vosoritide has been under tests in children with achondroplasia for years now and, according to the data already available, it helps to restore bone growth to an extent that is close to what happens in an average child. (10-12) The data that have been submitted to the European Medicines Agency (EMA) have been analyzed and, in last August, vosoritide was approved for the treatment of achondroplasia in the European countries that work with that agency. The same data have also been submitted to the Food and Drug Administration (FDA) which will be delivering their feedback in a few days more, as I mentioned above.

The future is present

The approval of vosoritide in Europe is a landmark for the treatment of achondroplasia and very likely to many other skeletal dysplasias where bone growth is impaired. One important characteristic of the CNP+NPR-B axis is that it works independently of FGFR3. The use of CNP analogues like vosoritide (there are others in development) may help improve bone growth in those other genetic disorders, thus not only improving height, but also medical complications related to other restricted growth conditions, as we expect to see in achondroplasia.

It may take a few years more to see whether children being treated with vosoritide will suffer fewer complications such as middle ear infections, sleep apnea, spinal stenosis, genu varum, etc. than what is frequently seen today, but the long term expectations about these potential benefits should not drive any conclusion that this drug, and all the other candidates to come, would not help to reduce those complications. 

And why is that so? Simply because the treatment is systemic, meaning that the drug reaches all bones at the same time. There is no logic in thinking that only one type of bone would be affected by the treatment. Therefore, the treatment not only should increase the length of long bones but also should help widening other bones such as the vertebrae, which grow through growth plates, too.

Children's health

Here is the World Health Organization definition of health:

• Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.

The accumulating evidence about the natural history of achondroplasia shows that both children and adults with this skeletal dysplasia endure impacts not only on the physical aspect but both in the mental (emotional) and social well being fields, too.(13,14) It will be good to see how the upcoming pharmacological treatments for achondroplasia will affect these aspects of health. Based on published evidence, individuals submitted to limb lengthening have improved quality-of-life after the surgery (15, 16), implying that the improved height was beneficial on those other aspects of health highlighted in the WHO definition. Someone pondering about this improvement seen after lengthening surgery needs to recall that the surgery only increases height, not having any effect in other characteristics of achondroplasia and its common complications, in contrast with what is expected with pharmacological therapies.  

We can foresee a time when babies and toddlers with achondroplasia won't need MRIs to rule out foramen magnum stenosis, or children attending repeated visits to a ENT specialist to insert ear tubes, or undergo amigdalectomy to improve their sleep apnea, just to cite a few of the stressful situations they frequently endure early in life. They might also be able to do anything an average child does, without common challenges they face today due to their restricted growth.

In conclusion, based on the current evidence, I believe that with improved bone growth, children with achondroplasia under treatment with vosoritide, and in the future with other potential therapies, will achieve benefits that go beyond the reduction of the risk of medical complications but also to improvement in mental and social aspects as well. These potential benefits must be kept in mind by stakeholders that will be in charge to decide whether to adopt therapies for achondroplasia or not. For me, the simple answer is yes.

References

* From Wikipedia: PDUFA date: In United States pharmaceutical regulatory practice, the PDUFA date is the colloquial name for the date by which the Food and Drug Administration must respond to a New Drug Application or a Biologics License Application.

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