There’s a possible new treatment for XLH just starting in the FDA process, which you can read about here. But first, to understand the article, we need to learn the basics of some new terminology. Ten years ago, we had to learn what a monoclonal antibody was, in order to understand how burosumab works. Now, it’s time to learn about aptamers.
As far as I understand it, aptamers are a lot like antibodies, but smaller, easier to produce, and easier to modify. According to “Aptamers and the next Generation of Diagnostic Reagents” in a journal on “proteomics” (the study of proteins): “Aptamers offer significant advantages over antibodies. They are in general more stable than antibodies, and have a longer shelf life. Aptamers are produced through a simple and inexpensive process and the time required to generate aptamers is comparatively short. … Because aptamers are chemically synthesized, chemical modifications can be introduced into them at any desired position in the nucleotide chain. Although antibodies can be chemically modified, site-specific modifications are extremely difficult. … Aptamers are smaller in size compared to antibodies, thus allowing improved transport and tissue penetration compared to antibodies.”
Basically, if I’m understanding it without the benefit of a medical degree, aptamers work like antibodies, clinging to the proteins they’re meant to cling to, but they’re different from antibodies at the molecular level (just please don’t ask me to explain HOW they’re different, because that’s where the explanation slips out of my grasp). The article providing the explanation is focused on the use of aptamers for diagnosis, rather than for treatment, but aptamers are apparently the new frontier for treatment research, just as monoclonal antibodies were a couple decades ago.
This potential new treatment, just starting the FDA process, is focused on a different pathway than burosumab. Burosumab blocks the protein (FGF23) that causes the kidneys to dump phosphorus, which results in more phosphorus getting to the bloodstream. It’s often referred to as getting to the root cause of the phosphate-wasting, although that’s a bit of an oversimplification, since while the excess FGF23 in the kidneys is closer to the beginning of the causation path a treatment that replaces the wasted phosphorus, we don’t yet know the ultimate root cause (the messaging that causes the bones to produce too much FGF23).
The new aptamer treatment about to undergo FDA review (I’m going to call it “new aptamer” for simplicity’s sake) instead gets to a different root cause, or perhaps a supplemental root cause. Apparently XLHers have many times more sclerostin than non-XLHers, and excessive sclerostin depresses bone formation. Sclerostin is a protein (sort of like FGF23), that is produced in bone cells (like FGF23) and So, just as burosumab wraps around excessive FGF23 to prevent phosphorus wasting, the new aptamer wraps around excessive sclerostin to allow normal bone formation. It’s not clear how this leads to better retention of phosphorus, so there’s a lot more to learn, but the earliest research suggests there is improved phosphorus retention when excessive sclerostin is blocked, even if we don’t understand the pathway the way we understand how blocking FGF23 allows for better phosphorus retention.
We’re a long way from knowing if this anti-sclerostin approach is safe or even if it’s effective. Assuming it is (both), it’s not clear to me whether this would be an alternative treatment, capable of treating XLH on its own, or possibly a co-treatment if XLHers on burosumab still have high levels of sclerostin. Another big question in my mind is whether non-X-linked hypophosphatemias (both the autosomal versions and TIO) have high levels of sclerostin, so they should be included in the research too. And if they don’t have high levels of sclerostin, what could that information tell us about the different forms of hypophosphatemia?
In any event, this is just a very early step in the process . So far, all they’ve done is get the FDA to authorize special treatment of this application based on the rarity of the condition to be treated. That lets them can proceed with smaller clinical trials (since there are fewer available patients) and have some fees reduced (again, because of the smaller potential market for recouping the cost). In theory, the designation can also expedite the process, but that’s a relative thing. We’re still probably looking at eight to ten years before it hits the market, even assuming the process goes smoothly and the proposed treatment turns out to be both safe and effective.
There are a lot of unknowns, and many treatments fail along the way, but it’s exciting to see researchers trying new things for the treatment of XLH (and, I hope, the other chronic hypophosphatemias). My one concern is that, as best I can tell, the developer of this new treatment hasn’t reached out to patient groups, at least not in the U.S. or Europe, for patient insights, and that is worrisome. It’s been said, over and over again, that consulting patient groups early in the process leads to better outcomes for everyone, and yet, too often patient groups are snubbed until external forces make the consultation necessary.
For now though I’m gong to assume that the developer is not, in fact, ignoring patients, and is pursuing a potentially useful treatment. We all need some positivity in our lives these days!
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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