HoFH Treatments on the Horizon

In their final thoughts, Drs Brinton, Baum and Michos provide insights on the trajectory of treatment in HoFH.

Eliot Brinton, MD: One of the questions that often comes up in the process of diagnosing and treating FH [familial hypercholesterolemia] is genetic testing. The good news here is that even though genetic testing is getting cheaper and it’s getting better, it’s still not very useful clinically, and here is why. You diagnose the patient by the LDL [low-density lipoprotein]. If that LDL is above 300, 350, or 400 [mg/dL], it’s presumptive homozygous FH [HoFH]. There’s an overlap between HoFH and [heterozygous] HeFH, milder HoFH, and more severe HoFH. And it doesn’t matter which one they have, because you’ve got to treat the LDL. The gene itself doesn’t kill them. Whatever gene defect it is, and there are several possible gene defects. That is not their problem. Their problem is the LDL is high, and that’s pickling their arteries, and their aortic valve, and whatever. So you don’t need genetic testing. I don’t ever do it for clinical purposes. I know there are people who do and I respect that, but I don’t think it’s ever warranted. It is expensive and the patient worries about all the ramifications of genetic testing. I don’t see how it helps me, because I go by the phenotype in terms of the diagnosis, and then of course the treatment. Gene testing doesn’t help you know how to treat the patient or how well they’re going to respond. You can guess based on a mutation how well they might respond, but that doesn’t tell you how well they will respond. So you go ahead and treat them. Empiric trials one by one, sequential trials of these various treatments is what I would strongly recommend.

Sometimes genetic testing is mentioned in the context of cascade screening, which is a big deal for both patients with homozygous and heterozygous FH. Why? It’s a monogenic disorder. Their first- and second-degree relatives are at super high risk to have this same monogenic disorder. But you can do cascade screening in the family without genotyping. You just do phenotyping, what’s their LDL, and is it high enough to be of concern? They could have normal LDL; they could have an LDL of 190 [mg/dL], which is our conventional cutoff for HeFH. It could be 390 [mg/dL], it could be wherever it could be. But you can go ahead and test everybody available for testing in the family with cascade screening without the use of genotyping. It’s a great tool. The genetic advances are huge to our whole field. But as a clinician, I don’t do that. Please do not delay making the diagnosis of HoFH or HeFH while you’re figuring out how to do the genetic testing, or waiting for the parent to say yes. Please don’t do that because it’s all based on the phenotype, really, truly, in terms of diagnosis and management. That’s the essence clinically. That’s the takeaway for the clinician, rather than for the researcher who maybe needs to do genotyping.

Seth Baum, MD: With regard to where I see HoFH management going, my hope is that we elevate the level of conversation among clinicians, and patients, but [more so] among clinicians so that all of us always have FH on the tips of our diagnostic tongues. So, if we diagnose the patients with HeFH, we’re more likely to diagnose those with HoFH, and frankly, vice versa. We need to be cascade screening, so this is not a therapeutic advance, this is a diagnostic advance. We need to understand that early and aggressive treatment is paramount when it comes to managing risk in patients with FH and HoFH. We need to utilize therapeutics more readily, both those that work by upregulating LDL receptor activity, and also those that work independently of LDL receptor activity, and those would be lomitapide, evinacumab, and LDL apheresis. We need to find a way to have more apheresis centers around the country, make it easier for us, the clinicians, to establish apheresis centers and to utilize the therapeutics we have for our patients with both HeFH and HoFH. And if we can work better with the payers, more hand in hand trying to help the patients, I think we’d all be far better off, and we’d make a much better dent in FH, and more specifically in HoFH.

Erin Michos, MD, MHS: In terms of what to look forward to, we have more therapies than we’ve ever had before, so that’s exciting. We just want to achieve better access to these therapies for our patients and have them be affordable and covered by their insurance. On the horizon, still a number of years away, but there’s been work in gene editing and CRISPR [technology], and gene editing might potentially even be curative. Someday this may be a curative disease by gene editing. We’re still a number of years away from that, but that’s exciting to look forward to. The important thing as of now is early diagnosis and to get these patients treated without delay and access to agents that we know already work.

Transcript edited for clarity.

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