It would not surprise me if many of you reading this have never heard of immune tolerance induction. That may be, in large part, because prior to the last two years, it was not a topic in our community AT ALL.
But it is now, and it’s long over due.
In Part 1, let’s look at some background on immunogenicity.
In Part 2, I’ll explore the issues of immunogenicity related specifically to idursulfase, the enzyme being replaced in MPS II.
In Part 3, I’ll address the takeaways from this week’s FDA/NORD workshop on the role of immune tolerance induction in enzyme replacement therapies.
Background on Immunogenicity as it Relates to ERT.
The genetic variation (deletion or mutation) that creates each of the MPS (or other LSD) disorders causes someone to be missing a key cellular enzyme. That’s the easy part. Yes, it’s a different enzyme in each disorder, but in all the disorders, the lack of the enzyme causes a substrate, whether its heparan sulphate or dermatan sulphate in MPS I and II, or heparan sulphate alone in MPS III, or keratan sulphate in MPS IV, etc, to accumulate in the cells.
The role of enzyme replacement therapy is to replace the enzyme that patients are lacking through a regular infusion, although a typical body makes the enzyme on an ongoing basis. Because of the relative instability of most of these enzymes (shaking and heat cause them to degrade and lose efficacy), it is unrealistic to consider an ongoing infusion more similar to a typical body.
But because patients’ bodies either (1) do not make the enzyme themselves at all, (2) make only a very small amount of the enzyme, or (3) make enzyme that doesn’t work properly, they can possibly recognize the enzyme replacement therapy product as a foreign substance and mount an immune response.
While patients and caregivers typically think of an immune response in terms of infusion-related reactions (a term that the FDA considers too general, by the way, and prefers that you refer to the specific symptom such as anaphylaxis, pyrexia, etc.), immune response is really the body’s cellular reaction to the protein which may or may not be seen in an obvious way to an observer.
Immune responses to ERT vary across the board. In some patients, they don’t happen. Their bodies accept the protein. In some patients, their bodies mount an immune response but then over time, it comes to accept the protein and the immune response dies down. In some cases, this involves the use of medications; in others it does not. However, in some cases, the body mounts a growing immune response, one that doesn’t necessarily begin early on in the use of ERT, but can sometimes occur even years into the use of a therapy, and the immune response remains high and/or continues to grow over time. This is often referred to as HSAT or high sustained antibody titers. Titer is just a term used to express concentration, so how strong/concentrated are the antibodies to the protein.
There are also different types of antibodies. There are non-neutralizing antibodies and neutralizing antibodies or nAbs, which actually inhibit the activity of the protein. In other words, someone can have significant enough neutralizing antibodies that prevent their ERT from making any difference at all.
So you see the problem here. Children and adults can be suffering greatly from a rare MPS or other enzyme deficiency, with all of the difficulty that that entails, they can be enduring the time, emotional energy, and in many cases, medical trauma that it requires for them or their child to undergo a weekly (or in some cases bi-weekly) infusion lasting many hours, insurance companies (and patients/caregivers) may be paying exorbitant amounts in costs, coverage, and co-payments for these enzyme replacement therapies, and in certain cases, it could be making little to no difference at all. That’s the efficacy issue.
But there’s also the issue of the danger inherent in immune response. So some types of immune response can cause life threatening reactions like anaphylaxis. Even if it doesn’t, if you speak to immunologists, they will tell you that there are potential downstream cellular effects and damage that we don’t yet fully understand that can come from having one’s body in a heightened state of immune response for an extended period of time. That’s the safety issue.
Now, HSATs may not be the norm. But I fear that it’s more common than we once would have thought. Thus, the importance for the FDA workshop and resulting recommendations, and for all patients and caregivers who use enzyme replacement therapies to become educated (and often to educate the physicians/nurses involved) about immune response and tolerance issues, and to be vigilant about antibody testing.
Next: Part 2 will explore issues of immunogenicity related specifically to idursulfase, the enzyme being replaced in MPS II.