In Part 1 of this series, I explored some of the background concepts related to immunogenicity. Now let’s begin examining immunogenicity in the context of a specific example – idursulfase / Elaprase, the enzyme replacement therapy for Hunter Syndrome or MPS II. Although I will be using idursulfase / Elaprase as an example, the analysis could help you research immune response issues related to other ERTs as well.
There are several sources from which to find information on immune response related to idursulfase (or another ERT). They are as follows:
Starting with the Elaprase product label, until mid-2013, there was less information on immunogenicity in the Elaprase labeling because certain post-marketing studies were not yet complete. But the current label has some great insights on this issue. I also wrote a summary of changes to the label in a previous post.
Specifically and importantly, it notes that those with the more severe mutations (complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations) experienced a higher incidence of hypersensitivity reactions, serious adverse reactions and anti-idursulfase antibody development, including neutralizing antibodies, which interfere with Elaprase uptake into the cell or enzyme activity, than patients with missense mutations.
Given that patients (especially severe patients, who are most affected by this issue) are more likely to be diagnosed younger and thus begin ERT younger, the information from the label on children aged 7 and younger was especially important:
In the clinical trial in patients 7 years and younger, 19 of 28 (68%) patients treated with ELAPRASE 0.5 mg/kg once weekly tested Ab-positive. Of the 19 Ab-positive patients, 16 (84%) tested positive for Ab at three or more different time points (persistent Ab). In addition, 15 of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) NAb-positive patients having persistent NAb.
All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations tested positive for Ab (Table 2). Of these 15 patients, neutralizing antibodies were observed in 13 (87%) patients. The NAbs in these patients developed earlier (most reported to be positive at Week 9 rather than at Week 27, as reported in clinical trials in patients older than 5 years of age) and were associated with higher titers and greater in vitro neutralizing activity than in patients older than 5 years of age. The presence of Ab was associated with reduced systemic idursulfase exposure [see Clinical Pharmacology (12.3)].
There are many published articles about the use of idursulfase in general and some will mention immune response issues as one component. There are also specific articles about immune response issues alone. I searched PUBMED with “idursulfase” and “antibody” and found several articles specifically on immune response. The difficulty often is obtaining the full article. Don’t pay, e-mail and request it from your or your child’s physician or genetic counselor or sometimes you can google the title and find a full copy.
The relationship between anti-idursulfase antibody status and safety and efficacy outcomes in attenuated mucopolysaccharidosis II patients aged 5 years and older treated with intravenous idursulfase. (full text available). Significantly, this article is about the relationship in attenuated patients, not the entire patient pool, and cannot be generalized to the severe Hunter Syndrome patient population.
IgE-mediated anaphylaxis and allergic reactions to idursulfase in patients with Hunter syndrome.(must pay for full text or request from physician)
Incidence and timing of infusion-related reactions in patients with mucopolysaccharidosis type II (Hunter syndrome) on idursulfase therapy in the real-world setting: a perspective from the Hunter Outcome Survey (HOS). (must pay for full text or request from physician)
Did you know that you can search the FDA’s website and databases for information about drugs and devices that affect you? If you did, you would find a 2013 Letter from FDA to Shire regarding additional post-marketing obligations related to Elaprase and immune tolerance. The letter sets forth certain obligations regarding the study of immune response that Shire has already completed, but importantly, it also notes:
Since Elaprase (idursulfase) was approved on July 24, 2006, we have become aware of literature reports of highly sustained antibody titers, increased hypersensitivity reactions, and poorer clinical outcomes in patients who are classified as cross-reactive immunologic material (CRIM) negative and treated with enzyme replacement therapy. We consider this information to be “new safety information” as defined in section 505-1(b)(3) of the FDCA.
As such, the letter then requires Shire:
to develop a validated cross-reactive immunologic material (CRIM) assay for patients with Hunter syndrome and test patient samples in a cohort of patients prior to Elaprase (idursulfase) treatment. Results will be correlated with antibody response (binding, neutralizing and IgE), genetic mutations, enzyme activity level, urinary GAG level, hypersensitivity reactions, and clinical outcome in patients who are receiving Elaprase (idursulfase) treatment. Patients with severe genetic mutations, such as complete deletions or large rearrangements, will be represented in the study. Banked patient samples from other clinical studies may be used.
The timeline for the information requires the Final Protocol Submission: 06/2014; Study Completion: 06/2016; and Final Report Submission: 01/2017. In Part 3 of this series, where I’ll write about the discussions and conclusions from the FDA meeting on the role of immune tolerance induction, I’ll discuss more the importance of having a CRIM assay. Kudos to FDA and Dr. Andrew Mulberg of FDA Division of Gastroenterology and Inborn Errors Products (DGIEP) for following up on this important issue. As I become aware of additional information regarding this study, I will update our community.
The Phase II/III trial for Elaprase was a large enough trial to have information on immune tolerance and the results have already been published here. Significantly, while almost half of the enrolled patients developed antibodies, it appears that some tolerized over time:
IgG anti-idursulfase antibodies were detected in 15 patients (46.9%) in the idursulfase weekly group and in 15 patients (46.9%) in the idursulfase EOW group. IgM antibodies occurred in 2 patients, one in each active treatment group. The highest prevalence of IgG antibodies was seen at Week 27 of the study , when 44.4% of the patients treated with idursulfase were antibody positive. After 53 weeks, only 31.7% of patients in the idursulfase groups remained antibody-positive. The reduction in urine GAG levels in antibody-positive patients was about two-thirds of that seen in antibody-negative patients. In contrast, there was no association with the presence of antibodies and adverse events or with clinical assessments (such as 6MWT or FVC measurements). No anti-idursulfase IgE antibodies were detected in any patient during the study.
However, the deficiency in this analysis would be seen later, in retrospect, given that the early and pivotal trials for Elaprase did not include any severe patients and thus, none with severe mutations. The article on the relationship between antibodies status and efficacy in attenuated patients mentioned above notes:
Genotyping was not a requirement of the phase II/III or extension studies. When performed, it was not done at a central laboratory, but at a local laboratory of the investigator’s choice and using DNA analytic techniques common to that locale and time. Because more than 260 different types of mutations in the IDS gene have been identified and because the number of patients in the study with genotype data was small, we conceptualized the genetic classification as representing two major types of genotype: the group where only a single nucleic acid change was introduced (missense) and a group where major disruptions of the protein were expected (nonsense and frameshift). We acknowledge that there are potential exceptions to this rule. Because of the age (5 years and above) and enrollment criteria (required to be able to perform walking and pulmonary function tests) for the phase II/III study, there were no patients with the severe phenotype in this study; such patients would be more likely to have major deletion and/or rearrangement genotypes.
Studies of other drugs in various research stages are also helpful in considering the immune response issues in Hunter Syndrome. For example, GlaxoSmithKline is collaborating on a drug to treat physical and neurological effects of Hunter Syndrome and it has published its results of a study of how its drug reacts with any antibodies a patient may have already formed to Elaprase. In analyzing this information, patients and caregivers need to understand that antibodies developed to Elaprase may also bind to second generation enzyme replacement products, thus, it is all the more important to prevent them altogether or address them as effectively as possible.
We have yet to see data from the Phase I/II IT Idursulfase intrathecal trial regarding serum and CSF antibodies. This will be important information not only to future research, but in therapeutic decision-making in our community.
Most geneticists, unfortunately, are not up to date on issues related to immune tolerance to ERTs, much less the state of research on an individual ERT. So many in our community are left to anecdotal information from clinicians and other parents.
However, individual case studies may still be available for particular conditions and their therapies. While these do not create the ability to generalize to other patients as well as a full-blown clinical study, they can definitely give us insight and hypotheses as to how the immune response is operating. In the case of Hunter Syndrome, we were lucky enough to have two case studies presented at the FDA workshop and available for others to review:
Anti-Drug Antibodies in Patients with Lysosomal Storage Disorders (LSD’s): Clinician’s Perspective by Barbara K. Burton, MD
Non-Cytotoxic, Non-Immunosuppressing Approach to Tolerance Induction During ERT Treatment by Jeanine R Utz, PharmD BCOP BCPS
I listed patient/parent reports last, not because they are the least important, but because our community already knows to look here and does, usually before any of the above. Were it not for several parents, in collaboration with their childrens’ physicians, waving the flag on this issue, I doubt it would be in the forefront of our community. Their steadfast efforts to find solutions, raise awareness of this issue, and encourage research, not only for their children, but for the community at large, is both heroic and often unrecognized.
Next: Part 3 will explore the takeaways from last week’s FDA/NORD workshop on the role of immune tolerance induction in enzyme replacement therapies.