Immune Tolerance to Enzyme Replacement Therapies, Part 3: FDA/NORD Workshop on the Role of Immune Tolerance Induction

Posted Wednesday August 27, 2014 by Melissa

Immune response is one of the most important issue in enzyme replacement therapy today. At least it is to many patients. That’s why I’ve waited several months to publish this last part in the series until I’d gathered the thoughts of many patients on the issue, after they explored the meeting’s discussions, and incorporated it into my analysis.

In Part 1 of this series, I explored some of the background concepts related to immunogenicity. In Part 2, I examined immunogenicity in the context of a specific example – idursulfase / Elaprase, the enzyme replacement therapy for Hunter Syndrome or MPS II.

In this part, I want to summarize the salient points from this summer’s FDA/NORD workshop on the role of immune tolerance induction in enzyme replacement therapies and present important takeaways and recommendations from the patient perspective. I had hoped to have a recorded webcast version of the meeting to post as well, but as yet, it is unavailable, so I will update if and when it does. You can read an entire written transcript of the meeting provided by NORD. In addition, we expect a meeting summary or white paper will be submitted for publication as well.

Although I would encourage everyone to review the presentations and summaries I prepared below, I fully realize that patient families may not have the free time to do so. As such, I wanted to begin with the takeaways and recommendations that I have formulated based on the meeting presentations and discussions.

Important takeaways:

  1. Lack of knowledge.  The majority of physicians and ERT patients are wholly unfamiliar with this issue at all. Patients who seek to be informed are often met with confusing medical terminology and healthcare and insurance providers who are not educated or supportive in addressing the issue. Many, if not most, physicians who prescribe and monitor ERT therapies refuse to monitor substrates or antibodies, believing no correlation to clinical efficacy and/or a lack of response options given abnormal results. Other than the interested parties at the FDA meeting and a few others, patients are often leading the effort to become educated with their physicians often being drug by them into the discussion. In addition, an immunologist is often needed as part of the team to understand and interpret the antibody results for all parties and neither patients nor their primary physicians are engaging them.
  2. Prevention versus treatment. It is more effective and efficient to prevent an immune response with a prophylactic immune tolerance protocol than to address an entrenched immune response. Some entrenched responses are never able to be fully overcome. The key issue is how to determine who is most likely to develop an immune response and/or the benefit/risk of prophylactic immune tolerance for all patients.
  3. Testing delays. Patients are unable to make appropriate decisions given the lack of CRIM assays for ERT-treatable conditions and the source and timing constraints of a sole provider (the pharma ERT developer) of antibody testing. Results of antibody panels are often many, many months delayed which, in itself, can allow an immune response to become entrenched before patients or clinicians even realize it exists. Given the variability of antibodies, the importance of trending in assessing treatment response and antibody development, and especially the difficulty of treating an entrenched immune response, the slow response is unacceptable and detrimental to patients. In Hunter Syndrome, for example, patients are just now getting some results from 2013.
  4. Testing and treatment model. The infantile onset Pompe disease community, and Dr. Priya Kishnani in particular, have developed working protocols for prophylactic immune tolerance induction and for entrenched immune response. These models have been tweaked for other conditions as well, including Hunter Syndrome. Because CRIM status results and antibody testing in Pompe have rapid turnaround (approx. 2 days for CRIM status), patients and clinicians are able to make treatment decisions regarding ERT and immune tolerance in a timely manner.
  5. FDA standards of safety and efficacy. Once ERT products are FDA approved, they are assumed to meet a particular level of safety and efficacy. However, in certain populations, particular CRIM negative patients and others who may develop entrenched immune responses, it should be expected that the product will not meet those standards in the same way as patients who do not develop entrenched immune responses. Thus, FDA must take into account immune tolerance issues in sub-populations prior to FDA approval or at the very least, in post-marketing obligations.


  1. Publication. The meeting’s discussion and analysis should be published in white paper or other form to serve as a basis for physician, insurer, and patient education.
  2. CRIM status test development. ERT developers should develop CRIM analysis in conjunction with their product and prior to FDA approval.
  3. Antibody panel development. ERT developers should develop antibody testing in conjunction with their product and prior to FDA approval.
  4. Clinical trials – testing.  CRIM analysis and regular antibody testing should be incorporated into any ERT clinical trial, whether intravenous or intrathecal.
  5. Clinical trials – enrollment. All ERT clinical trials should also be required to enroll both CRIM negative and CRIM positive patients if the therapy is contemplated as a treatment for both classes of patients.
  6. Prompt test results. CRIM status and antibody analysis results should be available in a timely manner, whether through internal testing by the ERT manufacturer, an outside contracted lab, or open testing. Ideally, as in infantile onset Pompe disease, CRIM status turnaround should be less than a week. Antibody testing turnaround should be less than four weeks to allow for adequate medical decisionmaking.
  7. Disclosures in clinical trials. Clinical trial participants should be apprised of CRIM and antibody results as part of such clinical trials given that it affects disease management and ongoing risks as part of the clinical trial.
  8. ERT informed consent. Disclosures related to CRIM status and antibodies should be incorporated as an important part of informed consent for ERT and should be discussed with patients/caregivers prior to ERT initiation. An immunologist, and not just a geneticist, should be part of the team assessing ERT initiation and monitoring such treatment.
  9. Pre-ERT screening. If screenings are available, patient CRIM status should be determined prior to ERT initiation.
  10. Prophylactic treatment. Prophylactic immune tolerance induction should generally be recommended for CRIM negative patients.
  11. Data compilation and analysis. Data regarding CRIM status, antibody development, and immune tolerance induction protocols and results should be compiled and analyzed, whether via a research trial or some other method.

Below is the agenda and the slide presentations from the workshop. Although you could simply walk through the presentations as they are below, I’ve attempted to categorize their perspectives thereafter in order to give a better summary of the entire workshop. I would recommend reviewing the summaries, but then also going back through each presentation as I believe they can overall give you a great education on the issue and a context for my comments.

Immune Tolerance Workshop Agenda – FDA CDER

Immune Responses and the Role of Immune Tolerance Induction in Enzyme Replacement Therapies for Lysosomal Storage Diseases: the FDA Perspective – Amy S. Rosenberg, MD

Anti-Drug Antibodies in Patients with Lysosomal Storage Disorders (LSD’s): Clinician’s Perspective – Barbara K. Burton, MD

Assessing Immunogenicity During Clinical Development: An Industry Perspective – Rekha Abichandani, MD

Pharmacologic Approaches to Immune Tolerance – Laurence A. Turka, MD

Immune Tolerance Induction in ERT to Treat Infantile-Onset Pompe Disease: Current Practice – Priya Kishnani, MD

Non-Cytotoxic, Non-Immunosuppressing Approach to Tolerance Induction During ERT Treatment – Jeanine Utz, PharmD BCOP BCPS

If you were present at the meeting or participated in the webcast and would like to comment on or correct any of my points below, feel free to comment on this post or send a private message. I’m trying to present both an accurate, albeit condensed, summary of the discussion as well as my and the community’s perspective on it. For a review of all comments, read the full transcript.

My meeting summary is broken down into commentary on background, from clinicians, immunologists, FDA, pharma, and patients.

  • Background of the Field of Immune Response/Tolerance Induction to ERT:
    • Dr. Rosenberg from FDA:
      • Comprehensive background of how immune response works generally,
      • How FDA analyzes immune response scenarios in ERTs,
      • Some example immune tolerance induction strategies,
      • How CRIM status affects immune response,
      • Conundrum of antibodies potentially affecting safety and efficacy in a negative way, but sometimes possibly positively.
    • Dr. Kishnani from Duke Children’s Hospital:
      • Summary of her long-term research on the immune response and immune tolerance induction in infantile-onset Pompe patients.
      • Current practice for that condition and how that might be applied in other LSDs.
  • Clinicians:
    • Dr. Burton from Chicago Lurie Children’s Hospital:
      • Distilled the concerns into ones of efficacy (will the drug work as well if antibodies are present?) and safety (will antibodies increase the risk of potentially life-threatening infusion-related reaction?).
      • Notably, it appears that patients with antibodies are more likely to have infusion related reactions AND patients with infusion related reactions are more likely to have antibodies but there is not a 1:1 relationship and how the relationship works has not yet been established.
      • One challenge is that antibody testing for LSDs is only available through the pharma company that makes the ERT and only on their schedule, which is often delayed.
      • In addition, where the disease course is more varied and lengthy than the very short disease course in infantile-onset Pompe disease (a few years), such as in Hunter Syndrome for example, it is difficult to assess whether the clinical efficacy of the ERT is impacted by the presence of antibodies.
      • She described an example of an MPS II patient with a complete gene deletion, thus CRIM negative, who after more than two years of ERT developed high sustained antibody titers (HSAT) (over 200,000 with 100% Nabs, IgE positive) and showed declining efficacy of ERT. Immune tolerance induction protocol was developed to include ofatumumab, methotrexate, IVIG and bortezomib for 12 weeks, then additional rounds thereafter to bring antibodies to their lowest range after 8 months.
    • Dr. Utz from University of Minnesota:
      • Spoke about an alternative immune tolerance induction protocol that did not use immunosuppressant medications.
      • Instead, it involved a dose-intensive regimen of ERT infusions spread over 2x/day, every day, plus IVIG. This protocol was based on what has been used in Hemophilia A.
      • She described its use in a CRIM negative MPS II patient who had Nabs at close to 100% for a period of one year.
      • She noted that this option might be appropriate for a patient who is more susceptible to infection risk and for whom 1-2 years is an acceptable time period for immune tolerance.
    • Dr. Kishnani from Duke Children’s Hospital, not only spoke from a researcher perspective, but also from a clinician’s perspective:
      • She noted that the Pompe patients she treats fall into one of the four following immune response categories: (1) Seronegative (never develop antibodies), (2) Downward trend (develop antibodies but continued use of ERT accompanies the antibodies reducing), (3) High sustained antibody titers (HSAT), and (4) Tolerized (use of regimen).
      • CRIM negative patients fared poorly overall and often developed HSAT (an entrenched immune response) while CRIM positive patients, although less likely, still sometimes developed HSAT.
      • Importantly, early exposure to ERT did not alter these results.
      • A very important conclusion was the learning that preventing HSAT through a prophylactic regimen in infantile-onset Pompe disease was much easier than bringing them back to a manageable level (which was sometimes unable to be done and involved prolonged immune suppression).
      • Thus, they developed a protocol whereupon diagnosis, the lab identifies the patient’s CRIM status within 2 days (ideally via western blot and mutation analysis). If the patient is CRIM negative, a 5-week prophylactic immune tolerance regimen is initiated with ERT with additional courses if needed and including monitoring of antibodies.
      • If the patient is CRIM positive, it remains questionable whether to use prophylactic immune tolerance induction.
      • The prophylactic regimen involves rituximab, methotrexate, and IVIG.
      • Patients receiving prophylactic ITI had reduced antibody status and better clinical efficacy (ventilator-free survival, left ventricular mass, survival) over ERT monotherapy.
      • ITI for entrenched immune response / HSAT involves the prophylactic regimen plus bortezomib.
      • The safety profile of the drugs involved is generally good and are at doses below that used in chemotherapeutic regimens.
  • Immunologists:
    • Dr. Turka of Massachusetts General Hospital:
      • Spoke about three methods of achieving immune tolerance: (1) antigen specific, (2) antigen non-specific where you block the signals necessary to maintain the immune response, and (3) delivering negative/regulatory signals.
      • One problem is that humans are exposed to many pathogens and have many memory T cells that cross-react to alloantigens. Memory T cells are hard to delete or suppress – a problem for entrenched immune responses to ERT.
      • He advised to treat early because memory cells are hard to eliminate and ERT is a unique opportunity to intervene before initial exposure to the antigen (ERT). Combination therapies targeting B and T cells – in particular look for what is working in antibody mediated autoimmune diseases.
      • Low-dose continuous antigen may be less immunogenic than episodic high dose therapy.
  • FDA:
    • Dr. Rosenberg of FDA:
      • Spoke about the fact that high titer antibody response, not CRIM status per se, confers a negative clinical outcome in ERT-treated Pompe patients, but that CRIM status correlates with the likelihood of a high titer antibody response.
      • She noted that the ideal immune tolerance regimen would be approaches that are highly antigen specific with consequent preservation of global immunity, but that current approaches target components of the adaptive immune response since conditions often require immediate treatment to prevent organ damage.
      • She analyzed lessons from Factor IX immune strategies such as avoidance, desensitization, and immune tolerance using potential new methods such as anti-CD20 mAb, anti-IgE mAb for IgE positive patients with anaphylaxis, and gene therapy.
      • She discussed how in rh-GAA in Pompe and elosulfase alpha in Morquio, it was possible that the inhibitory antibodies were delaying clearance of the enzyme and thus promoting efficacy but that the response was not well understood. Apparently “favorable” antibody responses are unpredictable and uncontrolled and may not be a stable condition.
      • Validated biomarkers that predict clinical efficacy of ERT and reveal impact of immune response to ERT are lacking for most LSDs. Most CRIM negative MPS 1 patients do not tolerize to laronidase over time and antibodies are associated with increased substrate levels. Tolerization in MPS 1 dogs shows increased uptake of enzyme across tissues.
      • A preponderance of evidence indicates that persistent, moderate to high titer or neutralizing antibody responses interfere with ERT uptake and/or activity in critical target tissues and thus very likely diminish efficacy.
      • Prophylactic immune tolerance regimens allow for unimpeded ERT activity, eliminate the potential for an antibody response to cause irreversible tissue damage and reduce the intensity and duration of immune suppression associated with therapeutic tolerance induction protocols
      • Given the very favorable safety experience with the prophylactic tolerance induction protocol in Pompe (worst case scenario), should tolerance induction be considered in all CRIM negative patients with LSDs?
      • Immune tolerance to ERT has additional potential benefits:
        • Reducing or eliminating immune response to potentially more highly efficacious therapies: biobetter ERT, gene therapy and exon skipping approaches to therapy
        • Establish tolerance to enzyme to diminish immunogenicity and enhance engraftment in the setting of transplant
    • Dr. Pariser of FDA: commented on the potential need for clinical studies to assess immune responses and tolerization protocols.
  • Pharma Industry: Dr. Abichandani from Shire:
    • Spoke on the perspective from the biotech/pharmaceutical industries. She discussed strategies for immunogenicity testing of ERTs during and post clinical development such as establishing a comprehensive testing scheme with frequent sampling early on in clinical trials, developing an IgE-specific assay early (before Phase II/III) to assess proven/suspected hypersensitivity, enzymatic and uptake or receptor binding neutralizing antibodies for pivotal or post approval trials, and CRIM assay when antibodies are associated with safety concerns and/or attenuation of efficacy for ERTs.
    • She discussed the host of patient-specific and product-specific factors that can potentially affect immunogenicity issues.
    • She noted that in development of ERTs, we have to consider the small orphan populations and limited understanding of genotype, enzyme deficiency and CRIM status as related to immunogenicity outcome.
    • She discussed the importance of collecting genotype data and making early interpretations as to the significance of anti-drug antibodies in the development of ERTs. One question in the early stages is to consider whether clinical response is due to the presence of antibodies or lack of efficacy of the ERT?
    • Key considerations for immune tolerance trials include assessing the level of clinical impact warranting tolerance regimens, optimal timing of such trials, choice of regimen, risk-benefit of immune tolerance regimens.
    • Some key challenges in conducting immune tolerance trials would be the small population samples, using unapproved regimens for the indication and pediatric population (labeling impact?), infection risks, timing of regimen before assessment of clinical response, and choice of regimen.
  • Patients:
    • Steve Holland, President of the National MPS Society and parent to three MPS I patients, commented on his family’s experiences with ERT and immune responses.
    • Melissa Hogan (myself) commented as a panelist on behalf of parents whose children had not undergone immune tolerance induction therapy. Specifically, I noted that the majority of physicians and LSD patients are wholly unfamiliar with this issue at all. Patients who seek to be informed are met with confusing terminology and healthcare and insurance providers who are not educated or supportive in addressing the issue. Physicians refuse to monitor substrates or antibodies, believing no correlation to clinical efficacy and/or a lack of response options. Patients are unable to make appropriate decisions given the lack of CRIM assays in most LSDs and the source and timing constraints of a sole provider (the pharma ERT developer) of antibody testing. Results are often many months delayed.
    • I also read comments from Jamie Fowler, mother to Jack Fowler, on the perspective of having undergone immune tolerance induction. Her comments inform many of the takeaways and recommendations above.

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