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Home / Specialties / Dermatology / ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #10: Interdiction, Part 2 of 3

ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #10: Interdiction, Part 2 of 3

Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor

ADA-JDRF-Type-1-Diabetes-Sourcebook-image

Interdiction: Prevention of Beta-cell Destruction and Preservation for Those with Existing Type 1 Diabetes

Jane Lee Chiang, MD, and Stephen E. Gitelman, MD
Anti-Inflammatory Agents

European Nicotinamide Diabetes Intervention Trial (ENDIT). Like DPT-1, ENDIT represented a concerted European effort to screen over 30,000 individuals to identify first-degree relatives with autoantibodies and normal beta-cell function.12 Investigators enrolled subjects in a randomized, double-blinded, placebo-controlled trial. Rather than an antigen-based approach, the trial evaluated nicotinamide, which has demonstrated efficacy in T1D animal models and in smaller pilot studies. Nicotinamide presumably acts as a scavenger of a favorable safety profile but failed to document an effect, possibly due to insufficient doses, its use at a later stage in autoimmune destruction, or its inability to effectively block autoimmunity….

Immunosuppressants

Anti-CD3: Teplizumab. TrialNet has recently launched a study utilizing an immunosuppressant, teplizumab, a mAb directed against the CD3 portion of the T-cell receptor, for the highest-risk members of the prevention group, with ≥2 autoantibodies and dysglycemia (see Preservation section). This approach has shown early initial success in new-onset T1D trials. Subjects in this risk category are considered to be one step upstream from T1D, and the hypothesis is that earlier intervention may result in even greater efficacy than seen with this agent in new-onset T1D (NCT01030861).

Future Considerations

In the preceding decades, investigators have clearly delineated algorithms to identify populations at risk for T1D. Much of this work has centered on first-degree relatives, yet the majority of new-onset T1D cases occurs in families without a positive family history. At some point investigators will need to shift the focus to the general population. Initial screening to identify high-risk genotypes, as done by the Finnish study group in the intranasal insulin prevention trial, is a means to identify this higher-risk population, although more diverse populations like the U.S. may require additional modifications for race and ethnicity.13,18

There is a high hurdle for conducting T1D prevention trials. Earlier interventions may have the greatest chance to prevent T1D development. However, predicting disease requires conducting larger trials over longer time periods. Therefore, it is critical to ascertain, prior to study initiation, that the time and expense are warranted. Toward that end, one would expect to see preclinical studies and pilot studies that indicate convincing rationale in both safety and feasibility, although as noted from past trials, there is no guarantee of success.

The next iteration may require a different tack, with smaller trials utilizing surrogate measures as an end point rather than using T1D onset. The benefits include reducing trial size and time required to evaluate a particular therapy. These measures may be tailored to a particular therapy, such as an immunologic change that is predicted to lower disease risk. Studies have defined a risk score from DPT-1 data incorporating body mass index (BMI), age, fasting, and stimulated C-peptide from 2-h OGTT that may also be useful in evaluating incremental change before progression to overt T1D.19,20 Further analysis from the TrialNet natural history study may define possible intermediate end points that could be employed for early prevention trials, reducing sample size and trial time (Krischer, Diabetologia, under review). Two-year changes in A1C and C-peptide from baseline, along with progression to abnormal OGTT and dysglycemia all appear to be promising. Changes in autoantibody status (such as number of anti-bodies, the particular antibody profile present, and titer) may also be helpful in marking progression along the continuum toward T1D. Surrogate measures that reflect other changes in immunological status, such as changes in T-cells, have proven elusive to date.

The other notable feature of prevention trials is that they have employed a single arm vs. comparison to a placebo or control group. Future studies may benefit from multiple arms, testing a range of doses for a particular agent, or evaluating a variety of other agents while all utilizing a single control group. The studies may benefit from incorporation of an adaptive or factorial trial design.

New Approaches for T1D Prevention

Those therapies that have proven safe and effective in new-onset T1D are obvious and logical considerations for use just upstream for those at high risk for developing T1D, such as the anti-CD3 mAb. For these reasons, CTLA4 Ig (Abatacept) is also being considered for use in a prevention trial. However, those agents that have not proven effective in new-onset T1D may still be worth considering for use earlier in the autoimmune process, as has been the case with oral insulin. Furthermore, not all therapeutics to be considered for diabetes prevention need to be necessarily evaluated first in new-onset T1D, although use in those with recent-onset or established diabetes may help determine if there are any unique safety or tolerability issues in this particular disease.

Antigen-based therapies will continue to be carefully considered for prevention trials. The challenge with antigen-based therapies lies in optimizing the administration route, dosing frequency, and adjuvant use; selecting the best antigen(s); and determining the best intervention time in the disease process. In evaluating insulin, for example, parenteral, oral, and intranasal, exposure has been utilized, and consideration has been given not only to the whole processed molecule, but also to proinsulin, B-chain, and peptide fragments that are considered to be of greatest relevance in the autoimmune response. Some of the groundwork has been laid in new onset trials. For example, insulin B-chain in incomplete Freund’s adjuvant (IFA) and administered intramuscularly may induce a regulatory T-cell population (NCT00057499).21 The safety and efficacy of a proinsulin DNA vaccine in T1D, with an intramuscular injection of a plasmid carrying proinsulin (NCT00453375), has been evaluated. Finally, investigators have identified peptide fragments from the insulin molecule that activate autoreactive, cytotoxic T-cells.22 A cocktail of such peptides may be utilized in a future prevention trial. Other antigens, such as GAD and Hsp60 (Diapep277) may also have efficacy in T1D prevention (see Preservation section).

Aside from antigen, various other approaches are being considered. These include anti-inflammatory drugs. Even though IL-1 blockade was not effective in new-onset T1D (see Preservation section), use earlier in the course of the autoimmune process may prove effective. There is also interest in non-steroidal anti-inflammatories and further assessment of omega-3 fatty acids, possibly in combination with vitamin D. Nonspecific immunostimulants, such as OM85 and BCG, could also prove effective. Emerging evidence links the intestinal micro-biome with mucosal immunity and T1D risk. Probiotics, helminthes (such as trichuris suis ova), and even lactobacillus modified to over-express IL-10 may alter T1D risk.23 As noted with antigen-based therapies, optimizing dose, frequency, and timing of administration in the disease course will be necessary for success. It may be that a combination of drugs working by different mechanisms is necessary to accomplish the task. Investigators will continue to closely monitor advances in related autoimmune diseases and transplantation, in search of therapies that warrant assessment in T1D prevention.

III. PRESERVATION

Preservation trials focus on halting further pancreatic beta-cell destruction after T1D diagnosis. At the time of diagnosis, it has been estimated that 15–40% of beta-cell function remains. However, this remnant can serve one well while it lasts, as evidenced by better overall glycemic control during this remission or honey-moon phase, with lower A1Cs, less glycemic variability, and less hypoglycemia risk. For several decades, investigators have attempted to define a safe and effective means to preserve beta-cell function following diagnosis. However, intervening late in the process poses the challenge of daring to be aggressive enough to arrest further destruction while finding an intervention that is safe and tolerable. In those with long-standing disease, such therapy could be used in conjunction with a beta-cell replacement strategy: even if replacement islets are generated from host stem cells, one must control the chronic autoimmune response to enable long-term cell survival. Over the past few decades, numerous agents have been evaluated with varying levels of success, with many efforts conducted with smaller number of subjects and often lacking a contemporaneous control group. A subset of these efforts is reviewed herein, with a focus on the well-powered randomized, placebo-controlled studies.

Antigen-Based Therapies

Antigen-based therapies have yielded disappointing results in new-onset T1D patients. Given its known role as a primary antigen in the NOD mouse and in humans, it is not surprising that various forms of insulin as an antigen- based therapy have been attempted in new-onset T1D studies. While some have shown early promise after disease onset, no large, placebo-controlled study has shown efficacy to date (reviewed in Prevention section). Animal studies and pilot human clinical studies with glutamate decarboxylase (GAD) were promising, but subsequent phase II and III trials have shown no effect.24,25 As with the insulin antigen experience, there may be numerous reasons for the negative findings to date and opportunities to optimize responses. These include 1) antigen use earlier in the course of disease (as a preventive measure), 2) use of specific peptides vs. whole molecules, 3) an alternate dose or frequency of antigen administration, 4) an alternate route of administration, or 5) use of an alternate adjuvant to improve efficacy.

Diapep277, an epitope of heat shock protein 60, is another antigen that may be involved in autoimmune responses against the beta-cell, though it does not appear to be one of the primary initial targets. Phase II trials showed mixed results with statistically significant preservation of -1-cell function in adults but not in children, and there was no change in A1C and insulin requirements.26 Results from a recently completed randomized, double-blind, phase III trial for adults with new-onset T1D reached the primary outcome, showing modest improvement in glucagon stimulated C-peptide at 24 months for the treated group, with improvement in some secondary measures of metabolic control (A1C, insulin use, hypoglycemia frequency), yet there was no difference in stimulated C-peptide on MMTT between the two groups (NCT01103284).27 A follow-up phase III trial will soon be underway to confirm these findings. None of the Diapep277 trials has raised any safety concerns.

Anti-Inflammatory Agents

Beta-Cell destruction may result from inflammation as well as autoimmunity, and thus another approach to preserving beta-cell function is through use of anti-inflammatory agents. Recent focus has centered on responses generated by the innate immune system, and IL-1 has been implicated as a primary proinflammatory cytokine and mediator of beta-cell destruction. A TrialNet-sponsored phase II new-onset T1D clinical trial with the IL-1beta receptor antagonist canakinumab failed to demonstrate efficacy in the initial analysis of the primary end point at 1 year (NCT00947427) (Moran, submitted manuscript).28 Similarly, a phase II/III study with the IL-1 receptor antagonist anakinra also failed to reach the primary end point (NCT00711503) (Mandrup-Poulsen, TR, submitted manuscript). As with other therapies, it may be that dosing earlier in the course of autoimmune destruction is needed and may have efficacy in T1D prevention. In addition, IL-1 blockade in combination with an immunomodulatory drug such as anti-CD3 may offer synergy and prove effective in new-onset T1D. This combination has proven highly effective in NOD mice with new-onset T1D.29

Another anti-inflammatory approach of interest is utilizing α-1 anti-trypsin. Once again, this approach appeared promising in the NOD mouse. An ITN-funded, initial lead-in, dose-finding study has been conducted for adults and children with recent-onset T1D, and plans are underway for a phase II, placebo-controlled, randomized, new-onset T1D trial to follow (NCT01183468). Encouraging results have also been noted in independent smaller phase 1 trials conducted by P. Gottlieb et al., and by Y. Lebenthal et al. in Israel.

Immunosuppressants

Cyclosporine. Immunosuppression is capable of halting beta-cell destruction, as demonstrated by a series of early studies with cyclosporine.30,31 This drug is a general immunosuppressant that has been used widely in transplantation and suppresses humoral immunity but is even more effective against T-cell–dependent mechanisms. In the 1980s and 1990s, a series of clinical trials demonstrated clinical efficacy in new-onset T1D, but important limitations were noted. Not all treated subjects responded, and for those who did, continuous therapy was required. Furthermore, cyclosporine may be hepato and nephrotoxic, and continuous immunosuppression may confer risk for infection and possibly cancer. Thus, while cyclosporine established proof of principle, it has not become a viable standard therapy for preserving beta-cell function. Following these studies, further trials with immunosuppression were relatively quiescent as investigators sought novel, more targeted therapies, especially those not requiring continuous use.

Anti-CD3 monoclonal antibodies. One novel approach has been to block activation of potentially autoreactive T-cells (see chapter 2), which occurs following interaction between T-cells and antigen-presenting cells (APCs), via the T-cell receptor and costimulatory receptors at the immunologic synapse with antigen peptide/major histocompatability complex (MHC) and costimulatory molecules from APCs (Figure 3.1). Investigators have utilized a mAb that targets the CD3-ε subunit of the T-cell receptor, thereby altering the primary signaling between T-cell and APC. This approach exhibited remarkable findings in the NOD mouse, where a short-term course of antibody induced lasting remission in mice with new-onset diabetes. Investigators have since modified the parent OKT3 antibody in two ways to make a better-tolerated product for humans. These products are teplizumab (hOKT3γ1 (Ala-Ala)) and otelixizumab (ChA-glyCD3).

In an initial phase I/II trial, it was noted that a single 14-day course of teplizumab administered within 2 months of diagnosis preserved beta-cell function in treated subjects out to 1 year, as opposed to ~50% decline for those in the open-label control group.32 However, beyond 12 months the effect appeared to wane, although there was a statistically significant difference between treated and control subjects at 24 months, with long-term follow-up demonstrating persisting effects even at 5 years.33,34 Related findings were seen with otelixizumab, in which a single 8-day course preserved beta-cell function.35 More extensive long-term follow-up confirmed beta-cell preservation up to 4 years after the treatment was received.36 Side effects from teplizumab have generally been mild, consisting of a flu-like reaction and skin rash in ~50%, with a much smaller percentage having a more marked cytokine release syndrome that necessitates early drug termination; somewhat greater side effects have been noted with otelixizumab, including transient Epstein-Barr viral reactivation in some subjects.

These initial observations have galvanized the field, and spawned a series of downstream trials with these drugs, and related approaches. The phase II AbATE trial evaluated the efficacy of a second course of teplizumab given 12 months after the initial dose (Herold, manuscript submitted, Lancet 2012). The trial achieved the primary outcome at 24 months, with loss of C-peptide delayed by 15.9 months, on average, in treated versus control subjects. In the post-hoc analysis, the treated subjects could be divided into two discrete groups: 45% of the treated subjects were considered responders, showing virtually no change in C-peptide by 24 months, whereas the remaining 55% were nonresponders, and were not distinguishable from controls, with progressive C-peptide loss of more than 40% at 24 months. One would ideally hope to determine why the drug works in some people but not others, and have a means to predict those more likely to respond. Analysis to date suggests that, at baseline, responders exhibited reduced frequencies of peripheral Th1-like T-cells as well as lower A1C levels and exogenous insulin use. Responders are also less likely to develop antidrug antibodies.

The Protégé trial was a similar industry-sponsored phase III placebo-controlled trial to evaluate the efficacy of teplizumab administered at baseline statistical significance for the composite end point (A1C <6.5% and exogenous insulin use <0.50 units/kg/day). However, the trial did achieve similar effects in preserving beta-cell function to that observed in the aforementioned AbATE study: those enrolled earlier in their disease course, at younger ages, and treated in North America all appeared to have more favorable outcomes. The Protégé trial also evaluated dosing with several treatment arms, and the original full 14-day course of teplizumab was shown to be more effective than lower drug doses. Based on these promising findings in new-onset subjects, TrialNet launched a prevention trial with teplizumab (as mentioned in the Prevention section) (NCT01030861).

The phase III DEFEND trial evaluated the related anti-CD3 mAb, otelixizumab, electing to use a significantly lower dose to minimize side effects. There were no significant safety concerns, but the study failed to meet its primary efficacy end point of preserving C-peptide at 12 months in new-onset T1D subjects (www.gsk.com).37

Anti-thymocyte Globulin (ATG). Based upon the successful anti-CD3 mAb approach, investigators have postulated that a polyclonal antibody approach against T-cells may have even greater efficacy. In the NOD mouse, ATG is one of the few drugs that can induce a lasting remission for animals with recent-onset disease.38 Although ATG is an effective T-cell depleting agent, that effect alone would not account for its lasting effects in T1D, as T-cells repopulate quickly via a mechanism called homeostatic proliferation. ATG may also foster induction of regulatory T-cells, and animal models suggest that G-CSF may enhance this effect. Several smaller clinical pilot studies with ATG alone have suggested that this approach may be effective.39–41 The most successful approach to date in any of the new-onset T1D trials has come from combination therapy conducted in Brazil, with an aggressive attempt at immunological “re-booting” using an autologous nonmyeloablative hematopoietic stem cell transplant procedure.41 Subjects were initially pretreated with cyclophosphamide and then G-CSF to mobilize a hematopoietic stem cell population. The emerging CD34+ bone marrow precursors were harvested and stored. The subjects were allowed to recover and then returned for an immune ablative conditioning regimen with ATG and cyclophosphamide. They received an infusion of their previously harvested cells and were then observed over time. Twenty of 23 subjects were able to discontinue insulin, 12 for a mean of 31 months. Some have remained off insulin with euglycemia for over 4 years. Side effects included infusion reactions, reports of azospermia, and opportunistic infection. Small follow-up studies (again open label, without a control group) have been conducted in China and Poland with this protocol, validating these findings.42,43

While this trial yielded impressive metabolic effects, many investigators remain concerned that the associated risks do not justify this approach for more widespread therapy. Investigators are now deconstructing the cocktail of ATG, G-CSF, and cyclophosphamide used in the Brazil study, with phase II recent-onset T1D trials evaluating ATG alone (NCT01106157), G-CSF alone (NCT00662519), and ATG plus GCSF (NCT01106157) to determine if an equally efficacious but safer approach is attainable.

Costimulatory Blockade

CTLA4 Ig (abatacept). Following on the heels of the anti-CD3 mAb successes, investigators have pursued trials with other drugs that provide co-stimulatory blockage of the interactions between APCs and T-cells, targeting secondary pathways. A phase II, double-blinded, randomized, placebo-controlled trial with CTLA4 Ig (abatacept) in new-onset T1D showed a 9.6-month delay in beta-cell decline in the treated versus control group, although therapy was provided continuously over a 24-month period (NCT00505375).44 Follow-up out to 3 years, with 1 year of observation off therapy, showed that beta-cell function did not deteriorate at an accelerated rate in the treated group, with C-peptide decline in the treated group parallel to that of the control group and a statistically significant difference remaining between the two (Orban et al, Lancet, submitted 2012). It remains unclear why the treatment effect did not persist beyond the initial 9.6-month period. A T1D-prevention trial is being planned with abatacept, as earlier intervention may prove even more effective, and overall there was a favorable safety and tolerability profile in those with recent onset T1D (see Prevention section).

 

LFA-3 Ig (alefacept). Another approach with costimulatory blockade is an ongoing ITN-sponsored phase II new-onset T1D trial with alefacept (LFA-3 Ig, Amevive). This drug binds CD2, which is expressed on the T-cell surface, and blocks interactions with the costimulatory molecule LFA-3 on APCs and thereby interferes with activation and depletes autoreactive memory T-cells. This approach has proven quite effective and well tolerated in psoriasis patients, and may have long-term tolerizing effects when therapy is withdrawn (NCT00965458). The study has completed enrollment, and results are expected soon.

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