Updates from Type 1 Diabetes Clinical Trials: ADA 2013

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Hot off the press– my raw notes from the American Diabetes Association 2013 on immunotherapy trials in type 1 diabetes. My apologies that these are unedited and not guaranteed– but let me know if anything you see piques your interest, and I can elaborate!

Il2/Rapamycin treatment for T1D

Alice Long

  • Can T1D be treated by addressing both Tregs and Teffs at the same time?
  • Rapamycin addresses Teff, IL2 preferentially boosts Treg proliferation
  • Combo txt has been shown to cure t1d in NOD
  • Study design
    • 20 – 36 yro
    • t1d for 3 – 48 mo
    • C-peptide >= .4/pmol/ml
  • Published last year in Diabetes. Highlights here.
  • For all patients, a decline in C-peptide.
  • In fact, C-pep decreased more than control arm
  • But some rebound of C-peptide with withdrawal of therapy
  • Trial indicated that beta cell function decreased with therapy.
  • Why?
  • Tregs were increased with therapy.
    • Absolute numbers increased
    • p-Stat5 increased
    • But confirm that t1d Tregs have decreased responsiveness to Il2 in vitro
    • But that defect is repaired with therapy
    • So Tregs were doing what we wanted; what went wrong?
  • Teffs?
    • Same ratios of CD8s, NK, etc. with Rapamycin alone
    • But Il2 increases NK cells and Eosinophils
    • Combo therapy enhanced Teff responses to Il2
  • So, we boosted Treg responses. But, pleitropic effects of IL2 + Rapa in sum had pro-inflammatory effects via Teffs, NK cells, eosinophils
  • What is behind the rescue of IL2 signaling in Tregs in t1ds?
    • Isolate t1d T cells, culture ex vivo
    • Without cytokine milieu, how do they respond to Il2?
    • At day 1, and ever after stimulation, a decreased response to Il2
    • But high levels of Il2 in the culture normalize t1d and control responses
    • In conclusion, the presence of Il2 hae an effect on a cell-intrinsic deficiency of t1d Tregs
  • Were the effects of therapy specific to t1d? That is, do non-D also see increase of inflammation with Il2+Rapa? The effect seems less prevalent in non-diabetics.
  • Importantly, we see that response to IL2 in t1d can be enhanced, and it’s possible we might leverage that in other ways
  • Q: Did you look at function? How did you characterize your Tregs?
    • No functional studies, but all the classic markers. They don’t produce IFNg or IL7
    • Questioner is doubtful; can you be sure these are Tregs?
  • Q: How do you know this wasn’t just a toxic effect of rapa on beta cells?
    • Not sure– still working to rule that out
    • But recent animal studies imply this is unlikely
  • Q: Have you looked earlier? Pre-diabetic? Is that decreased responsiveness to IL2 already there?
    • We would love to do that, but have not been able to yet.

Low dose IL2 in T1D

David Klatzmann

  • Started with interest in Treg deficiency in HCV-induced vasculitis. A quantitative defect in Tregs in these patients.
  • Continued to study these patients, including treatments given for vasculitis
  • Treg recovery correlated with response to anti-viral
  • Similarly, Treg recovery correlated with responsiveness to Retuximab
  • Chicken or the egg? Is Treg deficiency a cause of autoimmunity or a response to it?
  • Try major Treg induction with Il2 in cancer patients. Failure as a trial. But noticed dramatic increases in Treg counts.
  • So can this same treatment be used for HCV-induced vasculitis? (NEJM 2011)
    • Multiple doses at 1.5-3mio UI/day
    • Well tolerated
    • Good Treg induction
    • And, clinical improvement in 8/10 patients!
  • Similar observation with low-dose IL2 in GVHD (NEJM 2011)
  • Next turn to T1D. Previously established that IL2 increases Tregs, cures t1d in NOD.
  • Effect in t1d humans? DF-IL2 trial.
  • A dose-finding, double blind, placebo controlled, randomized trial
  • First question: what dose will stimulate Tregs but not Teffs?
  • Treated 5 day course, 0.33, 1, or 3 mio UI/day
  • 24 patients, >= 18 yro
  • Not expecting clinical improvement– just looking for Treg response.
  • Safety? Very well tolerated. No serious adverse events at any dose. Some local reactions (not detected in placebo, only in some patients). Flu-like syndrome with higher doses. Considering all adverse events, more reported in placebo group overall.
  • Primary criteria: increase in Tregs. Follow for 60 days, but best response at day 6 – 10. Increase detected for all doses, dose-dependently.
  • Patient variability; some patients didn’t respond much at all, others responded quite well.
  • No marked increase in T cells across doses. At highest dose, some increase in NK cells (though NS, technically)
  • A dose-dependent effect of Il2 on Tregs at <= 1.0 MUI a day. No response in NK cells at that dose.
  • Evaluate a variety of Treg parameters– CD25, GITR, CTLA4. Seem to be increases. Increase in regulatory cytokines.
  • Notably, highest dose increases IL17 slightly. Il5 increased at early timepoint with highest dose. IFNg slightly increased with two higher doses.
  • Look at T cells response to specific beta cell antigens in vitro. Tendency for increased responses to beta cell antigens (..maybe)
  • A dose-dependent tipping of Treg/Teff balance
  • Change during treatment of C-peptide? Nothing, as for A1c. But here we’re just looking for negative effect– just a short term test.
  • Why such differences between this trial and the Rapa+IL2 trial?
    • Rapa works against anti-CD3 and Il2 in vivo
    • Rapamycin reverses curing of NOD mice with anti-CD3 or low-dose IL2
    • Mechanism still TBD. Beta cell toxicity?
  • What’s next? Multiple trials. In US:
    • Recruiting for clinical trial (NCT01862120)
    • Recently diagnosed
    • 1 year treatment
  • Q: A narrow therapeutic window. Even at a low dose, you’re dealing with a range of patients. How do you individualize this therapy so that you hit patients in exactly the right dose in exactly the right window to increase Tregs and not Teffs?
    • Even the dose of .3 is quite good in terms of inducing Tregs. But effect is shortlived.
    • But highlights that dosage is key issue. In next trial, we start lower, move up.
    • Trying to find biomarkers of Tregs and pathology is a very important effort, and we are seeking grants.
  • Q: Combine an anti-inflammatory strategy? Giving immune therapy in the presence of inflammatory milieu can have unpredictable effects.
    • We published previously that Il2 has anti-inflammatory effects on whole PBMC transcriptome
    • But supplementing is something we are considering; will have to see how this trial goes

T1DAL

Mark Rigby

  • Hypothesis: depleting peripheral mem T cells will ameliorate disease progressions, preserve beta cell mass at diagnosis.
  • Strategy: target CD2, which is preferentially expressed on Tems
  • Using Alefacept, LFA3-Ig, which binds to CD2+ T cells and deactivates, depletes
  • Developed and approved for psoriasis. Used in GVHD, some others.
  • Study design
    • 66 patients, with 2:1 drug:placebo.
    • 2 year follow-up
    • C-peptide > .25pmol/ml
    • 12 week course of alefacept, 12 weeks off, another 12 weeks on. Same as used do demonstrate durable remission in psoriasis.
    • Primary endpoint: AUC of C-peptide after 1 year
  • Recruitment
    • 19 participating centers, 14 with patients enrolled
    • January 10 2010 start, Mar 2012 last patient enrolled
    • Unfortunately, in Dec 2011, manufacturer cut off production for business reasons (not safety), so only 75% participant enrollment (49 instead of 66)
    • Groups were demographically well-matched, except that alefacept group was more evenly age distributed than control, and control was skewed male
  • Safety and tolerability
    • No serious adverse events in either arm
    • Same adverse in txt and control groups
    • Hypoglycemic event rate was statistically higher in control than txt
  • Efficacy
    • After 52 weeks, Alefacept does not have same trend down in AUC as control.
    • Change in AUC over 1yr? +0.015 in Alefacept, -0.115 in placebo.
    • Looks good on a plot, but p = .065. Not significant
    • 4h MMT AUC looks similar, but passes the threshold of statistical significance.
    • A1c not sig different
    • But insulin requirements did not increase as much over the year with Alefacept versus control (p = 0.02)
  • Mechanistic effects
    • Total CD4s: txt decreases total number, but re-increases by 52 weeks
    • Ditto for CD8s
    • Looking at percentage of naive, memory (central and eff) with flow, relative increase in naive cells versus memory in txt arm, for both CD4 and CD8
    • Tregs seem better retained in txt versus control arms.
  • Conclusions?
    • Seems to have effects, but unclear if that is because of statistical power rather than biology for primary endpoints
    • But two secondaries met–> much promise for preserving beta cell function
  • Q: Compare your results to other studies. How does it look?
    • We have done so. Our preservation looks better.
    • Also, our placebo groups seem to be declining less than others–> could affect our ability to differentiate

Anti-thymocite gloculin in New Onset T1D (START Trial)

Stephen Gitelman

  • Anti-thymocyte gloculin (ATG).
  • mAbs have had some success directed at T1d. ATG is a polyclonal approach.
  • ATG is used in a number of therapies. Create rabbit polyclonal Abs to human thymocytes
  • Induces lasting remission in t1d
  • Useful in inducing “partial” tolerance in transplantation
  • Early studies in t1d? Pilot by George Eisenbarth in 1985, follow up by Saudek in 2004
  • Mechanisms?
    • T cell depletion. But this would be transient.
    • Modulation and/or anergy of remaining T cells?
    • Induction of Tregs?
  • Study design
    • 66 subjects, 12 – 35 yro
    • Within 100 days of t1d
    • Peak C-peptide > 0.4 pmol/ml
    • Had to have prior evidence of EBV infections
    • 4 day infusion. 6.5mg/kg total dose.
    • Txt group only has pre-txt with steroids. (Why not control?)
  • 58 enrolled, 38 in txt, 20 to placebo
  • Adverse events
    • Every subject reported at least one, txt and placebo.
    • But more in txt group.
    • 37/38 had cytokine release syndrome, all 38 had serum sickness
    • Increase in infections and infestations in txt
    • Notably, txt group received antimicrobials for 3months until cd4s were replenished.
  • Efficiency
    • Nope. The same endpoint
    • But maybe biphasic? Steady decline with placebo, but fast down then steadying with txt?
  • But why this change in response? Maybe cytokine release syndrome? Abrupt increase in IL6, etc. increases inflammation, disease progression, but then this normalizes by 1 month?
  • Comparing T cell subsets
    • Overall, initial acute depletion followed by reconstitution. Not normal yet at 12mo
    • CD8 slightly faster than CD4 at reconstitution
    • Tem not affected significantly by ATG
    • Tregs? A profound initial decline and very slow recovery, especially as compared to other T cells.
  • Slice and dice patient groups?
    • Maybe effective in age 22 – 35? Stabilization from baseline without initial decline?
    • Seems that young patients decrease C-pep rapidly first then stabilize, but older stay stable.
    • Why might this be? Age? Our ability to regenerate immune cells decreases with age.
    • Indeed, it seems that the young populations are recovering CD4, CD8, B cells, etc more rapidly
  • Conclusions
    • A warning about extrapolating from NOD to man.
    • Response appears to be dependent on age. This is different from other recent onset studies where younger subjects seem to fare better.
    • Subjects will be followed out to month 24. How long will that stabilization last?
  • Mechanisms behind decline of beta cell functions initially?
    • Nonspecific activation because of serum response, cytokines
    • Persistence of Tem following ATG
  • What’s next?
    • Try to identify responders versus non-responders
    • Compare changes to related trials to evaluate differing responses
    • Combo therapies? ATG + IL6 blockade, or with GCSF?
  • Q: The effect on Tem was unexpected. Is there any other data that supports those findings? A: Yes, there seems to be corroboration from transplant studies.
  • Q: How much steroids did you use? Effect of that?
    • 1mg/kg prednisone per day
    • Plus others, for 7 days
    • WHy not in control? Regulatory agencies guided them to not doing so.

Combo ATG-GCSF in Established and New Onset T1D

Mike Haller

  • Given the effect of ATG just talked about, our rationale for using low-dose ATG plus GCSF
  • An ongoing clinical trial, so no efficacy/patient data
  • But some mechanistic findings so far
  • Current trials in established t1ds; planning new onset
  • To date, no mono or combo therapy that provides long-term preservation of beta cell function.
  • Anti-CD3 (Teplizumab) study shows early differences, but then slope is the same; a delay, but then the txt arm catches up eventually.
  • What amount of risk are we willing to tolerate to generate the benefit we want to see?
  • Extreme combo therapy: the Brazil approach
    • Cyclophosphamide + GCSF + stem cell harvesting. Deplete and replace.
    • 20 of 23 subjects became insulin free for 1 month, 12 for 14 – 52 months (average 2.5 years)
    • A1c < 7% and AUC c-pep increases after 24 months
  • But that’s major. Brazil light?
  • ATG + GCSF cure in NOD
  • GCSF?
    • Many mechanisms
    • Mobilizes DCs (tolerogenic)
    • Induces Tregs (?)
    • Skewing cytokine profile to tolerogenic
    • But doesn’t work as a monotherapy to preserve c-peptide. But is tolerated well.
  • Funded entirely by the Helmsley trust. Unique in that it was intentionally designed to addressed established disease.
  • Combo trial performs better along many mechanistic endpoints
    • Total CD4+CD8 T cell counts go lower with ATG alone
    • ATG alone reduces Tregs; combo maintains Tregs
    • ATG depletes naive; combo maintains naive
    • Combo induces transient increase in Treg/Teff ratio
  • Very preliminary data! But not the same as high-dose ATG therapy.
  • New onset trial
    • Randomized, 1:1, with 80 subjects.
    • Low dose (2.5mg/kg) ATG
    • 80% power to detect 60% duff in AUC of c-pep
    • Over-enroll by 10 people to mitigate loss due to dropout
  • Results to come. But actively discussing the parameters for the next clinical trial.

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