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703 Gut-Homing CD4+ Lymphocytes Are Specifically Targeted in Cynomolgus Monkeys Dosed with Anti-Beta7 Antibodies
rates, -11.2, 1.9). Both doses also provided efficacy in secondary endpoints: clinical remission; rectal bleeding, stool frequency, and sigmoidoscopy improvement. Evidence of a therapeutic advantage of 4.8g/d was seen in patients with a clinical history of more difficult to treat disease as evidenced in the Table below: The 4.8g/d dose was well tolerated and had a safety profile comparable to 2.4g/d. Conclusion: In this study, delayed-release mesalamine 4.8g/d (800mg tablet) was shown to be efficacious and well tolerated in patients with moderately active UC. Treatment Success (ITT Set to Failure) at Week 6
*including oral 5-ASAs, rectal therapies, steroids, or immunomodulators 703 Gut-Homing CD4+ Lymphocytes Are Specifically Targeted in Cynomolgus Monkeys Dosed with Anti-Beta7 Antibodies Franklin Fuh, Clarissa David, Olivia Hwang, Shweta Gadkari, Quyen Nguyen, Chikara Takahashi, Jeffery Lutman, Khanh Pham, Anahid Storn, Kathleen Howell, Karen Berry, Sharon O'Byrne, Dimitry M. Danilenko, Thomas Gelzleichter, Hong Wang, Eric Stefanich, Marna Williams rhuMAb Beta7 is a humanized anti-human integrin β7 monoclonal antibody that binds the integrins αEβ7 and α4β7. Cells that express these integrins have been associated with inflammatory diseases of the gut such as ulcerative colitis. rhuMAb Beta7 is being investigated as a potential therapeutic for immune system-mediated diseases such as inflammatory bowel disease. To investigate safety, pharmacokinetics (PK), and pharmacodynamics (PD) of rhuMAb Beta7, studies were conducted in cynomolgus monkeys. In one study, rhuMAb Beta7 was administered intravenously (IV) at 5 or 25 mg/kg in 4 weekly doses. The second study involved 12 weekly doses of rhuMAb Beta7, administered intravenously at 5, 15, or 50 mg/ kg, or subcutaneously at 15 or 50 mg/kg. Elevation of peripheral blood CD45RA-β7high CD4+ lymphocytes (phenotypically similar to gut-homing cells) was used as a PD biomarker. In each of these studies, group mean absolute numbers of peripheral blood CD45RAβ7high CD4+ lymphocytes increased approximately 3 to 6-fold over baseline levels following administration of rhuMAb Beta7. In contrast, animals dosed with vehicle showed no substantial changes in group mean numbers of peripheral blood CD45RA-β7high CD4+ lymphocytes. CD45RA+β7int CD4+ lymphocytes (phenotypically similar to naïve cells) and CD45RAβ7low CD4+ lymphocytes (phenotypically similar to peripheral-homing cells) showed no substantial differences in cynomolgus monkeys dosed with vehicle or rhuMAb β7. In addition, β7 receptors on peripheral blood T cells appeared to be fully saturated following the first of 4 weekly doses of 5 or 25 mg/kg rhuMAb Beta7. Furthermore, loss of receptor occupancy correlated with return to predose levels of CD45RA- β7high CD4+ lymphocytes. The PD observed in cynomolgus monkeys appeared to be related to PK because the observed reversibility and return to baseline of the PD effects correlated with clearance of rhuMAb Beta7.Variability in the rate of return of PD effects between animals in the same dose groups correlated with changes in clearance of rhuMAb Beta7, which was associated with the presence of anti-therapeutic antibodies in some animals. These results are consistent with the proposed mechanism of action of rhuMAb Beta7: inhibition of homing of β7 positive lymphocytes to the gut, through blocked α4β7 binding to its ligands. This mechanism is expected to lead to accumulation of CD45RA-β7high CD4+ lymphocytes in the peripheral circulation, as observed in both the 4-week and 12-week studies. Based on the preclinical data, rhuMAb Beta7 exhibits encouraging PK, PD, and safety profiles that support clinical development for potential treatment of IBD.
701 A Randomized, Double-Blind, Placebo-Controlled Trial of a Probiotic Preparation, Vsl#3, for the Treatment of Mild to Moderate Active Ulcerative Colitis Govind K. Makharia, Ajit Sood, Vandana Midha, Vineet Ahuja, Dinesh K. Singal, Reenu Arora, Shaman Sood, Pooja Goswami, Claudio De Simone, Aditya R. Sahu, Rakesh K. Tandon Background: Treatment with probiotics has been shown to be effective in maintenance of remission in patients with Ulcerative Colitis (UC). The role of probiotics in induction of remission in patients with active UC remains to be determined. Objectives: To assess the safety and efficacy of a probiotic preparation VSL#3 in the treatment of mild to moderate active UC. Methods: A randomized, double-blind, placebo-controlled multicentric study involving 3 centers was done recruiting 147 adult patients with UC. Patients with mild to moderate UC on oral 5-ASA were randomized to receive orally either 2 sachets twice daily of VSL#3 (900 billion CFU per sachet; Group A, 77 patients) or placebo (Group B, 70 patients). The duration of treatment was 12 weeks. The primary endpoint was a decrease in Ulcerative Colitis Disease Activity Index (UCDAI) scale of 50% or more from baseline at week 6. The secondary endpoints included attainment of remission after 12 weeks, changes in individual UCDAI parameters and a decrease in UCDAI of 3 points or more from baseline at 12 weeks. A per protocol analysis was done. Results: The mean age of the patients was 39.1 ± 12 yrs (Male 59.9%). 56.9%, 44.7%, 52.9% in Group A and 43.1%, 55.3%, and 47.9% in Group B had procto-sigmoiditis, left sided colitis and pancolitis, respectively. Fifty five patients in Group A and 29 patients in Group B completed entire duration of the study. Significantly higher number of patients in group A showed improvement in UCDAI score by 50% at 6 weeks as compared to those who received placebo (41.7% vs. 17.9% patients in VSL#3 group as compared with the placebo group (72.7% vs. 41.9% patients p 0.005). There was a significant decrease in the stool frequency and rectal bleeding score, mean endoscopic score and physician's global assessment score both at 6 weeks and 12 weeks in VSL#3 group as compared with the placebo group. There was a significant decrease in UCDAI at 12 weeks in those who were in VSL#3 group in comparison to placebo (5.8+1 to 2.1+1.8 vs 6+1.4 to 3.7+2.9, p 0.001). There was no difference in the two groups in attaining remission at 12 weeks (56.4% vs. 38.7%, p 0.1). Six patients in VSL#3 and 7 in placebo group had mild side effects. Conclusions: VSL#3 is significantly better than placebo in improving activity of ulcerative colitis at 6 weeks as well as at 12 weeks. There was however, no difference in the remission rates in the 2 groups at 12 weeks. Significant improvement was seen in subjective symptom scores like stool frequency score and rectal bleeding score as well as the endoscopic score.
704 A Phase 1 Open-Label, Single-Dose, Dose-Escalation Study of Mdx-1100, a High-Affinity, Neutralizing, Fully Human Igg1κ Anti-CXCL10 (Ip10) Monoclonal Antibody, in Ulcerative Colitis Robert Hardi, Lloyd Mayer, Stephan R. Targan, Michael Yellin, Pina M. Cardarelli, Kiron M. Das Background: Chemokines play key roles in regulating mucosal inflammatory cell trafficking in Crohn's disease, ulcerative colitis (UC) and other inflammatory diseases. Inhibition of the chemokine CXCL10, an IFNγ induced chemokine, abrogates colitis in some murine models. Mucosal expression of CXCL10 and its cell surface receptor, CXCR3, are markedly upregulated in inflammatory bowel disease (IBD). Therefore, CXCL10 neutralization may have therapeutic potential in the treatment of IBD. Methods: The primary objective of this open-label, dose-escalation study was to evaluate the safety of single doses of MDX-1100 in patients with UC flaring (UCDAI of 4-9) on stable doses of standard therapy and off anti-TNF therapy for at least 8 weeks prior to the study. Cohorts of 3-6 patients were administered a single infusion of MDX-1100 at doses of 0.3, 1.0, 3.0, or 10 mg/kg and were followed for at least 70 days post infusion. Decrease in the UCDAI by ≥ 3 points at Day 29 compared to baseline was considered a response. Responders were permitted up to 3 additional MDX-1100 infusions at the time of relapse. Peripheral blood mononuclear cells and colon biopsy specimens were studied for expression of CXCL10 and CXCL10-induced proteins. Serum anti-MDX-1100 antibody responses and MDX-1100 concentrations were determined by ECL and ELISA, respectively. This study was approved by the appropriate Investigational Review Boards. Results: To date, the 0.3 (n=3), 1.0 (n=4) and 3.0 (n=4) mg/ kg cohorts have been completed and the 10 mg/kg cohort (n=1) is actively enrolling. MDX1100 has been well tolerated. No drug related adverse events have been reported. There has been 1 SAE; a patient in the 3.0 mg/kg cohort admitted to the hospital for anemia and
702 Efficacy and Safety of Delayed-Release Oral mesalamine At 4.8g/D (800mg Tablet) in the Treatment of Moderately Active Ulcerative Colitis: Results of the Ascend III Study William J. Sandborn, Jaroslaw Regula, Brian Feagan, Elena A. Belousova, Njegica V. Jojic, Milan -. Lukas, Bruce R. Yacyshyn, Piotr Krzeski, Chyon-Hwa Yeh, Stephen B. Hanauer Purpose: To confirm the clinical benefit of delayed-release mesalamine 4.8g/d using an investigational 800mg tablet by comparing its efficacy to that of 2.4g/d (marketed Asacol 400mg tablet) for the treatment of moderately active ulcerative colitis (UC). Methods: ASCEND III was a Phase III, 6-week, double-blind, randomized, multi-national, activecontrol study designed to assess the non-inferiority of 4.8g/d (800mg tablet) versus 2.4g/d (400mg tablet) in patients with moderately active UC (Physician's Global Assessment [PGA] of 2). The primary endpoint was treatment success defined as improvement from baseline at 6 weeks in the PGA (which was based on the clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy) and no worsening in any of the individual clinical assessments. Results: A total of 772 patients were randomized and dosed. The primary objective of non-inferiority was met and treatment success was achieved in 70% (273/389) and 66% (251/383) of patients receiving 4.8g/d and 2.4g/d, respectively (95% CI for 2.4 - 4.8 success
A-99
AGA Abstracts
AGA Abstracts
role of Ucns and CRF receptors in GI diseases is unclear. Aim: To evaluate the contribution of CRFR2 to inflammation, using a murine model of Crohn's colitis, and to test whether Ucn1 exerts its anti-inflammatory effects via CRFR2. Methods: An intracolonic enema of trinitrobenzene sulfonic acid (TNBS) was used to induce colitis in male C57 mice. An enema of vehicle was given to control group. First, the effect of TNBS was evaluated on the mortality rate and severity of colitis in wild type mice (Wt), CRFR2-/- (KO), and CRFR2+/- (Ht) mice. Second, Ucn1 was given (ip) when TNBS colitis was induced, to test whether Ucn1 could still exert its anti-inflammatory effects and ameliorate colitis in CRFR2 KO mice. Results: At a 5 mg dose of TNBS, resultant colitis in Wt C57 mice caused a ~20% mortality rate 2 days after injection of TNBS. Surprisingly, 5 mg of TNBS did not cause any mortality in CRFR2-/- KO mice. In contrast, TNBS resulted in over 60% mortality rate within 3 days of TNBS injection in CRFR2+/- micE. colitis resulted in marked shortening of colon length in from 8.4±0.16 cm (controls) to 6.1±0.27 cm, p<0.05 (Wt), and the length was further shortened in KO and Ht mice to 5.6±0.2 cm. Adrenals were hypertrophied in mice with colitis, weighing twice as much as control adrenals. Colitis significantly increased histologic damage seen in H&E stained colon tissue of Wt and CRFR2 KO or Ht mice. Ucn 1 injection did not alter the mortality rate in Wt or KO mice with colitis, whereas Ucn1 dramatically rescued CRFR2+/- mice with colitis; none died until the experiment ended. This increase in survival rate was accompanied by significant improvement in colon histology as seen in H&E stained sections from CRFR2+/- mice. MPO levels were significantly decreased in Wt and Ht mice treated with Ucn1+TNBS (1.53±0.3 and 2.4±0.9 mU/mg) compared with KO Ucn1+TNBS mice (7.9±1.9 mU/mg, p<0.05). Interestingly, adrenal weights of CRFR2+/mice treated with Ucn1 were comparable to control levels, whereas adrenal weights remained elevated in Wt and KO mice treated with Ucn1. Conclusions: Perturbations in the CRFR2 receptor expression levels dramatically alter mice' ability to handle acute inflammatory stress. Complete lack of CRFR2 probably results in major developmental compensatory changes that enable the KO mice to better survive acute inflammatory stress. Supported in part by Hellman Foundation award to AB.
*including oral 5-ASAs, rectal therapies, steroids, or immunomodulators 703 Gut-Homing CD4+ Lymphocytes Are Specifically Targeted in Cynomolgus Monkeys Dosed with Anti-Beta7 Antibodies Franklin Fuh, Clarissa David, Olivia Hwang, Shweta Gadkari, Quyen Nguyen, Chikara Takahashi, Jeffery Lutman, Khanh Pham, Anahid Storn, Kathleen Howell, Karen Berry, Sharon O'Byrne, Dimitry M. Danilenko, Thomas Gelzleichter, Hong Wang, Eric Stefanich, Marna Williams rhuMAb Beta7 is a humanized anti-human integrin β7 monoclonal antibody that binds the integrins αEβ7 and α4β7. Cells that express these integrins have been associated with inflammatory diseases of the gut such as ulcerative colitis. rhuMAb Beta7 is being investigated as a potential therapeutic for immune system-mediated diseases such as inflammatory bowel disease. To investigate safety, pharmacokinetics (PK), and pharmacodynamics (PD) of rhuMAb Beta7, studies were conducted in cynomolgus monkeys. In one study, rhuMAb Beta7 was administered intravenously (IV) at 5 or 25 mg/kg in 4 weekly doses. The second study involved 12 weekly doses of rhuMAb Beta7, administered intravenously at 5, 15, or 50 mg/ kg, or subcutaneously at 15 or 50 mg/kg. Elevation of peripheral blood CD45RA-β7high CD4+ lymphocytes (phenotypically similar to gut-homing cells) was used as a PD biomarker. In each of these studies, group mean absolute numbers of peripheral blood CD45RAβ7high CD4+ lymphocytes increased approximately 3 to 6-fold over baseline levels following administration of rhuMAb Beta7. In contrast, animals dosed with vehicle showed no substantial changes in group mean numbers of peripheral blood CD45RA-β7high CD4+ lymphocytes. CD45RA+β7int CD4+ lymphocytes (phenotypically similar to naïve cells) and CD45RAβ7low CD4+ lymphocytes (phenotypically similar to peripheral-homing cells) showed no substantial differences in cynomolgus monkeys dosed with vehicle or rhuMAb β7. In addition, β7 receptors on peripheral blood T cells appeared to be fully saturated following the first of 4 weekly doses of 5 or 25 mg/kg rhuMAb Beta7. Furthermore, loss of receptor occupancy correlated with return to predose levels of CD45RA- β7high CD4+ lymphocytes. The PD observed in cynomolgus monkeys appeared to be related to PK because the observed reversibility and return to baseline of the PD effects correlated with clearance of rhuMAb Beta7.Variability in the rate of return of PD effects between animals in the same dose groups correlated with changes in clearance of rhuMAb Beta7, which was associated with the presence of anti-therapeutic antibodies in some animals. These results are consistent with the proposed mechanism of action of rhuMAb Beta7: inhibition of homing of β7 positive lymphocytes to the gut, through blocked α4β7 binding to its ligands. This mechanism is expected to lead to accumulation of CD45RA-β7high CD4+ lymphocytes in the peripheral circulation, as observed in both the 4-week and 12-week studies. Based on the preclinical data, rhuMAb Beta7 exhibits encouraging PK, PD, and safety profiles that support clinical development for potential treatment of IBD.
701 A Randomized, Double-Blind, Placebo-Controlled Trial of a Probiotic Preparation, Vsl#3, for the Treatment of Mild to Moderate Active Ulcerative Colitis Govind K. Makharia, Ajit Sood, Vandana Midha, Vineet Ahuja, Dinesh K. Singal, Reenu Arora, Shaman Sood, Pooja Goswami, Claudio De Simone, Aditya R. Sahu, Rakesh K. Tandon Background: Treatment with probiotics has been shown to be effective in maintenance of remission in patients with Ulcerative Colitis (UC). The role of probiotics in induction of remission in patients with active UC remains to be determined. Objectives: To assess the safety and efficacy of a probiotic preparation VSL#3 in the treatment of mild to moderate active UC. Methods: A randomized, double-blind, placebo-controlled multicentric study involving 3 centers was done recruiting 147 adult patients with UC. Patients with mild to moderate UC on oral 5-ASA were randomized to receive orally either 2 sachets twice daily of VSL#3 (900 billion CFU per sachet; Group A, 77 patients) or placebo (Group B, 70 patients). The duration of treatment was 12 weeks. The primary endpoint was a decrease in Ulcerative Colitis Disease Activity Index (UCDAI) scale of 50% or more from baseline at week 6. The secondary endpoints included attainment of remission after 12 weeks, changes in individual UCDAI parameters and a decrease in UCDAI of 3 points or more from baseline at 12 weeks. A per protocol analysis was done. Results: The mean age of the patients was 39.1 ± 12 yrs (Male 59.9%). 56.9%, 44.7%, 52.9% in Group A and 43.1%, 55.3%, and 47.9% in Group B had procto-sigmoiditis, left sided colitis and pancolitis, respectively. Fifty five patients in Group A and 29 patients in Group B completed entire duration of the study. Significantly higher number of patients in group A showed improvement in UCDAI score by 50% at 6 weeks as compared to those who received placebo (41.7% vs. 17.9% patients in VSL#3 group as compared with the placebo group (72.7% vs. 41.9% patients p 0.005). There was a significant decrease in the stool frequency and rectal bleeding score, mean endoscopic score and physician's global assessment score both at 6 weeks and 12 weeks in VSL#3 group as compared with the placebo group. There was a significant decrease in UCDAI at 12 weeks in those who were in VSL#3 group in comparison to placebo (5.8+1 to 2.1+1.8 vs 6+1.4 to 3.7+2.9, p 0.001). There was no difference in the two groups in attaining remission at 12 weeks (56.4% vs. 38.7%, p 0.1). Six patients in VSL#3 and 7 in placebo group had mild side effects. Conclusions: VSL#3 is significantly better than placebo in improving activity of ulcerative colitis at 6 weeks as well as at 12 weeks. There was however, no difference in the remission rates in the 2 groups at 12 weeks. Significant improvement was seen in subjective symptom scores like stool frequency score and rectal bleeding score as well as the endoscopic score.
704 A Phase 1 Open-Label, Single-Dose, Dose-Escalation Study of Mdx-1100, a High-Affinity, Neutralizing, Fully Human Igg1κ Anti-CXCL10 (Ip10) Monoclonal Antibody, in Ulcerative Colitis Robert Hardi, Lloyd Mayer, Stephan R. Targan, Michael Yellin, Pina M. Cardarelli, Kiron M. Das Background: Chemokines play key roles in regulating mucosal inflammatory cell trafficking in Crohn's disease, ulcerative colitis (UC) and other inflammatory diseases. Inhibition of the chemokine CXCL10, an IFNγ induced chemokine, abrogates colitis in some murine models. Mucosal expression of CXCL10 and its cell surface receptor, CXCR3, are markedly upregulated in inflammatory bowel disease (IBD). Therefore, CXCL10 neutralization may have therapeutic potential in the treatment of IBD. Methods: The primary objective of this open-label, dose-escalation study was to evaluate the safety of single doses of MDX-1100 in patients with UC flaring (UCDAI of 4-9) on stable doses of standard therapy and off anti-TNF therapy for at least 8 weeks prior to the study. Cohorts of 3-6 patients were administered a single infusion of MDX-1100 at doses of 0.3, 1.0, 3.0, or 10 mg/kg and were followed for at least 70 days post infusion. Decrease in the UCDAI by ≥ 3 points at Day 29 compared to baseline was considered a response. Responders were permitted up to 3 additional MDX-1100 infusions at the time of relapse. Peripheral blood mononuclear cells and colon biopsy specimens were studied for expression of CXCL10 and CXCL10-induced proteins. Serum anti-MDX-1100 antibody responses and MDX-1100 concentrations were determined by ECL and ELISA, respectively. This study was approved by the appropriate Investigational Review Boards. Results: To date, the 0.3 (n=3), 1.0 (n=4) and 3.0 (n=4) mg/ kg cohorts have been completed and the 10 mg/kg cohort (n=1) is actively enrolling. MDX1100 has been well tolerated. No drug related adverse events have been reported. There has been 1 SAE; a patient in the 3.0 mg/kg cohort admitted to the hospital for anemia and
702 Efficacy and Safety of Delayed-Release Oral mesalamine At 4.8g/D (800mg Tablet) in the Treatment of Moderately Active Ulcerative Colitis: Results of the Ascend III Study William J. Sandborn, Jaroslaw Regula, Brian Feagan, Elena A. Belousova, Njegica V. Jojic, Milan -. Lukas, Bruce R. Yacyshyn, Piotr Krzeski, Chyon-Hwa Yeh, Stephen B. Hanauer Purpose: To confirm the clinical benefit of delayed-release mesalamine 4.8g/d using an investigational 800mg tablet by comparing its efficacy to that of 2.4g/d (marketed Asacol 400mg tablet) for the treatment of moderately active ulcerative colitis (UC). Methods: ASCEND III was a Phase III, 6-week, double-blind, randomized, multi-national, activecontrol study designed to assess the non-inferiority of 4.8g/d (800mg tablet) versus 2.4g/d (400mg tablet) in patients with moderately active UC (Physician's Global Assessment [PGA] of 2). The primary endpoint was treatment success defined as improvement from baseline at 6 weeks in the PGA (which was based on the clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy) and no worsening in any of the individual clinical assessments. Results: A total of 772 patients were randomized and dosed. The primary objective of non-inferiority was met and treatment success was achieved in 70% (273/389) and 66% (251/383) of patients receiving 4.8g/d and 2.4g/d, respectively (95% CI for 2.4 - 4.8 success
A-99
AGA Abstracts
AGA Abstracts
role of Ucns and CRF receptors in GI diseases is unclear. Aim: To evaluate the contribution of CRFR2 to inflammation, using a murine model of Crohn's colitis, and to test whether Ucn1 exerts its anti-inflammatory effects via CRFR2. Methods: An intracolonic enema of trinitrobenzene sulfonic acid (TNBS) was used to induce colitis in male C57 mice. An enema of vehicle was given to control group. First, the effect of TNBS was evaluated on the mortality rate and severity of colitis in wild type mice (Wt), CRFR2-/- (KO), and CRFR2+/- (Ht) mice. Second, Ucn1 was given (ip) when TNBS colitis was induced, to test whether Ucn1 could still exert its anti-inflammatory effects and ameliorate colitis in CRFR2 KO mice. Results: At a 5 mg dose of TNBS, resultant colitis in Wt C57 mice caused a ~20% mortality rate 2 days after injection of TNBS. Surprisingly, 5 mg of TNBS did not cause any mortality in CRFR2-/- KO mice. In contrast, TNBS resulted in over 60% mortality rate within 3 days of TNBS injection in CRFR2+/- micE. colitis resulted in marked shortening of colon length in from 8.4±0.16 cm (controls) to 6.1±0.27 cm, p<0.05 (Wt), and the length was further shortened in KO and Ht mice to 5.6±0.2 cm. Adrenals were hypertrophied in mice with colitis, weighing twice as much as control adrenals. Colitis significantly increased histologic damage seen in H&E stained colon tissue of Wt and CRFR2 KO or Ht mice. Ucn 1 injection did not alter the mortality rate in Wt or KO mice with colitis, whereas Ucn1 dramatically rescued CRFR2+/- mice with colitis; none died until the experiment ended. This increase in survival rate was accompanied by significant improvement in colon histology as seen in H&E stained sections from CRFR2+/- mice. MPO levels were significantly decreased in Wt and Ht mice treated with Ucn1+TNBS (1.53±0.3 and 2.4±0.9 mU/mg) compared with KO Ucn1+TNBS mice (7.9±1.9 mU/mg, p<0.05). Interestingly, adrenal weights of CRFR2+/mice treated with Ucn1 were comparable to control levels, whereas adrenal weights remained elevated in Wt and KO mice treated with Ucn1. Conclusions: Perturbations in the CRFR2 receptor expression levels dramatically alter mice' ability to handle acute inflammatory stress. Complete lack of CRFR2 probably results in major developmental compensatory changes that enable the KO mice to better survive acute inflammatory stress. Supported in part by Hellman Foundation award to AB.