A phase II trial of ALXN1007, a C5a complement inhibitor, for use in lower GI-aGvHD

Acute graft-versus-host disease (aGvHD) commonly occurs after allogeneic hematopoietic stem cell transplant (HSCT) and, in 60% of patients, it will involve the lower gastrointestinal tract (LGI).¹ Generally, first line therapy for aGvHD is corticosteroids; however, the LGI is less responsive than other organs to steroid treatment and previous clinical trials have demonstrated that use of immunosuppressants does not improve outcomes.¹

Preclinical studies have suggested that complement C3 and C5 may be associated with GvHD, with inhibition of C5a in T-cell C5aR knockout shown to prevent the disease. Therefore, novel LGI aGvHD therapies which can inhibit the complement cascade may be beneficial, offering an alternative therapy option for steroid-refractory patients.

One therapy that targets the complement cascade is ALXN1007, an anti-C5a monoclonal antibody that has previously shown positive results in preclinical and phase I studies, which may act as a complete agonist of C5a. Complement C5a drives inflammation through phagocyte recruitment. Here, we report the results of a phase IIa non-randomized study (NCT02245412) evaluating the safety and efficacy of ALXN1007 in patients with aGvHD across three cohorts.¹

Study design¹

This study enrolled a total of 25 patients in three sequential cohorts who received ALXN1007 on three separate dosing schedules. The primary endpoints of the study included incidence and severity of adverse events and the LGI aGvHD overall response rate at Day 28. Secondary endpoints included LGI aGvHD response rates at Day 56. The study design is shown in Figure 1.

BIW, twice weekly; IV, intravenous; QW, once weekly.
*Adapted from Mehta, et al.¹

Results¹

The median follow-up was 11.3 months in cohort 1, 8.6 months in cohort 2, and 2.7 months in cohort 3. Patient characteristics at baseline are shown in Table 1.

Table 1. Baseline patient characteristics*

CNI, calcineurin inhibitor; GvHD, graft-versus-host disease; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplant; LGI, lower gastrointestinal tract; MMF, mycophenolate mofetil; MTX, methotrexate. *Adapted from Mehta, et al.1
Characteristic, % (unless otherwise stated)	Cohort 1 n = 17	Cohort 2 n = 6	Cohort 3 n = 2	Total N = 25
Age(at HSCT (range), years	60 (25–69)	46 (36–70)	69 and 72	60 (25–72)
Gender
Female	47	33	50	44
Male	53	67	50	56
Donor
HLA-                matched                related	24	17	0	20
HLA-                matched                unrelated	47	50	100	52
Cord blood	24	17	0	20
HLA-mismatched related	6	17	0	8
GvHD prophylaxis
CNI	29	0	50	24
CNI + MTX	18	17	0	16
CNI + MMF                ± other	53	50	0	48
Median time from HSCT to LGI GvHD (range), days	50 (30–184)	38 (16–76)	30 and 75	48 (16–184)
Median time from HSCT to ALXN1007 treatment (range), days	48 (26–181)	37.5 (17–73)	29 and 73	48 (17–181)

Safety

Of the 25 patients enrolled, 17 completed 8 weeks of treatment. Of these patients, all experienced at least one adverse event (AE). The rate of AEs, rate of infections, and most common AEs is shown in Figure 2.

AE, adverse event.
*Adapted from Mehta, et al.¹

Efficacy

At Day 56, 15 of 24 patients had achieved a complete response. Responses at Day 28 and Day 56 are shown in Figure 3.

CR, complete response; PR, partial response.
*Adapted from Mehta, et al.¹

Survival rates and the rate of non-relapse mortality at 12 months are shown in Figure 4.

*Adapted from Mehta, et al.¹

The role of complement

In this study, most patients were found to have normal C3 and C4 levels at baseline (71% and 83% of patients, respectively). In addition, the levels of C3, C4, and C5 at baseline did not appear to be associated with GvHD severity. Although these data may not be fully representative of complement pathway activity, the findings suggest that systemic activation of complement may not occur in all patients with LGI-aGvHD.

Conclusion 

This phase II study showed that ALXN1007 can be safely used in patients with LGI-aGvHD in combination with corticosteroids.¹ The rate of AEs was similar to previous AE rates seen in patients with aGvHD treated with corticosteroids alone.¹ Overall, 63% of patients achieved a complete response at Day 56, with almost 50% of patients surviving to 12 months; these positive results warrant further clinical trials with ALXN1007 in patients with LGI-aGvHD. However, it should be noted that the findings of this study are limited by the small sample size of each cohort.¹