Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270-360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90-18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial.

PURPOSE: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN: Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS: Two hundred forty-six patients with GA. METHODS: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.

Vascularized lymph node transplantation induces graft-versus-host disease in chimeric hosts.

BACKGROUND: The role of lymph nodes (LNs) in adaptive immune responses has been the subject of extensive research. In previous studies, the surgical removal of lymph nodes from rat hind limbs prevented the development of lethal graft-versus-host disease (GVHD) after allogeneic hind limb transplantation to chimeric recipient rats. The purpose of this study was to establish the role of the cellular fraction versus the microenvironment of LNs in the development of GVHD in this model. METHODS: A rat model for vascularized LN transplantation was developed and graft-versus-host responses were compared after: 1) naive ACI LN cells were infused into Wistar-Furth (WF) rats as chimeric recipients (e.g. [ACI-->WF]); 2) vascularized WF lymph nodes were transplanted to syngeneic WF recipients; 3) nonvascularized ACI lymph nodes were transplanted to [ACI-->WF] chimeric recipients; 4) vascularized ACI lymph nodes were transplanted to [ACI-->WF] chimeric recipients. RESULTS: Transplantation of vascularized ACI lymph nodes to [ACI-->WF] chimeric recipient rats resulted in severe and sometimes lethal GVHD. In contrast, neither the infusion of purified ACI LN cells nor the transplantation of nonvascularized LNs led to GVHD in chimeric recipients. CONCLUSIONS: When introducing allogeneic cells into chimeric recipients, concomitant transplantation of the vascularized LN microenvironment makes a manifest difference between induction and absence of GVHD. This illustrates the important role of the LN microenvironment in adaptive immune responses.

Neuroregeneration in composite tissue allografts: effect of low-dose FK506 and mycophenolate mofetil immunotherapy.

BACKGROUND: The immunosuppressant FK506 has been reported to increase the rate of peripheral nerve regeneration in nerve crush injury and nerve allograft models. The purpose of this study was to determine whether low doses of FK506 and mycophenolate mofetil had a neuroregenerative effect in revascularized peripheral nerve allografts in a rat hind limb transplantation model. METHODS: Wistar Furth rat recipients received limbs from syngeneic Wistar Furth donors (group 1, n = 4) or from allogeneic August X Copenhagen Irish rat donors (group 2, n = 6). Wistar Furth recipients received limbs from August X Copenhagen Irish donors and were treated with FK506/mycophenolate mofetil for 5 months (group 3, n = 7). At the end of the follow-up period, histomorphometric analysis of sciatic and tibial nerves from transplanted and intact hind limbs was conducted. Sciatic and tibial nerves were examined at the level of coaptation and near the neuromuscular junction, respectively. RESULTS: Transplanted limbs in groups 1 and 3 completed the study without rejection, while the limbs in group 2 were rejected within a few days. Sciatic and tibial nerve analysis in groups 1 and 3 limbs showed myelinated axons of various diameters but in significantly fewer numbers than in nontransplanted contralateral nerves. The number and size of myelinated axons of transplanted nerves at corresponding levels were not significantly different between syngeneic and allogeneic (FK506/mycophenolate mofetil-treated) transplants. CONCLUSIONS: The authors conclude that long-term neuroregeneration of revascularized peripheral nerves using low-dose FK506/mycophenolate mofetil was similar to that of syngeneic transplants. The occurrence of acute rejection episodes with low-dose FK506/mycophenolate mofetil did not appear to benefit nor impair neuroregeneration.

Risk acceptance in composite-tissue allotransplantation reconstructive procedures.

Composite-tissue allotransplantation (CTA) is a new therapeutic modality to reconstruct major tissue defects of the face, larynx, and extremities. Unlike most life-saving organ-transplantation procedures, CTA is considered to improve quality of life. Therefore, the question arises, do the risks posed by the immunosuppression drugs that patients must take to prevent rejection justify the benefits of these procedures? The purpose of this study was to assess the relative risk that individuals are willing to accept in order to receive the benefits of CTA procedures. We used a psychometrically reliable and valid instrument to question two primary populations of individuals: those who live with the risks of immunosuppression, and healthy individuals. The level of risk acceptance for the seven transplant procedures tested (foot, single hand, double hand, larynx, kidney, hemiface, and full face) showed significant differences in research participants' risk acceptance for the different transplant procedures, but no significant differences between groups. Based on these findings, we conclude that certain CTA procedures convey benefits to recipients that are perceived by subjects, including individuals who live with the risks of immunosuppression, to warrant the risks of these procedures.

Ischemic preconditioning of skeletal muscle: duration of late-phase protection.

BACKGROUND: The time course of the late phase of ischemic preconditioning (IPC) was determined in latissimus dorsi muscle (LDM) flaps using viability and function as the endpoints. MATERIALS AND METHODS: LDM flaps from Sprague-Dawley rats were allocated into 6 groups. LDMs were preconditioned with 2 30-minute periods of ischemia separated by 10 minutes of reperfusion and subjected to a 4-hour ischemic insult after 24, 48, 72, and 96 hours from IPC. LDMs were evaluated for percent necrosis and muscle contractile function and compared with controls. RESULTS: The late phase of IPC provides significant protection against necrosis up to 72 hours. Conversely, when the end point used was muscle contractile function, the protection only lasted 48 hours. CONCLUSION: The time course of late-phase protection in skeletal muscle is 2-3 days. Late phase IPC appears to protect muscle flaps during the most critical time period following elevation.

Late-phase ischemic preconditioning in skeletal muscle: is the phenomenon protective?

Reports in the literature on the effectiveness of late-phase Ischemic preconditioning (IPC) in skeletal muscle are controversial. The purpose of this study was to determine in the same muscle flap model the effectiveness of various IPC protocols in inducing late-phase protection. Rat latissimus dorsi muscle (LDM) flaps were preconditioned with either 30 or 60 min of total ischemia, divided as follows: single cycles of either 30 or 60 min, two cycles of 15 or 30 min, and three cycles of 10 or 20 min. Ischemia cycles were separated by 10 min of reperfusion. A day after IPC, flaps were elevated and challenged with 4 h of ischemia. Three days later, flaps were assessed for viability. We found that IPC protocols of different total durations and comprised of two or three cycles of ischemia elicited a protective effect against necrosis. We conclude that IPC induces late-phase protection against necrosis in skeletal muscle, and that the protection requires more than one ischemia/reperfusion cycle.