on behalf of the HAWK and HARRIER Study Investigators* Purpose: Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a singlechain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD).Design: Double-masked, multicenter, active-controlled, randomized trials. Participants: Patients (N ¼ 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye.Intervention: Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing.Main Outcome Measures: The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes.Results: At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, þ6.6 [6 mg] and þ6.1 [3 mg] letters with brolucizumab vs. þ6.8 letters with aflibercept [HAWK]; þ6.9 [brolucizumab 6 mg] vs. þ7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mgetreated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mgetreated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P ¼ 0.001) and HARRIER (22.7% vs. 32.2%; P ¼ 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean À172.8 mm vs. À143.7 mm; P ¼ 0.001) and HARRIER (LS mean À193.8 mm vs. À143.9 mm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept.Conclusions: Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mgetreated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (Clin-icalTrials.gov; NCT02307682, NCT02434328).

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In patients with both SRF and PVD at baseline, similar BCVA outcomes were observed regardless of treatment frequency. These patients may require less frequent treatments compared with patients without SRF, without PVD, or without either who may require more frequent injections for maintenance of vision. This finding may have implications in clinical practice by helping to tailor an individualized re-treatment interval in nAMD patients.

Despite the considerable interest in the possibility that ATP may function as a peripheral pain mediator, there has been little quantitative study of the pain-producing effects of ATP in humans. Here we have used iontophoresis to deliver ATP to the forearm skin of volunteers who rated the magnitude of the evoked pain on a visual analogue scale. ATP consistently produced a modest burning pain, which began within 20 s of starting iontophoresis and was maintained for several minutes. Persistent iontophoresis of ATP led to desensitization within 12 min but recovery from this was almost complete 1 h later. Different doses of ATP were delivered using different iontophoretic driving currents. Iontophoresis of ATP produced a higher pain rating than saline, indicating that the pain was specifically caused by ATP. The average pain rating for ATP, but not saline, increased with increasing current. Using an 0.8 mA current, subjects reported pain averaging 27.7 +/- 2.8 (maximum possible = 100). Iontophoresis of ATP caused an increase in blood flow, as assessed using a laser Doppler flow meter. The increase in blood flow was significantly greater using ATP than saline in both the iontophoresed skin (P < 0.01) and in the surrounding skin, 3 mm outside the iontophoresed area (P < 0.05). The pain produced by ATP was dependent on capsaicin-sensitive sensory neurons, since in skin treated repeatedly with topical capsaicin pain was reduced to less than 25% of that elicited on normal skin (2.1 +/- 0.4 compared with 9.3 +/- 1.5 on normal skin). Conversely, the pain-producing effects of ATP were greatly potentiated in several models of hyperalgesia. Thus, with acute capsaicin treatment when subjects exhibited touch-evoked hyperalgesia but no ongoing pain, there was a threefold increase in the average pain rating during ATP iontophoresis (22.7 +/- 3.1) compared with pre-capsaicin treatment (7.8 +/- 2.6). Moreover, ATP iontophoresed into skin 24 h after solar simulated radiation (2 x minimal erythymic dose) resulted in double the pain rating of normal skin, increasing from 15.3 +/- 4.1 to 32.7 +/- 4.1. The pain response to saline was not significantly altered after UV irradiation at any time-point studied. We conclude that ATP produces pain by activating capsaicin-sensitive nociceptive afferents when applied to skin. The possibility that ATP activates nociceptors indirectly via its degradation products cannot be ruled out. The effects of ATP are dose-dependent and responses desensitize only slowly. In inflammatory conditions, ATP may be a potent activator of nociceptors and an endogenous mediator of pain.

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