Therapy in pipeline for age-related macular degeneration

Lampalizumab

Study name : MAHALO phase 2, and CHROMA and SPECTRI phase 3 study.

Objectives : To determine if intravitreal lampalizumab can halt the progression of GA in patients of the late stage of dry AMD. ^,

Sponsors : MAHALO study in the United States and Germany, CHROMA and SPECTRI phase 3 studies in 23 countries.

Study time : MAHALO study 18 months; CHROMA and SPECTRI phase 3 studies 48 weeks.

Patients enrolled ; 129 GA patients without CNV in MAHALO study, 906 GA patients without CNV in CHROMA and SPECTRI phase 3 studies.

Treatment regimen : Patients were randomized to receive either lampalizumab 10 mg or sham, administered monthly or every other month in the MAHALO study. Patients were randomized 2:1:2:1 to receive 10 mg of intravitreal lampalizumab every 4 weeks, sham procedure every 4 weeks, 10 mg of lampalizumab every 6 weeks, or sham procedure every 6 weeks in CHROMA and SPECTRI phase 3 studies.

Outcome measures : The primary outcome of MAHALO phase 2 was the mean change in GA lesion area from baseline to month 18.

Results : With an acceptable safety profile, monthly lampalizumab treatment demonstrated a 20% reduction in lesion progression versus sham control. By more substantial monthly treatment, that is,10 mg of lampalizumab every 6 weeks, the benefit of 44% reduction in GA area progression versus sham control was observed in a subgroup of complement factor I ( CFI ) risk-allele carriers. In CHROMA and SPECTRI trials, lampalizumab did not reduce GA enlargement versus sham during 48 weeks of treatment. A mean of GA enlargement was similar in treatment to sham group approximately 2 mm ² per year.

Present status : Despite the setback with lampalizumab in clinical trial phase 3, complement factor D (CFD) remains a target of interest in the treatment of AMD.

Comments : Lampalizumab is a humanized monoclonal antibody (Fab fragment), which is a selective inhibitor of CFD. MAHALO phase 2 is a proof-of-concept study, indicating the critical role of dysregulation of alternative complement pathway plays a pathogenic role in GA progression. However, the results of CHROMA and SPECTRI trials are disappointing. One of the limitations is that the treatment regimens only apply to 48 weeks. This short application may not be appropriate to all cases of GA, particularly GA cases in extremely chronic process. Another limitation of this study is that the design of the outcome measurement is before the advent of optical coherence tomography (OCT). The high quality of OCT imaging may be able to quantitatively reveal changes of RPE and the interplay of multiple cellular components of the macula.

Eculizumab

Study name : The COMPLETE study (phase 2), namely, systemic complement inhibition with eculizumab for GA in AMD.

Objectives : To determine if the usage of systemic eculizumab can halt GA progression in patients with AMD.

Sponsors : Alexion Pharmaceuticals.

Study time : 6 months.

Patients enrolled : 30 patients with GA but without choroidal neovascularization (CNV).

Treatment regimen : Patients were randomized 2:1 to receive eculizumab or placebo. Patients received eculizumab or placebo for 24 weeks with the primary endpoint at 26 weeks. The treatment was divided into an induction period and a maintenance period. The first 10 patients in the eculizumab group received the low dose of eculizumab (600 mg via intravenous infusion for 4 weeks followed by 900 mg every 2 weeks until week 24), whereas the next 10 patients received the high dose (900 mg eculizumab via intravenous infusion for 4 weeks followed by 1200 mg every 2 weeks until week 24). After 26 weeks, patients were followed up twice without treatment at 3-month intervals.

Outcome measures : The primary outcome was the growth rate measurements of GA area detected by SD OCT sub-RPE slab images. The secondary outcomes were the change in the area of GA measured with autofluorescence and fluorescein angiographic imaging.

Results : In both low- and high-dose treatment groups, there were no significant changes in the GA area. The COMPLETE study found that the progression of GA over 6 months was dependent upon the low luminance deficit at baseline of these patients.

Present status : The COMPLETE study failed to advance to phase 3 trial.

Comments : Eculizumab is an inhibitor of complement component (C5), a humanized monoclonal antibody. Eculizumab inhibits C5 and prevents terminal complement activation and formation of membrane attack complex (C5b-9) with excellent safety profile in systemic utilization. The COMPLETE study utilized accurate parameters currently available monitoring the changes of GA, that is, morphological OCT imaging and functional luminance vision test. However, the sample size of this study was small (30 patients). Most importantly, whether the inhibition of alternative complement pathways via intravenous eculizumab could reach the inhibitory status of C5-mediated cascade in the posterior outer retina may present a concern.

Pegcetacoplan

Study name : The Filly phase 2 study of Pegcetacoplan (APL-2) for GA in AMD.

Objectives : To test the safety and efficacy of intravitreal APL-2 on the reduction of GA growth.

Sponsors : Apellis Pharmaceuticals, Inc.

Study time : 18 months.

Patients enrolled : GA in single eyes of 246 patients without CNV.

Treatment regimen : Patients were assigned randomly in a 2:2:1:1 ratio to receive intravitreal 15 mg pegcetacoplan (APL-2) monthly or every other month or sham intravitreal injections monthly or every other month for 12 months with follow-up at months 15 and 18.

Outcome measures : The primary endpoint was the mean change in the GA area from baseline to month 12 by fundus autofluorescence imaging. The secondary outcome was any change of best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit.

Results : In APL-2 monthly or every other month groups, the GA growth rate was reduced by 29% and 20% compared with the sham treatment group. However, the eyes treated with both APL-2 regimens developed significantly higher exudative AMD as compared to the sham eyes (8.9%–20.9% in APL-2 groups and 1.2% in the sham group, respectively).

Present status : Completion of phase 2, enrolling for phase 3.

Comments : APL-2 is a pegylated complement C3 inhibitor peptide. The phase 2 results that show significant efficacy of intravitreal APL-2 as compared to the sham treatment on reduction of GA growth are encouraging. This is also a “proof-of concept” study emphasizing the pathogenic role of C3 in the progression of GA. It is of notice that C3 is the central element of the three complement cascades, that is, classical, lectin, and alternative cascades, which is located at the upstream of C5-mediated common pathway. Theoretically, the consequence of C3 inhibition may interfere with the function of whole innate complement systems as described in Chapter 7. Although the current Filly phase 2 study using a local delivery approach (i.e., intravitreal injection) minimized the systemic impact of C3 inhibition, the altered complement defense function in the macular neurovascular complex need to be further monitored. For instance, the APL-2 dose-dependent CNV development in the treated eyes is worrisome in the upcoming phase 3 trial. As this study pointed out, the possible accumulation of active C3 fragments could have continued. In other words, the subretinal macrophage infiltration, which induces an inflammasome activation, can cause the chronic release of inflammatory molecules and tissue damage. Therefore, when the upcoming phase 3 trial is designed, the assembly and activation of inflammasome complex should be monitored.

C5 inhibitor zimura (avacincaptad pegol)

Study name : C5 Inhibitor, Zimura (avacincaptad pegol), for GA in AMD: A phase 2/3 trial (GATHER1 study).

Objectives : To determine the safety and efficacy of intravitreal Zimura on the reduction of GA growth of patients with AMD.

Sponsors : Iveric bio.

Study time : 12 months.

Patients enrolled : 286 patients with GA due to AMD.

Treatment regimen : Patients were assigned randomly in two parts for intravitreal injections: in Part 1, patients were further randomized in a 1:1:1 ratio to receive Zimura 1 mg, Zimura 2 mg, and sham. In Part 2, patients were randomized in a 1:2:2 ratio to receive Zimura 2 mg, Zimura 4 mg, and sham.

Outcome measures : The primary outcome was the mean rate of change in GA over 12 months determined by fundus autofluorescence. Secondary endpoints included the change in best-corrected visual acuity.

Results : Zimura was generally well tolerated. There were no Zimura-related adverse events or serious adverse events. The reduction in the mean GA growth rate over 12 months was 27.4% for the Zimura 2 mg and 27.8% for Zimura 4 mg as compared to their sham-control groups.

Present status : GATHER1 study met its primary efficacy and safety endpoint. GATHER2 study phase 3 trial will compare Zimura 2 mg with a sham-control group.

Comments : There was a higher incidence of CNV or nAMD in study eyes treated with pegcetacoplan (APL-2), a C3 inhibitor as described earlier. In the GATHER1 study, the incidence of CNV for eyes who received Zimura was (9.0%–9.6%) much lower than the incidence of APL-2 (8.9%–20.9%). ^, The underlying mechanism of this difference causing CNV formation between C3 and C5 inhibition is not clear. One of the possibilities is that C5 inhibition targets the terminal alternative pathway, which may minimize the disturbance of the C3-mediated complement homeostasis. Larger trials are required to better understand this phenomenon.

CR2-fH

Study name : A preclinical trial of a fusion protein (CR2-fH) consisting of complement receptor 2 fragments (CR2) linked to the inhibitory domain of complement factor H (fH) for both dry and neovascular AMD.

Objectives : To determine the safety and efficacy of AAV-mediated delivery of CR2-fH on anticomplement activation and reduction of laser-induced CNV in a murine model (C57BL/6J mice).

Sponsors : Medical University of South Carolina, USA.

Study time : 1 month.

Treatment regimen : Subretinal AAV5-mediated delivery of CR2-fH to C57BL/6J mice.

Outcome measures : The safety profile of subretinal AAV5-CR2-fH and the efficacy on inhibition of complement activation in animal model.

Results : A safe concentration of AAV5-CR2-fH was identified using ERG, OCT, and RPE morphology. AAV5-mediated CR2-fH expression in the mouse RPE is comparable to that of intravenous injection. CR2-fH expressed in the RPE could reduce the development of laser-induced CNV, attenuate complement activation, as determined by a reduction in C3a production.

Present status : The safety and efficacy profile of CR2-fH to murine with AMD-like retina pathology have met in the preclinical study. Advancing CR2-fH clinical trials for GA and/or CNV is underway.

Comments : The result of this preclinical trial is a “proof-of-concept” work trying to understand the role of complement factor H (FH) in the regulation of alternative complement pathway. Numerous genetic studies have shown strong associations between AMD risk and common variations in genes encoding proteins of the complement system, specifically a variant in FH (Tyr402His). To date, the exact role of complement in AMD pathogenesis remains unclear. However, several structural and functional studies suggest that the 402His form of FH, or its smaller splice product FH-like 1 (FHL1) binds less well than the 402Tyr variant to Bruch’s membrane, thus resulting in a reduced inhibitory function of FH, namely, less protection against subretinal chronic inflammation. ^, This new product, CR2-fH, may act as a supplement of FH in the regulation of alternative pathways. In addition, the successful delivery of a therapeutic dose of FH to the macular region has validated that the gene delivery is safe and effective for future AMD treatment strategies. ^,

ANX007

Study name : Clinical trial phase 1b, intravitreal ANX007 (a C1q inhibitor), for patients affected with GA due to AMD.

Objectives : To determine the safety, tolerability, pharmacokinetics, and targeted endpoints in patients affected with GA.

Sponsors : Annexon bioscience.

Study time : The first evaluation time was 4 weeks after intravitreal ANX007. The designed study time for phase 2 is not available.

Treatment regimen : A single intravitreal ANX007 with varied doses in 17 patients affected with glaucoma was completed. In phase 1b, a single ANX007 injection achieved complete suppression of the C1q for at least 4 weeks, as monitored in aqueous humor samples.

Outcome measures : Primary endpoints are the tolerability of different doses after a single intravitreal injection. Secondary endpoints are the inhibitory effect on C1q.

Results : The primary outcome showed that ANX007 was well tolerated at all dose levels without serious side effects. At the two higher dose levels, a single intravitreal injection of ANX007 achieved complete suppression of the C1q target for at least 4 weeks, as measured in ocular fluid from aqueous humor taps.

Present status : advance to phase 2 clinical trial for GA.

Comments : The role of the alternative complement pathway and its mediation by retinal microglia and macrophages in pathogenesis of AMD has been described in Chapter 7. Recently, a novel approach by using photo-oxidative mice, either C1q a knockout ( C1qa ^−/− ) or mice treated with C1q inhibitor was used. First, this study demonstrated that in addition to alternative pathway, other complement pathway(s) such as classic pathway may contribute to the events of retinal degenerations. Second, for the photo-oxidative damaged mice, C1qa ^−/− mice showed reduced inflammasome and IL-1β expression in macrophages in the degenerative retina. Neutralization of C1q with intravitreal anti-C1q antibody reduced the progression of retinal degeneration. Third, retinal C1q was found to be expressed by subretinal microglia/macrophages located in the outer retina of early AMD donor eyes and in mouse photo-oxidative retinas. Fourth, most importantly, systemic delivery of anti-C1q antibody had no such effect in the outer retina, indicating the local regulation of classic complement pathway plays a pathogenic role in retinal degeneration. The regulatory mechanism of the classic complement pathway in the outer retina may be distinct. Although intravitreal ANX007 potently binds to C1q and inhibits activation of all downstream complement cascades, including C3 and C5, it does not interfere with the normal function of C3- and C5-mediated other complement pathways. Therefore, the MOA of ANX007 is via a distinct function of the local classic complement pathway. All these unique findings of ANX007 have met the criteria for the phase 2 trial.

CB2782

Study name : A complement factor C3-inactivating protease (CB2782) and potential long-acting treatment for dry AMD in the preclinical trial.

Objectives : To determine the efficacy of C3 inhibition and pharmacokinetics and pharmacodynamics of intravitreal CB2782 in rabbits.

Sponsors : Catalyst.

Treatment regimen : Intravitreal CB2782 PEG 2 mg, 3–4 times a year in rabbits.

Outcome measures : The inhibitory effect of Pegylated CB-2782 on C3-mediated complement pathway.

Results : Intravitreal CB2782 PEG on C3-mediated complement pathway was documented by using animal models.

Present status : Based on the verified inhibitory effect of intravitreal CB2782 PEG on C3-mediated complement pathway, it will advance to phase 1 clinical trial.

Comments : Despite multiple clinical failures in treating GA by blocking the alternative pathway or the downstream C5 pathways, interest in more completely blocking C3 complement activation in the eye, continues. Pegylated CB-2782 is an enzyme. The pegylated enzyme has indistinguishable enzymatic activity on a C3-mimicking peptide substrate, specifically hydrolyzing C3 at a single site into inactive components, and blocks ex vivo C3-dependent complement-mediated sheep red blood cell hemolysis. Pegylation is an established method to extend the vitreous half-life of macromolecules. The biophysical and biochemical properties of CB2782, which render potential for an extended half-life in the vitreous, may be useful as a long-acting drug for dry AMD treatment.

ALXN1720

ALXN1720 is a novel anti-C5 albumin-binding bispecific antibody that binds and prevents activation of human C5. Bispecific antibodies are antibodies that can simultaneously bind two separate and unique antigens (or different epitopes of the same antigen). Current applications have been explored for cancer immunotherapy and drug delivery. Alexion-developed ALXN1720 bispecific antibody can have an extended half-life. Alexion Pharmaceuticals, Inc., the sponsor company, has completed preclinical study and plans to initiate a phase 1 study of ALXN1720 for treating GA.

HMR59

Study name : Intravitreal HMR59 (AAVCAGsCD59) for the treatment of AMD phase 1 trial.

Objectives : To evaluate the safety of intravitreal HMR59, a transgene product blocking complement at membrane attack complex (MAC).

Sponsors : Hemera Biosciences.

Study time : 24 months.

Patients enrolled : 17 patients affected with GA due to AMD.

Treatment regimen : A phase 1 clinical trial evaluating a single intravitreal injection in patients with advanced dry AMD with 24 months follow-up.

Outcome measures : Primary outcome is to show no severe side effect after a single intravitreal injection. Secondary outcome is to show if HMR59 has the potential to slow down or stop the progression of GA due to AMD with a single intravitreal injection.

Results : HMR59 was delivered intravitreally. The treatment was well tolerated, and there was no dose-dependent toxicity. Four eyes developed mild inflammation. Two of these four patients required pressure-lowering drops as well. While this phase 1 trial was not powered to demonstrate efficacy, the majority of the patients in the high-dose group showed a slower growth rate of GA than the controls.

Present status : Advance to phase 2 for dry AMD clinical trial.

Comments : HMR59 is an AAV2 gene therapy administered as an intravitreal injection. The data of phase 1 showed that a single intravitreal injection with doses up to 1.071 × 10 ¹² vector genomes (vg) has been granted safe to proceed status from the FDA. This AAV-delivered soluble CD59 (sCD59) that inhibits the terminal complement pathway, potentially targets local MAC without disturbance of other defense functions of complement cascades, and appears to be a long-acting drug for dry AMD.

Danicopan (ACH-4471)

Study name : Discovery and development of the oral CFD Inhibitor danicopan.

Objectives : To evaluate if danicopan, a reversible small-molecule inhibitor of CFD is safe, and if oral uptake is feasible for effectiveness on CFD inhibition in preclinical trial and phase 1 clinical trial of healthy volunteers.

Sponsors : Achillion Pharmaceuticals.

Study time : Pharmacokinetic (PK) study of healthy volunteers after single oral dose.

Patients enrolled : 36 healthy volunteers enrolled for safety, tolerability, and PK study after taking single ascending oral doses.

Treatment regimen : In preclinical trial, oral danicopan was administered to cynomolgus monkeys in two oral doses of 200 mg/kg, 12 h apart. In phase 1 study of healthy volunteers, single doses of 200, 600, and 1200 mg, and with two doses of 1200 mg, 12 h apart, as well as placebo group were studied.

Outcome measures : Any side effects and tolerability issue.

Results : At pharmacological levels against CFD in serum of nonhuman primates, a pharmacodynamic study of danicopan on inhibition of alternative pathway (AP) was evaluated. Oral danicopan was well tolerated across all dose groups in healthy volunteers, although posttreatment, two transient, and self-limiting elevations in aspartate transaminase (ALT) were observed.

Present status : Phase 2 clinical trial for dry AMD is ongoing.

Comments : First, the discovery and development of small-molecule reversible CFD inhibitors such as danicopan for AP inhibition is an innovative achievement. This approach has alleviated the potential immunogenicity of irreversible inhibitors that generally are proteins as compared with their reversible counterparts. Second, the oral CFD inhibitors such as danicopan has been modified and identified to make the oral route feasible. Danicopan is the first clinically investigated orally administered small molecule inhibitor of CFD for the treatment of chronic diseases. Third, since CFD inhibitors selectively target the AP and preserve the classical, lectin, and terminal pathways, the antibody-elicited protection should be preserved or rapidly restored after cease of reversible CFD inhibitors.

IONIS-FB-LRX

Study name : Development of IONIS-FB-L _Rx to treat GA associated with AMD (phase 1 masked, placebo-controlled single and multiple ascending dose studies).

Objectives : To determine the clinical safety of a novel antisense oligonucleotide (ASO) targeting the human CFB gene, and to evaluate if this treatment can inhibit AP activity in the choriocapillaris.

Sponsors : Ionis Pharmaceuticals, Inc.

Study time : 43 days.

Patients enrolled : 54 healthy volunteers.

Treatment regimens : Subcutaneous administrations of 10 and 20 mg of IONIS-FB-L _Rx .

Outcome measures : Primary outcome is the safety profile after taking IONIS-FB-L _Rx by healthy volunteers in 43 days. Secondary outcome is to evaluate the inhibitory effect on reduction of circulating levels of CFB.

Results : There were no safety signals or clinically relevant changes in blood chemistry, hematology, urinalysis, ECGs, or vital signs.

Present status : A placebo-controlled phase 2 trial in patients affected with GA due to AMD in planning.

Comments : The preclinical study demonstrated that a second-generation ASO, that is, IONIS-FB-L _Rx , targets healthy mouse and monkey CFB mRNA by subcutaneous route. ASO administration reduced CFB mRNA level in the liver. When the plasma level of CFB protein fell by using ASO dramatically, the CFB level in the eye was almost undetectable. In phase 1 study, IONIS-FB-L _RX reduced plasma CFB levels of the volunteers in a dose-dependent manner. A larger reduction of CFB levels at the 20 mg dose than that of 10 mg dose was associated with greater suppression of AP activity. Although the mechanistic link between excessive CFB and subretinal/sub-RPE inflammation is still elusive, the upcoming phase 2 and possible phase 3 clinical trial may provide “proof-of-concept” evidence to support this hypothesis.