RO7446603 + Aflibercept/Faricimab for Diabetic Macular Edema

(THAMES Trial)

Recruiting at 51 trial locations

Overseen By Reference Study ID Number: GR43828 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Genentech, Inc.

Must not be taking: Anti-VEGF, Corticosteroids

Disqualifiers: Untreated diabetes, Uncontrolled blood pressure, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

546 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had certain eye treatments like IVT anti-VEGF or corticosteroids within specific time frames before starting the trial.

What data supports the effectiveness of the drug combination RO7446603, Aflibercept, and Faricimab for treating diabetic macular edema?

Research shows that Faricimab, one of the drugs in the combination, is effective in treating diabetic macular edema by targeting specific pathways that help reduce swelling in the eye. Aflibercept, another drug in the combination, has also been shown to improve outcomes in patients with diabetic macular edema, especially those who did not respond well to other treatments. ^{1 2 3 4 5}

Is Aflibercept safe for treating diabetic macular edema?

Research shows that Aflibercept is generally safe for treating diabetic macular edema, with studies focusing on its use in real-life practice and clinical settings. ^{6 7 8 9 10}

How is the drug combination of RO7446603, Aflibercept, and Faricimab unique for treating diabetic macular edema?

This treatment is unique because it combines Faricimab, a bispecific antibody targeting both VEGF and angiopoietin-2, with Aflibercept, which targets VEGF alone. This dual approach aims to improve treatment durability and outcomes by addressing both angiogenic and inflammatory pathways, potentially offering better results for patients with diabetic macular edema. ^{1 4 9 10 11}

What is the purpose of this trial?

This study aims to evaluate the ocular and systemic safety, tolerability and efficacy of RO7446603 in participants with diabetic macular edema (DME). The study consists of 2 segments: Phase I (Parts 1-4) and Phase II (Part 5). Phase I investigated the safety of RO7446603 following a single and multiple intravitreal (IVT) doses as monotherapy or co-administered with IVT aflibercept or IVT faricimab (in separate injections). Phase II will investigate the safety, tolerability, pharmacokinetics (PK) and efficacy of two dose levels of RO7446603 in combination with faricimab, with the two drugs co-mixed and administered as a single IVT injection, compared to faricimab alone. The first participant was enrolled in the Phase I segment on June 22, 2022. Phase I has been completed.

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

This trial is for individuals with diabetic macular edema, a condition that affects the retina in people with diabetes. Participants should be adults who can safely receive eye injections and have not had any recent eye surgery or other treatments that might interfere with the study.

Inclusion Criteria

I have diabetes with an HbA1c level below 12%.

My vision loss is mainly due to diabetic macular edema.

My eye condition is due to diabetes and affects the center of my vision.

Exclusion Criteria

Pregnancy or breastfeeding, or intention to become pregnant during the study

My study eye has advanced diabetic eye disease.

I have or had inflammation in my eye.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants received single and multiple intravitreal doses of RO7446603 as monotherapy or co-administered with aflibercept or faricimab

28 weeks

Multiple visits for dosing and monitoring

Phase II Treatment

Participants receive RO7446603 in combination with faricimab, co-mixed and administered as a single IVT injection

56 weeks

Regular visits for dosing every 4 weeks initially, then every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Aflibercept
• Faricimab
• RO7446603

Trial Overview The study tests RO7446603 alone or combined with Aflibercept or Faricimab to see if they're safe and effective for treating diabetic macular edema. It's given as an injection into the eye, comparing different doses and combinations.

Participant Groups

Group I: Part 5: MD Co-mixed With Faricimab Stage Experimental Treatment 2 Interventions

Participants will receive two different dose levels of RO7446603 (co-mixed with faricimab or faricimab alone) as IVT injection, Q4W for the first six doses followed by Q8W for four doses.

Group II: Part 4: MD Co-administration With Faricimab Stage Experimental Treatment 2 Interventions

Participants received a single dose of faricimab followed by a 4-week enrichment screening period. Eligible participants received two different dose levels (two doses at each planned dose level) of RO7446603 as IVT injection, Q8W, along with three doses of faricimab (co-administered with RO7446603 or alone) as IVT injection, Q4W.

Group III: Part 3: MD Co-administration With Aflibercept Stage Experimental Treatment 2 Interventions

Participants received two different dose levels (two doses at each planned dose level) of RO7446603 as IVT injection, Q8W along with four doses of aflibercept IVT injections, every 4 weeks (Q4W).

Group IV: Part 2: Multiple Dose (MD) Monotherapy Stage Experimental Treatment 1 Intervention

Participants received four different dose levels of RO7446603 (two doses at each planned dose level) as IVT injection, every 8 weeks (Q8W).

Group V: Part 1: Single Ascending Dose (SAD) Stage Experimental Treatment 1 Intervention

Participants received a single dose of RO7446603 at five different dose levels as IVT injection on Day 1.

Who Is Running the Clinical Trial?

Genentech, Inc.

Lead Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

In a study of 51 treatment-resistant diabetic macular edema patients, switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) resulted in significantly better outcomes, with 37.5% of the IVF group achieving a central macular thickness (CMT) of less than 300 µm compared to only 3.7% in the control group (p=0.001).

The IVF group also showed greater improvements in visual acuity, with 41.7% gaining two or more lines of vision compared to 11.1% in the control group (p=0.01), indicating that IVF may be a more effective option for patients who did not respond well to IVA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Faricimab for Treatment-Resistant Diabetic Macular Edema. Rush, RB., Rush, SW.[2022]

In a study of 49 eyes from 34 patients with diabetic macular edema (DME) who did not respond to bevacizumab, switching to aflibercept led to significant improvements in both visual acuity (from 0.55 to 0.46 logMAR) and reduction in central macular thickness (from 473 to 349 μm).

The results showed that patients with poorer vision before switching to aflibercept experienced greater improvements, indicating that pre-switch central macular thickness can predict the effectiveness of aflibercept treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aflibercept in diabetic macular edema refractory to previous bevacizumab: outcomes and predictors of success. Laiginhas, R., Silva, MI., Rosas, V., et al.[2018]

Aflibercept treatment for diabetic macular edema (DME) led to significant improvements in best-corrected visual acuity (BCVA) and reductions in central subfield retinal thickness (CST) across all morphological types of DME over a one-year period, with 115 patients included in the study.

The treatment was most effective in the diffuse retinal thickening (DRT) group, requiring fewer injections to achieve similar outcomes compared to the cystoid macular edema (CME) and serous retinal detachment (SRD) groups, which needed more injections for optimal results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Optical Coherence Tomography Patterns on One-year Outcomes of Aflibercept Therapy for Diabetic Macular Edema. Ozcaliskan, S., Balci, S., Karasu, B., et al.[2020]

Faricimab is a new bispecific antibody that targets both angiopoietin-2 and VEGF, which may enhance treatment durability and improve outcomes for patients with diabetic macular edema (DME).

The YOSEMITE and RHINE trials, involving 940 and 951 participants respectively, are the first to use a personalized treatment interval (PTI) approach, allowing for flexible dosing up to every 16 weeks, aimed at maximizing therapeutic results while reducing treatment burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

YOSEMITE and RHINE: Phase 3 Randomized Clinical Trials of Faricimab for Diabetic Macular Edema: Study Design and Rationale. Eter, N., Singh, RP., Abreu, F., et al.[2022]

In a study of 46 patients with diabetic macular edema and subfoveal retinal detachment, intravitreal aflibercept showed a higher rate of complete resolution of retinal detachment compared to ranibizumab after 12 months (100% vs 80.8%).

Both treatments were effective in improving anatomical and functional outcomes, but there was no significant difference in visual acuity improvement between the two groups throughout the 12-month follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of aflibercept and ranibizumab in diabetic macular edema associated with subretinal detachment. Ozkaya, A., Demir, G., Kirmaci, A.[2022]

In a study of 72 patients with diabetic macular edema (DME) who were resistant to previous treatments with ranibizumab or bevacizumab, 58.3% showed a positive response to three monthly injections of aflibercept, indicating its efficacy in this challenging patient group.

The treatment significantly improved visual acuity and reduced central foveal thickness in responders, but vitrectomized eyes had a notably lower response rate, suggesting that prior surgical intervention may affect treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal Aflibercept for Patients With Diabetic Macular Edema Refractory to Bevacizumab or Ranibizumab: Analysis of Response to Aflibercept. Chen, YY., Chang, PY., Wang, JK.[2022]

In a study of 94 patients with diabetic macular edema (DME), intravitreal aflibercept injections significantly improved best-corrected visual acuity (BCVA) by an average of +7.4 letters after 36 months, with treatment-naive patients showing even greater improvement (+8.9 letters).

The treatment was found to be safe, with only mild, non-sight-threatening ocular adverse events reported, indicating that aflibercept is a viable option for managing DME in a real-life setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aflibercept for Diabetic Macular Edema in Real-Life Practice in GREece: Three-Year Outcomes of the ADMIRE Study. Chatziralli, I., Agapitou, C., Dimitriou, E., et al.[2023]

In a study of anti-VEGF naïve patients with clinically significant diabetic macular edema (DME), intravitreal aflibercept significantly improved best-corrected visual acuity (BCVA) after 12 months, with all patients showing improvement and 89.6% gaining 10 or more ETDRS letters.

Aflibercept also led to a significant reduction in central macular thickness, from an average of 460.5 μm at baseline to 229.0 μm at 12 months, with no adverse events reported, supporting its safety and efficacy as a first-line treatment for DME.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aflibercept for clinically significant diabetic macular edema: 12-month results in daily clinical practice. Campos Polo, R., Rubio Sánchez, C., García Guisado, DM., et al.[2022]

In a study of 221 treatment-naïve patients with diabetic macula oedema treated with Aflibercept over 12 months, the average visual acuity gain was only 4.0 letters, which is significantly lower than outcomes reported in the VIVID and VISTA clinical trials.

The NWL cohort had worse baseline health indicators, such as higher HbA1c levels and more advanced diabetic retinopathy, which likely contributed to their lower treatment effectiveness compared to the clinical trial participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aflibercept for treatment-naïve diabetic macula oedema in a multi-ethnic population: Real-world outcomes from North West London. Dinah, C., Ghulakhszian, A., Sim, SY., et al.[2021]

In a study of 25 eyes with refractory diabetic macular edema (DME) that had not improved after multiple treatments with ranibizumab or dexamethasone, switching to aflibercept resulted in a significant mean visual acuity gain of +8 letters after 6 months (p = 0.01).

Additionally, there was a notable reduction in central retinal thickness from 470.8 μm to 303.3 μm (p = 0.001), indicating both functional and anatomical improvements after the switch to aflibercept.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Switching to Aflibercept in Diabetic Macular Edema Not Responding to Ranibizumab and/or Intravitreal Dexamethasone Implant. Herbaut, A., Fajnkuchen, F., Qu-Knafo, L., et al.[2022]

Aflibercept therapy significantly improved visual acuity and reduced central retinal thickness in 100% of treatment-naïve patients with diabetic macular edema (DME) after just three injections, with maximum improvement observed after six injections.

In patients who were previously unresponsive to ranibizumab, aflibercept also restored retinal morphology and improved visual function in 55% of cases, demonstrating its effectiveness as a second-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anti-VEGF therapy for diabetic macular edema. From theory to clinical practice]. Fursova, AZ., Chubar, NV., Tarasov, MS., et al.[2019]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Faricimab for Treatment-Resistant Diabetic Macular Edema. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Aflibercept in diabetic macular edema refractory to previous bevacizumab: outcomes and predictors of success. [2018]

3. Pakistan pubmed.ncbi.nlm.nih.gov

Effect of Optical Coherence Tomography Patterns on One-year Outcomes of Aflibercept Therapy for Diabetic Macular Edema. [2020]

4. Netherlands pubmed.ncbi.nlm.nih.gov

YOSEMITE and RHINE: Phase 3 Randomized Clinical Trials of Faricimab for Diabetic Macular Edema: Study Design and Rationale. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Comparison of aflibercept and ranibizumab in diabetic macular edema associated with subretinal detachment. [2022]

6. China pubmed.ncbi.nlm.nih.gov

Intravitreal Aflibercept for Patients With Diabetic Macular Edema Refractory to Bevacizumab or Ranibizumab: Analysis of Response to Aflibercept. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Aflibercept for Diabetic Macular Edema in Real-Life Practice in GREece: Three-Year Outcomes of the ADMIRE Study. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Aflibercept for clinically significant diabetic macular edema: 12-month results in daily clinical practice. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Aflibercept for treatment-naïve diabetic macula oedema in a multi-ethnic population: Real-world outcomes from North West London. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Switching to Aflibercept in Diabetic Macular Edema Not Responding to Ranibizumab and/or Intravitreal Dexamethasone Implant. [2022]

11. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Anti-VEGF therapy for diabetic macular edema. From theory to clinical practice]. [2019]