A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of RO7446603 Administered Alone or in Combination With Aflibercept or Faricimab in Participants With Diabetic Macular Edema (THAMES)

A Phase I/II Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of RO7446603 Administered Alone or in Combination With Aflibercept or Faricimab in Patients With Diabetic Macular Edema

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetic Macular Edema
• Intervention / Treatment: Drug: RO7446603; Drug: Aflibercept; Drug: Faricimab

• Study Type: Interventional
• Enrollment (Estimated): 546
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100730
    • Beijing Hospital
  • Beijing, China, 100730
    • Peking Union Medical College Hospital
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100730
      • Beijing Tongren Hospital, Capital Medical University
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200080
      • Shanghai General Hospital - North Campus
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300384
      • Tianjin Medical University Eye Hospital
  • Zhejiang
    • Wenzhou, Zhejiang, China, 325027
      • Eye Hospital,WMU(Zhejiang Eye Hospital)
• Puerto Rico
  • Arecibo, Puerto Rico, 00612
    • Emanuelli Research and Development Center LLC
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85053
      • Retinal Research Institute, LLC
    • Phoenix, Arizona, United States, 85020-5917
      • Arizona Retina and Vitreous Consultants
    • Phoenix, Arizona, United States, 85020
      • Associated Retinal Consultants PC
  • California
    • Campbell, California, United States, 95008
      • Retinal Diagnostic Center
    • Fullerton, California, United States, 92835
      • Retina Consultants of Orange County
    • Modesto, California, United States, 95356-9412
      • Retinal Consultants Medical Group
    • Mountain View, California, United States, 94040
      • Northern California Retina-Vitreous Associates
    • Sacramento, California, United States, 95825
      • Retinal Consultants Medical Group
    • San Francisco, California, United States, 94158
      • University of California San Francisco
    • Torrance, California, United States, 90503-3270
      • Macula Retina Vitreous Research Institute
    • Walnut Creek, California, United States, 94598
      • Bay Area Retina Associates;Study Department
  • Colorado
    • Aurora, Colorado, United States, 80045-2517
      • University of Colorado - Eye Center - PPDS
    • Colorado Springs, Colorado, United States, 80909
      • Retina Consultants of Southern Colorado PC
    • Denver, Colorado, United States, 80222
      • Retina Specialists of Colorado
    • Longmont, Colorado, United States, 80503-6499
      • Advanced Vision Research Institute
  • Connecticut
    • Waterford, Connecticut, United States, 06385-1215
      • Retina Group of New England
  • Florida
    • Fort Myers, Florida, United States, 33912
      • National Ophthalmic Research Institute
    • Jacksonville, Florida, United States, 32216-6347
      • Florida Retina Institute
    • Tampa, Florida, United States, 33609
      • Retina Associates of Florida;Retina Associates of Florida
  • Georgia
    • Augusta, Georgia, United States, 30909-6440
      • Southeast Retina Center
    • Marietta, Georgia, United States, 30060
      • Georgia Retina PC
  • Hawaii
    • ‘Aiea, Hawaii, United States, 96701
      • Retina Consultants Of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Illinois Eye and Ear Infirmary
    • Oak Forest, Illinois, United States, 60452
      • University Retina and Macula Associates, PC
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Raj K. Maturi, MD PC
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
    • Baltimore, Maryland, United States, 21209
      • The Retina Care Center
    • Chevy Chase, Maryland, United States, 20815
      • Retina Group of Washington
    • Hagerstown, Maryland, United States, 21740
      • Cumberland Valley Retina Consultants
    • Waldorf, Maryland, United States, 20602
      • Chesapeake Retina Centers - Waldorf
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Associated Retinal Consultants - Royal Oak
  • Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Retina Consultants Minnesota
  • New York
    • Hauppauge, New York, United States, 11788
      • Long Island Vitreoretinal Consultants;Opthalmology
    • Liverpool, New York, United States, 13088
      • Retina Vitreous Surgeons of CNY PC
    • Lynbrook, New York, United States, 11563
      • Opthalmic Consultants of LI
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Western Carolina Retinal Associate PA
    • Cary, North Carolina, United States, 27511
      • North Carolina Retina Associates
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
    • Hickory, North Carolina, United States, 28602
      • Graystone Eye
    • Wake Forest, North Carolina, United States, 27587-3803
      • North Carolina (NC) Retina Associates - Wake Forest Office
    • Winston-Salem, North Carolina, United States, 27103-6970
      • Piedmont Retina Specialists
  • Ohio
    • Blue Ash, Ohio, United States, 45242-5537
      • Cincinnati Eye Institute
    • Cleveland, Ohio, United States, 44016
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43212
      • Ohio State Eye and Ear Institute
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74114
      • Tulsa Retina Consultants
  • Oregon
    • Springfield, Oregon, United States, 97477
      • Cascade Medical Research Institute LLC
  • Pennsylvania
    • Erie, Pennsylvania, United States, 16505
      • Erie Retina Research
    • Philadelphia, Pennsylvania, United States, 19107-5109
      • Wills Eye Hospital
    • Sewickley, Pennsylvania, United States, 15143
      • Sewickely Eye Group
  • South Carolina
    • West Columbia, South Carolina, United States, 29169-2429
      • Palmetto Retina Center
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Charles Retina Institute
  • Texas
    • Abilene, Texas, United States, 79606
      • Retina Research Institute of Texas
    • Arlington, Texas, United States, 76012
      • Texas Retina Associates
    • Austin, Texas, United States, 78705
      • Austin Retina Associates
    • Austin, Texas, United States, 78750
      • Austin Clinical Research LLC
    • Bellaire, Texas, United States, 77401
      • Retina & Vitreous of Texas
    • Dallas, Texas, United States, 75231
      • Texas Retina Associates
    • McAllen, Texas, United States, 78550-9207
      • Valley Retina Institute P.A.
    • San Antonio, Texas, United States, 78240
      • Medical Center Ophthalmology Associates
    • San Antonio, Texas, United States, 78240
      • Retina Consultants of Texas - San Antonio
    • San Antonio, Texas, United States, 78251-4551
      • Brown Retina Institute
    • The Woodlands, Texas, United States, 77384
      • Retina Consultants of Texas
    • Willow Park, Texas, United States, 76087
      • Strategic Clinical Research Group, LLC
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Retina Associates of Utah, PLLC;Clinical Research
  • Virginia
    • Lynchburg, Virginia, United States, 24502-4271
      • Piedmont Eye Center
    • Norfolk, Virginia, United States, 23502
      • Wagner Kapoor Institute
    • Richmond, Virginia, United States, 23230
      • Virginia Eye Institute - Richmond - 7301 Forest Ave
    • Richmond, Virginia, United States, 23235-1962
      • Retina Institute of Virginia
  • Washington
    • Spokane, Washington, United States, 99204
      • Spokane Eye Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documented diagnosis of diabetes mellitus (DM) (Type 1 or Type 2) with glycated hemoglobin (HbA1c) < 12%
• Macular thickening secondary to DME involving the center of the fovea > 325 microns
• Decreased VA attributable primarily to DME between 25 and 73 ETDRS letters

Exclusion Criteria:

• Currently untreated DM or previously untreated participants who initiated oral anti-diabetic medication or insulin within 90 days prior to Day 1
• Uncontrolled blood pressure (BP)
• Pregnancy or breastfeeding, or intention to become pregnant during the study
• For Parts 1-4: IVT anti-VEGF treatment within 90 days prior to Day 1; For Part 5: IVT anti-VEGF treatment within 120 days prior to Day 1 or IVT anti-VEGF treatment prior to Day 1 for treatment naïve participants
• Treatment with SUSVIMOTM (ranibizumab injection) prior to Day 1
• Any IVT or periocular (sub-tenons) corticosteroid treatment within 6 months prior to Day 1
• Any current or history of ocular disease other than DME that may confound assessment of the macula or affect central vision
• Proliferative diabetic retinopathy (PDR) in the study eye
• Active or history of uveitis, vitritis (grade trace or above), and/or scleritis in either eye Other protocol-specified inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Single Ascending Dose (SAD) Stage; Participants received a single dose of RO7446603 at five different dose levels as IVT injection on Day 1.	Drug: RO7446603; Participants will receive RO7446603 as an IVT injection per the schedule described in the treatment arms.
Experimental: Part 2: Multiple Dose (MD) Monotherapy Stage; Participants received four different dose levels of RO7446603 (two doses at each planned dose level) as IVT injection, every 8 weeks (Q8W).	Drug: RO7446603; Participants will receive RO7446603 as an IVT injection per the schedule described in the treatment arms.
Experimental: Part 3: MD Co-administration With Aflibercept Stage; 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).	Drug: RO7446603; Participants will receive RO7446603 as an IVT injection per the schedule described in the treatment arms.; Drug: Aflibercept; Participants will receive aflibercept as an IVT injection per the schedule described in the treatment arm.
Experimental: Part 4: MD Co-administration With Faricimab Stage; 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.	Drug: RO7446603; Participants will receive RO7446603 as an IVT injection per the schedule described in the treatment arms.; Drug: Faricimab; Participants will receive faricimab as an IVT injection per the schedule described in the treatment arms.; Other Names: Vabysmo
Experimental: Part 5: MD Co-mixed With Faricimab Stage; 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.	Drug: RO7446603; Participants will receive RO7446603 as an IVT injection per the schedule described in the treatment arms.; Drug: Faricimab; Participants will receive faricimab as an IVT injection per the schedule described in the treatment arms.; Other Names: Vabysmo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parts 1-5: Percentage of Participants With Adverse Events (AEs)		From study start through end of study (Up to approximately 58 months)
Parts 1-5: Percentage of Participants With Ocular AEs		From study start through end of study (Up to approximately 58 months)
Part 1: Change in Best Corrected Visual Acuity (BCVA) Over Time	BCVA will be measured via Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters using a set of three precision VisionTM or lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity (VA) examiner. The range of EDTRS is 0 to 100 letters. Higher scores indicate improvement in VA.	From Baseline up to Week 16
Parts 2-4: Change in BCVA Over Time	BCVA will be measured via ETDRS chart at a starting distance of 4 meters using a set of three precision VisionTM or lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified VA examiner. The range of EDTRS is 0 to 100 letters. Higher scores indicate improvement in VA.	From Baseline up to Week 28
Part 5: Change From Baseline in BCVA Averaged Over Weeks 52 and 56	BCVA will be measured via ETDRS chart at a starting distance of 4 meters using a set of three precision VisionTM or lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified VA examiner. The range of EDTRS is 0 to 100 letters. Higher scores indicate improvement in VA.	From Baseline up to Week 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 5: Proportion of Participants Gaining ≥ 15 Letters in BCVA From Baseline Averaged Over Weeks 52 and 56	BCVA will be measured via ETDRS chart at a starting distance of 4 meters using a set of three precision VisionTM or lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified VA examiner. The range of EDTRS is 0 to 100 letters. Higher scores indicate improvement in VA.	From Baseline up to Week 56
Part 5: Percentage of Participants Gaining ≥ 15, ≥ 10, ≥ 5, or ≥ 0 Letters in BCVA From Baseline Over Time	BCVA will be measured via ETDRS chart at a starting distance of 4 meters using a set of three precision VisionTM or lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified VA examiner. The range of EDTRS is 0 to 100 letters. Higher scores indicate improvement in VA.	From Baseline up to Week 56
Part 5: Percentage of Participants Avoiding a Loss of ≥ 15, ≥ 10, ≥ 5, or ≥ 0 Letters in BCVA From Baseline Over Time	BCVA will be measured via ETDRS chart at a starting distance of 4 meters using a set of three precision VisionTM or lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified VA examiner. The range of EDTRS is 0 to 100 letters. Higher scores indicate improvement in VA.	From Baseline up to Week 56
Part 5: Change From Baseline in BCVA Score Over Time	BCVA will be measured via ETDRS chart at a starting distance of 4 meters using a set of three precision VisionTM or lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified VA examiner. The range of EDTRS is 0 to 100 letters. Higher scores indicate improvement in VA.	From Baseline up to Week 56
Parts 1-4: Serum Concentration of RO7446603 Total Fab		Part 1: From Baseline up to Week 16; Parts 2-4: From Baseline up to Week 28
Parts 1-5: Aqueous Humor Concentration of RO7446603 Measured as Total Fab		From study start through end of study (Up to approximately 58 months)
Parts 1-5: Number of Participants With Serum Treatment-emergent Anti-drug Antibody (ADA) Formation to RO7446603		From study start through end of study (Up to approximately 58 months)

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2022
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): April 30, 2027

Study Registration Dates

• First Submitted: February 26, 2025
• First Submitted That Met QC Criteria: February 26, 2025
• First Posted (Actual): February 28, 2025

Study Record Updates

• Last Update Posted (Actual): April 27, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Retinal Diseases; Retinal Degeneration; Macular Degeneration; Edema; Macular Edema; Antineoplastic Agents; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; aflibercept; faricimab
• Other Study ID Numbers: GR43828; ISRCTN14152148 (Registry Identifier: ISRCTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No