What is WET AMD?
Age-related macular degeneration (AMD) is a common degenerative disease of the retina, the light-sensitive tissue in the back of the eye. Wet AMD occurs when the abnormal blood vessels (choroidal neovascularization) grow underneath the retina. Choroidal neovascularization leads to fluid and blood under the retina causing visual distortion and acute vision loss. If untreated or undertreated, wet AMD leads to hemorrhage, scar formation, and permanent damage that results in blindness.
There are medicines approved to treat wet AMD, called anti-VEGF agents, that when injected into the eye on an intensive regimen allows patients to gain vision and maintain this gain over many years.
But in real-life practice, many patients can’t get treated frequently enough and do not receive high intensity (i.e. per label) treatment. Because of this, in the real world, visual acuity fairly rapidly returns to baseline or even worse.
Each time the patient or the physician or the health system overextends the treatment interval, the patient’s disease can reactivate, which leads to incremental and cumulative damage to the retina. Over time this may lead to permanent loss of vision.
In summary, despite the availability of anti-VEGF therapies, many patients are still losing vision and even going blind because of undertreatment. The next generation of retinal therapy for wet AMD needs to have a durability of effect that is matched to how it will be used in the real world, not just in clinical trials.
How this investigational therapy can help:
Our therapeutic candidate KSI-301, currently in clinical development, is a novel anti-VEGF biologic designed to have extended ocular half-life, high potency and high ocular tissue bioavailability and biocompatibility.
We designed KSI-301 with the goal to keep the disease under control for longer, aiming to dose as infrequently as every 3, 4, or even 5 months. This has the potential to improve patients’ lives by providing meaningful and tangible benefits:
- Fewer injections and clinic visits
- Early improvements in vision
- Vision improvements maintained over the long term
What is Diabetic Retinopathy?
Diabetes is the leading cause of blindness among working-age adults. Diabetic retinopathy (DR) is caused by long-standing hyperglycemia (elevated blood sugar levels) and additional chronic metabolic problems that arise due to diabetes over time.
When DR is in its early stages, blood vessels in the retina are damaged and can begin to leak fluid into the retina, a problem called diabetic macular edema (DME). In advanced stages, new and abnormal blood vessels form which may break and bleed. Fluid and hemorrhage interfere with vision and may further cause irreversible visual impairment due to retinal scarring and even retinal detachment.
The worldwide epidemic of diabetes is putting more working-age individuals at risk of blindness. Improving and maintaining vision in eyes with diabetic retinopathy is possible today but requires frequent injections at the eye doctor.
How this investigational therapy can help
Our therapeutic candidate KSI-301, currently in clinical development, is a novel anti-VEGF biologic designed to have an extended ocular half-life. Anti-VEGF agents have been shown to improve vision and reduce edema in patients with DME. As in wet AMD, an intensive treatment frequency is required to achieve optimal outcomes with currently-approved anti-VEGFs agents. The result is that many patients are undertreated and real-world outcomes in DME are not as good as they are in clinical trials. By extending the on mechanism treatment interval, KSI-301 may relieve the high treatment burden for patients, their family members, and physicians.
In DR without DME, anti-VEGF agents may prevent the worsening of diabetic eye disease and, in fact, can lead to an improvement in disease severity. But the frequent injections required by these agents is too high a barrier and only the minority of DR patients – those with severe, vision-threatening diabetic eye disease like DME – are currently receiving treatment. KSI-301 is being developed towards a once every four to six month treatment regimen which may enable the large majority of patients with earlier disease to be maintained on effective therapy.
What is Diabetic Macular Edema?
Diabetic Macular Edema (DME) is the most common cause of vision loss in people with Diabetic Retinopathy (DR). DME occurs when there is abnormal leakage and accumulation of fluid in the macula from damaged blood vessels in DR patients. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of DME.
How This Therapeutic Candidate Could Help
KSI-501 is a dual inhibitor biconjugate targeting vascular leakage, abnormal angiogenesis and concurrent inflammation that can be present in DME. KSI-501 consists of an α-VEGF Trap and α-IL-6 Antibody Fusion (TAF) protein, and uses ABC PlatformTM technology with durability, potency availability, and biocompatibility. KSI-501 could provide an effective treatment option for DME patients, especially those who do not respond to anti-VEGF alone.
What is Uveitis?
Uveitis refers to a spectrum of inflammatory diseases that produce swelling and could potentially lead to permanent eye tissue damage. When severe, uveitis can result in irreparable complications including vision loss and pain.
How This Therapeutic Candidate Could Help
By targeting both the potent immune mediator IL-6 as well as the angiogenic cytokine VEGF, KSI-501 may provide synergistic action towards reducing the inflammatory drive and swelling in patients with uveitis, potentially improving their vision and preventing sight-threatening complications.
What is treatment-resistant wet AMD?
Not everyone responds in the same way to anti-VEGF therapy. For example, some people may still lose vision despite frequent re-treatment. In some cases, the variability in outcomes may be due to other biological processes whose activity differ among patients and AMD, for instance, inflammation or wound healing response. We refer to patients whose disease activity persists despite anti-VEGF therapy and who lose vision despite anti-VEGF therapy as “treatment resistant.”
How this therapeutic candidate could help
KSI-201 is a novel single agent Antibody Boppolymer Conjugate that inhibits VEGF along with other pleiotropic biologic pathways that have been implicated in VEGF-independent wound healing, angiogenesis, and inflammation. By combining inhibition of VEGF plus these pathways, KSI-201 may be able to address cases of treatment-resistant wet AMD. KSI-201 is currently in the pre-IND stage of development.
What is dry AMD?
Dry AMD is a disease caused by sustained local inflammation in the eye. Deposits of inflammatory substances accumulate on the retina. Over years and even decades, photoreceptors become damaged permanently. Biochemical, genetic, and clinical data suggest that a hyperactive complement system is a primary driver of this inflammation. The complement system is part of our innate immunity which is an evolutionary ancient arm of our immune system. In healthy tissues, the complement system is tightly regulated. In dry AMD, the complement system is out of balance leading to disease and eventual blindness.
How this therapeutic candidate could help you
KSI 401 is a novel Antibody Biopolymer Conjugate in development that blocks activation of the complement system, potentially lessening disease activity in dry AMD patients.
KSI-301 Clinical Development Strategy Overview
KSI-301 Phase 1 Study Design
KSI-301 Phase 1 open-label, single injection, dose escalation study in retinal vascular disease has reached its primary endpoint
KSI-301 Phase 1 Study Conclusions
- KSI-301 safe and well-tolerated at all 3 dose levels
- No dose-limiting toxicities, inflammation, or test article related adverse events
- Optically clear media after each injection
- No anti-drug antibodies detected in any patient
- 5mg top dose selected for Phase 2/3
- Bioactivity observed at every dose level
- Pharmacodynamic effect (OCT imaging)
- Improvements in patient function (visual acuity)
- Rapid time to onset and high magnitude Best Corrected Visual Acuity (BCVA) gains and OCT retinal thickness reductions
- Clinical durability through extended follow-up
- BCVA and OCT improvements sustained to 12 weeks
Dr. Diana Do | Highlights of KSI-301 Phase 1 Study
Dr. Diana Do | Clinical case examples from KSI-301 Phase 1 Study
KSI-301 Phase 1 Study Reactions
Dr. David Brown
“Really exciting stuff. The potential of a real game-changer”
Dr. Nancy Holekamp
Kodiak is “using real-science to create durability in the anti-VEGF era”
Dr. Carl Regillo
“The next generation of anti-VEGFs could give us 4 or 5 months of durability”
Clinical Trials Snapshot
- Phase 1b evaluating multiple doses in treatment-naïve wet AMD, DME, and RVO currently enrolling (NCT03790852)
- Phase 2 in treatment-naïve wAMD starting in 2019 with dosing as infrequently as Q20W and all patients ≥ Q12W (NCT04049266)
- Additional studies in DME, RVO, NPDR in planning
- Dedicated China pivotal programs in planning