KSI-301 anti-VEGF biopolymer conjugate
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 macula leading to leakage of fluid and blood leading to visual distortion and acute vision loss. If untreated or undertreated, wet AMD leads to scar formation and permanent damage that results in blindness. Wet AMD is the leading cause of vision loss among individuals 50 years of age and older in the United States and other developed countries.
Are there medicines available to treat wet AMD?
Excess VEGF levels inside the eye play a role in the development of abnormal blood vessels in wet AMD. Current approved therapies for wet AMD involve frequent injections of proteins, every 4 to 8 weeks, that block VEGF.
Are these medicines effective?
Although intravitreal injections of anti-VEGF agents can be effective, the frequent visits to the doctor’s office are burdensome and difficult to maintain. Non-compliance to these regimens results in vision loss from undertreatment.
Each time the treatment interval is overextended, 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.
How KSI-301 Can Help
Our therapeutic candidate KSI-301 is a novel anti-VEGF biologic built on our propriety antibody biopolymer conjugate (ABC) platform.
KSI-301 is administered as an intravitreal injection and designed to provide sustained inhibition of VEGF for up to 6 months. The unique properties of KSI- 301 aim to provide patients with long-term control of their wet AMD with improved vision outcomes while reducing the burden of frequent anti-VEGF injections.
What is Diabetic Macular Edema (DME)?
The worldwide diabetes epidemic is putting more working-age individuals at risk of blindness.
Diabetes is the leading cause of blindness among working-age adults. Diabetic retinopathy (DR) is a complication of diabetes. Long-standing elevated blood sugar levels (hyperglycemia) due to diabetes damages blood vessels in the retina and cause them to leak fluid into the retina. Elevated levels of intraocular VEGF play a role in the development and progression of DR.
Diabetic macular edema (DME) is a complication of diabetic retinopathy. DME is the most common cause of vision loss in patients with diabetic retinopathy. Abnormal leakage and fluid from damaged blood vessels accumulate in the macula, the region within retina responsible for central vision, and result in blurry vision. DME can occur at any stage of diabetic retinopathy.
KSI-301 for DME
Our therapeutic candidate KSI-301 is a novel anti-VEGF biologic built on a propriety antibody biopolymer conjugate (ABC) platform KSI-301 is designed to have extended ocular half-life, higher potency, and improved ocular tissue bioavailability.
KSI-301 is administered as an intravitreal injection and designed to provide sustained inhibition of VEGF for up to 6 months. The unique properties of KSI- 301 aim to provide patients with long-term control of their DME with improved vision outcomes while reducing the burden of frequent anti-VEGF injections. In addition, KSI-301 is designed to halt and reverse DR progression with long-term efficacy that can reduce the risk of vision-threatening complications from DR.
What is Retinal Vein Occlusion (RVO)?
The retina needs a constant supply of oxygen and nutrients delivered by blood vessels. In retinal vein occlusion (RVO), a blockage occurs in either the central retinal vein (CRVO) or a branch retinal vein (BRVO). As a result of the RVO, ischemia develops within the retina and VEGF levels are elevated. Patients with RVO are at risk for developing:
- Macular edema: Fluid leakage into the center of the retina causing decreased vision
- Retinal and Anterior Segment Neovascularization: Abnormal, blood vessels grow in response to ischemia and excess VEGF. Neovascularization easily bleeds and may lead to severe vision loss and neovascular glaucoma.
KSI-301 FOR RVO
Our therapeutic candidate KSI-301, currently in clinical development, is a novel anti-VEGF biologic designed to have an extended ocular half-life. Ischemia due to vein occlusion results in secretion of vascular endothelial growth factor (VEGF) that causes further vascular leakage and edema. Anti-VEGF agents have become a very common treatment to improve the clinical outcomes in patients with RVO. As in wet AMD, an intensive treatment frequency is required to achieve optimal outcomes with currently-approved anti-VEGFs agents. However, many patients are lost to follow up due to the frequent injections and real-world outcomes in RVO do not meet the promise shown 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.
KSI-301 is being developed towards a once every two months or longer treatment regimen.
What is Diabetic Retinopathy?
Diabetic retinopathy is a complication of diabetes. High blood sugar levels (hyperglycemia) damages and weakens blood vessel in the retina and precedes further complications that irreversibly damage vision.
Non-proliferative diabetic retinopathy (NPDR) is the early stage of diabetic retinopathy. Many diabetic patients have NPDR which is characterized by weakened blood vessels that lead to microaneurysms. The microaneurysms rupture and form hemorrhages within the retina and weakened blood vessels can leak and cause fluid to seep into the retina. These complications this can interfere with the normal function of the macula and cause vision loss. As NPDR progresses, vessels eventually become obstructed and block off blood flow.
Proliferative diabetic retinopathy (PDR) is the more advanced stage of diabetic eye disease. Retinal cells release angiogenic signals (VEGF) to stimulate growth of new retinal blood vessels to bypass the damaged or obstructed vessels (neovascularization). The new vessels are abnormal, fragile and easily tear leading to vitreous hemorrhage and sudden vision loss.
KSI-301 for Diabetic Retinopathy
Our therapeutic candidate KSI-301, currently in clinical development, is a novel anti-VEGF biologic designed to have an extended ocular half-life. Ischemia due to vein occlusion results in secretion of vascular endothelial growth factor (VEGF) that causes further vascular leakage and edema. Anti-VEGF agents have become a very common treatment to improve the clinical outcomes in patients with diabetic retinopathy. As in wet AMD, an intensive treatment frequency is required to achieve optimal outcomes with currently-approved anti-VEGFs agents. However, many patients are lost to follow up due to the frequent injections and real-world outcomes in diabetic retinopathy do not meet the promise shown in clinical trials. By extending on mechanism treatment interval, KSI-301 may relieve the high treatment burden for patients, their family members, and physicians.
KSI-301 is being developed towards a once every four to six-month treatment regimen – a possible gamechanger that may provide the opportunity for real prevention.
KSI-501 anti-IL6 and anti-VEGF bispecific biopolymer conjugate
How does inflammation contribute to retinal diseases?
In addition to abnormal vessel growth (angiogenesis), inflammation has been implicated in the pathogenesis of several retinal diseases. Anti- inflammatory therapies such as steroids have been effective in treating both uveitis (a spectrum of diseases with intraocular inflammation as a defining characteristic) and DME. Similarly, genetically inherited variations in the interleukin 6, or IL-6, gene have been associated with higher PDR incidence in patients with type 2 diabetes.
Moreover, disease progression in AMD, DR and RVO have been reported to be associated with increased serum and/or ocular levels of IL-6. Additionally, chronic inflammatory cells have been seen on the surface of the basement membrane behind the retina in eyes with wet AMD. Interestingly, IL-6 has been implicated in resistance to anti-VEGF treatments in DME patients. This in part is believed to be an indirect result of IL-6 mediated upregulation of VEGF expression as well as more direct VEGF-independent angiogenic functions mediated by IL-6 signaling that occur in the presence of VEGF inhibitors.
How KSI-501 Can Help
Our KSI-501 product candidate is a dual inhibitor Trap-Antibody-Fusion, or TAF, bioconjugate molecule designed to target concurrent inflammation and abnormal angiogenesis observed in the pathogenesis of retinal vascular diseases. KSI-501 acts through an anti-VEGF mechanism and an anti- inflammatory mechanism that targets the potent cytokine IL-6. Similar to KSI-301, KSI-501 uses the ABC Platform and is a bioconjugate of the TAF protein conjugated to our phosphorylcholine-based biopolymer. Preclinical binding and functional studies demonstrate that the TAF protein binds specifically and simultaneously to its intended targets. We believe that this dual inhibition may provide a superior treatment option for patients with retinal vascular diseases and in particular those patients with diseases known to have a high inflammatory component such as DME, as well as in ocular inflammatory diseases such as uveitis.
KSI-601 triplet biopolymer conjugate
What is Dry AMD?
Of the nearly 11 million individuals affected by AMD in the U.S., approximately 80-90% are the “dry” atrophic type. Dry age-related macular degeneration is characterized by deteriorating macula function caused by the formation of debris (drusen) on the retina causing the macula to deteriorate overtime. Dry AMD is thought to be caused by a combination of hereditary and environmental factors. Dry AMD patients can experience some vision loss and frequently experience substantial functional limitations, including vision fluctuations, loss of peripheral vision, and reduced night vision.
How KSI-601 Can Help
The etiology of dry AMD and its advanced stages is multifactorial. Monotherapies evaluated for clinical utility in this disease have exhibited nominal or no improvement in clinical outcomes. The multiple pathogenic mechanisms in dry AMD initiation and progression include hyperinflammation, cell degeneration and atrophy, hypoxia, and dysfunctional lipid metabolism, among others. These warrant the development of therapies which can interface with these many disease mediators. Furthermore, different disease targets, which may be inside of the cell or located extracellularly, may require multiple therapeutic modalities; for example, a small molecule may be tailored for intracellular targets that are considered undruggable by antibodies. Therefore a single molecule triplet therapy enabled by our platform accommodates large and small molecules alike and facilitates, for the first time, the modulation of multiple distinct pathological processes in parallel.
Our 2022 Vision
KSI-301 PRODUCT VISION
We are developing KSI-301 to be the only Generation 2.0 anti-VEGF biologic agent, with the objective to provide patients, physicians, and health systems with a new first line agent for wet AMD, DME, RVO and DR
A DIFFERENTIATED PROFILE SUPPORTED BY DATA
Data from our ongoing Phase 1b study1 in treatment-naïve patients inform the design of our pivotal studies
and support a meaningfully differentiated profile in each of the four major retinal vascular diseases
1. Time to first retreatment per protocol-specified criteria, after 3 initial monthly doses of 2.5 mg or 5 mg KSI-301. Data from Phase 1b KSI-301 presentation at ASRS 2020 Virtual Annual Meeting, complete presentation available at ir.Kodiak.com
2. Data from Phase 1b KSI-301 presentation at AAO 2019 Annual Meeting, complete presentation available at ir.Kodiak.com
current medicines must be dosed on an intensive regimen
to maintain vision
Patients are undertreated and losing vision today1
Adherence to an intensive treatment regimen is difficult for patients and caregivers.
Without frequent treatment, vision loss due to under-dosing can begin quickly and within 3 months.
1. Retrospective studies demonstrate that most patients receive ~5 injections a year.
2. The AURA Study, adapted from Holz FG et al. BR J Ophthalmol 2015; 99 (2): 220-226.
3. Adapted from Sierra AMD, Khanani A, et al. Ophthal. Retina 2020 Feb; 4(2):122-123. EMR= Electronic Medical Records
KSI-301 aims to maintain therapeutic activity for longer
KSI-301 is a novel anti-VEGF biologic designed to rapidly inhibit VEGF and provide extended durability of action to reduce the burden of frequent anti-VEGF injections. Delivering potent and sustained VEGF inhibition enables patient compliance, results in long-term efficacy and improves visual acuity outcomes.