- The near absence of intraocular inflammation in the phase I / Ib data from KSI-301 reinforces optimism for favorable safety.
- Phase I / Ib durability data for KSI-301 shows its potential for six months without treatment.
- The non-inferiority data compared to Eylea might be enough for the KSI-301 to enter the AMD wet market.
Kodiak Sciences’ KSI-301 may have an advantage over its approved competitors in age-related macular degeneration (AMD) due to the potential absence of intraocular inflammation (IOI) as a contraindication on its FDA label, if approved.
Another advantage of KSI-301 is that its dosage is more spread out compared to its potential competition, which allows the patient to be less exposed to the risk of side effects.
Considering the very low level of IOI in the phase I / Ib KSI-301 study (NCT03790852), this may be a valuable selling point against Beovu (brolucizumab) from Novartis and Eylea (aflibercept) from Regeneron Pharmaceuticals, because both have this side effect problem. . In addition, data from KSI-301 shows that it has lasting effectiveness; Phase I / Ib patients went untreated for at least six months during the first year of treatment.
DAZZLE has Eylea as an active comparator, which can be a high efficiency bar.
However, experts told this news service that such market benefits would still depend on the success of the ongoing DAZZLE Phase IIb / III study (NCT04049266). While the phase I / Ib reports of the positive efficacy of KSI-301 raised some optimism about the success of DAZZLE, the early phase trial did not have an active comparator arm. DAZZLE has Eylea as an active comparator, which can be a high efficiency bar. Nevertheless, KSI-301 need only declare non-inferiority to allow it to enter the market.
DAZZLE’s baseline data is expected in the first quarter of 2022. GlobalData’s consensus forecast estimates that KSI-301 will have peak global sales of $ 1.23 billion in 2027. Kodiak, which has a market cap of 5.21 billion dollars, did not respond to a request for comment.
Possible lack of IOI as a distinguishing feature
Experts note that KSI-301 could potentially overcome IOI, as seen with Beovu and Eylea, giving KSI-301 a long-term business advantage. IOI, also known as uveitis, is a form of inflammation that often affects the middle layer of the eye and can lead to vision loss. In the phase I / Ib KSI-301 study, only two of the 710 total doses applied to 130 subjects resulted in OI, a rate of 0.28%, according to a company presentation from August 2021.
On the other hand, in Beovu Phase III trials, HAWK (NCT02307682) and HARRIER (NCT02434328), the 6 mg dose had a rate of 2.2% (eight events in 360 subjects) and 0.8% (three events in 370 subjects), respectively. Likewise, data pooled from the phase III trials of Eylea VIEW1 (NCT00509795) and VIEW2 (NCT00637377), which included 1,223 subjects at a 2 mg dose, had a rate of 3%, according to its FDA label. Both have IOI as a contraindication.
While the three approaches target vascular endothelial growth factor A (VEGF-A), they have different mechanisms. KSI-301 is an antibody biopolymer conjugate that binds to VEGF-A to prevent the formation of new blood vessels. Eylea is a recombinant fusion protein that also binds to VEGF-A, but also to placental growth factor (PIGF). Beovu is a single chain antibody fragment that works by inhibiting VEGF-A by preventing it from interacting with its receptors. However, studies so far show that linking the incidence of IOI to a single cause remains difficult, possibly linked to multiple factors.
If the benefit of the side effect profile of KSI-301 remains in DAZZLE, this may be an avenue where it can potentially exceed available treatments.
If the benefit of KSI-301’s side effect profile remains in DAZZLE, this may be an avenue where it can potentially exceed available treatments, says Tennessee Retina vitreoretinal uveitis and vitreoretinal surgeon Dr Sruthi Arepalli. She expects this positive safety profile to be reflected in DAZZLE because its trial design avoids potential cases of IOI. DAZZLE excludes subjects with active eye or periocular infection or inflammation in either eye, meaning patients predisposed to IOI were excluded, she explains. These patients were also excluded from the phase I / Ib trial, which allows for consistency, she adds. The Beovu phase III trials also excluded these patients. The two phase III Eylea studies excluded patients with a history of IOI.
While KSI-301 may have this IOI advantage, Axon Clinical Director of Clinical Research Dr Martin Wallisch notes that it is important to remain cautious when drawing conclusions based on early data. In the HAWK study of Eylea, a lower dose of 2 mg was also studied and had a rate of 0.3% (single event in 360 subjects), with no IOI event reported in the 2 mg arm of the HARRIER test. The 5 mg dose of KSI-301 could potentially carry higher risks of side effects, adds ophthalmologist Dr Matias Iglicki. In phase I / Ib, doses of 2.5 mg and 5 mg of KSI-301 were studied, with detailed data to come. DAZZLE is enrolling 550 patients, while the phase III Beovu and Eylea trials enrolled a total of 1,817 and 2,412 patients, respectively.
Patients satisfied with available therapies are unlikely to switch to KSI-301 if they don’t have an IOI problem, Arepalli adds. GlobalData consensus forecasts estimate that Beovu will peak worldwide sales of $ 508 million in 2027. Bayer is the former US distributor of Eylea. Eylea has total peak sales estimates of $ 9.15 billion in 2027.
Longer dosage range of the intriguing KSI-301
KSI-301 has another feature that might prompt patients to change. KSI-301 may have a longer processing interval compared to its competitors, Arepalli says. In the Phase I / Ib KSI-301 trial, approximately 66% of subjects with wet AMD were untreated for at least six months in the first year.
In DAZZLE, KSI-301 is administered at 12, 16 and 20 week intervals. In contrast, Beovu and Eylea are given once every four weeks for the first three months. Beovu switches to treatment every eight to 12 weeks, while Eylea switches to treatment every eight weeks. Indeed, KSI-301 can serve as a longer-term treatment than the other anti-VEGFA active ingredients, Beovu and Eylea, adds Arepalli.
Beovu, Eylea, and KSI-301 are administered intravitreally, which involves injection into the back of the eye.
The need for repeated treatments is a major challenge for retinal physicians, says Arepalli. Beovu, Eylea, and KSI-301 are administered intravitreally, which involves injection into the back of the eye. Reducing the number of injections will reduce the risk of side effects, agrees Iglicki.
The larger dosage of KSI-301 could potentially serve as a bridging treatment, Arepalli adds. For example, KSI-301 could be used in patients switching from Eylea, which has more frequent dosing, to long-term delivery systems such as Susvimo ââfrom Roche (ranibizumab), she explains. . Susvimo ââis a rechargeable implant, which may only require two treatments per year.
The phase I / Ib KSI-301 trial also enrolled patients with diabetic macular edema (DME) and macular edema due to retinal venous occlusion (RVO). KSI-301 is also in phase III in these indications. With phase I / Ib also showing lasting results for KSI-301 in these two indications, these patients would also have potentially fewer injection treatments each year, Arepalli says.
DAZZLE remains crucial
According to Arepalli, the results of DAZZLE could follow the positive trends in safety and efficacy defined by the phase I / Ib data. Phase I / Ib had a secondary endpoint of mean change in best corrected visual acuity (BCVA) measured through week 72. Data showed a mean increase in BCVA of 5.7 in ETDRS, a visual acuity chart, in wet AMD.
However, the experts remained cautious in stating DAZZLE as a safe bet to get a positive result. There have been previous ophthalmic actives that have shown disappointing Phase III results despite positive Phase II data, Iglicki says.
There have been previous ophthalmic actives that delivered disappointing Phase III results despite positive Phase II data.
With DAZZLE using Eylea as an active comparator, this may set the bar high for KSI-301 to provide positive results, says Wallisch, who is a DAZZLE investigator. Phase I / Ib did not have an active comparator. DAZZLE uses BCVA as the primary endpoint. In the VIEW1 trial, Eylea subjects in the four week dosing arm had a mean change of 10.9 in ETDRS at 52 weeks.
Eylea is the gold standard in wet AMD and studies use Eylea as an active comparator, Wallisch adds. In that sense, if KSI-301 shows non-inferiority over Eylea, that would argue in favor of approval of KSI-301 and its use in the real world, he notes.