Kodiak Discontinues Further Development of Tarcocimab After Phase 3 Trial Data
Kodiak Sciences has announed it discontinuing further development of tarcocimab tedromer, a novel antibody biopolymer conjugate, being evaluated for wet AMD and DME. The decision comes after the GLEAM and GLIMMER studies failed to meet their primary efficacy endpoints.
The GLEAM and GLIMMER studies are identically designed, randomized, double-masked, active comparator-controlled studies evaluating the efficacy, durability and safety of tarcocimab tedromer in 460 and 457 treatment-naïve subjects with DME, respectively. Although high proportions of patients on meaningfully longer treatment intervals were observed with tarcocimab, with half of patients on every 24-week dosing at the primary endpoint, the GLEAM and GLIMMER studies did not meet their primary efficacy endpoints of showing noninferior visual acuity gains for tarcocimab dosed every 8 to 24 weeks after 3 monthly loading doses compared to aflibercept given every 8 weeks after 5 monthly loading doses.
An unexpected increase in cataracts was observed over time in the tarcocimab arms of both GLEAM and GLIMMER, and Kodiak's initial evaluation suggests that this contributed meaningfully to the failure of each study.
The DAYLIGHT study was a randomized, double-masked, active comparator-controlled study evaluating the efficacy and safety of a high intensity dosing regimen of tarcocimab tedromer in 557 treatment-naïve subjects with wet AMD. The DAYLIGHT study met the primary endpoint of noninferior visual acuity gains for tarcocimab dosed monthly compared to aflibercept dosed every 8 weeks following 3 monthly loading doses. Tarcocimab was safe and well tolerated in the study and with a low rate of intraocular inflammation. In the DAYLIGHT study, no imbalance in cataracts was observed between wet AMD patients receiving tarcocimab or aflibercept throughout the one-year study period despite the intensive monthly tarcocimab dosing regimen.
"A successful efficacy, durability and safety outcome in both GLEAM and GLIMMER was the basis of our regulatory and clinical development strategy for tarcocimab," Victor Perlroth, MD, Kodiak's Chief Executive Officer, said in a company news release. "After our unsuccessful phase 2b study in wet AMD last year, we made a number of changes to the GLEAM and GLIMMER study design to increase their probability of success, and we saw the positive impact of those changes in the GLEAM and GLIMMER data. Notably, the conjugate delivered on the promise of early potency and strong consistent durability through the study. After getting these results, the immediate question is why did the GLEAM and GLIMMER studies fail?"
"We have gained three main insights from the initial data analysis. First, through the matched three loading doses, vision and anatomic improvements were strong and comparable between tarcocimab and aflibercept. Second, in a subset of patients to be determined, additional loading doses with tarcocimab might have helped better achieve early disease control to set an even higher visual acuity base entering into the dose interval adjustment phase, but the overall effect of this was not a primary driver of study failure. Third, and most critically, an unforeseen imbalance in cataract adverse events emerged in the last third of the study (19% of patients on tarcocimab versus 9% of patients on aflibercept by the primary endpoint), and we believe this likely was the primary driver for tarcocimab failing to achieve BCVA non-inferiority to aflibercept in these studies," Dr. Perlroth said.
"A sub-analysis of the pseudophakic patients (who enter the study having already had cataract surgery) and who represented 25% of the total study population supports this view as does initial analysis of the OCT anatomic data from the two studies. The development of cataracts did not appear to correlate with the timing or number of tarcocimab doses patients had received. Importantly, in the DAYLIGHT study which explored a maximal, monthly regimen of tarcocimab 5mg in wet AMD patients, a median of 12 tarcocimab doses were given over one year and patients experienced fewer events of cataract on tarcocimab than on aflibercept (3% versus 5%). Thus, what drove the increased incidence of cataracts with tarcocimab in DME remains unclear at this time. Given these findings and results, we are discontinuing development of the tarcocimab program," added Dr. Perlroth.
"While vision improvements were more closely matched in the first two-thirds of each study, at the primary efficacy endpoint of the GLEAM study patients treated with tarcocimab gained an average of 6.4 eye chart letters (to 73.1 letters) compared with 10.3 letters for patients treated with aflibercept (to 76.5 letters)," said Jason Ehrlich, MD, PhD, Kodiak's Chief Medical Officer.
In GLIMMER, patients treated with tarcocimab gained an average of 7.4 eye chart letters at the primary endpoint (to 72.5 letters) compared with 12.2 letters (to 76.4 letters) for patients treated with aflibercept. Half of tarcocimab treated patients were on every 6-month dosing at the primary endpoint, two-thirds achieved at least one 6-month dosing interval during the studies, and three-quarters achieved at least one 5-month or longer treatment interval. Aside from the increase in cataracts, no new or unexpected safety signals were identified in GLEAM and GLIMMER. Intraocular inflammation was rare, occurring in 1.3% and 0.2% of tarcocimab and aflibercept treated patients, respectively. No cases of intraocular inflammation with vasculitis or vascular occlusion were observed. In the DAYLIGHT study, intraocular inflammation occurred in 3.3% of patients treated with monthly tarcocimab and 0.4% of patients treated with aflibercept, again with no vasculitis or occlusion.
Dr. Perlroth said Kodiak remains well financed with approximately $379 million cash and cash equivalents as of June 30, 2023 (unaudited) providing the company with optionality following the wind-down of the tarcocimab program.
"We will be assessing our capabilities and the many learnings gained by Kodiak during the development of tarcocimab as we reset our near-term plan," he said.
"While we have not come to a final conclusion, we remain committed to our vision and mission of developing transformative therapies for high prevalence diseases. In this regard, we believe our KSI-501 program has a differentiated mechanism of action targeting both IL-6 mediated immune-inflammation as well as VEGF mediated angiogenesis and vascular permeability. The KSI-501 clinical program is underway with enrollment in the phase 1 multiple dose escalation study nearly complete. In light of the emergence of late onset cataracts observed with tarcocimab in GLEAM and GLIMMER but not DAYLIGHT, we are assessing whether to continue development of KSI-501 both as (i) its unconjugated protein which is itself a novel bispecific anti-IL-6 antibody / anti-VEGF trap fusion protein and (ii) its bioconjugate form," Dr. Perlroth said. "In this manner, we would continue development of this novel retina program while decreasing our reliance on the ABC platform, thus allowing a more thorough exploration of platform versus product profiles. Meanwhile, we look forward to advancing our triplet platform and other protein therapeutic and small molecule programs. Our triplet platform is designed to enable multi-mechanism targeting of multifactorial diseases by embedding small molecules in the biopolymer backbone to provide a high drug-antibody ratio (DAR). The small molecules can be released over time to achieve sustained inhibition of targeted biological pathways. We plan to explore the utility of this unique combination of high DAR and extended therapeutic benefit in retinal and systemic diseases."
Detailed results of the GLEAM and GLIMMER studies are scheduled to be presented by study investigator Dr. Charles C. Wykoff, MD, PhD, as a late-breaking presentation at the ASRS meeting, which will be held beginning next week in Seattle. The presentation is currently scheduled for Sunday, July 30, 2023 at 3:51pm Pacific Time.