Table 1: Percent IRAK4 Change from Baseline in PBMC at 48 Hours Post-Dose using Mass Spectrometry
| | | | | | | | | | | | | | | | |
| | | Placebo
(n=13) | | Cohort 1
(n=6) | | Cohort 2
(n=6) | | Cohort 3
(n=6) | | Cohort 4
(n=6) | | Cohort 5
(n=7) | | Cohort 6
(n=5) | | Cohort 7
(n=6) |
KT-474 dose | | — | | 25 mg | | 75 mg | | 150 mg | | 300 mg | | 600 mg | | 1000 mg | | 1600 mg |
Mean IRAK4 Change | | -1% | | -26%
(p=0.1) | | -73%
(p<0.0001) | | -81%
(p<0.0001) | | -84%
(p<0.0001) | | -96%
(p<0.0001) | | -93%
(p<0.0001) | | -95%
(p<0.0001) |
The Company also announced that proof-of-biology was also established, with inhibition of ex vivo R848- or LPS-mediated induction of multiple pro-inflammatory cytokines in whole blood at doses and exposures associated with mean IRAK4 reduction in PBMC of ³85% at 24-48 hours post-dose. In Cohort 7, where mean IRAK4 reduction at 24 and 48 hours was 89% and 95%, respectively, mean maximum cytokine inhibition as great as 97% was observed (see Table 2). KT-474 demonstrated oral bioavailability, a half-life supportive of daily dosing, and dose-dependent plasma exposures that plateaued after 1000 mg. KT-474 was observed to be well-tolerated; mild to moderate, self-limited headache and nausea were the most common possible or probable treatment-related adverse events, and there were no serious adverse events.
Table 2: Mean Maximum Percent Change from Baseline at 24-48 Hours in Ex Vivo Proinflammatory Cytokine Induction by R848 and LPS in Whole Blood at Cohort 7
| | | | | | | | | | | | | | | | |
Proinflammatory Cytokine | | IFNg | | IL1ß | | IL6 | | IL8 | | IL10 | | IL12 | | IL17 | | TNFα |
R848 (TLR 7/8 agonist) | | -97%2 | | -92%1 | | -88%1 | | -54% | | -89%1 | | -93%1 | | -79%1 | | -88%2 |
LPS (TLR 4 agonist) | | -42% | | -68%1 | | -62%1 | | -81%1 | | -83%1 | | -35%2 | | -43%2 | | -42%2 |
1 = p value < 0.01; 2 = p value < 0.05, for comparison to placebo
The disclosure under this Item 8.01 contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, express or implied statements regarding the Company’s views on KT-474 as validating its platform and approach to drug development; strategy, business plans and objectives for its IRAK4 degrader program; and plans and timelines for the clinical development of its product candidates, including the therapeutic potential and clinical benefits thereof. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, those risks and uncertainties related: the Company’s ability to execute on its strategy; the therapeutic potential and safety of KT-474; the timing and completion of the Company’s Phase 1 study of KT-474 and final audit and quality controlled verification of initial data and related analyses; positive results from initial data analyses not necessarily being predictive of final results; the Company’s planned regulatory submissions and developments; and other risks identified in the Company’s SEC filings, including those risks discussed under the heading “Risk Factors” in the Company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2021, as well as other risks detailed in the Company’s subsequent filings with the SEC. We caution you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. The Company disclaims any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. Any forward-looking statement included in this Item 8.01 speaks only as of the date on which it was made. The Company undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.
