NEWARK, CA / ACCESSWIRE / August 1, 2024 / Protagonist Therapeutics, Inc. ("Protagonist" or the "Company") today announced publication of preclinical and phase 1 clinical data on JNJ-2113 in the journal Scientific Reports, a Nature publication and the 5th most-cited journal in the world, according to the publisher. A link to the publication can be found HERE.

JNJ-2113 is the first- and only-in-class targeted oral peptide inhibitor of the IL-23 receptor in clinical development. Based on the robust efficacy observed in Phase 2 study of moderate to severe plaque psoriasis described in a recent New England Journal of Medicine (NEJM) publication, JNJ-2113 is currently being evaluated in five Phase 3 psoriasis studies in the ICONIC-program. PASI-90 is one of the co-primary endpoints for the ongoing ICONIC-LEAD and ICONIC-ADVANCE 1 and 2 Phase 3 studies, reflecting a higher bar in comparison to the traditional PASI-75 for treatment goals in moderate to severe psoriasis. In addition, a Phase-2b ANTHEM-UC study with JNJ-2113 in ulcerative colitis is also currently in progress.

The Scientific Reports manuscript presented data on the in vitro potency, pharmacokinetic, pharmacodynamic, and safety data of JNJ-2113 in biophysical assays, human immune cells, preclinical rodent models, and in a first-in-human clinical trial in normal healthy volunteers (NHVs). The studies demonstrated that JNJ-2113 is a highly potent peptide that selectively targets IL-23R and inhibits IL-23 signaling, binding to IL-23R with affinity in the single-digit picomolar range. JNJ-2113 inhibition was selective for IL-23R, with no apparent impact on IL-12 signaling, in contrast to the TYK2 inhibitor, deucravacitinib (BMS-986165), which inhibits both IL-12 and IL-23 signal transduction, in addition to Type 1 IFN signaling. JNJ-2113 demonstrated minimal activity against a panel of 44 potential secondary targets at pharmacodynamically active concentrations.

JNJ-2113 demonstrated efficacy in both an IL-23 induced skin inflammation model and a trinitrobenzene sulfonic acid (TNBS) induced colitis model, providing preclinical proof-of-concept (POC) and rationale for its clinical evaluation in both psoriatic and inflammatory bowel diseases. In blood from rats receiving oral JNJ-2113, dose-dependent inhibition of ex-vivo IL-23-stimulated IL-17A production was observed. These effects were attributed to JNJ-2113's potency for inhibition of IL-23 signaling and downstream cytokine production, combined with the low in vivo expression of IL-23R. Nonclinical data in monkeys showed that JNJ-2113 was distributed to a variety of tissues compared to the limited tissue distribution reported for monoclonal antibodies. In rat inflammation models, tissue-specific signs of inflammation and IL-23-induced signaling were lower in response to oral JNJ-2113 treatment, with the effect of oral JNJ-2113 comparable to that of an IL-23 monoclonal antibody given via intraperitoneal injection.

The activity of JNJ-2113 observed in vitro in human immune cells and in preclinical models translated to pharmacodynamic activity in healthy human volunteers. In a first-in-human study, JNJ-2113 demonstrated dose-proportional pharmacokinetics across a 100-fold dose range from 10 mg to 1000 mg. Even in the presence of supra-physiological levels of IL-23 stimulation, robust, dose-dependent inhibition of signaling was observed in ex vivo assays of whole blood from participants receiving JNJ-2113. In healthy volunteers, JNJ-2113 was well tolerated following single- or multiple-dose administration, in line with previously published and presented data from the Phase 2 FRONTIER 1 and FRONTIER 2 clinical trials. Adverse events were mild or moderate and no dose-related trends were identified.

"The preclinical data in this manuscript translates very well to the pharmacodynamic activity observed in healthy human volunteers and provides strong scientific rationale for the highly positive clinical impact we have seen thus far in the FRONTIER 1 and FRONTIER 2 clinical trials of JNJ-2113 in plaque psoriasis. JNJ-2113 continues to distinguish itself as a first- and only-in-class oral IL-23 receptor antagonist," said Dinesh V. Patel, Ph.D., President and CEO of Protagonist. "The ongoing ICONIC clinical program involving five different Phase 3 psoriasis studies and the ANTHEM Phase 2b study in ulcerative colitis are all expected to reach primary endpoint completion in the next 3 to 9 months, yielding critical clinical data that will shape the future of JNJ-2113. The success of JNJ-2113 has encouraged us to evaluate other biological targets beyond IL-23 that are validated through injectable antibodies, where our oral peptide platform may offer a significant differentiation and meaningful impact in bringing new medicines to patients."

About JNJ-2113

JNJ-2113 is a first and only targeted oral peptide that is designed to selectively block the IL-23 receptor that was jointly discovered and is being developed pursuant to the license and collaboration agreement between Protagonist and Janssen. Protagonist completed a Phase 1 study of JNJ-2113 in 2021 and Johnson & Johnson retains exclusive, worldwide rights to develop it in Phase 2 and beyond, and to commercialize compounds derived from the research conducted pursuant to the agreement which covers a broad range of indications.

JNJ-2113 is currently being studied in the ICONIC program, which includes five Phase 3 studies for moderate-to-severe psoriasis. The FRONTIER 1 (16-week) and FRONTIER 2 (52-week) Phase 2B studies of JNJ-2113 in moderate-to-severe- plaque psoriasis (PsO) have been successfully completed. The pivotal Phase 3 ICONIC clinical development program of JNJ-2113 in adult and adolescent patients with moderate-to-severe plaque PsO was initiated with two studies in Q4 2023 - ICONIC-LEAD and ICONIC-TOTAL. ICONIC-LEAD is a randomized controlled trial (RCT) to evaluate the safety and efficacy of JNJ-2113 compared with placebo in participants with moderate-to-severe plaque PsO, with the higher efficacy bar set with the co-primary endpoints of PASI-90 and IGA score of 0 or 1 with at least a 2-grade improvement. ICONIC-TOTAL is a RCT to evaluate the efficacy and safety of JNJ-2113 compared with placebo for the treatment of PsO in participants with at least moderate severity affecting special areas (e.g., scalp, genital, and/or palms of the hands and the soles of the feet) with overall IGA score of 0 or 1 with at least a 2-grade improvement as the primary endpoint. Other Phase 3 studies in the development program are ICONIC ADVANCE 1 and ICONIC ADVANCE 2, which will evaluate the safety and efficacy of JNJ-2113 compared with both placebo and the TYK2 inhibitor deucravacitinib approved for treatment of psoriasis, and a Phase 3 study in pustular and erythrodermic psoriasis.

A Phase 2b study, ANTHEM-UC, has been initiated to evaluate the safety and effectiveness of JNJ-2113 compared with placebo in participants with moderately to severely active ulcerative colitis. Details regarding ANTHEM-UC and the five Phase 3 PsO trials can be found on clinicaltrials.gov.

About Protagonist

Protagonist Therapeutics is a biopharmaceutical company with peptide-based new chemical entities (NCEs) rusfertide and JNJ-2113 (formerly PN-235) in advanced Phase 3 stages of clinical development, both derived from the Company's proprietary technology platform. Protagonist and JNJ scientists jointly discovered PN-235 as part of Protagonist's Interleukin-23 receptor (IL-23R) antagonist collaboration with JNJ and followed it through IND-enabling pre-clinical and Phase 1 studies, with JNJ assuming responsibility for further clinical development. Rusfertide, a mimetic of the natural hormone hepcidin, is the Company's lead drug candidate currently in a global Phase 3 development program for polycythemia vera (PV). The randomized portion of the Phase 2 REVIVE study has been successfully completed, and results were published in The New England Journal of Medicine in February 2024. The open-label extension (OLE) component of REVIVE has also been completed and is followed by an additional 2-year long-term extension (LTE) THRIVE study. Enrollment has been completed in the global Phase 3 VERIFY study of rusfertide in polycythemia vera. Rusfertide is being co-developed and co-commercialized with Takeda pursuant to a worldwide collaboration and license agreement with Takeda announced in January 2024.

More information on Protagonist and its pipeline drug candidates and clinical studies can be found on the Company's website at www.protagonist-inc.com.

Cautionary Note on Forward-Looking Statements

This press release contains forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements regarding the potential benefits of JNJ-2113 and the timing of JNJ-2113 clinical trials. In some cases, you can identify these statements by forward-looking words such as "anticipate," "believe," "may," "will," "expect," or the negative or plural of these words or similar expressions. Forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, our ability to develop and commercialize our product candidates, our ability to earn milestone payments under our collaboration agreements with Janssen and Takeda, our ability to use and expand our programs to build a pipeline of product candidates, our ability to obtain and maintain regulatory approval of our product candidates, our ability to operate in a competitive industry and compete successfully against competitors that have greater resources than we do, and our ability to obtain and adequately protect intellectual property rights for our product candidates. Additional information concerning these and other risk factors affecting our business can be found in our periodic filings with the Securities and Exchange Commission, including under the heading "Risk Factors" contained in our most recently filed periodic reports on Form 10-K and Form 10-Q filed with the Securities and Exchange Commission. Forward-looking statements are not guarantees of future performance, and our actual results of operations, financial condition and liquidity, and the development of the industry in which we operate, may differ materially from the forward-looking statements contained in this press release. Any forward-looking statements that we make in this press release speak only as of the date of this press release. We assume no obligation to update our forward-looking statements, whether as a result of new information, future events or otherwise, after the date of this press release.

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