Protagonist Therapeutics, Inc. is a discovery through late-stage development biopharmaceutical company focused on peptide therapeutics.
The company’s clinical programs fall into two broad categories of diseases: (i) hematology and blood disorders, and (ii) inflammatory and immunomodulatory (‘I&I’) diseases. Two novel peptides derived from the company’s proprietary discovery technology platform, rusfertide and icotrokinra (formerly known as JNJ-2113), are currently in advanced Phase 3 clinical d...
Protagonist Therapeutics, Inc. is a discovery through late-stage development biopharmaceutical company focused on peptide therapeutics.
The company’s clinical programs fall into two broad categories of diseases: (i) hematology and blood disorders, and (ii) inflammatory and immunomodulatory (‘I&I’) diseases. Two novel peptides derived from the company’s proprietary discovery technology platform, rusfertide and icotrokinra (formerly known as JNJ-2113), are currently in advanced Phase 3 clinical development, with New Drug Application (‘NDA’) submissions to the U.S. Food and Drug Administration (‘FDA’) potentially in 2025.
Rusfertide, an injectable mimetic of the natural hormone hepcidin, is currently in Phase 3 development for the treatment of the rare blood disorder polycythemia vera (‘PV’). Rusfertide is being co-developed and will be co-commercialized with Takeda Pharmaceuticals, Inc. (‘Takeda’) and the company remains primarily responsible for development through NDA filing. Icotrokinra is a first-in-class investigational targeted oral peptide that selectively blocks the Interleukin-23 receptor (‘IL-23R’) and is licensed to J&J Innovative Medicines (‘JNJ’), formerly Janssen Biotech, Inc. Following icotrokinra’s joint discovery by the company and JNJ scientists pursuant to the company’s IL-23R collaboration, the company was primarily responsible for the development of icotrokinra through Phase 1, with JNJ assuming responsibility for development in Phase 2 and beyond.
We also have a number of pre-clinical stage oral drug discovery programs to address clinically and commercially validated targets, including IL-17 oral peptide antagonist PN-881, an oral metabolic/obesity peptide program, and an oral hepcidin mimetic/ferroportin blocker program.
Product Pipeline
Rusfertide
Rusfertide is in Phase 3 development for the treatment of PV. VERIFY (ClinicalTrials.gov identifier NCT05210790) is a global double-blind, placebo-controlled Phase 3 clinical trial of rusfertide in PV for approximately 250 patients. The trial evaluates the efficacy, symptom burden and safety of once-weekly, subcutaneously self-administered rusfertide in patients with uncontrolled hematocrit who are phlebotomy dependent despite standard of care treatment. The trial enrolled patients across North and South America, Europe, Asia and Australia. The company expect to announce top-line data for the trial’s 32-week primary efficacy endpoint in March 2025, potentially leading to an NDA filing in the fourth quarter of 2025.
The company’s rusfertide Phase 2 clinical trials include the following:
REVIVE – A Phase 2 proof of concept (POC) trial, was initiated in the fourth quarter of 2019. The company completed enrollment of patients in the first quarter of 2022 and 70 patients were enrolled through the end of the randomized withdrawal portion of the trial, which was completed during the first quarter of 2023 and is continuing in an ongoing open-label extension (OLE);
THRIVE – A Phase 2 long-term OLE for REVIVE patients on years three through five of treatment; and
PACIFIC – Another Phase 2 trial for rusfertide for patients diagnosed with PV and with routinely elevated hematocrit levels (>48%), was initiated during the first quarter of 2021, and the 52-week trial was completed during the second quarter of 2023.
In January 2024, the company entered into a worldwide license and collaboration agreement for rusfertide with Takeda (the Takeda Collaboration Agreement). The company is primarily responsible for the development of rusfertide through a potential NDA filing.
Icotrokinra
The company’s IL-23R antagonist compound icotrokinra, licensed to J&J, is an orally delivered drug that is designed to block biological pathways currently targeted by marketed injectable antibody drugs. The company’s orally stable peptide approach may offer a targeted therapeutic approach for gastrointestinal and systemic compartments as needed. It believes that, compared to antibody drugs, icotrokinra has the potential to provide clinical improvement in an oral medication with increased convenience and compliance and the opportunity for the earlier introduction of targeted oral therapy.
JNJ has initiated the following icotrokinra trials:
ICONIC-LEAD – A 684-patient randomized, controlled Phase 3 trial to evaluate the safety and efficacy of icotrokinra compared with placebo in participants with moderate-to-severe plaque psoriasis, with PASI-90 and IGA scores of 0 (clear) or 1 (almost clear) as co-primary endpoints;
ICONIC-TOTAL – A 311-patient randomized, controlled Phase 3 trial to evaluate the efficacy and safety of icotrokinra compared with placebo for the treatment of plaque psoriasis in participants with at least moderate severity affecting special areas (scalp, genital, and/or palms of the hands and soles of the feet) with overall IGA scores of 0 or 1 as the primary endpoint;
ICONIC-ADVANCE 1 – A 774-patient randomized, controlled Phase 3 trial to evaluate the effectiveness of icotrokinra in participants with moderate-to-severe plaque psoriasis compared to placebo and Sotyktu (deucravacitinib). The trial’s primary co-endpoints are PASI-90 and IGA scores of 0 or 1;
ICONIC-ADVANCE 2 – A 731-patient Phase 3 trial similarly designed to ICONIC ADVANCE 1 in participants with moderate-to-severe plaque psoriasis;
Pustular/Erythrodermic Psoriasis – A 19-patient open label Phase 3 trial to evaluate the effectiveness of icotrokinra in participants with pustular or erythrodermic psoriasis;
ICONIC-PsA 2 – A 750-patient randomized, controlled Phase 3 trial to evaluate the efficacy and safety of icotrokinra compared with placebo in biologic-experienced patients with active psoriatic arthritis (PsA); and
ANTHEM-UC – A 252-patient randomized, controlled Phase 2b trial to evaluate the safety and effectiveness of icotrokinra compared with placebo in participants with moderate-to-severely active ulcerative colitis (UC).
In the fourth quarter of 2024, the company announced positive topline results for the ICONIC-LEAD and ICONIC-TOTAL Phase 3 trials. In the ICONIC-LEAD trial, once daily icotrokinra showed significant skin clearance versus placebo in adults and adolescents with moderate to-severe plaque psoriasis. At week 16, nearly two-thirds (64.7%) of patients treated with icotrokinra achieved IGA scores of 0 or 1 and 49.6% achieved PASI-90, compared to 8.3% and 4.4% on placebo, respectively. In addition, topline results from the Phase 3 ICONIC-TOTAL trial showed that once daily icotrokinra met the primary endpoint of IGA scores of 0 or 1 at week 16 as compared to placebo. Comprehensive results from both ICONIC-LEAD and ICONIC-TOTAL are expected to be presented at upcoming medical congresses and shared with health authorities in planned submissions.
Topline results for the ANTHEM trial are expected in the first quarter of 2025. Topline results for the ICONIC-ADVANCE 1, ICONIC-ADVANCE 2, and pustular/erythrodermic psoriasis trials are expected in the second quarter of 2025.
On July 27, 2021, the company entered into an Amended and Restated License and Collaboration Agreement with JNJ, which amended and restated the License and Collaboration Agreement, effective July 13, 2017, by and between the company and JNJ, as amended by the first amendment, effective May 7, 2019 (together, the JNJ License and Collaboration Agreement) for the development and commercialization of icotrokinra.
PN-881
In the fourth quarter of 2024, the company announced the selection of PN-881, a potential best-in-class oral peptide IL-17 antagonist, as a development candidate for the treatment of immune-mediated skin diseases. PN-881 targets three IL-17 dimers (IL-17 AA, AF and FF), which may offer potential treatment options for hidradenitis suppurativa (HS), spondyloarthritis, plaque psoriasis and psoriatic arthritis (PsA). Investigational New Drug (IND), or foreign equivalent, enabling studies are ongoing, and the company expects to initiate a PN-881 Phase 1 study in the fourth quarter of 2025.
Discovery Platform
The company’s clinical and pre-clinical assets are all derived from its proprietary discovery platform. The company’s platform enables it to engineer novel, structurally constrained peptides that are designed to retain key advantages of both orally delivered small molecules and injectable antibody drugs while overcoming many of their limitations as therapeutic agents.
The company’s discovery pipeline has strategically focused on hematology and blood disorders, I&I diseases and metabolic diseases, including obesity.
The company has a pre-clinical stage program to identify an orally administered hepcidin mimetic/ferroportin blocker, which it believes to be complementary to the injectable rusfertide for offering the best treatment options for PV and other potential erythropoietic and iron imbalance disorders, and the company expects to nominate a development candidate in the fourth quarter of 2025. It also has an oral peptide-based metabolic/obesity program and expect to nominate a development candidate in the second quarter of 2025.
RUSFERTIDE: AN INJECTABLE HEPCIDIN MIMETIC
Rusfertide, an injectable hepcidin mimetic, was discovered through the company’s peptide technology platform. Hepcidin is a natural hormone that regulates iron metabolism. The company is developing rusfertide for the treatment of PV.
Clinical Development of Rusfertide in PV
In the fourth quarter of 2019, the company initiated REVIVE, a Phase 2 trial of rusfertide in PV designed to evaluate safety and preliminary efficacy in patients requiring phlebotomy (PHL). The REVIVE trial was expected to enroll approximately 60 patients and consisted of a 16-week open-label dose finding stage every 4 weeks from 10 mg to 80 mg and a 12-week maintenance period at doses which generate desired hematocrit levels, followed by a 12-week randomized and blinded withdrawal stage. The endpoints of this clinical POC trial include measurement of blood parameters (hematocrit and hemoglobin levels), reductions or delay in phlebotomy requirements, and improvements in quality-of-life symptoms. The company initiated THRIVE, a Phase 2 long-term extension trial, to monitor long-term safety and benefits of rusfertide for REVIVE patients on years three through five of treatment.
Preliminary results showed that the vast majority of patients treated with rusfertide in the REVIVE clinical trial were able to eliminate therapeutic phlebotomies and maintain a target hematocrit level of less than 45 percent. Treatment with rusfertide was also shown to reverse iron deficiency, an important side effect of regular therapeutic phlebotomies as a treatment for PV. Preliminary results indicated that rusfertide therapy resulted in rapid, sustained and durable hematocrit control without clinically meaningful changes in white blood cell and platelet counts. Rusfertide demonstrated similar efficacy in all categories of patients, independent of the PV patient risk category or concurrent therapy with hydroxyurea, interferon or ruxolitinib.
In March 2023, the company announced positive topline results from the blinded, placebo-controlled, randomized withdrawal portion of the REVIVE trial. Subjects receiving rusfertide achieved statistically significant improvements versus placebo in the trial’s primary endpoint. The double-blind, placebo-controlled, 12-week randomized withdrawal portion was included as Part 2 of the REVIVE trial to evaluate rusfertide in PV patients with frequent phlebotomy requirements. In the REVIVE trial, subjects were initially enrolled in the 28-week open label dose-titration and efficacy evaluation Part 1 of the trial, followed by 1:1 randomization of 53 subjects to placebo versus rusfertide therapy for a subsequent duration of 12 weeks. More subjects receiving rusfertide during the blinded randomized withdrawal portion of the REVIVE trial were responders compared with placebo (69.2% versus 18.5%, p=0.0003). A trial subject was defined as a responder if the subject completed 12 weeks of double-blind treatment while maintaining hematocrit control without phlebotomy eligibility and without phlebotomy. During the 12 weeks of the blinded, randomized withdrawal, 92.3% of subjects on rusfertide (24 out of 26) were not phlebotomized.
In addition, in subjects with moderate or severe Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) symptom scores at baseline, the change from baseline was statistically significant in fatigue, problems with concentration, inactivity and itching during the 28-week open label Part 1 of the trial. Meaningful comparison of symptoms assessments in Part 2 are not possible since a majority of subjects randomized to placebo discontinued prior to the 12-week assessment of MPN-SAF symptoms.
Rusfertide continued to be generally well tolerated in the REVIVE trial, with localized ISRs comprising the majority of reported adverse events. No new safety signals were observed in safety data disclosed in connection with the Part 2 efficacy results, relative to the safety data from the REVIVE trial presented at the December 2022 ASH Annual Meeting, which indicated that 84% of TEAEs were Grade 2 or below. 16% of patients experienced Grade 3 TEAEs and there were no Grade 4 TEAEs.
In December 2023, the company presented two-year follow up data from patients in the Phase 2 REVIVE trial who continued into the OLE at the ASH 2023 Annual Meeting. The Phase 2 trial consisted of three parts, including 70 patients in the dose-finding Part 1 (28 weeks), 59 patients in the placebo-controlled, randomized withdrawal Part 2 (13 weeks), and 58 patients in the OLE (52 weeks). At the end of Part 2, 69% (18/26) of rusfertide patients achieved hematocrit control and remained phlebotomy free at 12 weeks, compared to only 19% (5 out of 27) on placebo (p=0.0003). Among the 58 patients that continued into the OLE, as of October 17, 2023 (data cut-off date for the ASH presentation), 57 had been treated for over one year and 37 had been treated for over two years. The median follow-up was 2.1 years and data were provided out to 2.5 years in 21 patients.
Results showed that rusfertide, when used in patients previously treated with phlebotomy with or without cytoreductive therapy through two years, resulted in durable hematocrit control, decreased phlebotomy use, long-term tolerability, and no new safety signals in patients with PV. An analysis of the PACIFIC Phase 2 trial was also presented which showed that rusfertide improved markers of iron deficiency in patients with PV. In addition, data was presented regarding the prevalence of thromboembolic events and secondary cancers in PV patients not treated with rusfertide.
In February 2024, the full Phase 2 REVIVE trial results, including efficacy and safety data, were published in the New England Journal of Medicine (NEJM). Updated long-term results from the REVIVE trial presented at the European Hematology Association Congress in June 2024 continued to show a durable positive effect on PV symptomology and other benefits, including iron deficiency, as well as an encouraging safety profile.
In November 2024, final data from the REVIVE trial was presented at the ASH 2024 Annual Meeting. As of October 18, 2024 (the data cut-off date for presentation at ASH), 50 (71%), 38 (54%), and 17 (24%) patients received rusfertide for, respectively. Of the 58 patients who entered the REVIVE Part 3 OLE, the median duration of therapy was 131.4 weeks (2.5 years). As of October 18, 2024, 46, or over 80%, of patients have rolled over to the THRIVE trial and are eligible to receive up to two additional years of rusfertide treatment. Trial results showed that rusfertide, when added to therapeutic phlebotomy with or without cytoreductive therapy, achieved long term durable control of hematocrit below the 45% threshold for over three years.
Prior to enrollment, the estimated mean phlebotomy rate (EPHL) in patients who enrolled in the trial was >5 per year. In Part 1, the EPHL was <1 per year in patients who received rusfertide (N=70). In Part 2 (randomized withdrawal phase), the EPHL was <1 per year and approximately 6.1 per year in the rusfertide and placebo groups, respectively. For patients who continued to Part 3 (Week 42+), the EPHL remained at <1 per year. Patients showed increased mean corpuscular volume and continued improvement and normalization of serum ferritin levels. Platelet levels increased following initiation of rusfertide therapy and stabilized over time and mean leukocyte counts remained stable throughout the trial.
The MPN-SAF was used to assess mean change from baseline in the individual symptom score in patients with moderate (score of 4-6 out of 10) or severe (score of 7-10 out of 10) symptoms at baseline. In patients who had moderate or severe symptoms at baseline (score of =4 out of 10), there were significant improvements from baseline in fatigue, early satiety, abdominal discomfort, inactivity, problems with concentration, night sweats, and itching at the end of Part 3.
Overall, 18 (26%) patients experienced serious adverse events (SAEs); most SAEs were unrelated and likely associated with the underlying disease. One patient developed acute myeloid leukemia after treatment discontinuation. After more than 150 patient-years of rusfertide exposure, malignancies were reported in 11 patients (nine patients had skin malignancies); all of these patients had prior risk factors that may have contributed to development of these malignancies. There was no obvious correlation between increased exposure to rusfertide and the malignancies reported. Seven thrombotic events (six arterial and one venous) occurred in six patients who all had high-risk PV. No thrombotic events have been reported in patients with low-risk PV as of October 18, 2024.
These results indicate that rusfertide continued to demonstrate a positive clinical impact in the treatment of PV patients. With more than three years of data showing strong and continued improvements in hematocrit as well as encouraging evidence of symptoms improvement.
Rusfertide Phase 3 PV Trial Design
The company initiated VERIFY, a global double-blind, placebo-controlled Phase 3 clinical trial of rusfertide in PV for approximately 250 patients, in the first quarter of 2022. The company expects to announce top-line data for the trial’s 32-week primary efficacy endpoint in the first quarter of 2025, potentially leading to an NDA filing in the fourth quarter of 2025.
The company has the following designations for rusfertide in PV:
The FDA granted orphan drug designation for rusfertide for the treatment of PV in June 2020;
The European Medicines Agency (EMA) granted orphan drug designation for rusfertide for the treatment of PV in October 2020; and
The FDA granted fast track designation for rusfertide for the treatment of PV in December 2020.
Rodent Carcinogenicity Studies
Rat carcinogenicity study. In the fourth quarter of 2024, the company received the draft audited pathology report from its two-year study evaluating the carcinogenicity potential of rusfertide when administered once weekly. The draft report concluded that there were no carcinogenicity-related findings associated with rusfertide. The company expects to receive the final audited report during the first quarter of 2025, which will then be submitted to the FDA.
RasH2 mouse carcinogenicity study. In 2021, the company completed a 26-week rasH2 transgenic mouse carcinogenicity study related to rusfertide. In the rasH2 study, there were rusfertide related findings associated with benign squamous cell papilloma and malignant squamous cell carcinoma. The company’s rusfertide clinical trials were placed on a brief clinical hold from mid-September to early October 2021 following its receipt of the results of the RasH2 mouse study.
Icotrokinra: An Oral Il-23 Receptor Antagonist
JNJ License and Collaboration Agreement
The company has a worldwide license and collaboration agreement with JNJ to research, develop and co-detail IL-23R antagonist compounds for all indications, including IBD. JNJ is an experienced innovator in therapeutics targeting the IL-23 pathway. Stelara is a monoclonal antibody targeting IL-12 and IL-23 through their common p40 subunit is approved in psoriasis, PsA, CD and UC. Tremfya is a specific IL-23 monoclonal antibody. It is approved in psoriasis and PsA and has completed successful Phase 3 trials in UC and CD. In both psoriasis and IBD, there is an urgent need for safe and effective oral therapies. It is notable that Stelara lost patent exclusivity in 2023 with biosimilar competition expected.
Icotrokinra, an orally delivered IL-23R specific antagonist for the potential treatment of psoriasis, PsA and IBD indications, was discovered through the company’s peptide technology platform. IL-23, a member of the IL-12 family of pro-inflammatory cytokines, is a protein that regulates inflammatory and immune function and plays a key role in the development of IBD. By blocking IL-23R, icotrokinra may improve disease symptoms while potentially minimizing the risk of systemic side effects. During the fourth quarter of 2021, a decision was made by JNJ to advance development of icotrokinra. For icotrokinra, JNJ is primarily responsible for the conduct of all further development, and the company was primarily responsible for the discovery, IND-enabling studies and the initial Phase 1 study.
Clinical Development of Icotrokinra
In February 2022, JNJ initiated FRONTIER 1, a 255-patient Phase 2b clinical trial of icotrokinra in moderate-to-severe plaque psoriasis, which was completed in December 2022. FRONTIER 1 was a randomized, multicenter, double-blind, placebo-controlled trial that evaluated three once-daily dosages and two twice-daily dosages of icotrokinra taken orally. The primary endpoint of the trial was the proportion of patients achieving PASI-75 at 16 weeks. In July 2023, the company announced updated positive topline results from the trial, which were presented by JNJ at the World Congress of Dermatology in Singapore. Icotrokinra achieved the trial’s primary and secondary efficacy endpoints. A statistically significant greater proportion of patients who received icotrokinra achieved PASI-75 responses, as well as PASI-90 and PASI-100 responses compared to placebo at week 16 in all five of the trial’s treatment groups. A clear dose response was observed across an eight-fold dose range. Treatment was well tolerated, with no meaningful difference in frequency of adverse events across treatment groups versus placebo.
At JNJ’s Enterprise Business Review in December 2023, JNJ highlighted icotrokinra as a potential first- and best-in-class targeted oral IL-23 peptide antagonist with potential across multiple indications, including plaque psoriasis, PsA and inflammatory bowel disease. JNJ IL-23 monoclonal antibody drugs Stelara and Tremfya.
In February 2024, the icotrokinra Phase 2b FRONTIER 1 trial results in adults living with moderate-to-severe plaque psoriasis were published in the NEJM. In March 2024, data presented at the American Academy of Dermatology 2024 Annual Meeting showed that, in the Phase 2b FRONTIER 2 trial, icotrokinra maintained high rates of skin clearance through 52 weeks in adults with moderate-to-severe plaque psoriasis. In August 2024, positive pre-clinical and clinical pharmacokinetic, pharmacodynamic and safety data for icotrokinra was published in the journal, Scientific Reports. Three company-sponsored poster presentations and one company-sponsored oral presentation were delivered at the 2024 European Academy of Dermatology and Venereology Congress in September 2024.
JNJ initiated six additional icotrokinra trials in psoriasis and one in UC, as discussed above. All of the trials in the ICONIC program use the 200 mg q.d. immediate release formulation of icotrokinra from the FRONTIER 1 trial.
In November 2024, the company announced positive topline results from ICONIC-LEAD and ICONIC-TOTAL Phase 3 trials of icotrokinra in individuals 12 years of age and older with moderate to severe plaque psoriasis. In the ICONIC-LEAD trial, once-daily icotrokinra showed significant skin clearance versus placebo in adults and adolescents with moderate to severe plaque psoriasis. At week 16, nearly two-thirds (64.7%) of patients treated with icotrokinra achieved IGA scores of 0/1, and 49.6% achieved PASI 90, compared to 8.3% and 4.4% on placebo, respectively. Further increases in response rates continued to be observed at week 24, with 74.1% of patients treated with icotrokinra achieving IGA scores of 0/1, and 64.9% achieving PASI 90. Safety data was found to be consistent with the Phase 2 FRONTIER 1 and 2 trials. A similar proportion of patients experienced adverse events between icotrokinra and placebo, with 49.3% and 49.1% of participants experiencing a TEAE at week 16. In addition, positive topline results from the Phase 3 ICONIC-TOTAL trial showed once-daily icotrokinra met the primary endpoint of IGA of 0/1 at week 16 compared to placebo.
PN-881: AN ORAL IL-17 RECEPTOR ANTAGONIST
In the fourth quarter of 2024, the company announced the selection of PN-881, a potential best-in-class oral peptide IL-17 antagonist, as a development candidate for the treatment of immune-mediated skin diseases. PN-881 has been evaluated in extensive preclinical studies, including oral stability, potency, tissue distribution, and pharmacokinetics measurements, and evaluation in immunologic pharmacodynamics and preclinical efficacy models.
PN-881 has demonstrated in vitro blockade of IL-17 AA homodimer, FF homodimer and AF heterodimer. In assays using the HT-1080 human fibrosarcoma cell line stimulated with a combination of IL-17 and TNF-a produce IL-6, blocking IL-17 was shown to inhibit IL-6 production. In this assay, PN-881 inhibited 50% of IL-6 production (the IC50) at a concentration of 120 picomoles (pM) and showed an IC 90, or 90% inhibition, at 560 pM. This potency was approximately 100-fold greater than the potency of secukinumab, and similar potency to the most potent approved antibody drugs and nanobody therapeutics in development. In multiple preclinical studies with oral dosing, PN-881 showed effective blockade in vivo of IL-17 in serum and skin and achieved pre-clinical proof-of-concept in a skin inflammation rodent disease model.
IND-enabling, or foreign equivalent, studies of PN-881 are ongoing or planned, including 7-day and 3-month toxicology studies. Planned clinical studies include a Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study expected to begin in the fourth quarter of 2025. Results of the Phase 1 trial are expected to inform the design and dosing in a subsequent dose-ranging psoriasis trial. Rapid expansion into other IL-17 mediated diseases, including PsA, HS and axSpA, is expected to be based on results observed in psoriasis studies.
PN-943
PN-943 is a wholly owned investigational orally delivered gut-restricted alpha 4 beta 7 specific integrin antagonist for IBD. The company completed a Phase 2 trial of PN-943 in patients with moderate-to-severe UC in early 2023. The company does not intend to dedicate further internal resources to clinical development or contract manufacturing activities for its PN-943 clinical program.
Discovery and Pre-clinical Activities
The company has built a versatile, well-validated and unique discovery platform. For example, this peptide technology platform has been used to develop product candidates for diverse target classes, including G-protein-coupled receptors, ion channels, transporters, cytokines and their receptors for a variety of therapeutic areas. In the future the company may tackle other I&I, metabolic and blood disorders and expand the company’s technology platform to provide potential opportunities to pursue a wider variety of diseases that may include oral, topical and systemic approaches. The company also intends to progress the company’s platform to achieve systemic bioavailability and activity with oral peptides, macrocycles and peptidomimetics, thereby enabling the company to address systemic diseases. Examples of this approach are the discovery and development of icotrokinra, the company’s IL-23R antagonist in collaboration with JNJ, and PN-881, its recently announced IL-17 peptide antagonist product candidate, as described above.
Rusfertide
Bimekizumab (anti-IL-17A and F, UCB) has completed a positive Phase 3 program in psoriasis. Otezla (Amgen) was the first oral agent approved in both psoriasis and PsA. The oral JAK inhibitors Xeljanz (Pfizer) and Rinvoq are approved in PsA. Several oral small molecules that inhibit the Janus kinase TYK2 are advancing in development. The Bristol Myers Squibb (BMS) TYK2 inhibitor, Sotyktu, was approved for psoriasis in 2022. Second generation allosteric TYK2 inhibitors from Nimbus Therapeutics (recently in-licensed by Takeda) are moving into Phase 3 development, and a molecule from Ventyx Biosciences has initiated Phase 2 development. Several small molecules that inhibit IL-17 have completed Phase 1 development.
In addition, orally delivered agents with novel mechanisms of action that are approved for or in development and may be approved for UC and/or CD prior to or shortly after the launch of the company’s product candidates can have significant impact in the competitive environment, including:
JAK inhibitors: The pan-JAK tofacitinib (Xeljanz) is approved in UC. The next-generation selective JAK1/3 inhibitors, including Abbvie’s upadacitinib (Rinvoq), were approved in UC and CD in 2022. Pfizer’s selective JAK1/TEC inhibitor ritlecitinib is in Phase 2 development for UC and CD;
S1P1 receptor modulators: BMS’s ozanimod (Zeposia) and Pfizer’s etrasimod (Velsipity) are approved in UC. Etrasimod is being studied in CD, though ozanimod was not found to show efficacy in CD; and
Eli Lilly is developing MORF-057, an oral small molecule targeting a4ß7, which is progressing in Phase 2 development in UC and CD. Other oral small molecules targeting a4ß7 from Gilead and Ensho Therapeutics are in early clinical development. Many other agents are in early-stage development in IBD, including injectable anti-TLIA antibodies by Pfizer and Merck, and Teva and Sanofi, which have recently presented positive Phase 2 results in IBD.
PN-881
The injectable mAbs Cosentyx and Taltz targeting IL-17 AA and AF are approved in psoriasis, PsA, and SpA. Cosentyx was also recently the first IL-17 inhibitor approved in HS. Siliq, a mAb to the IL-17 receptor, is approved in psoriasis only and carries a black box warning for suicidal ideations. Bimzelx is a mAb that targets IL-17 AA, AF and FF. It is approved in psoriasis, PsA, HS, SS and nr-axSpA. Sonelokimab (MoonLake) is an injectable nanobody with IL-17 AA, AF and FF activity and has demonstrated POC in Phase 2 in psoriasis, PsA, and HS. There are several oral IL-17 small molecules in clinical development with the most advanced, DC-853 (Lilly via acquisition of DICE Therapeutics) in a Phase 2b trial in psoriasis. JNJ and Sanofi are also developing small molecules.
Material Agreements
Takeda Collaboration Agreement
In January 2024, the company entered into the Takeda Collaboration Agreement.
JNJ License and Collaboration Agreement
On July 27, 2021, the company entered into an Amended and Restated License and Collaboration Agreement (the JNJ License and Collaboration Agreement) with JNJ, which amended and restated the License and Collaboration Agreement, effective July 13, 2017, by and between the company and JNJ (the Original Agreement), as amended by the first amendment, effective May 7, 2019 (the First Amendment). The JNJ License and Collaboration Agreement, which relates to the development, manufacture and commercialization of oral IL-23 receptor antagonist drug candidates and enables JNJ to develop collaboration compounds for multiple indications, was further amended in November 2024.
Research Collaboration and License Agreement with Zealand Pharma A/S
In June 2012, the company entered into a Research Collaboration and License Agreement (the Zealand Agreement) with Zealand Pharma A/S (Zealand) to identify, optimize and develop novel disulfide-rich peptides to discover a hepcidin mimetic. The company amended this agreement on February 28, 2014, at which point it assumed responsibility for the development program.
Intellectual Property
The company owns or co-owns 30 issued U.S. patents, over 68 granted ex-U.S. patents, and numerous U.S. and ex-U.S. patent applications related to the company’s clinical assets. Applications are pending in the United States and other major jurisdictions, including Australia, Canada, China, Japan, and Europe. The company expects its patents and patent applications, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire from October 2033 to December 2044 (excluding possible patent term extensions).
Research and Development
The company’s research and development expenses were $138.1 million for the year ended December 31, 2024.
Government Regulation
The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs, such as those the company is developing. These agencies and other federal, state and local entities regulate, among other things, the research and development, testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export, and import of its product candidates.
History
Protagonist Therapeutics, Inc. was founded in 2006. The company was incorporated under the laws of the state of Delaware in 2006.
