Apogee Therapeutics, Inc.’s APG777 a novel, subcutaneous extended half-life monoclonal antibody targeting IL-13, exceeded expectations in a first-in-human Phase 1 healthy volunteer trial, the Company reports.
APG777 is the first clinical-stage product candidate from the company’s strategic collaboration with Paragon Therapeutics, Inc.
Pharmacokinetic (PK) data showed a half-life of approximately 75 days across doses tested and pharmacodynamic (PD) data showed, deep and sustained inhibition of key atopic dermatitis (AD) biomarkers pSTAT6 and TARC for ~3 months (longest follow-up available, with inhibition still ongoing at time of the data cut).
Results from the study exceeded the Company’s trial objectives and support the potential for APG777 to optimize exposure levels in 16-week induction and be dosed once every three or six months in maintenance.
These findings represent the potential for improved clinical responses from greater exposures in induction and significantly less frequent dosing in maintenance compared to currently approved biologic therapies, which are dosed every two to four weeks,
APG777, in single doses of up to 1,200mg and multiple doses of 300mg, was well tolerated and showed a favorable safety profile, in line with the existing body of third-party evidence for the safety of the anti-IL-13 class.
Based on these data, the company plans to initiate a randomized, placebo-controlled, Phase 2 clinical trial in patients with moderate-to-severe AD in the first half of 2024 ahead of schedule.
The Phase 1 trial is a first-in-human, randomized, double-blind, placebo-controlled study designed to evaluate the safety and PK of APG777 in healthy volunteers. The study enrolled 40 healthy adult participants into three single-ascending dose (SAD) and two multiple-ascending dose (MAD) cohorts. Doses of subcutaneous APG777 evaluated in the study included 300mg, 600mg, and 1,200mg. Detailed findings from the SAD portion and interim results from MAD portion of the Phase 1 trial are as follows:
- PK differentiation supports further development of APG777 as a treatment for moderate-to-severe AD and other inflammatory diseases
- Potentially best-in-class PK profile, including a half-life of approximately 75 days, supporting:
- Testing higher exposures of drug in induction to potentially achieve improved clinical responses
- Testing of maintenance dosing of every 3- or 6-months, representing 2-4 injections per year compared to the current treatment paradigm of 13-26 injections per year
- Dose-proportional increases in serum concentrations and key parameters (e.g., Cmax, AUC) were observed in the Phase 1 trial
- PK was consistent across subjects with low variability
- Potentially best-in-class PK profile, including a half-life of approximately 75 days, supporting:
- Single doses of APG777 demonstrated a deep and sustained effect on PD markers for ~3 months (longest follow-up available with inhibition still ongoing at the time of data cut)
- Single doses of APG777 suppressed pSTAT6, one of the first downstream markers of IL-13 pathway inhibition, with near-complete inhibition for ~3 months
- Single doses of APG777 suppressed TARC, an inflammatory mediator and the most strongly correlated biomarker to AD severity, with deep and sustained inhibition for ~3 months
- Well tolerated across all dose groups. Single doses of APG777 up to 1,200mg and multiple doses of 300 mg were well tolerated with a favorable safety profile consistent with the existing third-party data supporting the safety of the anti-IL-13 class.
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- The most common treatment-emergent adverse events (TEAEs) were vascular access site pain, vessel puncture site bruise, headache, and vascular access bruising
- 60% of participants observed at least one TEAE; 15% of participants observed at least one drug-related AE
- There were no Grade 3 TEAEs or severe adverse events (SAEs). No AEs led to study discontinuation
- The most common treatment-emergent adverse events (TEAEs) were vascular access site pain, vessel puncture site bruise, headache, and vascular access bruising
Phase 2 trial in AD
Following the positive interim results, Apogee plans to advance APG777 into a randomized, placebo-controlled, 16-week Phase 2 clinical trial in patients with moderate-to-severe AD.
- Phase 2 AD trial is expected to initiate in the 1H of 2024 with 16-week topline data from Part A expected in 2H 2025
- Part A is expected to enroll approximately 110 patients randomized 2:1 to APG777 vs placebo with primary endpoint of mean percentage changes in EASI score from baseline to Week 16
- Part B of the Phase 2 trial is a randomized, placebo-controlled dose optimization with approximately 360 patients randomized 1:1:1:1 to high, medium, or low dose APG777 vs placebo with primary endpoint of mean percentage changes in EASI score from baseline to Week 16
- All patients benefiting from treatment will continue to APG777 maintenance, which will evaluate 3- to 6-month dosing
- Integrated design expected to provide for significant timeline acceleration by combining Ph2a and Ph2b elements into a single study protocol
- All Part A sites are also expected to participate in Part B, avoiding delays for site startup between the two parts
- Doses in the Phase 2 trial are enabled by APG777’s potentially best-in-class PK profile, extended half-life, and high-concentration formulation
- 180 mg/mL formulation enables 44% higher dose of APG777 vs lebrikizumab in the same volume
- APG777 Phase 2 induction regimen is designed to exceed lebrikizumab (an IL-13 inhibitor with an overlapping epitope with APG777) exposures by ~30 to 40% with potential for improved clinical responses and maintenance regimen is designed to equal lebrikizumab’s exposures
- In Phase 3 studies, ~30% higher exposure seen in lebrikizumab low bodyweight group resulted in numerically higher efficacy than the overall study population across all key endpoints, including EASI-75 and more stringent endpoints such as EASI-90 and IGA 0/1
- ~30-40% higher induction exposures for APG777 than lebrikizumab are based on a planned six-injection induction regimen given in the first sixteen weeks of APG777 treatment. This is approximately half as many of the 11 injections of lebrikizumab given during the same period
- At 52 weeks, exposures of APG777 dosed every three months are designed to exceed those of lebrikizumab, and exposures of APG777 dosed every six months are designed to equal those of lebrikizumab
- In head-to-head preclinical studies, APG777 demonstrated equivalent or better potency to lebrikizumab in the inhibition of IL-13 signaling. Based on its potentially best-in-class PK profile, APG777 has the potential for improved clinical responses from greater exposures to drug in induction and dosing as infrequently as once every three or six months, the Company states.
“The positive PK, PD, and safety findings from our Phase 1 trial mark the first clinical data ahead of schedule from our portfolio of potentially differentiated biologics and underscore the promising potential of APG777 to offer patients a transformational therapy that could drive improved clinical responses than the current standard of care and extend dosing to every three or six months,” says Michael Henderson, M.D., Chief Executive Officer of Apogee, in a news release. “We are excited to embark on the next phase of development for APG777, with plans to initiate our Phase 2 clinical trial in the first half of this year while rapidly progressing the rest of our pipeline forward. At Apogee, we refuse to stop at good enough and are dedicated to advancing innovative solutions for patients. Today’s announcement brings us an important step closer to achieving this goal.”
“Currently approved therapies for atopic dermatitis and other immunology indications typically call for injections every two to four weeks, which can lead to poor treatment adherence and long-term disease control,” adds Dermatology DigestÒ editorial advisory board member Jonathan Silverberg, MD, PhD, MPH, Professor of Dermatology at The George Washington University School of Medicine and Health Sciences in Washington, DC. “I am very encouraged by the initial data from this study, which demonstrate the potential for APG777 as a well-tolerated treatment with a half-life that would support less frequent injections.”
“Significant unmet need remains for patients with moderate-to-severe AD, many of whom continue to have symptomatic disease on current therapies,” adds Dermatology DigestÒ editorial advisory board Emma Guttman-Yassky, MD, PhD, the Waldman Professor of Dermatology and Immunology and Health System Chair of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City. “APG777’s Phase 2 trial will test an important hypothesis, greater inhibition of the pathway during induction, to see if improved clinical responses can be delivered for patients living with AD.”
