evorpacept (ALX148)

P1, N=14, Terminated, ALX Oncology Inc. | Phase classification: P1/2 --> P1 | N=97 --> 14 | Active, not recruiting --> Terminated; While intended to be a Phase 1/2 clinical study, the study never moved forward to Phase 2.

P1/2, N=258, Recruiting, Sanofi | N=197 --> 258

P1/2, N=52, Active, not recruiting, Jazz Pharmaceuticals | Trial completion date: Apr 2025 --> Sep 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

P2, N=80, Active, not recruiting, University of Colorado, Denver | Trial primary completion date: Sep 2024 --> Dec 2024

P2, N=31, Recruiting, Haider Mahdi | Trial completion date: Dec 2027 --> Dec 2031 | Trial primary completion date: Sep 2025 --> Sep 2029

However, a series of setbacks unfolded recently, starting with the July 2023 announcement of discontinuing the phase 3 ENHANCE study on Magrolimab plus Azacitidine for higher-risk myelodysplastic syndromes (MDS). Subsequently, in August 2023, the termination of the ASPEN-02 program, assessing Evorpacept in combination with Azacitidine in MDS patients, was disclosed due to insufficient improvement compared to Azacitidine alone. These setbacks have cast doubt on the feasibility of targeting CD47 in the industry. In this review, we delve into the challenges of developing CD47-SIRPα-targeted drugs, analyze factors contributing to the mentioned setbacks, discuss future perspectives, and explore potential solutions for enhancing CD47-SIRPα-targeted drug development.

P2, N=172, Active, not recruiting, ALX Oncology Inc. | Recruiting --> Active, not recruiting

P2, N=189, Active, not recruiting, ALX Oncology Inc. | Recruiting --> Active, not recruiting

P1/2, N=197, Recruiting, Sanofi | Trial completion date: Dec 2027 --> Mar 2028 | Trial primary completion date: Dec 2027 --> Jun 2027

P1/2, N=52, Active, not recruiting, Jazz Pharmaceuticals | Recruiting --> Active, not recruiting | N=93 --> 52 | Trial primary completion date: Jul 2024 --> Oct 2024

P1, N=30, Recruiting, ALX Oncology Inc. | Trial primary completion date: Jan 2024 --> Dec 2024

P1, N=174, Active, not recruiting, ALX Oncology Inc. | Trial completion date: Feb 2024 --> Dec 2024

P2, N=29, Recruiting, University of California, San Diego | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2024 --> Aug 2026

P2, N=183, Recruiting, ALX Oncology Inc. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=168, Recruiting, ALX Oncology Inc. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=197, Recruiting, Sanofi | N=123 --> 197 | Trial completion date: Nov 2028 --> Dec 2027 | Trial primary completion date: Nov 2028 --> Dec 2027

P2, N=29, Not yet recruiting, University of California, San Diego | Initiation date: Aug 2023 --> Dec 2023

P1/2, N=93, Recruiting, Jazz Pharmaceuticals | Phase classification: P1b/2 --> P1/2 | Trial completion date: Oct 2024 --> Jan 2025 | Trial primary completion date: Apr 2024 --> Jul 2024

Patients 1 and 3 received treatment with CD47AB (Magrolimab), 5'-Azacitidine (Aza), and Venetoclax (Ven); Patient 2 received IMGN632 (CD123-targeting ADC), Aza and Ven. Patient 4 received p97 Inhibitor CB-5339; Patient 5 received CD47 inhibitor (ALX148), Aza, Ven... This study establishes a genotype-phenotype connection through single-cell proteogenomic profiling of TP53-mutated AML, describing the clonal evolution and immunophenotypic dynamics during treatment while proposing a potential mechanism of resistance.

P2, N=183, Recruiting, ALX Oncology Inc. | Trial completion date: Oct 2024 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Dec 2023

P1, N=174, Active, not recruiting, ALX Oncology Inc. | Trial completion date: Feb 2023 --> Feb 2024

P2, N=168, Recruiting, ALX Oncology Inc. | Trial completion date: Oct 2024 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Dec 2023

The addition of evorpacept to standard dose VEN and AZA for AML was well tolerated with no MTD reached. The maximum administered evorpacept dose was 60 mg/kg Q4W, and preliminary dose-proportional pharmacokinetics was seen along with full CD47 target occupancy in both peripheral blood and bone marrow across all dose levels evaluated. Initial anti-leukemic activity was observed in subjects with both ND and R/R AML (including VEN-naïve and prior VEN-exposed disease).

P2/3, N=450, Recruiting, ALX Oncology Inc. | Not yet recruiting --> Recruiting | Initiation date: Aug 2021 --> Jan 2022

The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC.

P2, N=183, Recruiting, ALX Oncology Inc. | N=111 --> 183

The myeloid checkpoint inhibitor evorpacept was well tolerated in combination with AZA with an initial safety profile similar to that of AZA monotherapy. The evorpacept RP2D in combination with AZA is 60 mg/kg Q4W. Promising initial activity has been observed, with objective responses and hematologic improvement at multiple dose levels in subjects with both ND and R/R MDS, including those with adverse risk features such as TP53 mutation with complex cytogenetics, therapy-related MDS, and prior HMA-failure.

In a Phase 1 study, ALX148 demonstrated antitumor activity when combined with trastuzumab in patients whose disease had progressed on prior HER2‑targeted therapies. Secondary endpoints in Part 2 include disease control rate, clinical benefit rate, duration of response, progression‑free survival, overall survival, safety, pharmacokinetics, and immunogenicity assessments. The study is currently open for enrollment in the United States and may enroll up to 93 patients (NCT: 05027139).

P2/3, N=450, Not yet recruiting, ALX Oncology Inc.

P2, N=111, Ongoing, ALX Oncology Inc.

The RP2D of ALX148 is 15 mg/kg QW in combination. Observed durable responses and initial survival estimates in patients with second-line disease that had progressed upon prior HER2-directed therapy warrants further study of this combination in patients with advanced HER2-positive G/GEJ cancer.

P2, N=111, Recruiting, ALX Oncology Inc. | Not yet recruiting --> Recruiting

P2, N=111, Not yet recruiting, ALX Oncology Inc.

The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity and favorable PK/PD characteristics in combination with rituximab were observed at all dose levels with greater objective response rates reported at the MAD of 15 mg/kg QW.

Recently, the combination of azacitidine with venetoclax, a BCL2 inhibitor, has shown increased efficacy compared to azacitidine alone in patients with AML (EHA 2020, #LB2601). Together, these in vitro and in vivo results provide rationale that ALX148 combinations may benefit AML and MDS patients. Clinical trials with ALX148 in patients with MDS (NCT04417517) and AML are currently planned.

ALX148 enhances innate and adaptive immune responses against cancer and has previously been shown to be well tolerated in combination with the checkpoint inhibitor (CPI), pembrolizumab (P), and trastuzumab (T) in a range of solid tumors (ASCO 2019 #2514)...Pts with ≥2L GC progressed on T+FU+platinum received AT +/- ramucirumab (ram)+paclitaxel (pac)... Initial data suggests ALX148 demonstrates excellent tolerability in combination with anti cancer antibodies and standard chemotherapy. Clinical activity in pts with advanced CPI naïve HNSCC (including PD-L1 negative) and GC compares favorably with historic controls. Final data from AP and AT cohorts and initial data from chemotherapy combination cohorts will be presented.