ViewPoints Interview: ALX Oncology’s Dr. Sophia Randolph Shares Insight on the Clinical Collaboration with Zymework

In an interview with PharmaShot, Dr. Sophia Randolph, Chief Medical Officer of ALX Oncology shared her views on the ALX Oncology’s collaboration with Zymework for evaluating the combination with ALX148 and zanidatamab for patients with advanced HER2-expressing breast cancer and other HER2-expressing solid tumors.

Shots:

• Zymeworks will conduct a P-Ib study to assess the safety and efficacy of the combination of zanidatamab and ALX148 in a two-part study
• The 1st part will evaluate the safety of the combination regimen while the 2nd part will assess  the safety, tolerability and anti-tumor activity in separate cohorts of subjects with HER2+ BC, HER2-low BC, and non-breast HER2-expressing solid tumors
• Zanidatamab is in the advanced clinical stage, actively enrolling a study in patients with prior treated HER2 gene-amplified BTC while five active P-II programs are underway. ALX148 is a next-generation CD47 blocker and has the potential to expand the chance for zanidatamab to benefits patients with HER2‑expressing BC

Tuba: Discuss the key points of ALX Oncology’s clinical trial agreement with Zymeworks. Can you unveil the financial terms of the agreement?

Sophia: Zymeworks and ALX Oncology entered into a clinical trial collaboration to evaluate the combination of ALX148, a CD47 blocker, and zanidatamab, a HER-2 targeted bispecific antibody, in a Phase 1 trial for patients with advanced HER2-expressing breast cancer and other HER2-expressing solid tumors. 

The Phase 1b trial will assess the safety and efficacy of the combination patients with HER2-positive breast cancer, HER2-low breast cancer, and non-breast HER-2 expressing solid tumors.

We are not disclosing additional details on the financial terms of the agreement.

Tuba: How collaboration improves the lives of patients living with advanced HER2‑expressing breast cancer?

Sophia:  Patients with advanced breast cancer have limited options once their disease as progressed upon standard of care therapies.  Approximately 81% of patients with HER2-expressing breast cancer have tumors that express low to intermediate levels of HER2, making them ineligible for treatment with currently-approved HER2-targeted therapies, such as Herceptin and Perjeta.  This collaboration will bring together two novel agents, ALX148, a CD47 blocker, and zanidatamab, a HER-2 targeted bispecific antibody. Together, these two agents may be able to address patient populations with all levels of HER2 expression, including those with low to intermediate HER2-expressing tumors, who are otherwise limited to chemotherapy or hormone therapy.

Zymeworks will conduct an open label, multi-center Phase 1b trial to assess the safety and efficacy of the combination of zanidatamab and ALX148 in a two-part trial.

• The first part of the trial will evaluate the safety of the combination treatment.
• The second part of the trial will evaluate the safety, tolerability, and anti-tumor activity of the combination in separate cohorts of subjects with HER2-positive breast cancer, HER2-low breast cancer, and non-breast HER2-expressing solid tumors.

Tuba: Can you through some light on the science behind the combination of HER-targeted bispecific antibody with CD47 blocker for the treatment of advanced Breast Cancer

Sophia:

• CD47 is a marker of self and when bound to its SIRPa receptor on myeloid cells provides an anti-phagocytic signal that spares the CD47 expressing cell from the innate immune response. Tumor cells overexpress CD47 to evade the macrophage component of immune surveillance.
• Phagocytosis of the tumor cell requires both the activation of pro-phagocytic signals and the disruption of the CD47-SIRPa myeloid checkpoint. Neither component alone is sufficient to trigger maximal phagocytic activity against tumor cells.
• ALX148, a high-affinity CD47 blocker, provides the blockade of the myeloid checkpoint signal. The pro-phagocytic signal can be provided to the same macrophages by zanidatamab’s Fc gamma domain binding to the Fc gamma receptors (FcγRs) to selectively direct the anticancer immune response to the HER2-expressing breast cancer cells.  As a therapeutic antibody, zanidatamab targets the HER2 receptor, and can also induce cellular phagocytosis, but through a slightly different mechanism.

Tuba: Discuss the Mechanism of Action of both therapies? How they are complementing each other?

Sophia:  By coupling ALX148’s blockade of the CD47 SIRPα myeloid checkpoint to the pro-phagocytic and tumor-selective signal provided by zanidatamab Fc gamma receptor, it is possible to selectively direct the anticancer immune response to the HER2 expressing breast cancer cells. Zanidatamab directs macrophages to cancer cells by binding to the tumor-specific antigen and activating the macrophage by engaging the Fcγ receptors to induce phagocytosis. However, if CD47 is not blocked, the myeloid checkpoint signal can limit the activity of this mechanism. Therefore, ALX148 may maximize zanidatamab’s clinical activity by overcoming the myeloid checkpoint signal that is co-opted by cancer cells.

Tuba: Do you think the combination will be eligible for the BTD, FT, and PR from regulatory authorities?

Sophia: The planned Phase 1 trial is designed to characterize the safety profile of the novel combination  as well as the dose of each compound to be used subsequently to evaluate anti-tumor activity in the Phase 2 setting.  Depending upon the combination safety profile, anti-cancer activity, and discussions with the regulatory authorities these regulatory designations will be considered.

Tuba: Can we have an overview of ALX Oncology’s collaboration with other global companies?

Sophia: ALX Oncology is also developing ALX148 in combination with pembrolizumab in collaboration with Merck in Phase 2 immuno-oncology trials in patients with head and neck squamous cell carcinoma (“HNSCC”).

Tuba: As you are advancing ALX148 in multiple hematologic malignancies and solid tumor indications, what next, we can expect from ALX Oncology in terms of advancing the programs?

Sophia:

• ALX148 is being evaluated in both hematologic (NHL, MDS, AML) and solid tumor (HNSCC, gastric/GEJ cancer, breast cancer) indications.  We have recently initiated our Phase 1b/2 trial in patients with higher risk MDS in combination with azacitidine.
• We have presented data from our solid tumor Phase 1b trials in HNSCC and gastric/GEJ cancer at the SITC 2020 Annual Meeting and will be presenting updates from our NHL program at the ASH 2020 Annual Meeting next week.  We believe these data suggest that ALX148 is a compound with encouraging activity and tolerability in solid tumor and hematologic disease.
• In the first half of 2021, we plan to initiate two Phase 2 trials in HNSCC in combination with pembrolizumab with and without chemotherapy.  In the second half of 2021, we plan to advance ALX148 into a Phase 1b/2 trial in combination with venetoclax and azacitidine for the first-line treatment of patients with AML as well as into Phase 2 trials in patients with HER2-positive gastric/GEJ cancer in combination with Herceptin, ramucirumab and paclitaxel.

Tuba: Can we have a glimpse of ALX Oncology’s pipeline?

Sophia:

• Solid Tumors
  • Head and Neck Squamous Cell Carcinoma
  • Gastric/Gastroesophageal Junction Cancer
  • Breast Cancer
• Hematology
  • Myelodyslastic Syndromes
  • Acute Myeloid Leukemia
  • Non-Hodgkin’s Lymphoma

Tuba: Are you looking for more collaboration to the advance the potential of ALX148 in other indications?

Sophia: Designed to be used in combination, we believe ALX148’s tolerability profile will allow for broad treatment of patient populations in a wide range of cancer types.  Additional areas to explore internally or in collaboration will build off of the encouraging data reported with the classes of combination agents that we have explored in the Phase 1/1b trials. Various tumor histologies will be evaluated that would support ALX148 in combination with checkpoint inhibitors, other monoclonal anti-cancer targeted therapies, and small molecule/cytotoxic chemotherapy combinations.

About Author:

Dr. Randolph is a CMO of ALX Oncology since June 2016. Dr. Randolph completed her oncology fellowship training at Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center.

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