MacroGenics, Inc. (NASDAQ:MGNX) Promising Pipeline and Improved Safety Profile for Lead ADC Candidate

Published on September 24, 2024 | Ticker: MGNX

Business Overview

MacroGenics, Inc. (NASDAQ:MGNX) is a biopharmaceutical company focused on discovering, developing, manufacturing, and commercializing innovative antibody-based therapeutics for the treatment of cancer. The company has a diverse pipeline of product candidates designed to target various tumor-associated antigens or immune checkpoint molecules, with several programs currently in clinical trials.

MacroGenics was founded in 2000 and is headquartered in Rockville, Maryland. The company's proprietary technology platforms, including the DART (Dual-Affinity Re-Targeting) platform, have enabled the development of its pipeline of oncology product candidates. MacroGenics' lead clinical-stage asset is vobramitamab duocarmazine (vobra duo), an antibody-drug conjugate (ADC) targeting the B7-H3 antigen, which is expressed across a wide range of solid tumors.

In addition to vobra duo, MacroGenics' pipeline includes other ADCs, bispecific T-cell engagers, and Fc-optimized monoclonal antibodies targeting various cancer antigens and immune checkpoints. The company's strategy is to advance its proprietary programs while also leveraging strategic collaborations to expand the reach and potential of its technologies.

Financials

For the full year 2023, MacroGenics reported annual revenue of $58.7 million and a net loss of $90.6 million. The company's annual operating cash flow was -$78.2 million, and its annual free cash flow was -$80.0 million. These financial results reflect the company's continued investment in research and development to advance its pipeline of oncology candidates.

In the first quarter of 2024, MacroGenics reported total revenue of $9.1 million, a decrease from $24.5 million in the same period of 2023. This decrease was primarily due to a $15 million milestone payment received from Incyte in the first quarter of 2023 that was not repeated in 2024. The company's net loss for the first quarter of 2024 was $52.2 million, compared to a net loss of $38.0 million in the first quarter of 2023.

Vobra Duo: Improved Safety Profile and Promising Efficacy

MacroGenics' lead clinical-stage asset, vobra duo, is an ADC designed to deliver a DNA-alkylating duocarmycin cytotoxic payload to tumors expressing the B7-H3 antigen. The company is currently evaluating vobra duo in the Phase 2 TAMARACK study in patients with metastatic castration-resistant prostate cancer (mCRPC).

In the latest interim data update from the TAMARACK study, MacroGenics reported that the safety profile of vobra duo has improved compared to the previous Phase 1 data. Specifically, the company noted a reduction in the incidence and severity of adverse events such as palmar-plantar erythrodysesthesia syndrome and pleural effusion, which were observed in the earlier Phase 1 study. The overall safety data showed that the majority of treatment-emergent adverse events were Grade 1 or 2, and were considered manageable by investigators.

Regarding efficacy, the interim data from TAMARACK demonstrated promising results. In the 2 mg/kg dosing cohort, 50% of evaluable patients experienced a greater than 50% reduction in their prostate-specific antigen (PSA), with 43.9% achieving a confirmed PSA50 response. In the 2.7 mg/kg cohort, 50.7% of evaluable patients had a greater than 50% PSA reduction, with 36.6% achieving a confirmed PSA50 response.

The confirmed objective response rates (ORR) were 17.8% and 25% in the 2 mg/kg and 2.7 mg/kg cohorts, respectively, with unconfirmed ORRs of 24.4% and 43.8%. Importantly, a majority of patients in both dosing cohorts remained on therapy at the time of the data cutoff, suggesting durable responses.

MacroGenics plans to continue evaluating the totality of the TAMARACK data, including future radiographic progression-free survival (rPFS) results, which is the study's primary endpoint. The company is currently undertaking the necessary steps to prepare for the potential initiation of a Phase 3 study in mCRPC in 2025.

Expanding Vobra Duo's Reach

In addition to the ongoing TAMARACK study in mCRPC, MacroGenics plans to expand the evaluation of vobra duo to other tumor types. The company expects to initiate dosing in additional cohorts, including non-small cell lung cancer, small cell lung cancer, melanoma, squamous cell carcinoma of the head and neck, and anal cancer, in mid-2024.

This expansion of the vobra duo program reflects the company's confidence in the potential of targeting the B7-H3 antigen across a broad range of solid tumors. By exploring vobra duo in additional indications, MacroGenics aims to maximize the therapeutic reach of this promising ADC candidate.

Complementary B7-H3 Targeting Approaches

In addition to vobra duo, MacroGenics is advancing two other B7-H3-targeted molecules in its pipeline: MGC026 and enoblituzumab.

MGC026 is an investigational ADC that incorporates a novel topoisomerase 1 inhibitor-based linker payload, SYNtecan E, licensed from Synaffix. Preclinical data has shown MGC026 to have greater potency than B7-H3-directed antibodies conjugated to other payloads, and the molecule has demonstrated a favorable tolerability profile in animal studies.

Enoblituzumab is an Fc-optimized monoclonal antibody targeting B7-H3. The molecule is currently being evaluated in an investigator-sponsored, randomized Phase 2 study in patients with high-risk localized prostate cancer.

By pursuing these complementary approaches to targeting B7-H3, MacroGenics aims to address different cancer types, tumor stages, or potentially use the molecules in combination to enhance their clinical utility.

Lorigerlimab and MGD024: Advancing Combination Strategies

MacroGenics' pipeline also includes lorigerlimab, a bispecific tetravalent PD-1 x CTLA-4 DART molecule, and MGD024, a next-generation bispecific CD123 x CD3 DART molecule.

The company is currently enrolling the Phase 2 LORIKEET study, which is evaluating lorigerlimab in combination with docetaxel versus docetaxel alone in second-line, chemotherapy-naive mCRPC patients. MacroGenics anticipates completing enrollment of the LORIKEET study this year and providing a clinical data update in the first half of 2025.

Additionally, the company is exploring the combination of vobra duo and lorigerlimab in a Phase 1/2 dose escalation study in patients with advanced solid tumors. MacroGenics plans to initiate a dose expansion study of this combination in mCRPC and at least one additional indication in 2024.

Regarding MGD024, the Phase 1 dose escalation study in patients with CD123-positive relapsed or refractory hematologic malignancies, including acute myeloid leukemia and myelodysplastic syndromes, is ongoing. Gilead Sciences has an option to license MGD024 and undertake further development.

Preclinical Pipeline and Collaborations

Beyond its clinical-stage assets, MacroGenics is also advancing several preclinical programs, including MGC028, an ADC targeting ADAM9 that has demonstrated promising antitumor activity in various solid tumor models. The company plans to submit an investigational new drug (IND) application for MGC028 by the end of 2024.

MacroGenics' pipeline and research efforts are further supported by its strategic collaborations, including the exclusive global collaboration and license agreement with Incyte for the development and commercialization of the PD-1 inhibitor retifanlimab, and the option and collaboration agreement with Gilead Sciences for the development of MGD024 and other bispecific cancer antibodies.

Liquidity

As of March 31, 2024, MacroGenics had cash, cash equivalents, and marketable securities of $184.2 million. The company believes this, combined with anticipated and potential collaboration payments, product revenue, contract manufacturing revenue, and royalties, should enable it to fund its operations into 2026.

MacroGenics' expected funding requirements reflect anticipated expenditures related to the ongoing Phase 2 TAMARACK and LORIKEET studies, as well as other clinical and preclinical programs. The company remains focused on advancing its pipeline of innovative oncology candidates and exploring combination strategies to maximize the potential of its therapies.

Conclusion

MacroGenics' diverse pipeline of oncology product candidates, led by the promising ADC vobra duo, positions the company for continued growth and value creation. The improved safety profile and encouraging efficacy data from the TAMARACK study support the further development of vobra duo, while the company's complementary B7-H3 targeting approaches and combination strategies provide additional avenues for expansion. With a strong financial position and a commitment to innovation, MacroGenics is well-equipped to deliver on its vision of developing life-changing medicines for cancer patients.

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