MacroGenics Stock

MacroGenics, Inc. (MacroGenics) operates as a biopharmaceutical company.

The company focuses on developing and commercializing innovative antibody-based therapeutics for the treatment of cancer. The company has a pipeline of product candidates being evaluated in clinical trials sponsored by the company or its collaborators in addition to several molecules in preclinical development. The company’s clinical product candidates include multiple oncology programs, many of which were created using its proprietary, antibody-based technology platforms.

The company’s product candidates have the potential, if approved for marketing by regulatory authorities, to have a meaningful effect on treating patients' unmet medical needs as monotherapy or, in some cases, in combination with other therapeutic agents. As of December 31, 2022, two products originating from MacroGenics’ pipeline of proprietary or partnered product candidates have received U.S. Food and Drug Administration (FDA) approval.

The company is developing product candidates that target various tumor-associated antigens and immune checkpoint molecules. The company’s lead pipeline program is vobramitamab duocarmazine (vobra duo), an antibody-drug conjugate (ADC) that targets B7-H3, a molecule in the B7 family of immune regulator proteins that is widely expressed by several different tumor types. The company has historically pursued development of other molecules that target B7-H3, including enoblituzumab, an Fc-optimized monoclonal antibody (mAb). The company is also developing molecules that target programmed cell death protein 1 (PD-1), a protein that is important in the regulation of the immune system’s response to cancer. The company’s clinical pipeline includes two product candidates based on its proprietary, bispecific DART technology that co-engage both PD-1 and other checkpoint molecules. These candidates include lorigerlimab, which targets PD-1 and CTLA-4, or cytotoxic T-lymphocyte-associated protein 4, and tebotelimab, which targets PD-1 and LAG-3, or lymphocyte-activation gene 3. In addition, the company is developing MGD024, a next-generation bispecific DART molecule that engages CD3 on immune effector cells to kill CD123-expressing cancer cells in certain hematological malignancies, including acute myeloid leukemia (AML).

The company and its collaboration partners are developing or commercializing product candidates for which the company retains certain economic rights. These molecules include IMGC936, a clinical-stage ADC that targets ADAM9, a cell surface protein over-expressed in several solid tumor types; retifanlimab, an anti-PD-1 mAb that the company out-licensed and TZIELD (teplizumab-mzwv), an anti-CD3 monoclonal antibody that the company sold to a partner.

In March 2021, the company and its commercialization partner commenced U.S. marketing of MARGENZA (margetuximab-cmkb), a human epidermal growth factor receptor 2 (HER2) receptor antagonist mAb the company developed that is indicated, in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

B7-H3 Programs

The company has two clinical-stage programs, vobra duo and enoblituzumab, that target B7-H3 (CD276), an immune checkpoint molecule that is overexpressed in cancer tissues while showing limited expression in normal tissues. B7-H3 is a member of the B7 family of immune regulator proteins that is widely expressed by different tumor types and may play a key role in regulating the immune response to various cancers. Of the two programs, only vobra duo is in active clinical development. There are no approved therapeutic agents directed against B7-H3.

Vobramitamab Duocarmazine

Vobra duo is an investigational ADC with a cleavable peptide linker designed to deliver a DNA-alkylating duocarmycin payload to dividing and non-dividing cells on solid tumors that express B7-H3. The underlying ADC technology was licensed from Byondis B.V. (Byondis). After completing a dose escalation study in 2020, the company initiated the Phase 1/2 dose expansion study of vobra duo in patients with metastatic castration-resistant prostate cancer (mCRPC), non-small cell lung cancer (NSCLC), melanoma, squamous cell carcinoma of the head and neck (SCCHN) and triple negative breast cancer (TNBC). The purpose of this fully-enrolled study was to evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of the molecule. In addition, in early 2022, the company initiated a Phase 1/2 dose escalation study of vobra duo in combination with lorigerlimab, a bispecific DART molecule designed to block PD-1 and CTLA-4, in patients with solid tumors. This study is ongoing.

In late 2022, the company initiated the Phase 2 portion of the TAMARACK Phase 2/3 study of vobra duo in patients with mCRPC who have had prior exposure to a taxane and at least one androgen receptor axis-targeted, or ARAT, agent (including abiraterone, enzalutamide or apalutimide), and a PARP (poly adenosine diphosphate-ribose polymerase) inhibitor, if appropriate. This study is designed to evaluate 100 patients across two experimental arms in which they receive vobra duo at either 2.0 mg/kg or 2.7 mg/kg once every four weeks (Q4W). This study initially included a control arm in which patients received a second ARAT agent. The treatment landscape for patients with mCRPC has evolved with declining acceptability regarding the use of a second ARAT agent in patients who progress on earlier therapies and the approval of a radiopharmaceutical medication. Given the company’s objective to enroll TAMARACK and determine an optimal dose expeditiously, as of the first quarter of 2023, the company has modified the trial by removing the ARAT control arm and the Phase 3 portion of the study, with regulatory approval for the modified protocol obtained to date in several countries. The removal of the control arm should allow the company to provide a clinical update in 2024 potentially in the support of a subsequent Phase 3 study in mCRPC.

Phase 1/2 Dose Expansion Study Results (as of August 2021)

Preliminary clinical results from the ongoing Phase 1/2 study of vobra duo in patients with solid tumors was presented at the 2021 European Society for Medical Oncology (ESMO) Meeting. As of the August 16, 2021 data cut-off, a total of 86 patients with advanced solid tumors were enrolled in the cohort expansion of vobra duo at the recommended Phase 2 dose (RP2D) of 3.0 mg/kg, administered intravenously every three weeks. The enrollment included 40 patients with mCRPC, 21 patients with NSCLC, 16 patients with TNBC and nine patients with melanoma. In addition, enrollment of patients with SCCHN had been initiated. The safety analysis included all enrolled patients, whereas the efficacy analysis was limited to mCRPC and NSCLC patients; enrollment was ongoing in the other tumor cohorts. In the cohort expansion, tumor response by investigator per RECIST was evaluated every nine weeks for all patients and PSA was assessed every three weeks in mCRPC.

Enoblituzumab

Enoblituzumab is an investigational monoclonal antibody that targets B7-H3 that has been engineered using the company’s Fc Optimization platform. A Phase 2 study evaluating enoblituzumab in combination with either retifanlimab (anti-PD-1 monoclonal antibody) or tebotelimab (PD-1 × LAG-3 bispecific DART molecule) in the first-line treatment of patients with recurrent or metastatic SCCHN was discontinued in July 2022.

The company had initiated a Phase 2 study of this agent in the first-line treatment of patients with relapsed or metastatic SCCHN not curable by local therapy in the first quarter of 2021. This trial included enoblituzumab in a chemotherapy-free regimen in combination with either retifanlimab in patients who are programmed death-ligand 1 (PD-L1) positive or with tebotelimab in patients who are PD-L1 negative. In July 2022, the company announced the closure of this study based on an internal review of safety data, which included the occurrence of seven fatalities potentially associated with hemorrhagic events in both arms of the study (of 62 total patients treated).

At the 2022 ASCO Annual Meeting, investigators presented data from an investigator-sponsored trial of a single-center, single arm, open-label Phase 2 study evaluating the safety, anti-tumor effect, and immunogenicity of neoadjuvant enoblituzumab given prior to radical prostatectomy in men with intermediate and high-risk localized prostate cancer. In this study, investigators reported that six weeks of treatment with enoblituzumab demonstrated favorable safety and encouraging clinical activity in high-risk prostate cancer patients with local disease prior to prostatectomy. These trial results, combined with demonstrated favorable safety profile observed by the investigators, provide the rationale for further development of enoblituzumab and other B7-H3 targeted agents in prostate cancer.

In July 2019, the company licensed the right to develop and commercialize enoblituzumab in mainland China, Hong Kong, Macau and Taiwan to I-Mab Biopharma (I-Mab). In August 2022, I-Mab notified the company of its intention to terminate the I-Mab License Agreement effective February 25, 2023.

Immune Checkpoint Inhibitors

The company’s clinical pipeline includes three product candidates in clinical development that target checkpoint molecules for the potential treatment of a broad range of solid tumors. These candidates include two bispecific DART product candidates that co-engage PD-1 and other checkpoint molecules and an anti-PD-1 monoclonal antibody that the company has out-licensed to a partner.

Lorigerlimab

Lorigerlimab is an investigational, bispecific tetravalent DART molecule designed to enable simultaneous and/or independent blockade of PD-1 and CTLA-4, with potentially enhanced CTLA-4 blockade on T cells co-expressing these immune checkpoint molecules.

Dose Escalation Study Results (as of July 21, 2020)

The company conducted a Phase 1/2 clinical trial of lorigerlimab in patients with advanced solid tumors. The study was designed to enroll patients with histologically proven, unresectable, locally advanced or metastatic solid tumors for whom no approved therapy with demonstrated clinical benefit is available or patients who are intolerant to standard therapy.

Dose Expansion Study Results (as of December 12, 2022)

The company is evaluating lorigerlimab in an ongoing Phase 1/2 dose expansion study in patients with MSS CRC, mCRPC, melanoma and checkpoint-naive NSCLC, and reported on preliminary data at the ASCO Genitourinary Cancers Symposium in February 2023.

Preliminary Safety Results: The safety analysis is based on 127 patients who received lorigerlimab at a dose of 6 mg/kg Q3W, including 118 enrolled in the four dose expansion cohorts plus nine patients from dose escalation.

Preliminary Anti-tumor Activity in mCRPC Cohort: As of the December 12, 2022 data cut-off, 42 patients had been enrolled in the mCRPC expansion cohort.

Based on the above data, the company plans to initiate a randomized Phase 2 study of lorigerlimab in combination with docetaxel vs. docetaxel in second-line, chemotherapy-naïve mCRPC patients in the second half of 2023. A total of 150 patients are planned to be randomized 2:1. The current study design includes a primary study endpoint of radiographic progression-free survival (rPFS).

Tebotelimab

Tebotelimab is an investigational, first-in-class bispecific, tetravalent DART molecule targeting PD-1 and LAG-3. The company has engineered tebotelimab to concomitantly or independently bind to PD-1 and LAG-3 and disrupt these non-redundant inhibitory pathways to further restore exhausted T-cell function. Tebotelimab was evaluated in a Phase 1/2 dose expansion study in several tumor types and was studied in combination with enoblituzumab in SCCHN.

Dose Expansion Study Results (as of April 25, 2020)

In May 2020, initial data was presented from a Phase 1 monotherapy dose expansion study of tebotelimab in patients with advanced solid and hematologic neoplasms. At the April 25, 2020 data cut-off, 205 patients had been treated with tebotelimab, of which 152 were evaluable for response. Anti-tumor activity of tebotelimab, as assessed by RECIST, was observed in evaluable patients across several of the tumor types in the selected dose expansion cohorts. Response to tebotelimab monotherapy was associated with LAG-3 expression and an IFN-gamma gene signature at baseline. The overall safety profile of tebotelimab in the Phase 1 study, including the incidence of immune-mediated adverse events, appeared generally consistent with anti-PD-1 antibody monotherapy with respect to event type and frequency.

Dose Expansion Results in Diffuse Large B-cell Lymphoma (as of October 23, 2020)

In December 2020, data was presented from the tebotelimab Phase 1/2 dose expansion study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). In this study, 20 DLBCL patients were enrolled, half of whom were chimeric antigen receptor (CAR) T cell therapy experienced. As of the October 23, 2020 data cut-off, there were 13 response-evaluable patients. A preliminary ORR of 53.8% (7 of 13 patients) was observed, including responses in five of seven CAR T cell-naïve patients and in two of six CAR T cell experienced patients, the latter of whom both had complete responses. A preliminary duration of response of up to 168 days was observed, with six of seven ongoing responses as of the cut-off date. In the study, baseline LAG-3 expression appeared to associate with clinical response. Tebotelimab was generally well-tolerated among heavily pre-treated R/R DLBCL patients, with manageable infusion-related reactions and no evidence of tumor lysis syndrome. The most common TRAE was pyrexia, which occurred in three (15%) patients. A single Grade 3 TRAE of anemia was observed.

As part of the company’s November 2018 license and collaboration agreement with Zai Lab Limited (Zai Lab), the company licensed to them the right to develop and commercialize tebotelimab in mainland China, Hong Kong, Macau and Taiwan. Zai Lab has led regional studies evaluating tebotelimab in various indications in its territory. Zai lab discontinued development of tebotelimab for indications they were enrolling in their territory and is evaluating future development plans in other indications.

T-cell Redirected Bispecific DART Molecules

The company is developing a bispecific DART molecule that can simultaneously target T-cells and tumor cell surface antigens to engage and promote redirected T-cell killing of cancer cells. CD123, the interleukin-3 receptor alpha chain, is widely overexpressed in various hematologic malignancies, including AML and myelodysplastic syndrome (MDS), making it an attractive therapeutic target. Various drugs have been developed to target CD123, but none have received FDA approval. The company has created a bispecific DART molecule that engages CD3 expressed on immune effector cells, such as T cells, to kill CD123-expressing cancer cells for the potential treatment of certain hematologic malignancies, including AML.

MGD024

MGD024 is an investigational, next-generation, bispecific CD123 × CD3 DART molecule designed to minimize cytokine-release syndrome, while maintaining anti-tumor cytolytic activity, and permitting intermittent dosing through a longer half-life. In December 2021, the company presented preclinical MGD024 data at the American Society of Hematology (ASH) Annual Meeting that showed the potential for anti-tumor activity from the combination of MGD024 with standard of care agents used to treat AML. The company initiated a Phase 1 study of MG024 in patients with CD123-positive hematologic malignancies in July 2022, and this dose escalation study is ongoing.

On October 14, 2022, the company and Gilead Sciences, Inc. (Gilead) entered into an exclusive option and collaboration agreement (Gilead Agreement) to develop and commercialize MGD024 and create bispecific cancer antibodies using the company’s DART platform and undertake their early development under a maximum of two separate bispecific cancer target research programs. Under the Gilead Agreement, the company will continue the ongoing phase 1 trial for MGD024 according to a development plan, during which Gilead will have the right to exercise an option granted to Gilead to obtain an exclusive license to develop and commercialize MGD024 and other bispecific antibodies of the company’s that bind CD123 and CD3 (CD123 Option).

Margetuximab

The company and its commercial partner, Eversana Life Science Services, LLC (Eversana), are marketing MARGENZA (margetuximab-cmkb), in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Margetuximab is an Fc-engineered, mAb that targets the HER2 oncoprotein. HER2 is expressed by tumor cells in breast, gastroesophageal and other solid tumors.

As part of the company’s November 2018 license and collaboration agreement, Zai Lab has the rights to develop margetuximab in mainland China, Hong Kong, Macau and Taiwan. On January 6, 2022, Zai Lab announced that the China NMPA had accepted the New Drug Application (NDA) for margetuximab for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease, in combination with chemotherapy.

Partnered Programs

Retifanlimab

Retifanlimab is an investigational mAb targeting PD-1. Marketed antibodies targeting this checkpoint molecule have shown clinical efficacy in the treatment of various tumors by releasing the ‘brakes’ of the immune system and helping to restore the immune system's ability to detect and kill tumor cells. In 2017, the company licensed retifanlimab to Incyte Corporation (Incyte) under a global collaboration and license agreement (Incyte Agreement), although the company retains the right to develop the molecule in combination with product candidates from the company’s pipeline.

Incyte has stated it is pursuing development of retifanlimab in potentially registration-enabling indications, including in patients with Merkel cell carcinoma, squamous carcinoma of the anal canal, microsatellite instability-high, or MSI-high, endometrial cancer and non-small cell lung cancer. Incyte is also pursuing development of retifanlimab in combination with multiple product candidates from its pipeline.

IMGC936

IMGC936 is an ADC that targets ADAM9, a cell surface protein over-expressed in several solid tumor types. IMGC936 is being advanced under a co-development agreement with ImmunoGen, Inc. (ImmunoGen). Under the 50/50 collaboration, ImmunoGen is leading clinical development and has completed Phase 1 dose escalation and initiated dose expansion in NSCLC and triple negative breast cancer. ImmunoGen has indicated they anticipate sharing initial data in the second quarter of 2023.

Teplizumab

In 2018, the company entered into an asset purchase agreement (Asset Purchase Agreement) with Provention Bio, Inc. (Provention) pursuant to which they acquired the company’s interest in teplizumab, a monoclonal antibody the company had been developing for the treatment of type 1 diabetes. Teplizumab has been granted Breakthrough Therapy Designation by the FDA and PRIority MEdicines (PRIME) designation by the European Medicines Agency.

On November 17, 2022, the FDA approved TZIELD (teplizumab-mzwv) to delay the onset of Stage 3 type 1 diabetes (T1D) in adult and pediatric patients aged 8 years and older with Stage 2 T1D.

In March 2023, the company sold its royalty interest in TZIELD to a wholly-owned subsidiary of DRI Healthcare Trust (DRI). The company retains its other economic interests related to TZIELD, including future potential regulatory and commercial milestones.

PRV-3279

In 2018, the company also entered into a license agreement with Provention pursuant to which the company granted them exclusive global rights for the purpose of developing and commercializing PRV-3279, a CD32B × CD79B DART molecule being developed for the treatment of autoimmune indications. Provention is initially developing PRV-3279 for the interception of systemic lupus erythematosus (SLE), a chronic autoimmune disorder characterized by an abnormal overactivation of B cells and subsequent pathologic production of auto-antibodies. Provention has disclosed that it believes PRV-3279 also has the potential to prevent or reduce the immunogenicity of biotherapeutics, including but not limited to gene therapy vectors and transgenes.

Provention disclosed in the first quarter of 2022 that they had initiated a Phase 2a trial in SLE of PRV-3279. The PREVAIL-2 study is a Phase 2a proof-of-concept (POC) study in moderate-to-severe SLE patients induced into response with a short course of corticosteroids, and then monitored for relapse, after randomization to either PRV-3279 or placebo treatment. Provention has indicated that it expects to report top-line results of the PREVAIL-2 study in the second half of 2024.

HIV DART Molecules

The company is developing MGD014 and MGD020 under a contract awarded to the company in September 2015 by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. These bispecific DART molecules are designed to target the viral envelope (Env) protein of human immunodeficiency virus (HIV) infected cells and CD3 on T cells to redirect the immune system's T cells to kill HIV-infected cells. These molecules may become a key part of a strategy to reduce or eliminate latent HIV reservoirs in conjunction with latency-reversing agents. MGD014 and MGD020 target the gp120 and gp41 subunits of HIV Env, respectively. A Phase 1 study of MGD014 in persons with HIV maintained on antiretroviral therapy has been completed and a Phase 1 study of MGD020 alone and combined with MGD014 initiated in 2022.

Intellectual Property

Pipeline Patent Protection

As of December 31, 2022, the company held 87 patents in the United States with 45 patent applications pending and 757 patents in other countries of the world with 487 patent applications pending. In addition to patents and patent applications generally providing protection for various aspects of the company’s Fc Optimization, DART, and TRIDENT platforms, the company has patent and patent applications for the composition of matter of each of the company’s clinical pipeline product candidates and, in some cases, the company also has other patents and patent application related to various aspects of the technology underlying these product candidates or their methods of use.

The company has submitted a request to obtain patent term extension of U.S. Patent No. 8,802,093, the primary composition of matter patent for margetuximab.

Manufacturing

The company relies on contract manufacturers, including Byondis, Synaffix and Millipore Sigma, for producing components of the company’s ADC candidates. The company has supplemented its drug substance manufacturing capacity through an arrangement with AGC Biologics, Inc. (AGC), a contract manufacturing organization, and commercially produced initial margetuximab commercial supply and inventory at AGC.

In addition, the company relies on contract fill-finish service providers, primarily Ajinomoto Bio-Pharma Services and Baxter Healthcare Corporation, to fulfill its fill-finish needs for its product candidates.

Commercialization

MARGENZA is the company’s only approved product in the U.S. In November 2020, the company partnered with Eversana, a pioneer of next-generation commercial services to the global life sciences industry, to commercialize margetuximab in the U.S. by leveraging their integrated commercial services. Under the terms of the agreement, the company maintains ownership of margetuximab, including all manufacturing, regulatory and development responsibilities for the product. Eversana received a co-exclusive right to conduct approved commercialization activities. Eversana utilizes its internal capabilities to support sales and marketing, market access, channel management services, data and analytics, medical affairs, and other patient access related services; the company books MARGENZA sales.

Outside the United States, the company’s strategy is to enter into arrangements with third-party commercial partners for any of the company’s product candidates that obtain marketing approval.

Government Regulation and Product Approval

All of the company’s product candidates are subject to regulation in the United States by the FDA as biological products (biologics).

The company is subject to various federal and state laws pertaining to health care ‘fraud and abuse,’ including anti-kickback and false claims laws, as well as laws related to health care transparency and data protection.

History

MacroGenics, Inc. was founded in 2000. The company was incorporated in Delaware in 2000.