LAVA Therapeutics N.V. (LAVA) operates as a clinical-stage immuno-oncology company. The company focuses on developing its proprietary Gammabody platform of bispecific gamma delta (gd) T cell engagers to transform the treatment of cancer.
The company acquired or exclusively in-licensed the development and commercial rights to certain clinical and preclinical programs and intellectual property from Amsterdam UMC. The company also has a research services agreement with Amsterdam UMC in support of...
LAVA Therapeutics N.V. (LAVA) operates as a clinical-stage immuno-oncology company. The company focuses on developing its proprietary Gammabody platform of bispecific gamma delta (gd) T cell engagers to transform the treatment of cancer.
The company acquired or exclusively in-licensed the development and commercial rights to certain clinical and preclinical programs and intellectual property from Amsterdam UMC. The company also has a research services agreement with Amsterdam UMC in support of its preclinical and clinical stage programs. Using its Gammabody platform, the company is developing a portfolio of novel bispecific antibodies designed to engage and leverage the potency and precision of gamma delta (gd) T cells to elicit a robust, anti-tumor immune response and improve outcomes for cancer patients. The company’s business is primarily conducted in the European Union and the United States
Proprietary Gammabody Platform
The company’s Gammabody platform enables it to develop off-the-shelf bispecific T cell engagers that leverage the advantages of antibody-based treatments, including favorable manufacturability and developability characteristics. The company’s Gammabody platform is designed to recruit the body’s own Vg9Vd2T cells resulting in tumor cell targeting and conditional cancer cell killing. One arm of the Gammabody recruits Vg9Vd2 T cells, while the other arm recognizes and binds to a specific tumor target present on hematological or solid tumors. The company designed its Gammabody drug candidates to activate the Vg9Vd2 T cells once the respective arms are bound to the gd T cell and the tumor target, thereby avoiding broad systemic activation.
The company has generated compelling preclinical data using patient tumor tissues that demonstrate the ability of its Gammabody platform to exert preferential activity against tumor cells expressing the target with relative sparing of healthy cells. Using surrogate Gammabody molecules, studies in non-human primates showed that its gd T cell engagers were well tolerated.
Pipeline
The company designed its Gammabody platform to be fully modular and compatible with existing anti-tumor antibodies to facilitate expedited discovery and development of novel compounds. The company is advancing its Gammabody pipeline for the development of potential therapeutics in both hematologic malignancies and solid tumors. The company’s lead clinical-stage candidate, LAVA-1207, is designed to target prostate-specific membrane antigen (PSMA)-expressing cancers. It is undergoing testing in a first-in-human Phase 1/2a clinical trial for patients with metastatic castration resistant prostate cancer (mCPRC). The company is also developing other Gammabody drug candidates, including LAVA-1266, which targets CD123 for the treatment of hematological malignancies, including acute myeloid leukemia and myelodysplastic syndrome. The company expects to file an IND for LAVA-1266 in mid-2024.
LAVA-1207
LAVA-1207 is designed using the company’s Gammabody platform to conditionally activate Vg9Vd2 T cells upon crosslinking to PSMA to trigger the potent and preferential killing of PSMA-positive tumor cells. PSMA, a transmembrane protein, is expressed by most prostate tumors, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas.
In 2022, the company dosed the first patient in a first-in-human clinical trial evaluating LAVA-1207 in patients with mCRPC. The open-label, multi-center, Phase 1/2a clinical trial evaluates safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of LAVA-1207. The Phase 1 dose-escalation phase is designed to determine recommended Phase 2a dose(s) for optimization in Phase 2a. The company has nine clinical trial sites open to enrollment in Europe and the United States.
In February 2023, at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), the company reported initial clinical data for the ongoing clinical trial of LAVA-1207.
In June 2023, the company announced that it had introduced cohorts of patients who would receive one of two schedules of low-dose interleukin-2 (LDIL-2) beginning the day after LAVA-1207 dosing for the first four doses. LDIL-2 has the potential to increase the number of Vg9Vd2-T cells available for engagement by LAVA-1207. The company has amended the DLT criteria for the duration of transaminase increases which are clearly immune-related.
As of December 31, 2023, the company had observed pharmacodynamics that support LAVA-1207’s mechanism of action and continue to see increasing Vd2-T cell receptor occupancy with increasing dose and it continues to see signs of preliminary anti-tumor activity, including long-term stable disease and decreases in PSA level.
In addition to investigating the potential role of patient selection based on gd2 T cells the company is exploring the role of tumor factors in understanding patient selection and antitumor activity. Patients have a PSMA-PET scan at baseline and it will study the relationship between PET positivity and likelihood of benefit. In addition, an amendment to the protocol has been submitted to add ctDNA and CTC assessments as an additional exploratory evaluation of antitumor effect.
In January 2024, the company announced it had entered into a clinical trial collaboration and supply agreement with Merck & Co., Inc. to evaluate its anti-PD-1 therapy KEYTRUDA (pembrolizumab) in combination with LAVA-1207. Under the terms of this agreement, it will be provided with pembrolizumab for the dose escalation and expansion phases of LAVA’s ongoing Phase 1/2a study of LAVA-1207 (NCT05369000) (KEYNOTE-F73), with the combination arm expected to be initiated in the first half of 2024.
The company plans to provide new data for LAVA-1207 at an upcoming medical conference in the second half of 2024, which may inform the design of a future pivotal trial.
LAVA-1266
LAVA-1266 is designed using the company’s Gammabody platform to conditionally activate Vg9Vd2 T cells upon crosslinking to CD123 (Interleukin-3 receptor-alpha) to trigger the potent and preferential killing of CD123-positive tumor cells. CD123 is a clinically validated target and CD123 is expressed in a range of hematological malignancies, including AML, myelodysplastic syndrome (MDS), acute lymphocytic leukemia (ALL) and Hodgkin Lymphoma. There is a clear unmet need in these indications. The company engaged in IND enabling activities and plan to seek an IND submission for LAVA-1266 in the second quarter of 2024.
Preclinical Programs
The company’s internal pipeline consists of several discovery and preclinical stage investigational assets for undisclosed targets in hematologic malignancies and solid tumors. The company’s preclinical stage assets, LAVA-1427 and LAVA-1433, were selected as development candidates at the end of 2023 and has progressed into GMP cell-line development. The company generated high yield cell lines producing high quality bispecific gamma delta (gd)TCEs for GMP manufacturing and further preclinical activities for potential IND/CTA filings in 2025 and beyond.
EGFRd2 (PF-8046052/formerly LAVA-1223)
In 2022, the company entered into the Pfizer Agreement to develop, manufacture and commercialize EGFRd2 (PF-8046052), an advanced preclinical asset that utilizes its proprietary Gammabody technology to target EGFR-expressing solid tumors. The Pfizer Agreement also provides Pfizer with the opportunity to exclusively negotiate rights to apply the company’s proprietary Gammabody platform on up to two additional tumor targets, which exclusive rights, if not exercised in 2024, will expire. In 2023, Pfizer received investigational new drug application clearance for EGFRd2 (PF-8046052) in advanced solid tumors from the FDA and initiated a Phase 1 trial (NTC0598133) of EGFRd2 (PF-8046052) to evaluate the safety and tolerability of this molecule as a monotherapy in advanced EGFR expressing solid tumors.
Discontinued program - LAVA-051
In June 2023, the company announced that the LAVA-051 clinical trial, targeting the CD1d expressing hematological tumors multiple myeloma (MM,) chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML), would be discontinued after no patients remained on treatment. CD1d is expressed by tumor cells of most patients with CLL, MM and (myelo)monocytic subtypes of AML.
From mid-2021 through 2023, the company treated patients in a first-in-human Phase 1/2a clinical trial evaluating LAVA-051 in patients with relapsed or refractory CLL and MM. Patients with AML were expected to be included later in the trial once biologically relevant dosing has been reached. The Phase 1/2a clinical trial for LAVA-051 had fifteen clinical trial sites in Europe and in the United States and orphan drug designation for LAVA-051 for the treatment of CLL.
Next Generation Gammabody platform
The company is also developing a novel proprietary platform of next generation Gammabody formats that have the potential to further stimulate and expand Vg9Vd2 T cells towards cells and potentially recruit alternative effector cells.
Gammabody platform
The company has developed a proprietary Gammabody platform that optimizes tumor-targeted activation of Vg9Vd2 cells for tumor cell killing, retains and leverages these cells’ inherent tumor cell recognition and killing capabilities and drives a downstream immune response cascade against tumor cells. The company’s platform combines the power and natural selectivity of Vg9Vd2 T cells and their ability to activate both arms of the immune system with the targeting advantages of small-sized bispecifics, providing the opportunity to significantly improve upon classical T cell engager approaches and earlier strategies for recruiting gd T cells for cancer therapy.
The company’s approach targets antigens frequently expressed at higher levels on tumor cells than healthy cells. In addition, the company’s Gammabody platform is designed to avoid the detrimental co-activation of immune-suppressive cells, such as Tregs, that is typically observed with CD3 or pan-T cell TCEs, which can dampen the development of effective antitumor responses. The company has conducted preclinical experiments showing that Treg activation, as assessed by flowcytometric detection of the early activation-marker CD69, is induced by a CD3-based TCE, but not by its Gammabody.
Intellectual Property
The company has developed or exclusively in-licensed numerous patent and patent applications, know-how and trade secrets relating to the development and commercialization of its product candidates and the underlying Gammabody platform. The company owns or in-licenses: four (4) issued U.S. patents, twenty (20) pending U.S. patent applications, thirteen (13) pending European regional-phase patent applications, six (6) pending PCT patent application, twenty (20) issued patents in other territories and eighty (80) pending patent applications in other territories that are important to the development of its business.
License Agreements
Pfizer Agreement
In 2022, the company entered into the Pfizer Agreement to develop, manufacture and commercialize EGFRd2 (PF-8046052), an advanced preclinical asset that utilizes its proprietary Gammabody technology to target EGFR-expressing solid tumors. Pfizer has also granted the company a one-time option to obtain increased royalties if it exercises a buy-up option within a certain amount of time from certain key early clinical data becoming available for the first licensed product.
Janssen Agreement
In May 2020, the company entered into the Janssen Agreement for the discovery and development of novel bispecific antibody-based gd T cell engagers for the treatment of cancer.
Amsterdam UMC agreements
In 2017, the company entered into the Amsterdam UMC Agreement. Under the Amsterdam UMC Agreement, Amsterdam UMC granted it an exclusive, although non-exclusive with respect to certain intangible know-how, worldwide, sublicensable license under certain patent rights and know-how owned by Amsterdam UMC, effectively, including research and other services provided in collaboration by Amsterdam UMC since 2017 to develop, make, and sell licensed products.
Merck & Co., Inc.
In January 2024, the company announced it had entered into a clinical trial collaboration and supply agreement with Merck & Co., Inc. to evaluate its anti-PD-1 therapy KEYTRUDA (pembrolizumab) in combination with LAVA-1207. Under the terms of this agreement, the company will be provided with pembrolizumab for the dose escalation and expansion phases of its ongoing Phase 1/2a study of LAVA-1207 (NCT05369000) (KEYNOTE-F73), with the combination arm expected to be initiated in the first half of 2024. Enrollment and dose escalation will also continue in the LAVA-1207 monotherapy and interleukin-2 arms of the study.
Manufacturing, Sales and Marketing
Given the stage of the company's lead programs, the company is in the process of building its United States (U.S.) commercial, medical affairs, and manufacturing infrastructure and intend to build, alone or with potential future partners, its global commercialization and distribution capabilities over time for its lead clinical candidates.
Patent Portfolio
As of December 31, 2023, the company’s patent portfolio included the U.S. and foreign patents and patent applications. The patents and patent applications in the company’s patent portfolio cover technology used in its own development programs, as well as technology used in its collaborations. The company has granted Pfizer an exclusive worldwide license for the development and commercialization of EGFRd2 (PF-8046052/formerly LAVA-1223), an advanced preclinical asset that utilizes LAVA’s proprietary Gammabody technology to target epidermal growth factor receptor (EGFR)-expressing solid tumors. The company has granted Janssen an exclusive worldwide license for the development and commercialization of a confidential product candidate.
The issued patents and patent applications directed to the company’s most advanced programs are summarized below:
LAVA-1207
For LAVA-1207, LAVA’s patent portfolio includes six (6) pending U.S. patent applications, one (1) pending European patent applications, thirteen (13) pending foreign patent applications containing claims or supporting disclosures directed to the LAVA-1207 composition of matter and to methods of treating diseases of interest using LAVA-1207. This issued patent and patents issuing from these pending patent applications, if any, are expected to expire between 2041 and 2044, excluding any potential patent term extensions or patent term adjustments.
LAVA-1266
For LAVA-1266, LAVA’s patent portfolio includes one (1) pending U.S. patent applications, one (1) pending European patent applications, fourteen (14) pending foreign applications containing claims or supporting disclosures directed to the LAVA-1266 lead composition of matter and to methods of treating diseases of interest using LAVA-1266 is issued patent and patents issuing from these pending patent applications, if any, are expected to expire in 2042, excluding any potential patent term extensions or patent term adjustments.
The company’s manufacturing and assay development patents, patent applications and related know-how may provide it with additional intellectual property protection relating to LAVA-1207, LAVA-1266 and preclinical candidates.
Platform Technology
The company’s patent portfolio also includes patent families relating to its Gammabody platform, including eight (8) patent families that are generally related to the antibodies that activate gd T cells, dosing of such antibodies, uses of such antibodies for certain patient groups, and combination of such antibodies with additional therapeutic agents. For the platform technology, LAVA’s portfolio includes two (2) granted U.S. patents, seven (7) pending U.S. applications, three (3) pending European applications, eleven (11) granted foreign patents, nine (9) pending foreign applications, and three (3) pending PCT applications.
Research and Development
The company’s research and development expenses were $33.8 million for the year ended December 31, 2023.
Competition
The company’s competitors in the field of gamma delta T cell therapy include Adicet Bio, Inc., Clade Therapeutics, Editas Medicine, Inc., Eureka Therapeutics, Inc., Takeda Pharmaceutical Company Ltd, ImCheck Therapeutics SAS, Immatics N.V., IN8bio, Inc., Leucid Bio Ltd, PhosphoGam Inc., Shattuck Labs Inc., Sandhill Therapeutics, Inc, and TC BioPharm Limited. The company’s bispecific gamma delta T cell product candidates may also compete with other T cell engaging therapies as well as NK cell-engaging therapies.
Government Regulation
Any products manufactured or distributed by the company pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product.
In the United States, the company's activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare & Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human Services (such as the Office of Inspector General and the Health Resources and Service Administration), the Department of Justice, or the DOJ, and individual U.S. Attorney offices within the DOJ, and state and local governments.
In Europe, the company is subject to Regulation (EU) 2016/679, the General Data Protection Regulation (GDPR), in relation to its collection, control, processing, and other use of personal data. The GDPR is directly applicable in each European Union Member State, however, it provides that European Member States may introduce further conditions, including limitations which could limit the company's ability to collect, use, and share personal data (including health and medical information), or could cause its compliance costs to increase, ultimately having an adverse impact on its business.
The company is also subject to European Union rules with respect to cross-border transfers of personal data out of the European Union and European Economic Area (EEA). Recent developments in the EU have created complexity and uncertainty regarding transfers of personal data from the EEA to the United States.
In addition to the foregoing, state, and federal U.S. and European Union laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act, and the Toxic Substances Control Act, affect the company's business.
History
LAVA Therapeutics N.V. was founded in 2016. The company was incorporated under the laws of the Netherlands in 2016.
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