ADC Therapeutics SA (ADCT) operates as a commercial-stage global pioneer company.
The company has a validated and differentiated technology platform with multiple payloads, linkers and conjugation chemistry, enabling the design of next-generation potent ADCs with an enhanced therapeutic index. The company is seeking to expand the label for its FDA-approved and marketed product, ZYNLONTA (loncastuximab tesirine), into new indications and earlier lines of therapy, while pursuing its early-stage s...
ADC Therapeutics SA (ADCT) operates as a commercial-stage global pioneer company.
The company has a validated and differentiated technology platform with multiple payloads, linkers and conjugation chemistry, enabling the design of next-generation potent ADCs with an enhanced therapeutic index. The company is seeking to expand the label for its FDA-approved and marketed product, ZYNLONTA (loncastuximab tesirine), into new indications and earlier lines of therapy, while pursuing its early-stage solid tumor programs. The company leverages its scientific and technical expertise and applies a disciplined approach to target selection to expand and advance its pipeline. The company's portfolio of ADCs utilizes its highly potent pyrrolobenzodiazepine (PBD) payload, a differentiated exatecan-based payload with a novel hydrophilic linker, and a next generation ADC toolbox.
In its hematology program, the company's flagship product, ZYNLONTA, a CD19-directed ADC, received accelerated approval from the U.S. Food and Drug Administration (FDA), conditional approval from the European Commission, and conditional approval from the China National Medical Products Administration (NMPA) for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. The company is seeking to continue expanding ZYNLONTA internationally, and into earlier lines of DLBCL and indolent lymphomas, including marginal zone lymphoma (MZL), and follicular lymphoma (FL), as a single agent and in combination through its LOTIS-5 confirmatory Phase 3 clinical trial, and LOTIS-7 Phase 1b clinical trial, as well as through investigator-initiated trials (IITs) at leading institutions. In addition, the company is investigating a CD-22 targeted compound, ADCT-602, in collaboration with the MD Anderson Cancer Center in a Phase 1/2 IIT in relapsed or refractory B-cell acute lymphoblastic leukemia.
In solid tumors, the company has early-stage preclinical research programs, including a portfolio of next-generation investigational ADCs targeting Claudin-6, PSMA, NaPi2b, and ASCT2, the most advanced of which are PSMA and Claudin-6. In addition, the company is advancing research with a range of payloads, linkers and conjugation technologies against undisclosed targets. The company is seeking strategic partnerships, collaborations or license arrangements to continue to fund these and other programs.
Strategy
Hematology
In the company’s hematology program, its strategy is to maximize and expand the ZYNLONTA opportunity in several ways include to maximize ZYNLONTA in third line plus (‘3L+’) DLBCL; seek to expand ZYNLONTA into earlier lines of DLBCL and indolent lymphomas as a single agent and in combination with other therapies; and to continue to advance the development and commercialization of ZYNLONTA outside of the United States through strategic partnerships.
The company is also developing ADCT-602 targeting CD22 in collaboration with the MD Anderson Cancer Center for patients with relapsed or refractory acute lymphoblastic leukemia. The company is in dose escalation with ADCT-602 and evaluating the 75 µg/kg dose.
Solid Tumors
In solid tumors, the company’s strategy is to pursue multiple exatecan-based ADC pre-clinical candidates in parallel. The company seeks to maximize the value of its solid tumor program through strategic partnerships, collaborations and licenses for one or more research programs. Specifically, the company seeks to advance a portfolio of investigational ADCs including those targeting Claudin-6, PSMA, NaPi2b, and ASCT2, the most advanced of which are PSMA and Claudin-6.
ADC Design
An ADC consists of three components include an antibody that selectively targets a distinct antigen preferentially expressed on tumor cells; a cytotoxic molecule, often referred to as the toxin or the warhead, that kills the target cell; and a chemical linker that joins together the antibody and the warhead. The warhead and the linker are together referred to as the payload. The figure below shows the three components of an ADC.
Within ADC Therapeutics, the company has a strong focus on technology development with the goal of developing best-in-class ADC candidates with an optimal therapeutic window for any given tumor target. The company has an expanding toolbox with a range of payloads, linkers and conjugation technologies.
Antibody
Different antibody technologies can be used to optimize targeting of the ADC to the tumor and/or to enhance uptake of the ADC into the tumor once it is bound to the target on the membrane of the tumor. while most of the ADCs in development are based on monoclonal antibody targeting, the company is also exploring the use of bispecific and/or biparatopic antibodies in its ADC selection to enhance the uptake of the ADC into the tumor. The company is also exploring the use of novel antibody formats in ADC design such conditionally binding antibodies. Conditionally binding antibodies bind stronger to target expressed in the more acidic local tumor environment and bind less strong to target expressed on healthy tissue which has neutral pH.
Toxins
The company’s pipeline consists of multiple programs targeting hematological and solid tumor targets for which it has selected ADC candidates employing the company’s proprietary exatecan platform or PBD dimer technology (under license from AstraZeneca). Exatecans belong to the family of camptothecins, which are naturally occurring pentacyclic quinoline alkaloids that bind to DNA topoisomerase I, inhibiting DNA relegation and finally causing apoptosis. Campothecins such as exatecan therefore possesses high cytotoxic activity against a variety of tumors. The potency of exatecan is slightly higher than DXd, the topoisomerase I inhibitor used in Enhertu and other ADCs in clinical development such as ifinatamab deruxtecan, patritumab deruxtecan and raludotatug deruxtecan.
PBD dimers are highly potent and bind irreversibly to two guanines from opposite DNA strands in minor groove of DNA without distorting the double helix, potentially evading DNA repair mechanisms. The interstrand cross-links block DNA strand separation, disrupting essential DNA metabolic processes, such as replication, and ultimately result in cell death.
Both exatecans and PBD dimers cause a bystander effect, which occurs when a released warhead (from a target positive cell which has internalized and processed the ADC) is able to diffuse into and kill neighboring cells in the tumor microenvironment, irrespective of those cells’ antigen expression.
In addition to its proprietary exatecan platform and PBD dimer technology, the company has access to another DNA alkylating cytotoxin, which it can access under a license agreement. The company is furthermore developing payloads based on immune modulators to create immune stimulating antibody conjugates (ISACs) based on TLR7 agonists. The company's ultimate objective is to has a variety of different toxins with orthogonal modes of action, which can be used to design dual conjugate ADCs (i.e., an ADC to which two different toxins are conjugated).
Linkers
The company's linker design focuses on different aspects. First, it emphasizes the spacer in the linker. The company's proprietary exatecan platform is based on a novel hydrophilic spacer, which allows conjugation of exatecan to antibodies at a high drug to antibody ratio (DAR). Secondly, the company has cleavable versus non-cleavable linker configurations. While cleavable linkers are the preferred choice if a bystander effect of the ADC is desired, in certain cases, bystander activity should be avoided, which can be achieved using non-cleavable linkers. Finally, the company has developed a set of branched linkers that allows it to increase the DAR or to generate ADCs with multiple toxins on a single conjugation site.
Conjugation Technologies
Depending on the desired DAR and other criteria, such as the need for Fc gamma receptor binding, the company can design the optimal ADC using a selection of different site-specific conjugation technologies, either enzymatic or non-enzymatic. The company also has access to multiple conjugation chemistries, such as classical maleimide and bio-orthogonal click chemistry, and is implementing additional proprietary approaches. Additionally, the company has a variety of tools that allow it to design dual conjugate ADCs (i.e., an ADC to which two different toxins are conjugated).
Regulatory Approval
On April 23, 2021, ZYNLONTA received accelerated approval from the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma and high-grade B-cell lymphoma. Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial, which the company intends to satisfy through its LOTIS-5 confirmatory Phase 3 clinical trial.
On December 20, 2022, the European Commission granted conditional marketing authorization for the use of ZYNLONTA for the treatment of relapsed or refractory DLBCL. The decision is valid in all European Union Member States, Iceland, Norway, and Liechtenstein. Continued approval for this indication is contingent upon verification of clinical benefit in a confirmatory trial, which the company intends to satisfy through its LOTIS-5 confirmatory Phase 3 clinical trial.
On December 06, 2024, ZYNLONTA received conditional approval in China from the NMPA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. This conditional approval is based on overall response rate and duration of response results from a single-arm clinical trial. The full approval for this indication will be contingent upon the results of the subsequent confirmatory randomized controlled trial. The company intends to satisfy this requirement through its LOTIS-5 Phase 3 clinical trial.
Commercialization
The company continues to directly commercialize ZYNLONTA in the United States through a commercial organization consists of cross-functional employees, including marketing, sales, market access, insights and analytics, and commercial operations functions. The company’s field sales team calls on healthcare providers across both the academic and community settings and has the potential to cover more than 90% of the DLBCL opportunity.
Outside of the United States, the company has entered into strategic agreements to maximize the commercial potential of ZYNLONTA, including an exclusive license agreement with MTPC in Japan, and a joint venture with Overland Pharmaceuticals in China (including Hong Kong and Macau), Singapore, and Taiwan, and an exclusive license agreement with Sobi for all other regions, excluding the U.S. and Japan. In Europe, ZYNLONTA has received conditional approval from the European Commission for the treatment of relapsed or refractory DLBCL after two or more lines of systemic therapy. In China, the company has received conditional approval from the NMPA for relapsed or refractory DLBCL after two or more lines of systemic therapy. In China, the company and the joint venture are exploring commercialization options for ZYNLONTA. In Japan, MTPC is undertaking a Phase 1/2 bridging study and joined the LOTIS-5 confirmatory Phase 3 clinical trial.
Confirmatory Phase 3 Clinical Trial (LOTIS-5)
LOTIS-5 is a Phase 3, randomized, open-label, two-part, two-arm, multi-center clinical trial of ZYNLONTA combined with rituximab compared to immunochemotherapy in patients with relapsed or refractory DLBCL.
Pivotal Phase 2 Clinical Trial in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS-2)
The company conducted a 145-patient Phase 2, multi-center, open-label, single-arm clinical trial to evaluate the safety and efficacy of ZYNLONTA in patients with relapsed or refractory DLBCL. This trial was used as the basis to obtain accelerated approval in the U.S. and conditional approvals in Europe and China.
Other ZYNLONTA Clinical Trials
LOTIS-7
Clinical Trial Design
LOTIS-7 is a Phase 1b global multicenter, multi-arm study in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL), including Part 1 (dose escalation) and Part 2 (dose expansion).
LOTIS-7 Initial Data
On December 11, 2024, the company announced preliminary data from LOTIS-7, the ongoing Phase 1b global multicenter, multi-arm study in patients with relapsed or refractory B-NHL that includes Part 1 (dose escalation) and Part 2 (dose expansion).
Phase 2 Investor Initiated Trials (IITs)
On December 9, 2024, the company announced updated data from a Phase 2 investigator-initiated clinical trial IIT evaluating ZYNLONTA in combination with rituximab for relapsed or refractory FL and data from a Phase 2 IIT evaluating ZYNLONTA for relapsed or refractory MZL were presented at the 66th American Society of Hematology (‘ASH’) Annual Meeting and Exposition. Both IITs were conducted at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.
LOTIS-10
LOTIS-10 is a Phase 1b open-label, multi-center study to evaluate the safety, pharmacokinetics and anti-cancer activity of ZYNLONTA in patients with relapsed or refractory DLBCL or high-grade B-cell lymphoma (‘HGBCL’) with hepatic impairment.
ADCT-602: PBD-Based ADC Targeting CD22
The Acute Lymphoblastic Leukemia Disease Setting
Acute lymphoblastic leukemia (‘ALL’) is a rare form of blood cancer with an annual incidence of ~6,000. Adults make-up ~50% of ALL patients. The five-year survival rate is 71%; however, it declines significantly with age. Allogeneic transplant is the standard of care for patients who are relapsed or refractory to induction therapy. Achieving a response without toxicities which can prevent a patient’s ability to get to an allogeneic transplant is an area of unmet need. The company is developing ADCT-602 (CD22) in this area of high unmet medical need.
Phase 1/2 Clinical Trial in Relapsed or Refractory Acute Lymphoblastic Leukemia
Pursuant to the company’s collaboration agreement with MD Anderson Cancer Center, a Phase 1/2, open-label, dose escalation and dose expansion clinical trial of the safety and anti-tumor activity of ADCT-602 (CD22), used as monotherapy, in patients with relapsed or refractory ALL is progressing, and additional clinical trial sites are being added to accelerate enrollment.
One additional patient at 50 µg/kg weekly dose level had marrow blast clearance without count recovery.
Solid Tumors:
The Solid Tumor Disease Setting
Research Strategy, Platform and Pipeline
The company's solid tumor research strategy is focused on three key elements. First, it has identified areas of high unmet need that feature a high use of chemotherapy. Second, the company is pursuing targets within these tumor types that are amenable to an ADC approach. Third, the company is utilizing its deep knowledge and broad toolkit to optimize the design of ADCs that fit with its first two criteria.
The company has developed four lead candidates with differentiated profiles based on a novel, proprietary linker approach to tracelessly release exatecan, and a high therapeutic index, which reflects the proprietary design of its ADCs: Claudin-6, PSMA, NaPi2b, and ASCT2, the most advanced of which are PSMA and Claudin-6. Details include:
Claudin-6 and NaPi2b: Preclinical studies demonstrated the company’s novel, exatecan-based ADCs, targeting Claudin-6 and NaPi2b, were well tolerated with potent and specific in vitro and in vivo anti-tumor activity.
PSMA: With PSMA-PL2202, the company is developing an optimized ADC directed against a validated target with high potential impact in metastatic castrate resistant prostate cancer.
ASCT2: And with ASCT2-PL2202, the company is designing an optimized ADC directed against a novel target with high potential impact in many indications including - but not limited to - colorectal cancer and non-small cell lung cancer.
Beyond this, the company is further diversifying its toolbox with drugs with other Mode of Actions, including other DNA damaging agents and immunomodulators and focus on conjugation technology to develop dual conjugate ADCs based on two different drugs with orthogonal modes of action.
Chemistry, Manufacturing and Controls
The company is a pioneer and leader in the ADC field with specialized end-to-end capabilities for developing optimized manufacturing processes for ADCs. The company’s robust in-house CMC capabilities utilize a highly experienced workforce to manage a top-tier external manufacturing network through third-party CMOs. The company’s third-party CMO network is capable of manufacturing highly potent molecules and complex biologics.
Instead, the company contracts with third-party Good Manufacturing Process-compliant CMOs that has the facilities and capabilities to manufacture on its behalf the intermediate components and the final product candidates for use in clinical trials and commercial supply. The company has sufficient commercial-grade drug product, ZYNLONTA, in stock, and it and its CMOs will be able to conduct additional manufacturing at the scheduled times. The company's in-house team oversees all aspects of the CMO manufacturing process, including defining the scope of work and monitoring all aspects of the manufacturing process, including conducting routine site visits and audits. The company also contracts with external specialist quality control and stability-testing organizations to monitor the quality of the materials manufactured by the CMOs.
Patent Portfolio
The company has over 350 patents issued in the U.S. and other countries with expirations ranging from 2031 to 2043, as well as numerous pending patent applications in the U.S. and other countries.
‘PBD Warhead,’ ‘PBD Warhead with Linker’ Platform Patent Protection
As of December 31, 2024, with respect to the PBD-based warhead and ADC technology the company uses to develop its product candidates, the company has exclusively licensed from MedImmune for target molecules, various patent families directed to different aspects of the chemistry of the PBD molecules and methods of using the molecules in the treatment of proliferative diseases. These families include approximately 7 issued U.S. utility patents. The issued utility patents, and any utility patents granted from the pending applications in these families, are expected to expire between 2023 and 2038.
Product-Specific Patent Protection
As of December 31, 2024, the company co-owned with MedImmune, and has exclusive rights to, approximately 12 patent families directed to ADCs with PBD warheads and targeting moieties that bind to specific target molecules, combinations of these ADCs with other therapeutic molecules and therapeutic uses of these ADCs. These families include approximately 13 issued U.S. utility patents. The issued utility patents, and any utility patents granted from the pending applications in these families, are expected to expire between 2033 and 2042. Further details in relation to marketed products. The company also solely owns eight patent families directed to antibodies, ADCs with Exatecan or other warheads, linker technology and therapeutic uses of these antibodies and ADCs. Any utility patents granted from the pending applications in these families are expected to expire between 2041 and 2044.
ZYNLONTA
As of December 31, 2024, there are six such patent families directed to the ADC product, methods of using the ADC as a single agent or in combination with other named molecules in the treatment of proliferative diseases, and dosing regimens. The issued utility patents, and any utility patents granted from the pending applications in these families, are expected to expire between 2033 and 2042.
Material Contracts
In 2011, the company (then operating under the name ADCT Sàrl) entered into a license and collaboration agreement with Spirogen (since renamed ADC Products UK Ltd.), pursuant to which Spirogen granted it access to its next-generation PBD-based warhead and linker technology.
In December 2020, the company entered a joint venture with Overland Pharmaceuticals (‘Overland’) to develop and commercialize ZYNLONTA, ADCT-602, ADCT-601 and ADCT-901 in greater China and Singapore. In connection with such joint venture, the company entered into a license and collaboration agreement with the joint venture entity, Overland ADCT BioPharma (CY) Limited (‘Overland ADCT BioPharma’) pursuant to which it granted Overland ADCT BioPharma an exclusive license or sublicense (as applicable) under all applicable patents and know-how or in the future owned or controlled by the company relating to ZYNLONTA, ADCT-602, ADCT-601 and ADCT-901 (collectively, the ‘Licensed Products’) in order to use, sell, offer for sale, import and commercialize such product candidates in China, Hong Kong, Macau, Taiwan and Singapore (the ‘Territory’).
In January 2022, the company entered into a license agreement with Mitsubishi Tanabe Pharma Corporation (‘MTPC’) to develop and commercialize ZYNLONTA in Japan, pursuant to which it granted MPTC an exclusive license under all applicable patents and know-how relating to ZYNLONTA in order to use, sell, offer for sale, import and commercialize ZYNLONTA for all cancer indications in Japan.
In July 2022, the company entered into a license agreement with Swedish Orphan Biovitrum AB (publ) (‘Sobi’) to develop and commercialize ZYNLONTA in all territories other than the United States, greater China, Singapore and Japan (the territories subject to the agreement, collectively, the ‘Covered Territory’).
Trademarks
The company owns various trademark registrations and applications, and unregistered trademarks, including ADC Therapeutics, ADCT, ZYNLONTA and its corporate logo.
Research and Development (R&D)
The company’s R&D expenses included to $109.6 million for the year ended December 31, 2024.
Government Regulation
Biological products, such as the company’s ADC product candidates, are approved for marketing under provisions of the Public Health Service Act (the ‘PHSA’), via a Biologics license application (‘BLA’).
History
ADC Therapeutics SA was founded in 2011. The company was incorporated in 2011.
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