CTLA-4 inhibitors- Competitive landscape, 2023

This “CTLA-4 inhibitors- Competitive landscape, 2023” report provides comprehensive insights about 40+ companies and 50+ drugs in CTLA-4 inhibitors Competitive landscape. It covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space.

Geography Covered

• Global coverage

CTLA-4 inhibitors: Understanding

CTLA-4 inhibitors: Overview

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T cell activation. A complex integration of positive and negative co-stimulatory signals in the well-defined B7:CD28/CTLA-4 pathway modulates the generation and maintenance of immune responses. Inhibiting negative regulation through binding of CTLA-4 has been shown to promote stimulation of adaptive immunity and potentiation of T cell activation. CTLA-4-blocking antibodies have demonstrated efficacy in various murine malignancy models when administered as monotherapy; additionally, they have shown synergistic anti-tumor activity when utilized with other agents, such as vaccines, chemotherapy, and radiation. The activation of T cells requires not only stimulation of the T cell receptor (TCR) by peptide-major histocompatibility complexes (MHCs) on antigen-presenting cells (APCs), but also an orchestrated balance of co-stimulatory and inhibitory signals that modulate the magnitude and effectiveness of the immune response. The activation of effector CD4+ and CD8+ T lymphocytes (Teffs) is tightly regulated by multiple mechanisms, including cell surface proteins which expand or downregulate T cell responses. Negative regulatory proteins on T cells, such as CTLA-4, programmed death-1 (PD-1), B7 family member B7-H4, T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and lymphocyte activation gene-3 (LAG-3), interact with their cognate ligands on various cells types, including APCs, regulatory T cells (Tregs), and nonhematopoietic cells, resulting in reduced T cell proliferation and functional activity. Strict expression control of these ligands is necessary in order to generate productive immune responses and rein in activated immune cells after antigen clearance. Chronic antigen exposure, as is common in cancer and in certain viral infections, drives sustained expression of CTLA-4, PD-1, and LAG-3 on antigen-specific lymphocytes, which culminates in peripheral cell tolerance to the antigens. Indeed, one of the primary goals of antibody-mediated negative regulatory blockade is the functional reversal, or reactivation, of tolerized T cells in settings of chronic antigen exposure. One of the best characterized T cell co-stimulatory signals is mediated by the constitutively expressed Ig-family protein, CD28. CD28 binding to ligands B7-1 and B7-2 on APCs leads to T cell proliferation by inducing production of interleukin-2 (IL-2) and anti-apoptotic factors. CTLA-4, an activation-induced T cell surface molecule with homology to CD28 may be detected on activated CD4+ and CD8+ T cells after TCR signaling. No detectable levels of CTLA-4 are found on the surface of naïve T cells, except on Tregs. Following MHC-peptide/TCR signaling, CTLA-4 is recruited to the immune synapse, an event controlled by the strength of TCR signals (i.e., stronger TCR signals result in greater recruitment of CTLA-4). Like CD28, CTLA-4 binds B7-1 and B7-2, but with greater avidity and affinity (particularly for B7-1). Thus, small amounts of CTLA-4 can efficiently out-compete CD28 ligand binding and attenuate T cell response.

Report Highlights

• In March 2023, Molecular Templates, Inc. had received clearance by the United States Food and Drug Administration (“FDA”) following review of its Investigational New Drug Application (“IND”) to proceed for clinical testing of its novel MT-8421 ETB program targeting CTLA-4 in patients with relapsed/refractory solid tumors previously exposed to checkpoint inhibitors. Preclinical data from MT-8421 showed that in a transgenic mouse model expressing human CTLA-4 and bearing syngeneic subcutaneous tumors, MT-8421 treatment depleted immune suppressive Tregs in the TME but not in the periphery.
• In October 2022, The FDA has approved the CTLA-4 immune checkpoint inhibitor tremelimumab (Imjudo) as part of a first-line immunotherapy combination for unresectable hepatocellular cancer (HCC). Under the specifics of the new indication, tremelimumab is given as a single 300 mg priming dose along with the PD-L1 inhibitor durvalumab (Imfinzi) at a dose of 1,500 mg every 4 weeks -- dubbed the STRIDE regimen (single tremelimumab, regular interval durvalumab).
• In August 2022, Biocytogen Pharmaceuticals and TRACON Pharmaceuticals, Inc., jointly announced that the U.S. Food and Drug Administration (FDA) has approved the Investigational New Drug (IND) application for the initiation of a Phase 1/2 clinical study of YH001 in combination with envafolimab and doxorubicin for the treatment of sarcoma patients, including patients who have not received prior therapy.
• In June 2022, Akeso, Inc. announced that its PD-1/CTLA-4 bi-specific antibody (Cadonilimab injection, AK104) has received marketing approval from the National Medical Products Administration (NMPA) of China, for the treatment of relapsed or metastatic cervical cancer (R/M CC) patients who progressed on or after platinum-based chemotherapy.
• In November 2022, Xencor, Inc. announced the presentation of data from the first patients in the Phase 2 combination study of vudalimab, a selective PD-1 x CTLA-4 XmAb® bispecific antibody, in patients with metastatic castration-resistant prostate cancer (mCRPC) and data from multiple preclinical-stage XmAb programs at the 37th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in Boston. A patient in Cohort E with an 89% reduction in PSA from baseline experienced a partial response (PR) at week 18 and was continuing treatment at 35 weeks. Treatment was continuing for one additional patient in Cohort C, at 4 weeks. In addition to the patient experiencing a PR in Cohort E, six other patients were efficacy evaluable and experienced a best response of stable disease (n=5) or non-complete response/non-progressive disease (non-CR/non-PD; n=1).
• In January 2022, - Vetigenics, an animal health biotechnology company, has announced preclinical data that paves the way for clinical evaluation of the first entirely canine, anti-CTLA4 antibody to promote anti-tumor immunity in dogs with immune-responsive cancers. Published in the current issue of mAbs,1 studies of Vetigenics' anti-CTLA4 antibody (A1mut2 mAb) demonstrated in vitro functionality as well as favorable in vivo safety and biodistribution properties in laboratory mice.

CTLA-4 inhibitors: Company and Product Profiles (Marketed Therapies)

1. Company Overview: Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.

Product Description: Yervoy

Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types. In July 2017, Bristol-Myers Squibb Company announced that the U.S. Food and Drug Administration (FDA) has expanded the indication for Yervoy ® (ipilimumab) injection for intravenous use to now include the treatment of unresectable or metastatic melanoma in pediatric patients 12 years of age and older.

CTLA-4 inhibitors: Company and Product Profiles (Pipeline Therapies)

1. Company Overview: Alphamab Oncology

Alphamab Oncology is focusing on innovation, production and commercialization of anti-tumor drugs. On December 12, 2019, the Company was listed in the mainboard of Hong Kong Stock Exchange with stock code 9966. Alphamab has fully integrated proprietary biologics platforms in bi-specifics and protein engineering. Its highly differentiated in-house pipeline includes fifteen tumor monoclonal antibodies and bispecific antibodies and a COVID-19 multifunctional antibody. The Company also has state-of-the-art manufacturing capabilities designed and built to meet NMPA and EU/FDA's cGMP standards and a complete quality system which has passed the on-site inspection of a European Union qualified person. Alphamab Oncology is committed to building a global leading, multi-dimensional drug development and commercialization platform, focusing on multi-functional biological innovative drugs, and to benefit patients in China and around the world.

Product Description: KN046

KN046 is PD-L1/CTLA-4 bispecific antibody independently developed by Jiangsu Alphamab. Its innovative designs include: a novel mechanism CTLA-4 domain fused with a PD-L1 single domain antibody; engineered to target the tumor micro-environment with high PD-L1 expression, and Treg suppress tumor immunity clearing function. There are about 20 clinical trials of KN046 in different stages covering more than 10 types of tumors including NSCLC, thymic cancer, pancreatic cancer, HCC, ESCC and TNBC in Australia and China. The results of these clinical trials have shown promising data in terms of survival for patients. Alphamab Oncology has received FDA clearance to enter later stage trials of KN046 based on the clinical results in China and Australia. Moreover, KN046 has obtained the U.S. FDA's orphan drug designation for thymic epithelial tumor in September 2020. Four pivotal clinical trials are currently being conducted. Currently the product is in Phase III stage of development for the treatment of Squamous Non-small-cell Lung Cancer.

2. Company Overview: Innovent Biologics

Innovent Biologics is a biopharmaceutical company that focuses on the research, development and manufacturing of monoclonal antibodies. It provides products for various diseases such as metabolic, cancer, autoimmune diseases and other therapeutic areas. The company oncology products include sintilimab injection, bevacizumab injection, rituximab injection, pemigatinib, olverembatinib, ramucirumab, and others. Its autoimmune drugs are adalimumab injection, IBI-353, IBI-112, IBI-314, among others. The company's metabolic and ophthalmology products include IBI-306, IBI-362, IBI-302, IBI-324, IBI-311.

Product Description: IBI-310

IBI-310 is under development for the treatment of advanced, recurrent or metastatic non-small-cell lung cancer(NSCLC), unresectable or relapsed or metastatic advanced Biliary tract cancer, metastatic solid tumors including advanced hepatocellular carcinoma, recurrent and metastatic nasopharyngeal carcinoma, acral melanoma, liver cancer, cervical cancer, renal cell carcinoma, EBV-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. The drug candidate is administered through intravenous route. It acts by targeting cytotoxic T-lymphocyte protein 4 receptor (CTLA4). It was also under development for the treatment of metastatic melanoma and metastatic colorectal adenocarcinoma. Currently the drug is in Phase III stage of Clinical trial evaluation for the treatment of Hepatocellular Carcinoma.

3. Company Overview: Agenus

Agenus is a clinical-stage immuno-oncology company focused on the discovery and development of therapies that engage the body's immune system to fight cancer and infections. The Company's vision is to expand the patient populations benefiting from cancer immunotherapy by pursuing combination approaches that leverage a broad repertoire of antibody therapeutics, adoptive cell therapies (through its subsidiary MiNK Therapeutics), and adjuvants (through its subsidiary SaponiQx). The Company is equipped with a suite of antibody discovery platforms and a state-of-the-art GMP manufacturing facility with the capacity to support clinical programs. Agenus is headquartered in Lexington, MA.

Product Description: Botensilimab

Botensilimab is a novel, multifunctional CTLA-4 investigational antibody that has been designed to extend clinical benefits to “cold” tumors that have not historically responded to standard of care or investigational therapies. In addition to binding to the CTLA-4 receptor, its Fc-enhanced structure induces a memory immune response, downregulates regulatory T cells, and delivers better priming and activation of T cells, thereby amplifying immune responses. In a Phase 1b clinical study of more than 350 patients, botensilimab has demonstrated clinical responses in nine, previously IO unresponsive, solid tumor cancers, either alone or in combination with Agenus' PD-1 antibody, balstilimab (data presented at ASCO GI 2023, SGO 2023, CTOS 2022, SITC 2022). Agenus is conducting global, randomized Phase 2 trials in non-MSI-H colorectal cancer, pancreatic cancer, and melanoma as part of its ACTIVATE trial programs.

4. Company Overview: Harbour BioMed

Harbour BioMed is a global clinical-stage biopharmaceutical company committed to the discovery, development and commercialization of novel antibody therapeutics in oncology and immunological disease areas to address unmet patient's needs. Company are building a robust pipeline with the integrated Harbour antibody platform, that enable to develop highly differentiated antibodies against various disease targets with great potency and safety profiles. The proprietary Harbour Mice® generate fully human monoclonal antibodies in the classical two heavy and two light chain (H2L2) format, as well as heavy chain only (HCAb) format. Building upon the HCAb antibodies, the HCAb-based immune cell engagers (HBICE®) are capable of delivering tumor killing effects unachievable by combination therapies. Integrated with our single B cell cloning platform, our antibody discovery engine is highly unique and efficient for development of next generation therapeutic antibodies. HBM's efforts are driven by the vision of delivering “Healthy life Breakthrough Medicines”. To realize this vision, HBM have been partnering with global academic institutions, biotechnology and pharmaceutical companies by leveraging the platforms. HBM have established a strong track record of portfolio includes strategically selected co-development clinical assets and internal innovative NextGen projects to address unmet patient's need. HBM also provide technology licensing for the proprietary Harbour antibody technologies to accelerate the industry innovation on antibody therapeutics.

Product Description: Porustobart

Porustobart (HBM4003) is a fully human anti-CTLA-4 monoclonal heavy chain only antibody (HCAb) generated from Harbour Mice®. By enhancing antibody-dependent cell cytotoxicity (ADCC) killing activity, porustobart has demonstrated significantly improved depletion specific to high CTLA-4 Treg cells in tumor tissues. The potent anti-tumor efficacy and differentiated pharmacokinetics with durable pharmacodynamic effect presents a favorable product profile. This novel and differentiated mechanism of action has the potential to improve efficacy while significantly reducing the toxicity of the drug in monotherapy and combo-therapy. As the first heavy chain only fully human antibody on clinical stage in the world, porustobart showed its good safety profile and strong efficacy on its monotherapy study of phase I trial. HBM is making all efforts to push forward to the studies of this product as treatment for multiple solid tumors, including melanoma, NSCLC, HCC, NET/NEC.

CTLA-4 inhibitors Analytical Perspective

In-depth Commercial Assessment: CTLA-4 inhibitors Collaboration Analysis by Companies

The Report provides in-depth commercial assessment of drugs that have been included, which comprises collaboration, agreement, licensing and acquisition - deals values trends. The sub-segmentation is described in the report which provide company-company collaboration (licensing/partnering), company academic collaboration and acquisition analysis in tabulated form.

CTLA-4 inhibitors Competitive Landscape

The report comprises of comparative assessment of Companies (by therapy, development stage, and technology).

CTLA-4 inhibitors Report Assessment

• Company Analysis
• Therapeutic Assessment
• Pipeline Assessment
• Inactive drugs assessment
• Unmet Needs

Key Questions Answered

Current Treatment Scenario and Emerging Therapies:

• How many companies are developing CTLA-4 inhibitors drugs?
• How many CTLA-4 inhibitors drugs are developed by each company?
• How many emerging drugs are in mid-stage, and late-stage of development for the treatment of CTLA-4 inhibitors?
• What are the key collaborations (Industry-Industry, Industry-Academia), Mergers and acquisitions, licensing activities related to the CTLA-4 inhibitors therapeutics?
• What are the recent trends, drug types and novel technologies developed to overcome the limitation of existing therapies?
• What are the clinical studies going on for CTLA-4 inhibitors and their status?
• What are the key designations that have been granted to the emerging and approved drugs?

Key Players

• Innovent Biologics
• Alphamab Oncology
• Agenus
• Harbour BioMed
• AstraZeneca
• Alpine Immune Sciences
• Henlix Biotech
• DotBio
• TrueBinding
• Ocean Biomedical
• Xencor
• Molecular Templates
• Akeso, Inc.
• TRACON Pharmaceuticals, Inc.
• Biocytogen Pharmaceuticals

Key Products

• KN046
• IBI-310
• Botensilimab
• Porustobart
• Tremelimumab
• Davoceticept
• HLX-13
• DB-002
• IMT-400
• OCX 909
• Vudalimab
• MT-8421
• AK104
• YH001

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