Nanobiotix S.A. is a late-stage clinical biotechnology company focused on developing first-in-class, physics-based product candidates that use the company’s proprietary nanotechnology to seek to improve treatment outcomes for millions of patients around the world.
The company has three platforms that each seek to bring the benefits of nanotechnology to human medical problems:
NBTXR3, the company’s potentially first in class radioenhancer designed to enhance radiation therapy.
Curadigm, the co...
Nanobiotix S.A. is a late-stage clinical biotechnology company focused on developing first-in-class, physics-based product candidates that use the company’s proprietary nanotechnology to seek to improve treatment outcomes for millions of patients around the world.
The company has three platforms that each seek to bring the benefits of nanotechnology to human medical problems:
NBTXR3, the company’s potentially first in class radioenhancer designed to enhance radiation therapy.
Curadigm, the company’s nanoprimer technology designed to enhance therapeutic index.
Oocuity, the company’s platform designed to help central nervous system (CNS) based ailments.
The company’s most advanced platform has produced its lead product candidate, NBTXR3, which is designed to improve local control of solid tumors by increasing the effect of radiotherapy in the tumor without increasing damage to surrounding healthy tissues, and to improve systemic control through its potential immune priming effect subsequent to the physical destruction caused by the physics-based mechanism of action (MoA). Through this approach the company is advancing a strategy that initially aims to build a potentially industry-leading head and neck cancer treatment franchise powered by NBTXR3, and then to scale this across other solid tumor indications.
Curadigm and Oocuity are at preclinical and discovery stages, respectively. Each shares with NBTXR3 the fundamental approach of Nanobiotix that seeks to bring nanotechnological approaches to affect the body’s chemistry at a physical level and have a positive impact on medical problems.
Curadigm’s technology is centered around transient blockage of the liver pathways involved in clearance to improve the ability of a subsequently administered treatment to reach its intended target at a relevant dose and thus potentially improving treatment efficacy and/or diminishing its toxicity.
Oocuity is similarly centered around nanotechnologically designed materials. In this case, the company’s research is focusing on using these materials to influence neuronal networks via their electrical properties. There are several potential applications for materials with such properties.
Potential first-in-class radioenhancer NBTXR3 is an aqueous suspension of functionalized, crystalline hafnium oxide nanoparticles designed for injection directly into a malignant tumor and then be activated by radiotherapy (RT-activated NBTXR3). When exposed to ionizing radiation, NBTXR3 increases the localized dose of radiotherapy (i.e., energy) delivered to the tumor cells where it is present, significantly increasing tumor cell death and does so, importantly, without increasing the dose delivered to surrounding healthy tissues. Preclinical and early clinical data suggest that subsequent to the physical cellular destruction caused by radiotherapy-activated NBTXR3, the product candidate may also prime an adaptive immune response and create long-term anti-cancer memory. Given the physics-based MoA, NBTXR3 could be developed as a tumor-agnostic treatment targeting all solid tumors that are treated with radiotherapy alone or in therapeutic combinations, including those that include immune checkpoints inhibitors, a type of therapy designed to stimulate a patient’s immune system to attack cancer cells.
Radiotherapy, also called radiation therapy (RT) or simply radiation, involves the use of X-rays or other high-energy particles or rays to kill cancer cells in tumors. It is among the most common cancer treatments, both as a standalone therapy and in combination with surgery, chemotherapy or biological therapies. In developed countries with access to radiotherapy, approximately 60% of all cancer patients will receive radiotherapy at least once, either alone or as a part of a more complex treatment protocol. Nevertheless, many of these patients still die from the progression of their cancer because, among other reasons, they are not able to receive a high enough radiation dose to completely destroy their tumor without resulting in an unacceptable level of damage to surrounding healthy tissues. By mitigating these limitations, NBTXR3 may improve the survival rate and quality of life for cancer patients.
Given NBTXR3’s potentially broad application across solid tumors and in order to bring the company’s innovation to as many patients as broadly and as quickly as possible, the company has engaged in strategic collaborations with large and reputable partners to expand development of the product candidate alongside clinical trials that Nanobiotix is conducting, as discussed in the section ‘NBTXR3 Development Pipeline’ of this annual report. In 2018 the company entered into a broad, comprehensive clinical research collaboration with The University of Texas MD Anderson Cancer Center (‘MD Anderson’) to sponsor several Phase 1 and Phase 2 studies in the United States to evaluate NBTXR3 across tumor types and therapeutic combinations, with up to 312 patients expected to be enrolled across these clinical trials. In July 2023, the company entered into the Janssen Agreement, a worldwide agreement for the co-development and commercialization of NBTXR3, excluding the Asia Licensing Territory. In December 2023, the exclusive rights to develop and commercialize NBTXR3 in the Asia Licensing Territory were assigned by LianBio to Janssen, in accordance with the terms of the Asia Licensing Agreement.
NBTXR3’s characteristics have lead the company to investigate its use in several tumor types including: head and neck, lung, pancreatic, esophageal, liver, prostate, soft tissue sarcoma and rectal. The company has seen positive signals or evidence of activity and safety in all of these tumor types. The product is likely to aid with local control of solid tumors and as such the company has focused on head and neck cancer in elderly patients who have few therapeutic options to achieve the local control that they need. In addition, there are types of lung cancer where local control is important, and through the company’s agreement with Janssen, the company seeks to serve these patients as well. In addition to specific tumor types the company’s data shows indications that NBTXR3 may also play a role combinations with immune oncology (I-O) therapeutics and the company is developing the product in such combinations, specifically in anti-PD-1/L1 combination regimens in head and neck cancer that is recurrent and or metastatic. PD(L)-1 inhibitors are approved now in more than ten different solid tumors most of which are also eligible to be treated with radiation therapy.
The company is building a comprehensive treatment franchise across head and neck cancers where radiotherapy alone or with immunotherapy is a part of the treatment protocol. It has been estimated that 74% of head and neck cancer patients will receive radiotherapy treatment, making this patient population a significant market opportunity for NBTXR3. Moreover, this model can be replicated across any solid tumor indication treated by radiotherapy alone or with immunotherapy that can be injected with NBTXR3, further expanding the market opportunity of NBTXR3.
The second tumor type of focus is non small cell lung cancer (NSCLC), a subtype of lung cancers2. As part of the agreement announced in July 2023, Janssen will be fully responsible for an initial Phase 2 study evaluating NBTXR3 for patients with NSCLC. MD Anderson is also investigating NBTXR3’s use in NSCLC with the approach of re-irradiation allowing patients to receive radiation again in combination with NBTXR3.
Strategy
The company’s strategy is to develop its three nanotechnology based platforms in sequence utilizing the first to achieve financial sustainability thus allowing the company to increasingly invest in the second and third platforms. The company’s platforms: NBTXR3, the company’s potentially first in class radioenhancer designed to enhance radiation therapy; Curadigm, the company’s nanoprimer technology designed to enhance therapeutic index; and Oocuity, the company’s platform designed to help central nervous system (CNS) based ailments.
The company has primarily focused on the development of NBTXR3, its potential first-in-class radioenhancer to treat a broad range of solid tumors. Based on its proprietary, physics-based properties and its administration via intratumoral injection, NBTXR3 could improve local control alone or in combination with other treatment modalities in any indication where radiotherapy is a part of the treatment regimen. Due to the potential immune priming effect the company has observed subsequent to the physical tumor destruction caused by radiotherapy-activated (RT-activated) NBTXR3, systemic treatment outcomes could be improved, such as by expanding the benefits of immune checkpoint inhibitors to more patients. Ultimately, the company’s intention is to integrate NBTXR3 into the treatment of solid tumor indications, starting with head and neck cancer, and then expanding to include multiple solid tumor indications, potentially materially improving the treatment of cancer for millions of patients around the world. The key elements of this strategy include: Complete the development of NBTXR3 for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC); Leverage I-O combination potential to advance treatment for patients with recurrent or metastatic (R/M) HNSCC that is resistant to prior immunotherapy; Leverage strategic collaborations to advance NBTXR3 opportunities and establish a global development, regulatory and commercial plan for NBTXR3; Expand the opportunity for NBTXR3 and build an effective development program in additional solid tumor indications; and pursue the development of its two other platforms Curadigm and Oocuity as the company strives to bring the benefits of nanotechnologically derived materials to help other medical conditions.
NBTXR3 Technology
NBTXR3 was developed through the company’s explorations of the potential for nanotechnologies to provide solutions to unmet therapeutic needs in oncology. It is a sterile aqueous suspension of crystalline hafnium oxide nanoparticles that is administered through a one-time image-guided local injection directly into the tumor prior to radiotherapy. The nanoparticles have a negative-charge surface coating, which allows them to accumulate inside the tumor cells. When the injected tumor is subsequently treated with radiotherapy the particles interact with the radiation increasing the dose of energy delivered to the tumor, but without causing incremental damage to surrounding healthy tissues. The company’s NBTXR3 technology improves the benefit-risk ratio of radiotherapy for patients. Radiation treatment with NBTXR3 is designed to destroy the tumor completely or render it more operable such as by shrinking its size.
NBTXR3 can easily be incorporated into the current standard of care in radiotherapy. Hospitals and medical facilities where radiotherapy is delivered do not need any new equipment or to otherwise make significant capital investments in new technology in order to treat patients with NBTXR3.
NBTXR3 has the potential to treat all solid tumors where radiotherapy can be used. The company is prioritizing the development of NBTXR3 in the United States and the EU for the treatment of head and neck cancers, although the company is also studying, or have studied, NBTXR3 across a broad range of indications, including locally advanced soft tissue sarcoma, primary and secondary liver cancers, prostate cancer, pancreatic cancer, esophageal cancer and non-small cell lung cancer. As noted, the company has also observed that NBTXR3 activated by radiotherapy could modulate the antitumor immune response, supporting the rationale for its use as an in-situ cancer vaccine, potentially in combination with immune oncology treatments, in particular, checkpoint inhibitors.
NBTXR3 and Radiotherapy
The amount of energy that can be deposited in a cell through radiotherapy is a function of the cell’s ability to absorb the radiation, which depends on the amount and form of energy used and the electron density of the receiving molecules. During radiotherapy, the interaction between the radiation and molecules in the targeted cell results in ionized atoms, freeing electrons from the orbit of the atoms. These free electrons dissipate their energy in multiple interactions with surrounding molecules, producing in the cell free radicals, which are highly reactive molecules. These highly reactive free radicals produced during radiotherapy have the capacity to break the covalent bonds of the molecules they interact with, including DNA, RNA, and proteins. These free radicals play an important role in the effectiveness of radiotherapy by causing damage in multiple ways in the cell, ultimately leading to cell death.
At an average size of approximately 50 nanometers in diameter, the company’s nanoparticles are directly injected into a malignant tumor prior to standard radiotherapy and can be internalized into the cell through endocytosis to function as radioenhancers. The nanoparticles have an inorganic core of crystallized hafnium oxide, which has a high electron density. The high electron density of the nanoparticles is essential for their effective interaction with radiation, while their physical and chemical properties do not by themselves cause incremental damage to surrounding healthy tissues.
NBTXR3 is a novel approach to the local treatment of cancer that provides a solution to the otherwise difficult to avoid limitation of radiotherapy - an inability to deliver sufficient amounts of radiation to eradicate the tumor and not cause unacceptably high levels of damage to the surrounding healthy tissues.
Clinical Programs
NBTXR3 has been, and is being evaluated in several clinical trials worldwide in various cancer patient populations. Because of the very broad potential of NBTXR3 to help millions of patients suffering solid tumor malignancies, Nanobiotix has formed collaborations with industry and academic leaders to allow NBTXR3 to be brought to benefit as many patients as possible as quickly as possible. The company has a broad, comprehensive clinical research collaboration with The University of Texas MD Anderson Cancer Center to sponsor several Phase 1 and Phase 2 studies in the United States to evaluate NBTXR3 across tumor types (such as lung and pancreatic) and therapeutic combinations, including relatively newer treatment modalities such as proton therapy and reirradiation. In 2023, the company entered into a worldwide agreement for the co-development and commercialization of NBTXR3 with Janssen Pharmaceutical NV, a Johnson & Johnson company. The clinical program detailed below is a collaborative effort between the company at its collaborative partners. Nanobiotix is focused on head and neck cancers as it’s first priority. and Janssen will be fully responsible for an initial Phase 2 study evaluating NBTXR3 for patients with stage III lung cancer.
Phase 3 Registration Trial (‘NANORAY-312’)
NANORAY-312 is a randomized (1:1), controlled, two-arm global Phase 3 clinical trial in elderly patients with locally-advanced head and neck cancer who are ineligible for platinum-based (cisplatin) chemotherapy. All the patients receive definitive radiation therapy with the option of cetuximab per investigator's choice, and patients in the experimental arm receive NBTXR3 in addition. The trial is expected to be conducted at more than 150 sites worldwide and approximately 500 patients will be randomized. As of the date of this report, patients in the NANORAY-312 study have been randomized in all planned major regions (the U.S., Europe and Asia).
The primary endpoint of the study is progression free survival (PFS) and the key secondary endpoint is overall survival (OS). The study is designed to demonstrate superiority of RT-activated NBTXR3 over the control arm on PFS with a statistical power of 89% and on OS with a statistical power of 80% (hazard ratio of 0.692 and 0.75 for PFS and OS, respectively). The Hazard Ratio is a measure of the risk of a particular event occurrence in one group compared to another group, over time. A median PFS of 9 months and median OS of 12 months is expected in the control arm. In addition, time to loco-regional and distant progression, head and neck cancer specific survival outcomes, overall response rate, safety and quality of life will be evaluated as secondary endpoints.
A futility analysis is planned after approximately 25% of PFS events (i.e., disease progression or death), a pre-specified interim efficacy analysis is planned after approximately 67% of planned PFS events, and the final analysis after 424 PFS and 389 OS events. In the event of clinically meaningful PFS improvement (e.g. = 6 months PFS difference) in the planned interim analysis with no detrimental OS effect having been observed, the company has previously received communication from FDA that this could potentially allow for the application of Accelerated Approval of NBTXR3 in the United States for this indication.
NANORAY-312 will utilize four stratification factors: (i) Investigator’s choice (cetuximab addition or not), (ii) HPV status (HPV-positive oropharynx versus other), (iii) age-adjusted Charlson Comorbidity Index, or ACCI score at screening (2 to 3 versus = 4) and (iv) region (North America & Western Europe versus Rest of World).
In February 2020, the company received Fast Track designation from the FDA for NBTXR3 for the treatment of locally advanced head and neck cancers that are not eligible for platinum-based chemotherapy. Fast Track designation is a process designed to facilitate the development of and accelerate the review of treatments for serious conditions that have the potential to address unmet medical needs.
Phase 1 (‘Study 102’) Dose-Escalation/Dose-Expansion Trial
The company conducted a Phase 1, dose escalation and dose expansion clinical trial of NBTXR3 activated by intensity-modulated radiation therapy in patients with locally advanced head and neck cancer (LA-HNSCC) (patients with squamous cell carcinoma of the oral cavity or oropharynx) who are ineligible for cisplatin or intolerant to cetuximab. The primary endpoint of dose escalation was to evaluate the safety of NBTXR3 and determine the recommended Phase 2 dose (RP2D) of RT-activated NBTXR3. The primary endpoints of dose expansion were to confirm that the recommended dose is safe and to obtain preliminary evidence of efficacy by observing the objective response rate and complete response rate of the NBTXR3-injected lesion by imaging according to RECIST 1.1.
The secondary endpoints of both parts were to evaluate the safety and tolerability of NBTXR3, to evaluate the overall response rate and the complete response rate (based on the RECIST 1.1) of injected (target) and non-injected lesions (non-target), to evaluate the local progression and PFS, assess the feasibility of local administration by intratumoral injection of NBTXR3, and characterize the body kinetics of NBTXR3 administered by intratumoral injection. Overall Survival was also planned to be analyzed.
Study 102 Escalation Part
In the escalation part of the study, the administered dosage of NBTXR3, calculated as percentage (%) of tumor volume was escalated (5%, 10%, 15% and 22%), with 19 patients in total receiving an injection of NBTXR3, followed by intensity-modulated radiation therapy (70 Gy in total, or 2 Gy per day, five days a week for seven weeks), in accordance with standard medical practice, commencing one to five days after NBTXR3 injection.
In each patient, the primary tumor was injected with NBTXR3, while involved lymph nodes were not injected. The NBTXR3-injected lesions and the non-injected lesions were treated with the same dose of intensity-modulated radiation therapy (IMRT).
The following graphic depicts shrinkage of the tumor in a patient in the trial over time following treatment. The tumor continued to shrink after the end of treatment, with the patient achieving a complete response at seven months.
Preliminary efficacy and safety results showed that NBTXR3 was well tolerated and the recommended dose was established as equivalent to 22% of tumor volume. Preliminary results included no observed serious side effects or serious adverse events related to NBTXR3, and feasibility of injection at all dose levels with no leakage to surrounding healthy tissues.
Study 102 Expansion Part
The expansion part of Study 102 was completed in February 2023 and the final safety and efficacy results were presented at the 65th Annual Meeting of the American Society for Radiation Oncology (ASTRO) in October 2023. A total of 56 patients were treated with the recommended dose of 22% of tumor volume established in the escalation part.
The main characteristics of the population at study entry were: advanced age (61% aged = 70) and a high burden of comorbidity as measured by the age-adjusted Charlson Comorbidity Index (ACCI) as 67% had ACCI scores of =47. The main tumor characteristics were: oral cavity tumor location (which is associated with poorer outcomes) in 45% of patients and oropharyngeal cancer with positive HPV-16 status (which is considered a positive prognostic factor in this cancer) in only 26% of patients.
The median duration of follow up was 18.2 months.
Lung cancer (Janssen and MD Anderson acting as sponsors of these trials)
Phase 2 Trial - Janssen
As part of the license and collaboration agreement announced on July 10, 2023, Janssen Pharmaceutica NV, a Johnson & Johnson company, will be fully responsible for an initial Phase 2 study evaluating NBTXR3 for patients with stage III lung cancer.
Phase 1 Trial - MD Anderson (‘Study 2020-0123’)
This trial is an open-label, two-cohort, prospective Phase 1 study of reirradiation in patients with inoperable locoregional recurrent NSCLC. This study is testing if patients with NSCLC can be treated with radiation a second time, which is generally not done due to the difficulties of using radiotherapy more than once. Patients are treated with a lower than normal dose of radiation along with NBTXR3.
The trial consists of two parts: (i) a radiation therapy safety lead-in, and RT-activated NBTXR3 therapy dose-escalation to determine the RP2D, and (ii) dose-expansion at RP2D with toxicity monitoring.
The patient population includes adults (age = 18) with inoperable LRR NSCLC stage IA to IIIC that are radiographically non-metastatic at screening and have previously received definitive radiation therapy. The number of participants enrolled will be determined based on the maximum number required to establish the RP2D. Cohort 1 evaluates the safety of intensity-modulated radiation therapy (IMRT) monotherapy. If the radiotherapy is deemed safe, cohort 2 will test that IMRT regimen with NBTXR3. Alternatively, a lower dose regimen can be used in cohort 2.
Enrollment is ongoing and the planned enrollment period is up to three years. The dose levels to be explored are 22% and 33% of baseline gross tumor volume.
Immuno-Oncology (‘I/O’) Program Trials
Supporting Rationale for I-O Combination Treatment Approach
RT-activated NBTXR3 followed by immune checkpoint inhibitors has the potential to improve the therapeutic response to I-O treatments by converting checkpoint inhibitor non-responders into responders, re-sensitizing patients who have previously responded to IO therapy and enhancing the response in those who supposed to benefit from the IO treatment. And this investigational treatment combination is being explored in multiple settings.
The company’s preclinical and early clinical trial results suggest that RT-activated NBTXR3 may stimulate an immune response, thereby rendering otherwise ‘cold’ tumors ‘hot;’ that is making the tumors more prone to recognition by the patient’s immune system and therefore more responsive to I-O treatments such as checkpoint inhibitors.
In preclinical experiments, the company observed RT-activated NBTXR3 kill more cancer cells in vitro than radiotherapy alone, leading to the release of a greater number of tumor-associated antigens. In addition, in in vitro experiments performed on different human cancer cell lines, the company observed RT-activated NBTXR3 enhance the expression of markers of immunogenic cell death, as well as activation of the cGAS-STING pathway (a component of the immune system that detects tumor-derived DNA and generates intrinsic anti-tumor immunity). These results suggest that RT-activated NBTXR3 could modulate the immunogenicity of the cancer cells.
The company also observed RT-activated NBTXR3 in vivo generate an abscopal effect, which is a reduction of metastatic burden outside the irradiated area. This abscopal effect depends on the increase of CD8+ T cell lymphocyte infiltrates (T lymphocytes that work to kill malignant tumor cells) in both treated and untreated tumors, induced by RT-activated NBTXR3.
In the company’s Phase 2/3 locally advanced STS clinical trial, based on immunohistochemistry analyses, the company observed that RT-activated NBTXR3 increased the density of CD8+ T cell lymphocytes and also decreased FOXP3+ (Treg) (regulatory T cells that work to suppress the immune response) compared to radiotherapy alone in the tumors, while macrophage number remained relatively constant.
In March 2021, researchers from the company’s collaborative partner MD Anderson shared preclinical data at the American Association of Cancer Research (AACR) Virtual Special Conference on Radiation Science and Medicine. This study examined RT-activated NBTXR3 in combination with anti-PD-1 along with TIGIT and LAG3 inhibitors in an in vivo anti-PD-1 resistant mouse model. The data showed that the Combo therapy (RT-activated NBTXR3 + anti-PD-1 + anti-LAG3 + anti-TIGIT) significantly promoted the proliferative activity of CD8+ T cells, improved local and distal tumor control, and increased survival rate. The data showed that the cured mice maintained significantly higher percentages of memory CD4+ and CD8+ T cells, as well as stronger anti-tumor immune activities than control, and the cured mice from the groups treated with the Combo therapy were immune to reinjections of tumor cells.
A subsequent analysis presented at the annual meeting of the AACR in April 2022, assessed immune gene expression associated with multiple combinations of NBTXR3, anti-PD-1, anti-LAG-3, and anti-TIGIT. The data showed that the Combo therapy outperformed all other tested treatment regimens in efficacy, survival, and induction of long-term anti-cancer memory. The Combo therapy promoted immune activation at the irradiated site. Abscopal immune responses were improved with the addition of LAG-3 and TIGIT to PD-1 and RT-activated NBTXR3, suggesting that the Combination therapy may be effective against metastatic cancers.
Together, these data suggest that RT-activated NBTXR3 could be able to modulate the anti-tumor immune response and transform the tumor into an in situ vaccine, which prompted the initial development of the company’s I-O program.
Development in I-O
The company is conducting, and continue to further develop, a global I-O development program to explore the use of NBTXR3 as a complement to immune checkpoint inhibitors across several solid tumor indications. Initially, the company intends to leverage the data collected from the company’s I-O Program to advance treatment for patients with R/M HNSCC that is resistant to prior immunotherapy. Study 1100, a multi-cohort Phase 1 trial of RT-activated NBTXR3 followed by an anti-PD-1 checkpoint inhibitor in patients with R/M HNSCC or with lung, liver, or soft tissue metastases from other solid tumors eligible for anti-PD-1 therapy is ongoing. In this study, patients failing a prior treatment with checkpoint inhibitors continue that treatment with additional therapy of RT-NBTXR3. Patients with no prior checkpoint inhibitor therapy are also eligible. The company is also working with MD Anderson, to evaluate NBTXR3 in combination with checkpoint inhibitors (anti-PD-1, or anti-PD-L1) across several cancer indications. Two trials are ongoing. The first one is a Phase 2 clinical trial evaluating RT-activated NBTXR3 followed by pembrolizumab for recurrent/metastatic HNSCC patients with limited PD-L1 expression or refractory to PD-1 blockade. The second trial is a randomized Phase 1/2 trial for NBTXR3 combined with an anti-PD-1 or PD-L1 +/- RadScopal in patients with lung or liver metastases from any advanced solid tumors. The first patient of this Phase1/2 trial was injected in July 2023.
I-O Program— R/M HNSCC and lung, liver or soft tissue metastases from any primary tumor
Multi-Cohort Phase 1 Trial (‘Study 1100’)
The company initiated a Phase 1 prospective, multi-center, open-label, non-randomized clinical trial evaluating the safety and efficacy of RT-activated NBTXR3 followed by anti-PD-1 checkpoint inhibitors (nivolumab or pembrolizumab). The trial has a dose escalation part followed by dose expansion. The dose escalation part of the trial includes three patient populations:
Patients with locoregional recurrent (LRR) or recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) amenable to irradiation of the head and neck field that are anti-PD-1 therapy naïve or non-responsive to an anti-PD-1 therapy (HNSCC Cohort),
Lung metastases from any primary cancer eligible for anti-PD-1 therapy (‘Lung Cohort’) or
Liver metastases from any primary cancer eligible for anti-PD-1 therapy (‘Liver Cohort’).
The dose expansion part of the trial has the following treatment cohorts:
LRR or R/M HNSCC and that is resistant to a prior anti-PD-1/L1 therapy with at least one lesion located in either the head and neck region, soft tissues, lungs or liver amenable for intratumoral injection and irradiation.
LRR or R/M HNSCC naïve to anti-PD-1/L1 therapy and eligible for an anti-PD-1 therapy with at least one lesion located in either the head and neck region, soft tissues, lungs or liver amenable for intratumoral injection and irradiation.
Lung or liver or soft tissue metastases from any primary tumor that are resistant to a prior anti-PD-1/L1 therapy and eligible for anti-PD-1 therapy with at least one lesion located in either soft tissue, lungs or liver that could be injected intratumorally and irradiated.
The trial’s main objective is to determine the safety profile and recommended Phase 2 dose of RT-activated NBTXR3 in combination with an anti-PD-1. Secondary endpoints include efficacy evaluation. The trial is ongoing and the company intends to enroll a total of approximately 145 evaluable patients in the United States.
In the study, patients could have cancer lesions located in different parts of the body. Specific lesions were selected for NBTXR3 injection and radiotherapy. Lesions that were not injected with NBTXR3 were not intended to be treated with radiotherapy unless they were located in the field of radiotherapy due to proximity to the injected lesion. Anti-PD-1 therapy was scheduled for all patients to begin after radiotherapy. Thus, in these data, there is differentiation between responses in ‘injected lesions’ versus ‘overall response’ with the latter being a measure of response from a patient’s total disease burden (i.e., lesions injected with NBTXR3 and irradiated and those neither injected with NBTXR3 nor irradiated).
Study 1100 Escalation Part
As of the cut-off date August 22, 2022, there were 28 patients evaluable for safety and 21 patients evaluable for early signs of efficacy: of them, 16 patients had LRR or R/M HNSCC. Ten of the 16 patients were resistant to prior anti-PD-1 treatment, 6 patients were anti-PD-1 naive. Eight patients were HPV+ (positive to Human Papilloma Virus, HPV), 7 patients were HPV- (and 1 patient had HPV status unknown).
Thirteen patients had metastatic disease; of them 9 patients were resistant to prior anti-PD-1 therapy and 4 patients were IO-naive. 46.2% (6/13) of patients with metastatic HNSCC were HPV-. 100% (6/6) of patients with HPV- metastatic HNSCC and 84.6% (11/13) of all patients with metastatic HNSCC has less than 2 metastatic sites involved.
The RP2D of RT-NBTXR3, in combination with pembrolizumab or nivolumab, was established at 33% of gross tumor volume in each of the three cohorts from the escalation part.
In June 2023, the results from the escalation part of the study were presented at ASCO 2023 with a focus on the early signals of efficacy in patients with LRR or R/M HNSCC.
Pancreatic cancer (MD Anderson acting as sponsor of this trial)
Phase 1 Trial - MD Anderson (‘Study 2019-1001’)
This MD Anderson led trial is an open-label, single-arm, prospective Phase 1 study consisting of two parts: (i) dose-escalation to determine the RP2D and (ii) expansion at RP2D. The objectives of the study are the determination of the incidence of dose-limiting toxicity, the maximum tolerated dose and determination of an RP2D.
The patient population includes adults (age = 18 years) with BRPC or LAPC that are radiographically non-metastatic at screening, having received between two to six months of chemotherapy prior to trial enrollment and that have not previously received radiation therapy or surgery for pancreatic cancer. In the dose-finding part, one patient was injected at the dose level one (33% of gross tumor volume) and nine patients at dose level two (42% of gross tumor volume). Up to 12 additional patients will be injected at the RP2D in the expansion part.
In the first quarter of 2022, researchers from MD Anderson published a peer-reviewed clinical case study reporting preliminary data on the first-in-human administration of NBTXR3 for the treatment of pancreatic cancer not eligible for surgery, demonstrating feasibility and no dose-limiting toxicity. At the end of the dose escalation phase in the fourth quarter of 2022, the RP2D for NBTXR3 in pancreatic cancer was determined to be 42% of the gross tumor volume. The ongoing dose expansion phase is enrolling patients with borderline resectable disease in addition to patients with unresectable disease.
In September 2023, preliminary data were presented at the Special Meeting on Pancreatic Cancer of the American Association for Cancer Research (AACR). NBTXR3 was administered prior to radiotherapy via an endoscopic ultrasound (EUS)-guided intratumoral injection. All patients received low-dose intensity-modulated radiation (IMRT; 45 Gy) in 15 fractions, and were followed up to one year. Importantly, all patients in the study had previously received a four-month course of chemotherapy and showed no radiographic evidence of metastases at screening. The first patient at dose level one and subsequent 14 patients at dose level two had no injection complications. One patient at dose level two had one dose-limiting toxicity related to radiotherapy (Grade 3 elevated liver function).
As of the data cut-off, 13 patients were evaluable for efficacy. Eleven patients had stable disease (SD), one had progressive disease in the injected lesion, and one had a pathological complete response after surgery. Taken together, these results represent a 92% local disease control rate (12/13) and a median Overall Survival of 21 months in evaluable patients. Notably, the patient who achieved pathological complete response entered the study with an unresectable tumor.
Updated results were presented at the 2023 Annual Congress of the European Society for Medical Oncology (ESMO). The data showed a 23 months median Overall Survival (mOS) observed in the 15 patients treated with cytotoxic chemotherapy followed by RT-activated NBTXR3. Interestingly, a review of a historical control dataset from the same center as this Phase 1 (a MD Anderson cancer center) in 243 patients with LAPC showed an mOS of 19.2 months in 144 patients who received cytotoxic chemotherapy followed by radiotherapy with or without concurrent or maintenance chemotherapy (80% received radiotherapy with concurrent chemotherapy). In addition, the preliminary data presented at the ESMO congress showed a normalization of the biomarker CA19-9, a surrogate indicator for longer survival, in 42% of patients who had elevated levels at diagnosis (n=12). Comparatively, the previously mentioned historical data have showed a normalization of CA19-9 in approximately 17% of patients treated with the standard of care who had elevated CA19-9 levels at diagnosis (n=183).
The dose-finding part of the study is complete, with achieved primary objective, establishing the RP2D at 42% of gross tumor volume and suggesting tolerable safety and promising early signs of anti-tumor efficacy. The expansion part remains ongoing.
Esophageal cancer (MD Anderson acting as sponsor of this trial)
Phase 1 Trial - MD Anderson (‘Study 2020-0122’)
This trial is an open-label, single-arm, prospective Phase 1 study consisting of two parts: (i) does-escalation to determine the RP2D of RT-activated NBTXR3 with concurrent chemotherapy, and (ii) expansion at RP2D with toxicity monitoring.
The patient population includes adults (age > 18 years) with stage II-III adenocarcinoma of the esophagus that are treatment naïve and radiographically non-metastatic at screening. The number of participants enrolled will be determined based on the maximum number required to establish the RP2D. Up to 24 subjects will be enrolled, including a maximum of 12 subjects for the dose-finding part. 12 additional subjects will be enrolled for the RP2D expansion.
The first patient was dosed in this trial in January 2021 and enrollment is ongoing. The objectives of the study are the determination of dose-limiting toxicity, the maximum tolerated dose and RP2D.
Liver Cancers
Phase 1/2 trial (‘Study 103’)
The company completed Phase 1 of a Phase 1/2 clinical trial to evaluate the use of NBTXR3 activated by SBRT in liver cancers. The Phase 1 dose escalation part of the study was conducted at six sites in the EU. For this part of the trial the company recruited 23 patients, divided in two subgroups: patients with primary liver cancer (HCC) and patients with secondary liver cancer (liver metastases).
The endpoint of the Phase 1 part of the trial was to determine the safety profile, the recommended dose of NBTXR3 and to assess early signs of anti-tumor activity. In this portion of the trial, patients received a single intratumoral injection of NBTXR3, at increasing dose levels, in each case activated by SBRT.
Final data with respect to the Phase 1 part of Study 103 was presented in October 2020 at the annual meeting of the American Society for Radiation Oncology (ASTRO) and in January 2021 at the annual meeting of the Gastrointestinal Cancers Symposium (ASCO-GI).
Results from the Phase 1 part of Study 103 showed feasibility of injection at each of the five tested dose levels (10%, 15%, 22%, 33% and 42%) with no leakage to surrounding healthy tissues. One SAE of bile duct stenosis was deemed to be related to NBTXR3 and no dose-limiting toxicities were observed. The RP2D was been set at 42%. In 11 patients evaluable for efficacy, early data showed a target lesion objective response rate of 91% in evaluable HCC patients and a target lesion objective response rate of 71% in evaluable patients with liver metastasis. For HCC patients, preliminary results showed that out of 11 evaluable patients, 10 responded at least partially and 5 of the 11 patients (45.5%) reached complete response. Out of the 7 patients evaluated for efficacy in the metastatic setting, 5 patients presented a partial response and 2 patients presented stable disease.
These results suggest meaningful potential to address an unmet medical need in an indication with typically an extremely poor prognosis. Although this data is preliminary, it further supports the potential for NBTXR3 to be helpful for patients across multiple solid tumor indications.
Locally Advanced Soft Tissue Sarcoma
Clinical Development
Following the positive results of the company’s Phase 1 trial, the company commenced a Phase 2/3 trial for EU registration (Study 301), which the company also refers to as the Act.In.Sarc trial, to measure the anti-tumor activity of preoperative NBTXR3 activated by radiotherapy, as compared to radiotherapy alone, in patients with locally advanced STS. The Act.In.Sarc trial was conducted at more than 30 sites worldwide, including 23 sites in Europe and seven sites in the Asia-Pacific region.
The primary endpoint of the Phase 2/3 trial was an increase in the pathological complete response rate (defined as less than 5% of residual viable cancer cells in the tumor) of intratumoral injection of NBTXR3 activated by external beam radiation therapy (EBRT), as compared against EBRT alone. The secondary endpoints were to evaluate the safety profile of RT-activated NBTXR3 and compare the rate of tumor surgery with R0 margins (meaning no remaining cancer cells could be seen microscopically within a widely accepted margin after resection), the percentage of tumor necrosis/infarction, limb amputation rates and tumor response as measured by RECIST 1.1.
The trial achieved its primary endpoint, with 16.1% of patients in the NBTXR3 arm having a pathological complete response compared to 7.9% of patients in the control arm. The difference was statistically significant, with a p-value of 0.0448.
In addition, in the subgroup of patients with a higher histology grade (i.e., a more aggressive disease), which represented the majority of patients in the trial, pathological complete response was achieved in four times as many patients in the NBTXR3 arm (17.1%) compared to patients in the control arm (3.9%).
Patients in the NBTXR3 arm were more likely to have a pathological response (not limited to a complete pathological response). The proportion of patients with pathological ‘nearly’ complete response (defined as less than 7% of residual viable cancer cells in the tumor) and pathological response with 10% or less of residual viable cancer cells were 24.7% and 34.6%, respectively, in patients in the NBTXR3 arm as compared to 14.8% and 19.8%, respectively, in patients in the control arm.
The main secondary endpoint of the trial, the rate of tumor surgery with R0 margins, was also met. R0 resection margin was observed in 77% of the patients in the NBTXR3 arm, compared to 64% of patients in the control arm. This difference was statistically significant, with a p-value of 0.0424.
Similar safety profiles were observed in the NBTXR3 arm and the control arm, including the rate of postsurgical wound complications. NBTXR3 did not impair the patients’ ability to receive the planned dose of radiotherapy. In the NBTXR3 arm, 7.9% of patients experienced grade 3-4 acute immune reactions, which were manageable and of short duration. Further, NBTXR3 showed a good local tolerance in patients and did not have any impact on the severity or incidence of radiotherapy-related AEs.
Long-term follow up data for patients enrolled in the Act.In.Sarc Study reinforced the favorable benefit-risk ratio of NBTXR3 plus RT in patients suffering from locally advanced STS of the extremity or trunk wall. This long-term evaluation showed that NBTXR3 did not negatively affect safety or health related quality of life (HRQoL). During the follow-up period, post-treatment SAEs (regardless of relationship) occurred in 13.5% of the patients in the NBTXR3 arm, compared to 24.4% of patients in the control arm. During the follow-up period, there was an improvement in scores across several instruments used for measuring health-related quality of life.
The Curadigm Platform
Beyond NBTXR3, Nanobiotix is also evaluating several additional potential development programs in nanomedicine. In July 2019, Nanobiotix formed a wholly-owned subsidiary — Curadigm SAS — with the mission of leveraging Nanobiotix’s expertise and know-how beyond oncology to expand treatment benefits across multiple therapeutic classes by increasing drug bioavailability while decreasing unintended off-target effects, specifically liver toxicity.
For most therapeutics today, only a small portion of the medicine administered is effective. After injection, the dose moves through the patient’s circulatory system within the blood. While a small portion reaches the targeted tissue, the remainder is either cleared from the body or accumulates—potentially with toxic effect—in organs such as the liver or spleen.
Leveraging the company’s deep expertise in nanotechnology, Curadigm is developing a nanoparticle, called Nanoprimer, that primes the body to receive treatment. Injected intravenously prior to a therapeutic, the Nanoprimer has been designed with specific physico-chemical properties that allow it to transiently occupy the liver cells responsible for therapeutic clearance. By preventing the liver clearance, the Nanoprimer is intended to increase the blood bioavailability and subsequent accumulation of therapeutics in the targeted tissues, thereby increasing therapeutic action.
The Curadigm technology could have broad implications across the healthcare system by increasing the efficacy of therapeutics at their current dose or lowering the necessary dose in order to decrease toxicity and cost, thus allowing for novel therapeutic approaches. Preclinical in vivo data evaluating Curadigm’s concept has been generated combining the Nanoprimer with different therapeutic agent families such as small molecules and nucleic acids and has been published in scientific journals.
As the Nanoprimer is a combination product candidate that does not alter or modify the therapeutic it is paired with, the company expects that Curadigm will continue to seek partnerships across drug classes-particularly with nucleic acid-based therapies. To support the development of its platform, Curadigm may pursue various funding opportunities, including, without limitation, partnership and collaboration arrangements, and/or licensing opportunities.
The Oocuity Platform
Nanobiotix continues to progress work on its neurobiology platform, in which the use of nanoparticles of different materials is being explored for the treatment of certain neurological diseases. The research is based on the principle that nanoparticle materials can interact with and influence neuronal networks via their electrical properties. Thus, nanoparticles may be able to modulate malfunctioning neuronal networks, bringing the neuronal activity towards a ‘normal’ state. In particular, the reduction of neuronal hyperexcitability associated with neuropathic pain is being investigated in in vitro studies and in mouse models with a number of nanoparticle candidates.
Commercialization
In April 2019, the company completed the regulatory process for the CE mark of NBTXR3 for soft tissue sarcoma. The company has not developed commercial infrastructure in either the United States or the EU. Furthermore, in July 2023 the company entered into the Janssen Agreement which includes the exclusive right for Janssen to commercialize NBTXR3,
Intellectual Property
The company’s technologies and product candidates are protected by more than 500 issued or pending patents and patent applications in over 25 patent families across the world. The company holds key patents and patent applications with respect to the concepts, products and uses of nanoparticles activated by ionizing radiation through NBTXR3 technology and for new applications in nanomedicine.
In addition to patent protection, the company has trademark protection in many countries for the company’s ‘Nanobiotix’ name and Nanobiotix logo. The company owns over 300 trademark registrations and applications related to the company’s products, product candidates, processes and technology worldwide.
Research and Development
The company's research and development expenses were €38.4 million for the year ended December 31, 2023.
Government Regulation
NBTXR3 and any other therapeutic candidates that the company develops must be approved by any relevant health authorities before they may be legally marketed in the relevant country and, in the case NBTXR3 or any other therapeutic candidates would be classified as medical device, must complete the conformity assessment procedure with the relevant Notified Body before they may be legally marketed in the relevant country. In addition, in the European Union, the company is subject to data protection rules.
Any drug products for which the company receives FDA approvals are subject to continuing regulation by the FDA. As manufacturers of medical devices, in the EU the company is required under the Medical Devices Regulation (Regulation (EU) 2017/745, the MDR) to affix a CE mark to it products in order to sell its products in Member States of the European Union (EU).
History
Nanobiotix S.A. was incorporated as a societe anonyme in 2003.
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