Innate Pharma
ENXTPA:IPH
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1,16
€
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1,16
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End-of-day quote: 04/06/2026
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Innate Pharma Company Info
EPS Growth 5Y
-14,50%
Market Cap
€0,11 B
Long-Term Debt
€0,01 B
Quarterly earnings
09/17/2026 (E)
Dividend
€0,00
Dividend Yield
0,00%
Founded
1999
Industry
Country
Website
ISIN Number
Website
Analyst Price Target
The Analyst Price Target shows the analysts’ low, high, and average target at a glance.
€5,35
361.21%
Last Update: 04/07/2026
Analysts: 2
Highest Price Target €6,20
Average Price Target €5,35
Lowest Price Target €4,50
In the last five quarters, Innate Pharma’s Price Target has fallen from €7,13 to €6,14 - a -13,88% decrease. Two analysts predict that Innate Pharma’s share price will increase in the coming year, reaching €5,35. This would represent an increase of 361,21%.
Top growth stocks in the health care sector (5Y.)
What does Innate Pharma do?
Innate Pharma S.A. (Innate Pharma or Innate) is a global, clinical-stage biotechnology company developing immunotherapies for cancer patients.
The company’s approach aims to harness the innate immune system through therapeutic antibodies and its ANKET (Antibody-based NK cell Engager Therapeutics) proprietary platform. Innate’s portfolio includes lead proprietary program lacutamab, developed in advanced form of cutaneous T cell lymphomas and peripheral T cell lymphomas; monalizumab developed wit...
Innate Pharma S.A. (Innate Pharma or Innate) is a global, clinical-stage biotechnology company developing immunotherapies for cancer patients.
The company’s approach aims to harness the innate immune system through therapeutic antibodies and its ANKET (Antibody-based NK cell Engager Therapeutics) proprietary platform. Innate’s portfolio includes lead proprietary program lacutamab, developed in advanced form of cutaneous T cell lymphomas and peripheral T cell lymphomas; monalizumab developed with AstraZeneca in non-small cell lung cancer, as well as ANKET multi-specific NK cell engagers to address multiple tumor types. The company has developed, internally and through its business development strategy, a broad and diversified portfolio including seven clinical product candidates and a robust preclinical pipeline. Innate has entered into collaborations with leaders in the biopharmaceutical industry, such as AstraZeneca and Sanofi. Innate Pharma believes its product candidates and clinical development approach are differentiated from current immuno-oncology therapies and have the potential to significantly improve the clinical outcome for patients with cancer.
The company’s approach to immuno-oncology aims to broaden and amplify anti-tumoral immune responses by leveraging both the adaptive and the innate immune systems.
The company is developing a pipeline of immunotherapies that have the potential to provide significant clinical benefits to cancer patients.
In addition to these assets, the company has an active development pipeline with programs in the discovery and preclinical stages.
Innate Pharma's collaborations with leaders in the biopharmaceutical industry, such as AstraZeneca and Sanofi, allow Innate to leverage the expertise and resources of large pharmaceutical companies and research institutions with the goal of accelerating the development, registration and launch of several of Innate Pharma's assets while providing the company with financing to expand the development of its proprietary product candidates.
Strategy
By leveraging its extensive experience in immuno-oncology research and development, the company strives to continue to discover and develop a broad and diversified portfolio of first- and best-in-class immunotherapies across various therapeutic modalities. The key elements of its strategy are to drive near-term value with Innate's wholly owned product candidate, lacutamab; advance its innovative R&D pipeline; and build a sustainable business.
Innate Pharma's Product Pipeline
Lacutamab (IPH4102), a Tumor Targeting Anti-KIR3DL2 Antibody
Mechanism & Rationale
The company is developing its wholly owned product candidate lacutamab for the treatment of certain subtypes of T cell lymphoma (TCLs), including cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL). Lacutamab is designed to bind to the KIR3DL2 receptor and to kill cancer cells by antibody dependant cellular phagocytosis (ADCP) and antibody dependant cell cytotoxicity (ADCC).
Indication
Cutaneous T Cell Lymphoma
In January 2019, the Food and Drug Administration (FDA) granted lacutamab Fast Track Designation for the treatment of adults with relapsed/refractory (r/r) Sezary syndrome who have received at least two prior systemic therapies. In November 2020, Innate Pharma received Priority Medicines (PRIME) designation from the EMA for lacutamab, for the treatment of patients with relapsed or refractory Sezary syndrome (SS) who have received at least two prior systemic therapies. Lacutamab has also been granted orphan drug designation by the FDA and orphan designation by the EMA for the treatment of CTCL. The U.S. Fast-Track and EU PRIME designations support the potential for lacutamab to benefit Sezary Syndrome patients in need of new treatment options. The ongoing Phase 2 TELLOMAK trial, initiated in May 2019, continues to evaluate lacutamab in different subtypes of TCL.
Peripheral T Cell Lymphoma
PTCL is a diverse group of aggressive non-Hodgkin’s lymphomas that develop from mature T cells and NK cells. PTCL arises in the lymphoid tissues outside of the bone marrow, such as in the lymph nodes, spleen, gastrointestinal tract and skin (Hsi, 2017).
Clinical Trials
Phase 1 Clinical Trial – CTCL
In November 2015, the lacutamab Phase 1 dose-escalating and cohort expansion clinical trial was initiated to evaluate lacutamab for the treatment of advanced CTCL. The trial was completed in April 2020, and enrolled 44 patients, including 35 patients with Sezary syndrome, eight patients with mycosis fungoides and one patient with CD4+ TCL not otherwise specified. The primary objective of the trial was to evaluate lacutamab safety, and to identify dose limiting toxicities (DLTs) and the maximum tolerated dose. Data from this trial were presented at the 2018 meeting of the American Society of Hematology (‘ASH’), and reported in Lancet Oncology in 2019 by Bagot et al. The company reported clinical activity in the subgroup of 35 Sezary syndrome patients, including an observed overall response rate of 42.9%, median duration of response of 13.8 months, median progression-free survival of 11.7 months and approximately 90% of patients experienced an improved quality of life. The overall response rate appeared to be higher (53.6%) in the 28 patients with no histologic evidence of large cell transformation. Clinical activity was associated with a substantial improvement in quality of life as assessed by the Skindex29 and Pruritus Visual Analog Scale scores. In a post hoc analysis of seven patients with Sezary syndrome who were previously treated with mogamulizumab, three (43%) achieved a global overall response and three others had stable disease as best response. The remaining patient had a progressive disease. The median duration of response in these patients was 13.8 months and median progression-free survival was 16.8 months.
Lacutamab was generally well tolerated. The most common adverse effects (AEs) were peripheral edema (27%) and fatigue (20%), all of which were grade 1 or 2. Lymphopenia was the most frequent IPH4102-related adverse event and occurred in six (14%) patients (three (7%) grade 3). One patient developed possibly treatment-related fulminant hepatitis six weeks after lacutamab discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Six possibly treatment-related, grade 3 or above adverse events were observed in five patients (11%) and only four patients (9%) stopped treatment as a result of an adverse event. One patient stopped treatment because of grade 2 peripheral neuropathy, one patient stopped treatment because of grade 3 general malaise, one patient because of grade 3 skin pain and one patient stopped treatment because of several adverse events, including renal injury, respiratory failure, dysphagia and sepsis.
Phase 2 Clinical Trial (TELLOMAK) - CTCL
Study Overview
In May 2019, the company initiated a global, open-label, multi-cohort Phase 2 clinical trial, known as TELLOMAK. This clinical trial is being conducted at approximately 50 sites within the United States and Europe (France, Italy, Spain, Germany, Belgium, Poland and Austria). The trial aims to evaluate the efficacy and safety of lacutamab in patients with advanced T cell Lymphoma. 160 patients have been recruited, approximately 60 patients with Sezary syndrome who have received at least two prior treatments (Cohort 1), and approximately 100 patients with MF who have received at least two prior systemic therapies (Cohorts 2, 3 and all-comers). Cohorts 2 and 3 recruited KIR3DL2 expressing and non-expressing patients respectively based on an IHC assay for use on frozen tissue. The cohorts were designed using Simon 2-stage approach which pre-defined an efficacy threshold in Stage 1 before continuing to stage 2. While Cohort 2 continues to Stage 2, the pre-specified threshold for Cohort 3 was not met, and was therefore closed in March 2022.
In March 2022, the company announced the opening of a new mycosis fungoides (MF) all-comers cohort in the TELLOMAK study. The all-comers cohort was planned to recruit both KIR3DL2 expressors and non-expressors to explore the correlation between the level of KIR3DL2 expression and treatment outcomes utilizing a formalin-fixed paraffin embedded (FFPE) assay as a companion diagnostic.
The primary endpoint of the trial is objective response rate, measured using the 2011 Olsen criteria for CTCL. Key secondary measures include incidence of treatment-emergent AEs, the effect of skin disease on quality of life as measured by the Skindex29 questionnaire, pruritus as measured by the Visual Analog Scale, progression-free survival and overall survival. The results of the dedicated Sezary syndrome cohort may support a future Biologics License Application (BLA) submission to the FDA.
The study started in 2019 and completed enrollment in June 2023 (n=170 patients).
The TELLOMAK study experienced some supply issues within 2019/2020 which lead to clinical hold, now resolved and summarized below:
November 2019, Impletio Wirkstoffabfüllung GmbH (formerly known as Rentschler Fill Solutions GmbH), the subcontractor in charge of the fill-and-finish manufacturing operations of lacutamab unilaterally decided to withdraw the certificates of conformance of all clinical batches produced at their facilities, including lacutamab. The company also filed for bankruptcy.
Discussions were held with the U.S. and European national regulatory authorities regarding GMP deficiencies resulting in a suspension of enrollment of new patients into TELLOMAK from December 2019.
In January 2020, the TELLOMAK trial in Sezary syndrome and MF in France and in the United Kingdom, was reactivated following authorization by the respective national authorities. In June 2020, the FDA lifted the partial clinical hold placed on the TELLOMAK Phase 2 clinical trial, based on a quality assessment of a new GMP-certified batch successfully manufactured for the lacutamab clinical development program, including the TELLOMAK trial. Regulatory agencies in Spain, Germany and Italy also lifted, in the third quarter of 2020, their partial clinical holds on the TELLOMAK trial, enabling Innate to resume recruitment of the trial in these countries.
Importantly, there were no safety issues related to the trial medication. This is consistent with the review conducted by the Independent Data Monitoring Committee (IDMC), which concluded there were no safety issues related to lacutamab, and the product appeared to be well-tolerated among current patients enrolled in the trial. Lacutamab fill and finish manufacturing operations were transferred to alternative CMOs.
In October 2023, the FDA placed a partial clinical hold on the lacutamab IND leading to a pause in new patient enrollment to the company’s lacutamab trials IPH4102-201 (Phase 2 TELLOMAK) and 102 (Phase 1b PTCL). The partial clinical hold followed one fatal case of hemophagocytic lymphohistiocytosis, a rare hematologic disorder. In January 2024, Innate announced that the U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold. The FDA decision to lift the partial clinical hold is based on the FDA review of the fatal case which Innate, together with a steering committee of independent experts, determined to be related to aggressive disease progression and lacutamab unrelated.
Based on the results of a planned futility interim analysis, however, and in consultation with FDA, the Phase 1b study will not enroll additional patients. Despite objective responses observed, the company-sponsored Phase 1b clinical trial evaluating lacutamab as monotherapy in patients with KIR3DL2-expressing refractory/relapsing PTCL will not be reopened to recruitment as the prespecified threshold for meaningful clinical activity was not reached.
Clinical results in Sezary Syndrome (SS) (Cohort 1)
Final results from the Phase 2 TELLOMAK study in Sezary Syndrome were presented at the ASH Meeting in December 2023.
As of May 1, 2023, the study’s data cutoff, patients in the Sezary Syndrome cohort (cohort 1, n=56) received a median of five prior systemic therapies, including mogamulizumab, and had a median follow-up of 14.4 months.
The data demonstrated that lacutamab showed robust clinical activity and an overall favorable safety profile. The global confirmed objective response rate, or ORR, was 37.5% (21 out of 56), including two complete responses and 19 partial responses. ORR in the skin was 46.4% (26 out of 56), including five complete responses and 21 partial responses and ORR in the blood was 48.2% (27 out of 56) with 15 CR and 12 PR. Median progression-free survival was 8.0 months (95% confidence interval 4.7-21.2). In patients who achieved a global response, the median duration of response is 12.3 months (95% confidence interval 5.1-NE).
In February 2021, the company announced that lacutamab demonstrated a positive early signal in Cohort 2 testing lacutamab in KIR3DL2 expressing MF patients in the TELLOMAK trial. This cohort reached the pre-determined number of responses needed to advance to stage 2, allowing the company to recruit additional patients.
The preliminary data from cohorts 2 and 3 were presented at the ICML and EORTC congresses in July and October 2021 respectively. Of note, the preliminary data concluded:
Lacutamab showed high level of clinical response in MF patients with KIR3DL2 expression = 1% with six global responses (four confirmed and two not confirmed at time of DCO but confirmed thereafter) in 17 patients with a median follow-up of 4.8 months. Expansion to stage 2 is underway.
In MF patients with KIR3DL2 expression < 1%, expansion to stage 2 would be triggered only if one additional confirmed response is observed during follow-up.
Lacutamab shows favorable safety profile in MF, with no relevant skin toxicities observed.
Long-term follow-up is required to provide mature conclusions on duration of response and progression free survival.
In September 2022, MF Cohorts 2 and 3 Stage 1 interim data were presented at the EORTC congress. As of the March 4, 2022 data cutoff:
Within the advanced and heavily pre-treated population enrolled in TELLOMAK, Lacutamab continues to demonstrates clinical activity with a favorable safety profile.
Lacutamab showed low immunogenicity and reached target concentration in both the KIR3DL2 expressing and non-expressing patients.
In 2023, MF Cohorts 2 and 3 interim efficacy results according to updated guidelines were presented at the International Conference on Malignant Lymphoma and EORTC Cutaneous Lymphoma Tumour Group Annual Meeting congresses in June and October 2023, respectively.
As of the March 4, 2022 data cutoff, patients in the KIR3DL2-expressing MF cohort (cohort 2, n=21) received a median of 4 prior systemic therapies, and had a median follow-up of 12.2 months. In the KIR3DL2 non-expressing cohort (cohort 3, n=18), patients received a median of 4.5 prior systemic therapies and had a median follow-up of 13.8 months.
Lymph Node assessment is an important component of staging and response assessment in CTCL (cutaneous T cell lymphomas). In a recent update to the Olsen 2011 guidelines, it was clarified that the pathological assessment of lymph nodes be limited to those that satisfy nodal lymphoma i.e. N3 designation (Olsen 2021). Based on these criteria, results showed that lacutamab produced an increased global objective response rate (ORR) of 42.9% (95% confidence interval [CI], 24.5-63.5) in patients with KIR3DL2 = 1% MF (cohort 2, n=21), including 2 complete responses and 7 partial responses. Clinical Benefit Rate remained unchanged at 85.7% [95% CI tbc]. In Cohort 3, comprising 18 patients with KIR3DL2 < 1% MF, findings remain unchanged.
Top-line final results for MF Cohorts 2 and 3 are expected in 2024 and when available Innate expects to share them at an upcoming medical conference.
Clinical Trials in PTCL
Despite objective responses observed, the company-sponsored Phase 1b clinical trial evaluating lacutamab as monotherapy in patients with KIR3DL2-expressing refractory/relapsing PTCL will not be reopened to recruitment as the prespecified threshold for meaningful clinical activity was not reached.
At the ASH Annual Congress 2023, Innate presented a poster with preclinical data demonstrating a synergistic effect between lacutamab and chemotherapy in preclinical models of PTCL, supporting the rationale for combination strategy in this clinical indication.
The Phase 2 KILT (anti-KIR in T Cell Lymphoma) trial, an investigator-sponsored, randomized trial led by the Lymphoma Study Association (LYSA) to evaluate lacutamab in combination with chemotherapy GEMOX (gemcitabine in combination with oxaliplatin) versus GEMOX alone in patients with KIR3DL2-expressing relapsed/refractory PTCL is ongoing.
Monalizumab, a Dual Checkpoint Inhibitor Targeting T Cells and NK Cells
Mechanism & Rationale
Monalizumab (IPH2201) is a potentially first-in-class immune checkpoint inhibitor targeting NKG2A receptors expressed on tumor infiltrating cytotoxic CD8+ T cells and NK cells. NKG2A is an inhibitory receptor for HLA-E. HLA-E is frequently overexpressed in the cancer cells of many solid tumors and hematological malignancies. By expressing HLA-E, cancer cells can protect themselves from killing by NKG2A+ immune cells. Monalizumab may reestablish a broad anti-tumor response mediated by NK and T cells, and may enhance the cytotoxic potential of other therapeutic antibodies (Andre et al., Cell 2018).
Rationale for combinations with monalizumab
The company is primarily focused on investigating monalizumab in combination with durvalumab, which is an antibody directed against PD-L1. PD-L1 and HLA-E are both up-regulated on many cancer cells, and they have both been observed to suppress tumor immune response and contribute to tumor progression. Innate Pharma's preclinical data support its hypothesis that a monalizumab and durvalumab combination therapy may result in a greater anti-tumor immune response than durvalumab alone by blocking both the PD-1/PD-L1 and the NKG2A/HLA-E inhibitory pathways.
The rationale for this combination is further supported by the favorable tolerability profile of monalizumab that the company observed in preclinical studies and earlier clinical trials, suggesting that monalizumab is generally not expected to negatively impact the safety profile of combination partner drugs.
Clinical Development Plan
Monalizumab has been evaluated in clinical trials in head and neck, lung and other cancer indications. Innate is responsible for the conduct of the IPH2201-203 study in head and neck squamous cell carcinoma, while AstraZeneca is conducting all other trials (except for the External Sponsored studies).
Clinical Development Plan in Lung Cancer
AstraZeneca conducted COAST, a randomized Phase 2 trial investigating durvalumab alone or in combination with either oleclumab (anti-CD73 monoclonal antibody) or monalizumab (anti-NKG2A monoclonal antibody) in patients with locally advanced, unresectable Stage III NSCLC who had not progressed after chemoradiotherapy (CRT). Following on the signal observed in this Phase 2 study, AstraZeneca has started a randomized Phase 3 study PACIFIC-9 of monalizumab or oleclumab plus durvalumab in unresectable, Stage III NSCLC setting for patients who have not progressed after concurrent chemoradiation therapy.
Separately, AstraZeneca evaluated the effectiveness and safety of neoadjuvant durvalumab alone or in combination with monalizumab or oleclumab in subjects with resectable, early-stage (Stage I [>2 cm] to IIIA) non-small cell lung cancer (NeoCOAST) and in 2022 initiated the Phase 2 trial, NeoCOAST-2, with neoadjuvant and adjuvant treatment, that includes an arm with durvalumab in combination with chemotherapy and monalizumab.
Clinical Development Plan in Head and Neck Cancer
In head and neck cancer, Innate and AstraZeneca evaluated monalizumab in combination with cetuximab in R/M SCCHN IO naïve or IO-pretreated in a Phase 1b/2 study (IPH2201-203). Based on the results and the unmet need in the IO-pretreated population, AstraZeneca and Innate elected to advance this program to a Phase 3 study (INTERLINK-1).
In 2022, Innate shared that a planned futility interim analysis of the INTERLINK-1 Phase 3 study sponsored by AstraZeneca did not meet a pre-defined threshold for efficacy. Based on this result and the recommendation of an Independent Data Monitoring Committee, AstraZeneca informed Innate that the study would be discontinued. There were no new safety findings.
IPH2201-203 was an open-label, Phase 1b/2 clinical trial in combination with cetuximab and/or durvalumab in patients with R/M SCCHN. This study, sponsored by Innate Pharma started in December 2015 and the last patient last visit was in March 2023. The study included:
Phase 1b dose-escalation portion
Phase 2 portion comprising three expansion cohorts:
Cohort 1, which enrolled 43 patients, evaluated the combination of monalizumab and cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) who had been previously treated with chemotherapy alone or chemotherapy followed by checkpoint inhibitors;
Cohort 2, which enrolled 41 patients and evaluated the combination of monalizumab and cetuximab in patients with R/M SCCHN who have received a maximum of two prior systemic regimens in the R/M setting and with prior exposure to a PD-(L)1 inhibitor (who Innate refers to as IO-pretreated patients); and
Cohort 3, which enrolled 40 patients, began recruiting in April 2019 and evaluated the combination of monalizumab, cetuximab and durvalumab in IO-naïve patients with R/M SCCHN.
Interlink-1 was a global, multi-center, randomized, double-blind Phase 3 study of monalizumab and cetuximab vs. placebo and cetuximab designed to enroll approximately 600 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) who have been previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors (‘IO-pretreated’). The study started on October 2, 2020 and on August 1, 2022, the company announced that the study will be discontinued.
Clinical Results
Lung Cancer: Phase 2 COAST Study
In September 2021, AstraZeneca presented a late-breaker abstract on the randomized COAST Phase 2 trial in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) at the European Society for Medical Oncology (ESMO) Congress. The presentation highlighted progression-free survival (PFS) and overall response rate (ORR) results for durvalumab in combination with monalizumab, Innate’s lead partnered asset, and oleclumab, AstraZeneca’s anti-CD73 monoclonal antibody. After a median follow-up of 11.5 months, the results of an interim analysis showed a 10-month PFS rate of 72.7% for durvalumab plus monalizumab, versus 39.2% with durvalumab alone in unresectable, Stage III NSCLC patients following chemoradiation therapy. The results also showed an increase in the primary endpoint of confirmed ORR for durvalumab plus monalizumab over durvalumab alone (36% vs. 18%).
Lung Cancer: Phase 2 NeoCOAST Study
In March 2022, the Phase 2 NeoCOAST multi-drug platform study assessing the safety and efficacy of neoadjuvant durvalumab in combination with chemotherapy and oleclumab, monalizumab or danvatirsen and adjuvant treatment in participants with resectable, early-stage non-small cell lung cancer was accepted for an oral presentation on April 11, 2022 at the Annual Meeting 2022 of the American Association for Cancer Research (AACR).’ The study demonstrated that a single cycle of neoadjuvant durvalumab combined with oleclumab, monalizumab, or danvatirsen produced numerically improved MPR rates (19, 30 and 31.2%, respectively) compared with durvalumab alone (11.1%). No differences in pCR rates were observed between treatment arms.
Lung Cancer: Phase 3 PACIFIC-9
In June 2023, AstraZeneca presented at the ASCO conference a trial-in-progress poster on the PACIFIC-9 study: ‘Phase 3 study of durvalumab combined with oleclumab or monalizumab in patients with unresectable stage III NSCLC (PACIFIC-9).’
PACIFIC-9 started in February 2022 and continues to enroll patients.
Lung Cancer: Phase 2 NeoCOAST-2
In June 2023, AstraZeneca presented at the ASCO conference a trial-in-progress poster on the NeoCOAST-2: study: ‘NeoCOAST-2: A Phase 2 study of neoadjuvant durvalumab plus novel immunotherapies (IO) and chemotherapy (CT) or MEDI5752 (volrustomig) plus CT, followed by surgery and adjuvant durvalumab plus novel IO or volrustomig alone in patients with resectable non-small-cell lung cancer (NSCLC).’
NeoCOAST-2 started in April 2022 and continues to enroll patients.
Head and Neck Cancer: IPH2201-203 Study
Phase 2: Expansion cohort 1
The primary endpoint for the Phase 2 portion of the trial is objective response rate, which is measured as the rate of patients who had a complete or partial response according to RECIST 1.1. Secondary endpoints for the Phase 2 portion of the trial include duration of response, progression-free survival and overall survival.
As of April 30, 2019, 40 patients were enrolled globally. The monalizumab and cetuximab combination demonstrated an acceptable safety profile.
Phase 2: Expansion cohort 2
As of August 31, 2020, 40 patients with R/M SCCHN post platinum and anti-PD-(L)1 were included in cohort 2 in the United States and France.
The monalizumab and cetuximab combination therapy demonstrates a good safety profile and promising activity in R/M SCCHN post platinum and post anti-PD-(L)1 where no treatment options were approved. In this population with a high medical need, the company observed a high response rate of 20% and promising 6- and 12-month OS of 80% and 33% with monalizumab combined with cetuximab. These results were presented at the ESMO IO conference in 2020.
Based on these results, a randomized Phase 3 trial, INTERLINK-1, was started to evaluate the combination monalizumab + cetuximab versus cetuximab + placebo in R/M SCCHN post platinum and post anti-PD-(L)1 patients.
Phase 2: Expansion cohort 3
As of August 1, 2021, 40 patients were enrolled in the cohort 3 evaluating monalizumab, cetuximab and durvalumab in first line treatment of R/M SCCHN. Median follow-up was 16.3 months (4.4-25.7); 13 patients had a confirmed response, ORR=32.5% [95%CI: 20-48], including three complete responses. Median time to response was 1.8 months [1.6-3.7]. 6/13 responders were still on treatment, with median duration of response not yet reached [7.1-NR]. Median PFS was 6.9 months [4.4-9.3], and 12 months OS was 59% [45-77]. These results were presented at the ESMO IO conference in 2021.
Head and Neck Cancer: INTERLINK-1
Interlink-1 was a global, multi-center, randomized, double-blind Phase 3 study of monalizumab and cetuximab vs. placebo and cetuximab designed to enroll approximately 600 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) who have been previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors (‘IO-pretreated’). On August 1, 2022, the company announced that a planned futility interim analysis did not meet a pre-defined threshold for efficacy. Based on this result and the recommendation of an Independent Data Monitoring Committee, AstraZeneca informed Innate that the study would be discontinued. There were no new safety findings. Clinical data presented at the ESMO conference on October 23, 2023 showed that OS and PFS were not improved with monalizumab plus cetuximab versus placebo plus cetuximab; and that ORR in the placebo plus cetuximab arm was higher than in previous reports of participants with R/M HNSCC with progression on / after platinum therapy. Exploratory biomarker analyses are ongoing to identify subpopulations that may benefit from monalizumab plus cetuximab treatment.
Phase 1/2 Clinical Trial in Solid Tumors, including Colorectal Cancer (in combination with durvalumab): D419NC00001
AstraZeneca has evaluated monalizumab in combination with durvalumab in a Phase 1/2 clinical trial in 383 patients with advanced solid tumor malignancies. The study consisted of three parts: dose escalation (Part 1), dose expansion (Part 2) and dose exploration (Part 3). In 2018, clinical data showed preliminary anti-tumor activity in patients with recurrent/metastatic microsatellite-stable colorectal cancer (MSS-CRC), a population historically unresponsive to PD-1/L1 blockade. Thirty-one percent disease control rate at 16 weeks (DCR: % of responses and stable disease) suggested that patients may benefit from stabilizing effect when 88% of patients had two or more prior lines of therapy for recurrent/metastatic disease. These data formed a basis for exploring the combination with standard of care therapies (SoC) in less heavily pretreated patients.
Partnership with AstraZeneca
On April 24, 2015, the company signed a co-development and commercialization agreement with AstraZeneca to accelerate and broaden the development of monalizumab. AstraZeneca obtained full oncology rights to monalizumab in October 2018. The financial terms of the agreement include potential cash payments of up to $1.275 billion to Innate Pharma. With the addition of the $50 million payment triggered by dosing the first patient in the Phase 3 PACIFIC-9 clinical trial, Innate Pharma has received $450 million to date. AstraZeneca will book all sales and will pay Innate low double-digit to mid-teen percentage royalties on net sales worldwide except in Europe where Innate Pharma will receive if it chooses to co-promote the licensed products in certain European countries a 50% share of the profits and losses in these territories. Should Innate Pharma elect not to co-promote, its share of profits in Europe will be reduced by a specified amount of percentage points not to exceed the mid-single digits. Innate will co-fund 30% of the costs of the Phase 3 development program of monalizumab with a pre-agreed limitation on Innate’s financial commitment.
IPH5201, an Anti-CD39 Antibody Targeting the Immunosuppressive Adenosine Pathway
Mechanism & Rationale
CD39 is an extracellular enzyme that is expressed in the tumor microenvironment, on both tumor infiltrating cells and stromal cells in several cancer types. CD39 inhibits the immune system by degrading adenosine triphosphate (ATP) into adenosine monophosphate (AMP), that is then further degraded into adenosine by CD73. By promoting the accumulation of immune-stimulating ATP, and preventing the production of immune-suppressive adenosine, the blockade of CD39 may stimulate anti-tumor activity.
IPH5201 is a blocking antibody targeting the CD39 immunosuppressive pathway.
Targeting the adenosine pathway has recently been reported to improve Durvalumab (anti-PD-L1) efficacy in early-stage Non-Small Cell Lung Cancer (NSCLC) patients, through the use of Oleclumab, an anti-CD73 mAb. Indeed, in the COAST randomized Phase 2 study, oleclumab in combination with durvalumab improved progression-free survival (PFS) and objective response rate (ORR) compared to durvalumab alone in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) (Herbst, JCO, 2022). Also, in the NeoCoast randomized Phase 2 study, one cycle of neoadjuvant oleclumab in combination with durvalumab improved major pathological response (MPR) and pathological complete response (pCR) rates versus durvalumab alone, in stage I-IIIA resectable NSCLC patients (Cascone, AACR 2022).
This supports the evaluation of the combined blockade of CD39 and PD-L1, with IPH5201 and durvalumab, respectively, that can hypothetically increase activity when compared to durvalumab monotherapy by altering the balance of ATP and adenosine in the tumor microenvironment.
Non Clinical Development
The rationale is supported by the analysis of anti-tumor immune responses in tumor-challenged CD39 deficient mice and by its non-clinical data for IPH5201 in mouse tumor models.
CD39-deficient mice are more resistant to developing lung or liver metastatic tumors after systemic challenge with syngeneic B16F10 or MC38 tumor cells (Sun, 2010). Subcutaneous (SC) syngeneic B16F10 tumors also grew more slowly in CD39-deficient mice, leading to improved overall survival versus wild-type mice, and correlated with reduced angiogenesis and improved effector function of tumor infiltrating T cells in CD39-deficient mice (Jackson, 2007; Sun, 2013). Furthermore, CD39 deficiency enhanced the anti-tumor activity of PD-1 blocking antibodies alone and in combination with oxaliplatin chemotherapy in tumor-bearing mice (Perrot, 2019).
The company’s non-clinical studies demonstrated that IPH5201 blocking CD39 mAb effectively targets and inhibits CD39 (soluble and membrane form) activity, reverses adenosine-mediated T cell suppression, and enhances ATP-dependent macrophages and DC activation (adenosine independent). IPH5201 synergized with a blocking mAb against CD73 to restore activation of T cells isolated from cancer patients in vitro (Perrot, 2019). In syngeneic tumor-bearing human CD39 knock-in mice, the company observed that a mouse version of IPH5201 enhanced the antitumor effects of PD-L1 blockade.
CD39 is expressed in both squamous and adenocarcinoma subtypes of NSCLC with expression noted across disease stages (Anceriz, ESMO-IO 2022, Poster 190P, abstract 384). In a mouse tumor model engrafted in huCD39KI mice, moIPH5201 was able to decrease the human CD39 enzymatic activity and to lower the Ado level in situ. In vitro, chemotherapies induced extracellular ATP release by tumor cells and IPH5201 was able to accumulate the released ATP, following chemotherapy treatment. Finally, as shown in the figure below, in vivo, in a mouse tumor model engrafted in huCD39KI mice, moIPH5201 improved the anti-tumor efficacy of gemcitabine and anti-PD-L1 combination. The three graphs on the left (A) show the best tumor volume change in percentage, for each treated group in comparison to the control group. The diagram on the right outlines survival in each group.
Altogether, the expression profile of CD39 in early-stage NSCLC and preclinical combination data support the clinical evaluation of IPH5201 in combination with Durvalumab and chemotherapies in early-stage NSCLC patients.
Clinical Development
Overview and Indications
IPH5201 has been evaluated in a Phase 1 clinical in advanced solid tumors, in monotherapy and in combination with durvalumab; and is being investigated in a Phase 2 clinical trial, MATISSE, in combination with durvalumab and chemotherapy in non-small cell lung cancer (NSCLC).
Phase I in Advanced Solid Tumors
A Phase 1 clinical trial (NCT04261075), sponsored by AstraZeneca, with first patient treated in March 2020, evaluated IPH5201, an anti-CD39 blocking monoclonal antibody, in adult patients with advanced solid tumors. The purpose of the study was to evaluate IPH5201 as monotherapy and in combination with durvalumab (anti-PD-L1) and with or without oleclumab (anti-CD73 monoclonal antibody). This multicenter, open-label, dose-escalation Phase 1 study evaluated the safety, tolerability, antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of IPH5201 alone, or in combination with AstraZeneca’s anti-PD-L1 therapy, durvalumab, with or without its anti-CD73 monoclonal antibody, oleclumab.
The current study status is completed and results were presented at the ESMO-IO congress (Imbimbo, Poster 188P, abstract 472). IPH5201 was well tolerated when used alone or in combination with durvalumab up to a dose of 3000 mg Q3W. The safety profile was manageable, with the most common treatment-related adverse events being infusion-related reactions and fatigue; no new safety signals were identified beyond those observed with durvalumab monotherapy. No maximum tolerated dose (MTD) was identified. PK of IPH5201 was non-linear at =300 mg and linear at =1000 mg. The PD profile, including inhibition of CD39 activity in the tumors of patients treated with IPH5201, was consistent with the proposed mechanism of action for IPH5201.
As clinical activity results, 22/57 patients (38.6%) had stable disease as their best overall response; there were no partial or complete responses. In IPH5201 monotherapy subgroup, 17/38 patients (44.7%) had stable disease as their best overall response.
Phase II MATISSE study in NSCLC
MATISSE is a Phase 2 multicenter single-arm study (NCT05742607), sponsored by Innate Pharma, evaluating neoadjuvant and adjuvant treatment with IPH5201, an anti-CD39 blocking monoclonal antibody, in combination with durvalumab (anti-PD-L1) and chemotherapy, in treatment-naïve patients with resectable early stage non-small cell lung cancer (NSCLC). The primary objectives of the study are to assess antitumor activity of neoadjuvant treatment based on pathological complete response (pCR) and safety. Innate is responsible for conducting the study and shares study costs with AstraZeneca. AstraZeneca supplies clinical trial drugs.
The first patient was dosed in June 2023. In October 2023, Innate Pharma presented at the ESMO conference a trial-in-progress poster on the MATISSE study: ‘A Phase II multicenter, open label, non-randomized study of neoadjuvant and adjuvant treatment with IPH5201 and durvalumab in patients with resectable, early-stage (II to IIIA) non-small cell lung cancer (MATISSE).’
Partnership
In October 2018, Innate Pharma and AstraZeneca entered into a development collaboration and option agreement for further co-development and co-commercialization for IPH5201.
In June 2022, the 2018 IPH5201 Option Agreement was amended. Innate received a $5 million milestone payment from AstraZeneca upon signature of the amendment and is responsible for conducting a Phase 2 multicenter, open label, non-randomized study of neoadjuvant and adjuvant treatment with IPH5201, durvalumab, and chemotherapy in patients with resectable, early-stage non-small cell lung cancer (NSCLC). The ‘MATISSE’ Study has started and is recruiting patients. AstraZeneca and Innate will share study costs and AstraZeneca will supply clinical trial drugs. Innate made a €0.6 million milestone payment to Orega Biotech SAS pursuant to Innate’s exclusive licensing agreement.
IPH5301, an Anti-CD73 Antibody Targeting the Immunosuppressive Adenosine Pathway
Mechanism & Rationale
The company is developing IPH5301 (anti-CD73) as a potential anticancer therapy for patients with advanced or metastatic disease in selected solid tumors. IPH5301 is a monoclonal antibody that selectively binds to and inhibits the activity of both membrane-bound and soluble human CD73 (NT5E, ecto-5’-nucleotidase).
IPH5301 inhibits CD73-mediated hydrolysis of adenosine monophosphate (AMP) to adenosine. CD73 has been shown to be expressed by tumor cells as well as stromal cells, endothelial cells and B and T lymphocytes within the tumor microenvironment, and it has been shown to play a significant role in promoting immunosuppression through the pathway degrading AMP into adenosine. Therefore, inhibition of CD73-mediated hydrolysis of AMP by IPH5301 has the potential to reduce the formation of immunosuppressive adenosine, thereby leading to increased antitumor immunity across multiple tumor types.
Indication
In the tumor microenvironment, CD73 is expressed by tumor cells as well as stromal cells, endothelial cells and B and T lymphocytes (Allard et al., 2017). Inhibition of CD73 enzymatic activity by IPH5301 has the potential to reduce the formation of immunosuppressive adenosine, thereby leading to increased antitumor immunity across multiple tumor types.
Preclinical Development
CD73 immunohistochemistry studies have revealed that in breast, pancreas and ovarian cancers the vast majority of patients expressed CD73 on either tumor or stromal cells (Wang et al; Oncotarget 2017, Innate Pharma Internal data). Additionally, high expression of CD73 in tumors has been associated with poor prognosis in a variety of cancer types: non-small cell lung cancer, prostate cancer, TNBC, ovarian cancer, colorectal cancer and gastric cancer (Inoue et al. 2017; Leclerc et al. 2016; Loi et al. 2013; Gaudreau et al. 2016; Wu et al. 2016; Lu et al. 2013).
CD73-deficient mice have been shown to have an increased resistance to the growth of tumors derived from a variety of certain tumor cell lines, as well as to metastasis (Stagg 2011). These mice were also resistant to the induction of fibrosarcomas by the carcinogen 3-methylcholanthrene (MCA), as well as to the continued growth of established MCA-induced tumors (Stagg 2012). Wild type mice showed decreased tumor growth and metastases in some models when administered with an anti-CD73 antibody alone (Antonioli, 2016, Antoniolli 2017). The small anti-tumor effect of anti-CD73 antibodies in mouse models was greatly enhanced by combination with checkpoint inhibition such as PD-1 or an adenosine receptor antagonist (Allard, 2013; Young, 2016).
The company published preclinical data further supporting the rationale of developing IPH5301. IPH5301 blocked the enzymatic activity of both CD73 expressed at the cell surface and the soluble form of CD73. IPH5301 was able to efficiently restore T cell proliferation inhibited by AMP in vitro. In addition, IPH5301 has been observed to have a differentiated and superior activity compared to benchmark antibodies that are in clinical development (Perrot, 2019).
In syngeneic murine tumor-bearing human CD73 knock-in mice, IPH5301 enhanced the antitumor effects of PD-1 blockade, as shown in the figure below. The four graphs show changes in tumor volume over time depending on the type of treatment group, which included a control group (black), an IPH5301 100 (mouse version) group (pink), an anti-mouse PD-1 group (blue) and an PD-1 and IPH5301 combination group (green).
Thus, IPH5301 could potentially exhibit a favorable efficacy profile in patients with advanced or metastatic disease in selected solid tumors, including serving as a candidate for combination treatments with chemotherapy or immune therapeutic agents.
As further evidence for the negative role of CD73 in anti-tumor response, Loi et al., 2013, examined gene expression data from 6,000 breast cancer patients and found that high CD73 expression was associated with poor prognosis in triple-negative breast cancer (TNBC), as was the association between high CD73 gene expression and pre-surgery treatment with the standard of care chemotherapy anthracycline. In mice inoculated with the syngeneic 4T1.2 breast tumor cell line, a combination of an anti-CD73 antibody and doxorubicin (an anthracycline) led to a greater reduction in tumor volume and increase in mouse survival than either treatment alone.
In HER2-positive breast tumors, high CD73 expression was shown to promote resistance to trastuzumab. In addition, targeting CD73 was shown to enhance efficacy of treatment with anti-HER2 therapy (Turcotte, 2017). On the other hand, several chemotherapeutic agents including taxanes, anthracyclines and platinum salts were shown to increase the release of ATP (Martins and Tesniere, 2009); (Martins and Wang, 2014).
All together, these preclinical results indicate that CD73 blockade with IPH5301 has also the potential to enhance antitumor activity observed with not only PD1 immunotherapy, but also with chemotherapy and trastuzumab.
Ongoing Clinical Trial
In December 2021, an investigator-sponsored Phase 1 trial of IPH5301 was initiated by the Institut Paoli-Calmettes. CHANCES-IPC 2021-008 (NCT05143970) is a First In Human, Phase 1, multicenter, European study evaluating an anti-CD73, IPH5301, in advanced and/or metastatic cancer. The trial will be conducted in two parts. The Part I-Dose escalation aims to identify the maximum tolerated dose (MTD) of IPH5301 agent in monotherapy and recommended Phase 2 dose (RP2D) for future trials, followed by a safety expansion study part cohort. In the Part II-Expansion cohort, a total of 12 HER2+ cancer patients, respectively six breast cancer patients and six gastric cancer patients, are planned to be enrolled into the next expansion cohort to select a recommended dose of IPH5301 to be administered in combination with chemotherapy and trastuzumab for evaluation in future trials with selected advanced solid tumors. In March 2022, The Institut Paoli Calmettes announced that the first patient had been dosed. In December 2022, a ‘Trial in Progress’ poster was presented by the Institut Paoli Calmettes at ESMO-IO 2022 congress (Goncalvez, ESMO-IO 2022, Poster 199, abstract 290). This trial is ongoing.
ANKET Platform
ANKET (Antibody-based NK cell Engager Therapeutics) is Innate’s proprietary platform for developing next-generation, multi-specific NK cell engagers to treat certain types of cancer.
This versatile, fit-for-purpose technology is creating an entirely new class of molecules to induce synthetic immunity against cancer. It leverages the advantages of harnessing NK cell effector functions against cancer cells and also provides proliferation and activation signals targeted to NK cells.
Innate's latest innovation, the tetra-specific ANKET molecule, is the first NK cell engager technology to engage activating receptors (NKp46 and CD16), a tumor antigen and an interleukin-2 receptor (via an IL-2 variant, IL-2v) via a single molecule. This innovation is built on its existing tri-specific NK cell engager technology, which has demonstrated potent NK cell activation, cytotoxicity and efficient control of tumor growth in preclinical models.
Because NKp46 is expressed on all NK cells and conserved on tumor infiltrating NK cells, and NK cells are not expected to produce a cytokine storm, ANKET molecules may overcome the limitations of both ADCC-inducing antibodies and T cell engagers.
ANKET Pipeline
Sanofi's Partnership
IPH6101/SAR'579, a CD123-targeting NK Cell Engager
Mechanism
IPH6101/SAR443579 is the first trifunctional anti-CD123 NK cell engager NKp46/CD16 using Innate’s proprietary multi-specific antibody format ANKET. It has shown anti-tumor activity in preclinical models, including supporting pharmacokinetic/pharmacodynamic (PK/PD) and safety data in non-human primate studies, leading to its selection as a drug candidate for development. It is part of the Sanofi 2016 research collaboration and licensing agreement, under which the companies collaborate on the development of innovative multi-specific antibody formats engaging NK cells through the activating receptors NKp46 and CD16 to kill tumor cells. Several NK cell therapies have been shown to induce antitumor responses, without the complications frequently associated with T cell therapies, such as cytokine release syndrome (CRS) or neurotoxicity.
Indication and Rationale
Cytotoxic antibodies targeting CD123 displayed limited antileukemic activity in several clinical trials, even when tested in the form of Fc-engineered antibodies designed specifically to increase antibody-dependent cell cytotoxicity (ADCC). By contrast, T cell engager molecules and CAR-T cell therapies have some clinical efficacy, but are also highly toxic, confirming the need for alternative targeted approaches for the treatment of AML. NK cell-based therapies may provide new treatment perspectives and a safer alternative for targeting tumor cells in this context.
Preclinical Development
In its preclinical studies, Innate and Sanofi investigated whether NKp46-based NKCE technology could provide more effective antitumor activity than regular IgG antibodies for AML treatment by generating a NKCE molecule targeting CD123. Innate and Sanofi evaluated the ex vivo antitumor activity of this molecule, comparing it with a regular IgG1 antibody derived from clone 7G3 (CD123-IgG1+) with an engineered Fc domain for enhanced ADCC.
The anti-CD123 antibody-mediated killing of primary blasts from AML patients (AML#1 to AML#4) was evaluated ex vivo with NK cells from healthy donors as effectors. The anti-CD123 antibody (CD123-IgG1+) mediated the killing of blasts from half the patient samples (AML#1 and AML#2) but was barely active against blasts from the other half of the primary samples (AML#3 and AML#4). The patient samples could therefore be separated into two distinct groups: CD123-IgG1+-responders and CD123-IgG1+-non-responders.
Innate and Sanofi observed that trifunctional CD123-ANKET displayed killing activity against all primary malignant AML cells, promoting significant antitumor activity in CD123-IgG1+-non-responders samples from AML patients against which the regular anti-CD123 cytotoxic antibody was completely inactive.
The minimal level of pro-inflammatory cytokine release following the treatment of human peripheral blood mononuclear cells (PBMCs) with NKCE in vitro (data not shown) was further confirmed in vivo, in dedicated pharmacokinetic (PK), pharmacodynamic (PD) and toxicology studies performed in non-human primates (NHPs).
Innate and Sanofi evaluated the PK/PD of CD123-NKCE administered by a single one-hour i.v. infusion of a high (3 mg/kg) or low (3 µg/kg) doses in male cynomolgus monkeys (two animals each for the 3 mg/kg and 3 µg/kg doses). Treatment with CD123-NKCE promoted a sustained and complete depletion of CD123+ cells in the blood of all monkeys, for more than 10 days, at both the 3 mg/kg and 3 µg/kg doses, with only very small amounts (< 50 pg/mL) of the pro-inflammatory cytokines IL-6 and IL-10 released without any associated clinical signs.
Ongoing Clinical Trial
IPH6101/SAR443579 is being evaluated in a Phase 1/2 clinical trial (NCT05086315) in patients with relapsed or refractory acute myeloid leukemia (R/R AML), B-cell acute lymphoblastic leukemia (B-ALL) or high risk-myelodysplastic syndrome (HR-MDS).
The purpose of the dose escalation and dose expansion study, which is sponsored by Sanofi, is to evaluate the safety, pharmacokinetics, pharmacodynamics and initial clinical activity of IPH6101/SAR443579, Innate’s lead ANKET asset, in various CD123-expressing hematological malignancies.
Innate Pharma announced that the first patient was dosed on December 16, 2021.
In June 2023, safety and preliminary efficacy were presented during an oral presentation at the ASCO Meeting. Preliminary data showed SAR443579 / IPH6101 was well tolerated and induced three complete responses in the eight patients at 1 mg/kg as the highest dose. In addition, Innate Pharma shared Sanofi’s news that the FDA has granted Fast Track Designation for SAR’579 / IPH6101 for the treatment of hematological malignancies.
In October 2023, a preliminary Pharmacokinetics (PK) and Pharmacodynamic (PD) Analysis of the CD123 NK Cell Engager SAR’579/IPH6101 in patients with relapsed or refractory AML, B-ALL or HR-MDS was presented at the ESMO congress.
In December 2023, updated efficacy and safety results were shared in a poster presentation at the ASH Annual Meeting. Abstract details included:
As of July 5, 2023, 43 patients (42 R/R AML and one HR-MDS) across eight dose levels at 10 – 6000 µg/kg/dose were included. Patients had received a median of 2.0 (1.0 – 10.0) prior lines of treatment with 13 patients (30.2%) reporting prior hematopoiectic stem cell transplantation and 36 patients (83.7%) with prior exposure to venetoclax.
In dose levels with a highest dose of 1000 µg/kg QW, 5 out of 15 (33.3%) AML patients achieved a complete remission, or CR, (4 CRs and 1 CR with incomplete hematological recovery) as of the cut-off date.
Data from preliminary pharmacokinetics / pharmacodynamic and in vitro mechanistic analyses studying dose-response relations were also presented.
SAR443579 was well tolerated up to doses of 6000 µg/kg QW with observed clinical benefit in patients with R/R AML. The results are consistent with the predicted favorable safety profile.
IPH6401/SAR’514, a BCMA-targeting NK Cell Engager
Mechanism
IPH6401/SAR’514 is a trifunctional anti-BCMA NKp46xCD16 NK cell engager, using Sanofi’s proprietary CROSSODILE multi-functional platform, which comprises the Cross-Over-Dual-Variable-Domain (CODV) format. It induces a dual targeting of the NK activating receptors, NKp46 and CD16, for an optimized NK cell activation, based on Innate’s ANKET (Antibody-based NK cell Engager Therapeutics) proprietary platform.
Clinical Trial
A Sanofi-sponsored Phase 1/2 clinical trial (NCT05839626) is evaluating SAR’514 / IPH6401 in relapsed/refractory Multiple Myeloma (RRMM) and Relapsed/Refractory Light-chain Amyloidosis (RRLCA). The purpose of the dose escalation and dose expansion study is to evaluate the safety, pharmacokinetics and preliminary efficacy of SAR’514 in monotherapy in patients with RRMM and RRLCA. The clinical trial is part of the Sanofi 2016 research collaboration and licensing agreement.
Innate Pharma announced that the first patient was dosed in November 2023.
IPH62, a B7-H3-targeting NK Cell Engager
IPH62 is a multi-specific NK cell-engaging antibody targeting B7-H3, using Innate's proprietary multi-specific antibody format, the ANKET platform.
IPH62 provides dual targeting of NK cell activating receptors, NKp46 and CD16, based on Innate's proprietary ANKET (Antibody-based NK cell Engager Therapeutics) platform for optimised NK cell activation.
Proprietary ANKET
IPH6501, a CD20-targeting tetra-specific NK Cell Engager
Mechanism
The IPH6501 program is developing a CD20-targeting tetra-specific Antibody-based NK cell Engager Therapeutics (ANKET). CD20 is an antigen expressed by a number of B cell malignancies, and its targeting by therapeutic antibodies has shown efficacy to treat the patients although a number of the tumors develop resistance and relapse. Compared to a classical IgG1-based antibody which engages Fc receptors and a tumor antigen, IPH6501 co-engages on one hand NKp46 and Fc receptors, as well as CD122 subunit of the IL-2 receptor (but not CD25 subunit), and on the other hand CD20 as a targeted antigen on malignant B cells, leading to potent NK cell activation, cytotoxicity and control of tumor growth.
IPH6501 was designed to induce NK cell mediated-cytotoxicity and cytokine secretion by co-engaging CD16a and NKp46. Only the binding of IPH6501 to CD20, bridging the NK cells to the target cells, was able to trigger the cytotoxic activity of NK cells. IPH6501 is thus a promising biologic designed to harness the anti-tumor functions of NK cells in CD20+ B cell malignancies.
Moreover, the IL-2R binding element incorporated in IPH6501 is an IL-2 variant (IL-2v) designed with point mutations that abolish binding to the IL-2R-a chain (CD25), with the intention of limiting toxicity and interaction with Tregs. IL-2v incorporated into IPH6501 is directed towards NK cells through the binding with high affinity to NKp46 and CD16a, providing its ability to interact with IL-2R preferentially on NK cells and to promote their activation and proliferation at pM doses.
Indication and Rationale
IPH6501 is being developed in patients with relapsed or refractory (R/R) CD20+ B-cell non-Hodgkin's lymphomas (NHL).
Preclinical Development
IPH6501 preclinical activity was explored both in vitro and in vivo. In vitro studies established that IPH6501´s main modes of action were NK cell proliferation and antibody-dependent cell cytotoxicity (ADCC) against CD20-expressing cells.
In vitro
Non-saturating doses of IPH6501 on NK cells and on CD20+ cells were sufficient to promote maximal killing activity. Furthermore, IPH6501 promoted NK cell cytotoxicity against tumor cells expressing very low levels of CD20. IPH6501 also demonstrated superiority to control tumor cell growth in vitro, as compared to the CD20-targeting clinical benchmark antibodies rituximab and the Fc-optimized obinutuzumab.
IPH6501 alone without NK cells did not induce direct killing of CD20+ cells. Culturing human purified NK cells with CD20+ B-lymphoma cell lines and IPH6501 induced the specific lysis of tumoral CD20+ cells. Alternatively, culturing human PBMCs with IPH6501 induced the specific depletion of normal CD20+ B lymphocytes without affecting other lymphocyte population numbers, as well as cytokine production in line with NK cell activation. Incubation of human PBMC with IPH6501 induced a preferential NK cell proliferation that occurred at lower doses as compared to the proliferating effect of IPH6501 on other CD8+ or CD4+ T lymphocytes (expressing the IL-2R).
In vivo
Updated preclinical data were presented at the European Hematology Association (EHA) congress in June 2023, including experiments on non-human primates and samples from R/R B-NHL patients. In preclinical settings, IPH6501 was shown to induce NK cell proliferation and to trigger high NK cell cytoxicity against CD20+ target cells in in vitro assays, in ex vivo assays with relapse/refractory (R/R) B-NHL patient samples who received at least one prior treatment, as well as in in vivo studies in non-human primates. A surrogate of IPH6501 mediated a potent anti-tumor activity in vivo in CD20+ tumor models in mice. In addition, in ex vivo assays with R/R B-NHL patient samples, IPH6501 was shown to be more efficient than a T cell engager targeting CD20.
Non-human primates
In non-human primates, a well-tolerated dose of IPH6501 resulted in NK cell expansion, with minimal increase in systemic cytokine levels, and to the depletion of CD20+ B cells in circulation and lymphoid tissues.
Analysis from samples from R/R B-NHL patients
Flow cytometric analysis of samples from R/R B-NHL patients revealed that NK cell numbers in blood were within normal range values, and NKp46 expression was maintained in blood and tumor-involved lymph nodes. Of note, in contrast to NKp46, cell surface expression of CD16 was down-regulated on NK cells in B-NHL patient’s lymph nodes, suggesting a potential therapeutic advantage of targeting NKp46 with IPH6501 in B-NHL compared with classical monoclonal antibodies. IPH6501 stimulated NK cell proliferation andCD20+ cell depletion ex vivo in PBMC samples from R/R B-NHL patients, which compared favourably with acontrol CD3xCD20 T cell engager.
IPH6501 is a first-in-class CD20-targeting tetra-specific NK cell engager designed to promote NK cell proliferation and specific cytotoxicity against CD20+ cells. IPH6501 is thus a promising biologic designed to harness the anti-tumor functions of NK cells in CD20+ B cell malignancies.
Clinical Trial
Capture d’ecran 2024-03-20 150626.jpgAn international, first-in-human, multicenter, open-label Phase 1/2 study will evaluate the safety profile, tolerability of IPH6501, and determine the recommended Phase 2 dose (RP2D) for patients with B-Cell non-Hodgkin lymphoma. The company received a Study May Proceed Letter from FDA in July 2023.
On March 6, 2024, the company announced that the first patient was dosed in its Phase 1/2 multicenter trial (NCT06088654), investigating the safety and tolerability of IPH6501 in patients with Relapsed and/or Refractory CD20-expressing B-cell non-Hodgkin’s lymphoma. The study is ongoing and planned to enroll up to 184 patients.
Antibody Drug Conjugates
Proprietary
To further the company’s R&D program, the company continues to develop different approaches for the treatment of cancer utilizing its antibody engineering capabilities to deliver novel assets, with its innovative ANKET platform and continuing to explore Antibody Drug Conjugates (ADC) formats. The company has a robust pipeline of additional preclinical product candidates. Its additional disclosed preclinical pipeline includes:
IPH45 is Innate’s proprietary pre-IND anti-Nectin-4 targeting antibody drug conjugate, including a Topoisomerase I inhibitor payload. IPH45 is progressing towards the clinic with IND targeted in 2024.
IPH43, an anti-MICA/B ADC.
Innate will share first preclinical data with IPH45 in an oral presentation at the American Association for Cancer Research (AACR) 2024.
Partnered
Innate announced in April 2023 that it granted Takeda exclusive worldwide rights to research and develop ADC using a panel of selected Innate antibodies against an undisclosed target, with a primary focus in Celiac disease.
Takeda will be responsible for the future development, manufacture and commercialization of any potential products developed using the licensed antibodies.
Under the terms of the license agreement, Innate has received an upfront payment of $5 million and is eligible to receive up to $410 million in future development, regulatory and commercial milestones if all milestones are achieved during the term of the agreement, plus royalties on potential net sales of any commercial product resulting from the license.
Intellectual Property
Patents
Monalizumab/IPH2201
As of December 31, 2023, the principal intellectual property rights related to monalizumab were in-licensed from Novo Nordisk A/S and included U.S. Patent Nos. 8,206,709 and 8,901,283, European patents EP 2 038 306 B1 and EP 2 426 150 B1 and counterpart patents in certain other countries. These patents are directed to the composition of matter of monalizumab and have a statutory expiration date in 2027, not including patent term adjustment or any potential patent term extension. Other patent rights include U.S. Patent No. 11,572,410, European patent 3 193 931 B1 and counterpart patents in certain other countries relating to use of monalizumab in combination with agents that neutralize PD-1 or PDL1, which patents are solely owned by the company and have a statutory expiration date in 2035, not including patent term adjustment or any potential patent term extension.
Lacutamab/Anti-KIR3DL2
As of December 31, 2023, the principal intellectual property rights related to lacutamab were wholly owned by Innate and included U.S. Patent Nos. 10,280,222 and 11,066,470, European patent EP 3 116 908 B1 and counterpart patent applications in certain other countries. These patents and patent applications are directed to the composition of matter of lacutamab, and such patents have, and any patents that issue from such applications would have, a statutory expiration date in 2035, not including patent term adjustment or any potential patent term extension.
IPH5201/Anti-CD39
As of December 31, 2023, the principal intellectual property rights related to IPH5201 were co-owned by Innate together with Orega Biotech, and included U.S. patent No. 11,377,503, one European patent application, and other patent applications in certain other countries. These patents and patent applications are directed to the composition of matter of IPH5201, and such have, and any patents that issue from such patent application would have, a statutory expiration date in 2039, not including patent term adjustment or any potential patent term extension.
IPH5301/Anti-CD73
As of December 31, 2023, the principal intellectual property rights related to IPH5301 were solely owned by the company, and included one U.S. non-provisional patent application, one European patent application, and other patent applications in certain other countries. If a patent directed to IPH5301 issues from such U.S. patent application, it would have a statutory expiration date in 2040, not including patent term adjustment or any potential patent term extension.
IPH6501
As of December 31, 2023, the principal intellectual property rights related to IPH6501 were solely owned by the company, and included one U.S. non-provisional patent application, one European patent application, and other patent applications in certain other countries. If a patent directed to IPH6501 issues from such U.S. patent application, it would have a statutory expiration date in 2042, not including patent term adjustment or any potential patent term extension.
Trademarks
The company owns the mark INNATE PHARMA in the United States, Australia and Europe (EU community trademark), and INNATE in Europe (EU community trademark). The company also owns registrations for the mark ANKET respectively in the United States and Europe (EU community trademark), the marks LONKIRLO and KIRTAMSY in France.
Research and Development
The company's research and development expenses were €56.0 million for the year ended December 31, 2023.
Regulation
The European Medicines Agency (EMA), the U.S. Food and Drug Administration, and the various national regulatory authorities impose considerable constraints on the development, manufacture, and sale of products that the company develops and clinical trials it conducts.
History
Innate Pharma S.A. was founded in 1999. The company was incorporated under the laws of France in 1999.
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