Purple Biotech Stock

Purple Biotech Ltd., a clinical-stage company, engages in developing first-in-class, effective and durable therapies that that harness the power of the tumor microenvironment to overcome tumor immune evasion and drug resistance.

The company is focused on oncology and the company’s pipeline includes CM24, a humanized monoclonal antibody that blocks the interactions of Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (‘CEACAM1’), an immune checkpoint protein that supports tumor immune evasion and survival through multiple pathways; NT219, a small molecule that simultaneously targets and inhibits Insulin Receptor Substrate 1 and 2 (‘IRS1/2’) and Signal Transducer and Activator of Transcription (‘STAT3’), two signal transduction pathways involved in the development of cancer drug resistance mechanisms; and IM1240, a conditionally-activated tri-specific antibody that engages both T cells and NK cells. The third arm of IM1240 specifically targets the Tumor Associated Antigen (TAA) 5T4. In developing these therapeutic candidates, the company addresses not only the tumor itself but also the tumor microenvironment, which may improve patient outcome.

The company is conducting a randomized, controlled, open label multicenter phase 2 study to investigate CM24 in combination with the anti-PD-1 checkpoint inhibitors nivolumab for the treatment of pancreatic ductal adenocarcinoma (PDAC) when administered in combination with standard of care chemotherapy compared to chemotherapy alone. The company has entered into a clinical collaboration agreement with Bristol Myers Squibb to evaluate the combination of CM24 with the PD-1 inhibitor nivolumab and nab-paclitaxel in this study. The company expects to release interim results in the second half of 2023 and a topline report on the overall study by the end of 2024.

The company is conducting a phase 1/2 dose escalation study of NT219 as a single agent in patients with solid tumors, and a dose escalation phase of NT219 in combination with cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck cancer or colorectal adenocarcinoma. These studies will be followed by an expansion phase of NT219 at its recommended phase 2 dose level in combination with cetuximab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. The company expects to release phase 1 topline results in the second half of 2023.

The company is conducting preclinical studies with IM1240 and expects to reach IND submission in approximately two years.

In addition, the company is seeking the acquisition of additional oncology therapeutic candidates at various stages of development to expand and diversify its portfolio and to leverage the company’s development capabilities.

Therapeutic Candidates

CM24 is a clinical stage humanized monoclonal antibody directed against CEACAM1, a multi-faceted membrane protein belonging to the Human CEA (Carcino-Embryonic Antigen) protein family that acts as an immune checkpoint inhibitor, a pro-angiogenic, anti-apoptotic agent and a promoter of tumor invasiveness and metastases. Evidence has shown that CEACAM1 is expressed on different white blood cells, including lymphocytes neutrophils and monocytes and its expression is up-regulated in several cancer types. Preclinical studies have shown evidence that CM24 enhances the cytotoxic activity of tumor-infiltrating lymphocytes (TILs) against various CEACAM1-positive tumor cell lines in vitro and in vivo. The company has recently shown that CM24 attenuates NET-induced tumor cell migration. CM24 is being developed for multiple oncological indications according to the expression pattern of its target protein. Preclinical studies provide strong justification for CM24’s mechanism of action in activating the immune system through multiple pathways. Additional preclinical studies showed that a combination of CM24 with PD-1 and PDL-1 antibodies resulted in a synergistic anti-cancer effect. In a Phase 1 dose escalation study of CM24 as a single agent, a stable disease rate of approximately 33% among the evaluable patients was noted. In a second Phase 1 dose escalation study of CM24 in combination with the PD-1 inhibitor nivolumab, a disease control rate of 36% among the evaluable patients was noted, including one partial response and three stable diseases. The company is developing CM24 as a combination therapy with anti-PD-1 checkpoint inhibitors and standard of care chemotherapy in a Phase 2 study in patients with pancreatic cancer. The company entered into a clinical collaboration agreement with Bristol Myers Squibb for this study.

NT219 is a novel small molecule that presents a new concept in cancer therapy by targeting two key oncology-related proteins, IRS1/2, as well as STAT3. The company’s NT219 therapeutic candidate’s anti-cancer effect is achieved by overcoming tumors’ cancer drug resistance, and it is being developed both as a standalone drug, as well as in combination with other cancer drugs or treatments. NT219 has been preclinically tested alone and in combination with various classes of cancer drugs, such as with chemotherapies, targeted therapies and immuno-oncology therapies. The company is conducting a phase 1/2 dose escalation study of NT219 as a single agent in patients with solid tumors, and a dose escalation of NT219 in combination with cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck cancer or colorectal adenocarcinoma, to be followed by an expansion phase of NT219 at its recommended phase 2 dose level in combination with cetuximab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

In February 2023, the company acquired Immunorizon, a private company developing multi-specific T cell and NK cell engager oncology therapy technology that selectively activates the immune response within the tumor microenvironment. The acquisition provided the company with an expanded portfolio of investigational tri-specific antibody compounds that target multiple antigens and offer the potential to further expand to additional targets. The lead asset, IM1240, is a conditionally-activated tri-specific antibody that engages both T cells (anti-CD3) and NK cells to mount a strong, localized immune response within the tumor microenvironment. The third arm of IM1240 specifically targets the tumor-associated antigen (‘TAA’) 5T4, which is expressed on a variety of solid tumors and is correlated with advanced disease, increased cancer invasiveness and poor clinical outcome. The IM1240 compound is distinguished from other multi-specific cell therapies targeting 5T4+ tumors by its cleavable capping technology, which confines the compound’s therapeutic activity to the tumor microenvironment, and thereby has the potential to increase the anticipated therapeutic index in patients. The acquired portfolio includes additional early-stage assets, targeting other receptors and TAA.

Strategy

The key elements of the company’s strategy are to focus on oncology therapeutic assets for the treatment of unmet medical need, representing a significant market opportunity; leverage the company’s expertise in the clinical and regulatory processes in the United States, together with the company’s research and development capabilities and network of professional advisors, to efficiently develop therapeutic candidates in pre-clinical and clinical stages of development and achieve marketing authorization; expand the company’s line of therapeutic candidates through the acquisition or in-licensing of technologies, products and drugs in the oncology space intended to meet clinical needs; develop new disruptive and innovative technologies in collaboration with third parties, as well as using the company’s in-house capabilities; and cooperate with third parties, to both develop and commercialize therapeutic candidates in order to share costs and leverage the expertise of others.

The company’s oncology therapeutic candidates, CM24, NT219 and IM1240, are further described below.

CM24

CM24 is a humanized monoclonal antibody directed against CEACAM1, a multi-faceted membrane protein belonging to the Human CEA (Carcino-Embryonic Antigen) protein family that acts as an immune checkpoint inhibitor, a pro-angiogenic, anti apoptotic agent, and a protein that promotes tumor invasiveness and metastases. Evidence has shown that CEACAM1 is expressed on tumor infiltrating lymphocytes and its expression is up-regulated in several cancer types. Moreover, CEACAM1 is associated with mechanisms of trophism and metastases in cancer, manifest through mechanisms, such as neutrophil extracellular traps.

MSD conducted a phase 1 clinical trial, including patients with metastatic melanoma, non-small cell lung cancer, bladder, gastric, colorectal and ovarian cancer patients. In this initial Phase 1 dose ranging study of CM24 as single agent, a stable disease rate of approximately 33% among the evaluable patients was noted as best overall response. Despite no known safety risks, MSD discontinued the clinical study and returned the rights of CM24 to former cCAM shareholders and founders of the company’s wholly owned subsidiary, FameWave Ltd. (FameWave). Review of the Phase 1 study results by external scientific advisors retained by the company suggested that while CM24 was generally safe, higher doses of the antibody along with a modified dosing regimen in a defined patient population would be warranted.

Therapeutic Candidate

CM24 is a humanized monoclonal antibody directed against CEACAM1, a multi-faceted membrane protein belonging to the Human CEA (Carcino-Embryonic Antigen) protein family that acts as an immune checkpoint inhibitor, a pro-angiogenic, anti apoptotic agent, and a protein that promotes tumor invasiveness and metastases.

CEACAM1 belongs to the CEA superfamily. CEACAM1 interacts with itself (i.e., hemophilic interaction) and with CEACAM5 (heterophilic interaction), as well as with various bacterial proteins. Different functions have been attributed to the CEACAM1 protein: anti-proliferative properties in carcinomas of the colon and prostate, or facilitation of proliferation in melanoma; central involvement in angiogenesis, insulin clearance and immune-modulation. CEACAM1 is expressed by many types of tumors and is associated with poor prognosis in cutaneous melanoma, uveal melanoma, hepatocellular carcinoma, colorectal cancer and lung cancer. In addition, increased CEACAM1 expression on cancer tissues and peripheral blood lymphocytes and elevated serum CEACAM1 were observed in patients with melanoma, osteosarcoma and pancreatic carcinoma. These collective observations provide a strong justification for the development of a therapeutic approach that targets the immuno-suppressive function of CEACAM1.

Earlier preclinical studies revealed CM24 reversed CEACAM1-mediated immune evasion by abrogating CEACAM1-CEACAM1 interactions, restoring ZAP70 phosphorylation and TCR-driven effector functions, while maintaining antigen-restricted recognition. This abrogates the immunosuppressive function of CEACAM1, promoting cell killing by T cells and NK cells.

CM24 is a blocking monoclonal antibody that prevents CEACAM1-CEACAM1 and CEACAM1-CEACAM5 interactions, thus enhancing the cytotoxic activity of lymphocytes, attenuating NET-induced and independent metastatic processes, preventing angiogenesis, and promoting tumor apoptosis.

Preclinical and Mechanism of Action and Target Validation

The preclinical studies have shown evidence that CM24 enhances the cytotoxic activity of tumor-infiltrating lymphocytes (TILs) against various CEACAM1-positive tumor cell lines. Recently, the company has demonstrated that CM24 binds to the NET structures, significantly suppresses the NET-induced cancer cell migration and inhibits metastases in mice xenografts.

Phase 1 Clinical Trial

MSD conducted an interventional, Phase 1, first in human, non-randomized, single group assignment, open-label, multi-centered and multiple escalating doses study to assess the safety, efficacy, pharmacokinetics and tolerability of the CM24 antibody in the treatment of subjects with selected advanced or recurrent malignancies, including melanoma, non-small cell lung adenocarcinoma (NSCLC) and bladder, gastric, colorectal or ovarian cancer.

The main objectives of the MSD clinical study were to assess the safety and tolerability of CM24 and to determine the recommended dose for Phase 2 trials, characterization of the pharmacokinetic profile and immunogenicity of CM24, and to evaluate the preliminary efficacy of the drug. The trial was conducted at four sites in the U.S. and Israel and was designed as a dose escalation stage that was to be followed by an expansion stage. The trial was concluded following administration of CM24 to 27 patients and prior to determining the recommended phase 2 level and reaching the expansion stage.

Main conclusions by the company from the Phase 1 clinical trials results:

CM24 was found to be generally safe and well tolerated. There were no DLTs up to 10mg/kg and no drug related morbidity.

Target saturation was not reached up to 10mg/kg. PK modeling suggests that slower clearance with increasing dose and higher half-life with increasing dose, PK variability across patients, and full receptor occupancy may likely require doses >10mg/kg administered every 2 weeks.

Treatment related adverse events noted in 17 subjects: 82% Grade 1, 16% Grade 2 and 2.7% Grade 3. Most frequent were increased liver function tests (LFTs) and anorexia. The two Grade 3 events were headache and abdominal pain; there were 2 deaths that occurred within 30 days from the last administration of CM24 due to disease progression.

A stable disease rate of approximately 33% among the 24 evaluable patients was achieved, mostly in the two highest dose groups, where approximately half of the evaluable patients achieved stable disease.

Clinical Development Plans for CM24

CM24 is a promising agent, which has a potential to be efficacious as a standalone and in combination with other anti-cancer agents, including anti PD-1 agents and other checkpoint inhibitors and chemotherapy for patients with cancer. The Phase 1 study noted above showed that CM24 was generally well tolerated and resulted in a stable disease rate of approximately 33% in the evaluable patients. The Phase 1 study was not designed to pre-screen CEACAM-1 levels on tumor tissue. Furthermore, in this Phase 1 study, no PD-1 inhibitor was tested in combination with CM24. And as noted, the doses used in the aforementioned study were below those required to reach target saturation as determined by pharmacokinetic evaluations.

A Phase 1/2 study that includes three parts is ongoing. The first part which has already been completed included a dose escalation of CM24 at 10, 15 and 20mg/kg, in combination with standard dose of the PD-1 inhibitor nivolumab, in patients with selected solid tumors who have received up to 2 prior regimens for their advanced and/or metastatic disease. The primary objective of this part of the study was to evaluate safety, tolerability, PK and determine the recommended Phase 2 dose (RP2D).

In June 2021, the company reported on the first dose cohort of the dose escalation phase (10mg/kg), where one patient with refractory advanced MSI-S pancreatic cancer having been previously treated with two previous regimens, had a confirmed partial response to CM24 and nivolumab, both with respect to imaging and biochemical markers. The responsive patient showed a 40% reduction in tumor size following two cycles of treatment with CM24 in combination with nivolumab 480mg/kg. In addition, levels of CA19-9 tumor marker dropped by 56%, compared to baseline levels. Additionally, there were no dose-limiting toxicities or serious adverse events observed in any of the three patients enrolled in the first dose cohort of the study.

In April 2022, the company presented interim data from this part of the study in 11 evaluable patients with refractory cancers, including 8 with PDAC, two with colorectal cancer (CRC) and one with papillary thyroid cancer (PTC). All patients but one had received two prior regimens for metastatic disease. No DLTs were observed across all dose levels; no Grade 4 AEs or treatment related deaths have been reported. Six Grade 3 adverse events (AEs), that were unrelated to CM24 or PD-1 inhibitor nivolumab, were observed, each in a single patient, including diarrhea, hypokalemia, abdominal pain, small bowel obstruction, atrial flutter, and GI bleed.

Of the evaluated patients, best overall response included one confirmed PR (PDAC patient) and three SD (two PDAC and one PTC patient), with a disease control rate of 36%. Pharmacokinetic analysis of CM24 showed exposure was dose-proportional across the three doses assessed in this study; Complete receptor occupancy of peripheral CEACAM1 receptors on T cells and neutrophils was demonstrated following the first administration of CM24 at doses of 15 or 20mg/kg. A number of other immune and adhesion-related parameters are being evaluated as potential biomarkers in the study.

The second part of the study that is designed as a safety (primary endpoint) run-in stage, enrolls patients with advanced/metastatic PDAC who have received up to one prior regimen for their disease. In this part of the study, PDAC patients are receiving CM24 at 20mg/kg plus nivolumab at 240mg and one of the following two standard of care chemotherapy regimens of either gemcitabine and nab-paclitaxel or liposomal-irinotecan (Nal-IRI), 5-fluorouracil and leucovorin. A total 12 and up to 18 PDAC patients are planned to be enrolled to this part of the trial. In February 2023, the company reported that 10 patients are being treated in this part and no DLTs have been noted in them, while enrolment of the remaining patients is ongoing.

In February 2023, the company reported enrolment of the first patient to the third part of the study. This part of the study is a randomized, controlled, opened labeled, multi-center study, comparing treatment of PDAC patients who have received up to one treatment regimen for their advanced/metastatic disease with CM24, nivolumab and standard of care (SoC) chemotherapy (experimental cohort) vs. SoC chemotherapy (control cohort). This randomized Phase 2 study is designed to include approximately 30 patients in the experimental cohort and approximately additional 30 patients in the control cohort. The study is being conducted in 11 sites in the United States, Spain and Israel, and the company expects to open approximately 10 additional sites in the upcoming months. The primary endpoint of this randomized part of the trial is overall survival while additional efficacy (e.g., PFS, OS rate at 6 and 12 months, PFS rates at 3 and 6 months, ORR and DOR) and safety measures will be part of the secondary endpoint of the trial. The study will also include different assessments of tumor tissue and blood aimed at exploring potential biomarkers. The trial is conducted in clinical collaboration with Bristol Myers Squibb.

NT219

NT219 is a small molecule that presents a new concept in cancer therapy by inhibiting two oncology-related pathways, namely the IRS 1 and IRS 2 and STAT3 pathways. NT219 technology has been tested in a number of PDX models where biopsies from patients are implanted into mice and used to test various cancer drugs. In such models, NT219, alone and in combination with several approved oncology drugs, displayed potent anti-tumor effects and increased survival in experimental animals harboring various cancers by preventing the tumors from developing resistance to approved cytotoxic, immune-oncologic, and targeted drug treatments, and by re-sensitizing tumors to the approved drugs even after resistance has been acquired.

The following are high-level summaries of the therapeutic areas the company is investigating for NT219:

Solid malignancies (e.g., head and neck, pancreatic, colon and non-small cell lung cancer). According to the Journal of Oncology Practice, in 2020 roughly one in every 19 people worldwide would either be diagnosed with a solid tumor or be a cancer survivor. According to the American Cancer Society, lung, pancreatic, and colon malignancies have high mortality rates and poor five-year survival prognosis. Novel, emerging therapeutic approaches for targeting solid tumors are being developed and tested.

Tumor Resistance to Cancer Therapies. Resistance to chemotherapy and to targeted therapies is a major problem facing oncology. The mechanisms of resistance to ‘classical’ cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific target proteins share many features, such as alterations in the drug target, activation of pro-survival pathways and ineffective induction of cell death.

Evidence suggests that among other mechanisms of resistance, inhibition of central oncological target kinases, such as EGFR, MEK and mutated-BRAF could trigger feedback activation of STAT3 and IRS-to-PI3K/AKT, major survival pathways that bypass (prevent) the anti-cancer effects of various drugs.

Mechanism of Action

The NT219 therapeutic candidate is a small molecule that presents a new concept in cancer therapy, acting as a dual inhibitor of IRS1/2 and STAT3, which putatively play major roles in oncogenesis and cancer drug resistance. While targeted anti-cancer drugs inhibit the ‘ON’ signal, NT219 activates the ‘OFF’ switch, leading to the degradation of IRS-1/2, altering STAT3 phosphorylation, and extensively blocking major oncogenic pathways.

There have been reports in peer reviewed academic literature describing the involvement of Insulin-like Growth Factor-1 Receptor (IGF1R) up-regulation in drug-resistance. In these cases, blockage of IGF1R direct substrates, IRS1/2, by NT219 could potentially overcome drug resistance.

The same principal is true for STAT3. Feedback activation of STAT3 is a common resistance mechanism to many targeted cancer therapies (such as the inhibitors of EGFR, MEK, HER2) and cytotoxic chemotherapies. Combining these cancer therapies with NT219, which disrupt this feedback mechanism, could potentially enhance cell death and delay resistance, suggesting a co-treatment strategy that may be broadly effective in oncogene-addicted tumors.

Degradation of IRS proteins and blockage of STAT3 by NT219 could potentially prevent resistance to multiple anti-cancer drugs, extend the duration of effective drug treatment, and restore drug sensitivity in resistant tumors.

NT219 has high affinity and selective binding to its target proteins. NT219 binds covalently to Insulin Receptor Substrates (IRS) 1/2 and with low nano-molar affinity to the Signal Transducer and Activator of Transcription 3 (STAT3). Data from preclinical work showed that a short exposure of cancerous cells to NT219 was sufficient to trigger irreversible shutdown of these pathways, resulting in a long-term anti-cancer effect.

In April 2021, the company reported additional preclinical data supporting the mechanism of action of NT219, that was presented in a poster entitled ‘Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2,’ at the American Association of Cancer Research (AACR) 2021 Annual Meeting. Colorectal cancer (CRC) represents the fourth most frequent cause of brain metastasis, which is the most common brain tumor. The preclinical data updates and expands on the results previously reported by the company in collaboration with Dr. Ido Wolf, Head of the Oncology Division at Tel Aviv Sourasky Medical Center. The study included an analysis of more than 16,000 human CRC local and metastasis samples and revealed an increased amplification of IRS2 in brain metastases. In an in vitro system mimicking the brain microenvironment, IRS2-overexpressed CRC cells showed prolonged survival. Importantly, transcriptomic analysis demonstrated significant enrichment of the oxidative phosphorylation (OXPHOS) pathway by IRS2. CRC cells expressing IRS2 showed increased mitochondrial activity and glycolysis-independent viability. Inhibition of IRS2 using NT219 dose- dependently inhibited IRS2-expressing cells viability and OXPHOS genes expression. The Wnt/ß-catenin pathway was among the most significantly enriched pathways in the brain metastasis, as IRS2-expressing cells showed increased transcriptional activity of the ß-catenin. In addition, NT219 decreased the transcriptional activity of ß-catenin in IRS2- expressing CRC cells to a greater extent than AKT and PI3K inhibitors, and most significantly suggested relevance of IRS2 in activating ß- catenin. It was further shown that 5-FU, a chemotherapy approved for treating CRC, elevated ß-catenin expression, and that NT219 diminished both 5FU-induced and the basal level of the ß-catenin expression. Utilizing an intracranial animal model, it was also demonstrated that while 5-FU alone had no significant effect, the combination of 5-FU and NT219 significantly inhibited the formation of brain metastasis and extended survival rates of the study mice.

In October 2021, an article was published in Nature Cancer demonstrating mechanisms behind cancer cell persistence frequency and potential of NT219 to reduce therapeutic resistance. The article titled, ‘IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy’. Specifically, it has been shown that higher phosphorylation of IRS1 multiple serine/threonine sites, which blocks IRS1 activity, results in increased susceptibility to EGFR inhibitors. A combination of NT219, which triggers serine phosphorylation and subsequent degradation of IRS1 and EGFR inhibitors, resulted in a synergistic effect, leading to tumor regression and delayed recurrence upon treatment withdrawal.

Preclinical Results

In preclinical studies, NT219, in combination with several approved cancer drugs, displayed potent anti-tumor effects and increased survival in various cancers by preventing the tumors from developing drug resistance and restoring sensitivity to the drugs after resistance is acquired. NT219 has shown efficacy in various PDX models originated from head and neck, cancer, non-small cell lung cancer (NSCLC), sarcoma, melanoma, pancreatic, and colon cancers.

Efficacy of NT219 was demonstrated in combination with three major classes of oncology drugs:

Antibodies, such as the anti-epidermal growth factor receptor (EGFR) antibody (Erbitux) and the immuno-oncology anti-PD1 antibody (Opdivo, Keytruda);

Kinase Inhibitors, such as blockers of EGFR (Tagrisso, Tarceva), MEK (Mekinist), Mutated BRAF (Zelboraf), and mTOR (Afinitor); and

Chemotherapy agents, such as gemcitabine (Gemzar), 5FU, and Oxaliplatin.

In 2021, the company expanded an existing research agreement, led by Menashe Bar-Eli, Ph.D., Professor, Department of Cancer Biology, at The University of Texas MD Anderson Cancer Center, to evaluate the potential efficacy of the combination of NT219 and immuno-oncology drugs, such as anti-CTLA4 or anti-PD1/PDL1 antibodies.

Clinical Plan

NT219 first in human studies consider primarily safety, particularly since the MOA relates to dual inhibition mechanisms. Within the context of single agent activity, it has been noted that in a variety of studies NT219 may have effect. As such, standard criteria in Phase 1 is used to assess the agent in this monotherapy context, primarily with respect to safety, and evidence for a signal of biologic relevance.

As a result, the first in human Phase 1 study, which the company commenced in the second half of 2020, is evaluating single agent NT219 at a dose escalation, in patients with advanced cancer diseases. Patients for this component of the trial (deemed Part A) are being evaluated for safety as the primary endpoint, and efficacy as a secondary endpoint. The escalation takes the form of a 3+3 standard design, together with a ‘backfill’ groups enrolling of up to 3 additional patients at doses which have already been deemed safe. Patients are being administered NT219 weekly until disease progression or study withdrawal for any other cause.

In December 2021, the company initiated Part B of its ongoing Phase 1/2 clinical trial of NT219, as a dose escalation study of NT219, beginning with 6mg/kg, in combination with the standard dose of cetuximab (ERBITUX), in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck cancer (SCCHN) or colorectal adenocarcinoma (CRC). In this arm, patients with advanced cancer, who are eligible for cetuximab therapy (e.g., SCCHN and CRC), receive a combination of the drugs, with NT219 being administered first, followed by cetuximab, in a similar course of weekly administrations. The combination is being evaluated in a similar 3+3 design and backfill groups as described for single agent part of the study. These two parts of the study will provide information regarding the safety of NT219 as a single agent and in combination with cetuximab, including the determination of the maximal tolerated dose (MTD), as well as preliminary efficacy signal of NT219 as a single agent and in combination with cetuximab. It may also provide the impetus for the expansion of the study into a given indication, either as single agent or in combination. The company reported data at the 2021 ASCO Annual Meeting from the first dose cohort of the single agent dose escalation, where a patient with gastro-esophageal cancer sustained a partial response to the treatment at 3mg/kg, manifested by a complete response at the target lesion, a complete response of one lymph node non-target lesion, and stable disease of another lymph node non-target lesion. In addition, initial results from the first dose level cohort revealed NT219 was well-tolerated with minimal adverse events. The trial is ongoing, and is enrolling in both the single agent dose escalation, and the double of cetuximab and NT219.

The company reported data at the 2022 ASCO Annual Meeting from the first three dose levels of the single agent dose escalation, showing that NT219 at doses up to and including 12 mg/kg were well tolerated without DLTs in advanced cancer patients. Furthermore, in addition to the partial response noted above, the company reported that stable disease was observed in three out of four patients with CRC while all were characterized with mutated KRAS.

The company plans to commence the third portion (Part C) of the study subsequent to completion of Part B. Part C will include the administration of NT219 at its recommend Phase 2 dose in combination with standard dose cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). This part of the study will evaluate preliminary efficacy and safety in a larger cohort of patients. The planning of further Phase 2 studies will be a function of the data from first in human studies. Based on erb-b pathway relevance, as well as data on the relevant inhibition of the dual pathways being evaluated, besides SCCHN, NSCLC, pancreatic cancer, and melanoma are also candidates for which the company may conduct future Phase 2 studies.

Competitive Oncology Drugs in Development that Target IRS1/2 or STAT3

The company is not familiar with other therapeutic candidates acting as dual inhibitor of both IRS1/2 and STAT3. Similarly, the company is not aware of any other inhibitor of IRS1/2 in active development. However, there are some clinical-stage STAT3 inhibitors, such as danvatirsen, an antisense nucleotide developed by AstraZeneca for pancreatic, NSCLC and mismatch repair deficient colorectal cancers. Although they are not direct competitors of NT219, inhibitors of Insulin Like Growth Factor 1 Receptor (IGF1R) acting upstream of IRS1/2, such as dalotuzumab, developed by Merck & Co for pancreatic cancer, or ganitumab, developed by Amgen in Ewing Sarcoma, are also closely monitored.

IM1240

IM1240 is a conditionally-activated tri-specific antibody that engages both T cells (through its anti-CD3 moiety) and NK cells (through its anti-NK cell inhibitor moiety) to mount a strong, localized immune response within the tumor microenvironment. The third arm of the molecule specifically targets 5T4, a well described TAA that is expressed on a variety of solid tumors and is correlated with advanced disease, increased invasiveness and poor clinical outcome. This compound is distinguished from other multi-specific therapies targeting 5T4+ tumors by its cleavable capping technology that is applied to the anti-CD3 moiety, which confines the compound’s therapeutic activity to the tumor microenvironment, and thereby is expected to increase the therapeutic index in patients.

T cell engagement is achieved through binding CD3 using a commercially validated antibody fragment. CD3 is protein complex associated to the T cell receptor on the surface of both CD4+ and CD8+ T cells. Agonistic binding to CD3e triggers T cell activation that is mediated by Lck/Zap70 and leads to downstream activation of multiple signaling pathways such as NK-kB or NF-AT. Anti-CD3 is the backbone of the vast majority of bispecific T cell engagers. Three were already approved by the U.S. FDA (Blinatumomab, CD3×CD19 in 2014 for acute lymphoblastic leukemia, Tebentafusp, CD3×IMCgp100 in 2022 for Uveal Melanoma, teclistamab, CD3xBCMA in 2022 for Multiple Myeloma) and a large number other BiTE are in clinical development.

Activation of NK cells by IM1240 is achieved through the blockade of the interaction between an NK cell inhibitory receptor and its target on cancer cells. Disruption of this inhibitory interaction with an antibody, releases the effector function of NK cells in a similar way to immune checkpoint inhibitors targeting PD1 or PDL1.

The third modality of IM1240 is directed towards 5T4 (also known as trophoblast glycoprotein (TPBG)), using a proprietary set of complementarity-determining regions (CDRs). 5T4 is an oncofetal surface protein that is not found on adult healthy tissues but is abnormally expressed in several cancer types. This specific expression pattern, as well as the correlation with poor prognosis in different cancer diseases, such as colorectal, ovarian or gastric cancers makes it an ideal TAA for various therapeutic approaches.

In addition to its unique combination of 5T4, CD3 and NK cells binding arms, IM1240 is also differentiated from competing products with a cleavable cap. This cap is attached to the anti-CD3 moiety and blocks its interaction with circulating CD3 positive T cells thereby impeding potential off-tumor adverse reactions. The cap is designed to be cleaved-off by specific enzymes termed proteases that are commonly expressed at the tumor microenvironment. Upon removal of this cap, the anti-CD3 moiety of the molecule is freed to bind and activate T lymphocytes via CD3.

Preclinical Data

IM1240 is the outcome of significant lead optimization work to maximize the compounds properties in terms of affinity, efficacy and safety. The different tribodies demonstrated high affinity for 5T4, CD3 and NK cell inhibitory receptor and efficient anti-tumor responses in in vitro killing assays.

Additional preclinical investigations are ongoing to complete the functional characterization of the compound and, in parallel, CMC activities have been initiated to produce the first GMP-batch required to conduct IND-enabling studies.

Consensi

In May 2018, Consensi was approved by the FDA for patients suffering from hypertension and osteoarthritis for whom treatment with amlodipine for hypertension and celecoxib for the treatment of osteoarthritis is appropriate.

The company had previously entered into a number of agreements in connection with the licensing, commercialization, manufacturing, marketing and distribution of Consensi in the United States and in several territories in Asia (subject to regulatory approval in such territories). The company commenced commercial sales of Consensi in the United States in May 2020, but COVID-19 adversely impacted the launch of Consensi in the United States and the company’s distributor did not achieve significant sales in the U.S. In October 2021, the company terminated the distribution agreement with the distributor for Consensi in the United States and engaged an advisor to assist with a search for an alternative distributor for Consensi in the U.S. market. During 2021, the company also terminated the agreements for Consensi concerning the territories of South Korea and China.

Accordingly, the company also ceased its operations related to the company’s engagements with Dexcel, which had manufactured batches of Consensi for sale of the drug in the United States by the company’s former U.S. distributor, and in September 2022, the company signed a termination and mutual release agreement with Dexcel, according to which the parties agreed to terminate all agreements entered into between them. Under the agreement the company assigned to Dexcel all intellectual property rights with respect to Consensi. In addition, the license that was granted to Dexcel to certain data to enable Dexcel to continue developing and/or commercializing Consensi became perpetual. The company also assigned to Dexcel all of the company’s rights in the joint intellectual property developed by Dexcel under the company’s previous development services agreement with Dexcel, subject to royalty payments based on net sales of all Consensi sold by Dexcel or any third party on its behalf.

Intellectual Property

Patents, Trademarks and Licenses and Market Exclusivity

CM24

FameWave’s patent and patent application portfolio, covering the entire CEACAM1 antibody termed CM24 and other antibodies and uses thereof, includes five patent families, covering anti CEACAM1 antibodies and their uses in the treatment of cancer and other diseases.

Patent Family 1 relates to anti-human CEACAM1 antibodies, hybridoma cells producing these antibodies and methods of using the antibodies. United States patents, as well as European counterparts were granted, as well as patents in Brazil, Canada, China, Israel, Japan, Korea, and Russia, all of which have a maximum term of April 28, 2030. The European patents were validated in France; Germany; Ireland; Italy; the Netherlands; Poland; Spain; Switzerland; and the United Kingdom.

Patent Family 2 relates to method of diagnosing melanoma or monitoring progression of melanoma, the method comprising determining a level of human CEACAM1 on isolated lymphocytes of a human subject in need thereof, wherein an upregulation of said level of CEACAM1 above a predetermined threshold is indicative of melanoma or stage thereof in said subject. Patents were granted in Israel and Europe. The European patent was validated in United Kingdom, Ireland, the Netherlands, Germany, Spain, Italy, France, and Switzerland. All granted patents have a maximum term of July 20, 2030.

Patent Family 3 relates to antibodies (in particular chimeric antibodies), as well as molecules having at least the antigen-binding portion of an antibody against the human protein CEACAM1. A United States patent, as well as European counterparts were granted and divisional applications are pending. The European patents are validated in Germany, France, Spain, Italy, the United Kingdom, Ireland, the Netherlands, Poland and Switzerland. Patents were also granted in Brazil, Canada, China, Hong Kong, India, Israel, Japan, Korea and Russia. The patents of this family have a maximum term of October 9, 2032, except for the U.S. patent that has a maximum term of May 22, 2030.

Patent Family 4 relates to compositions comprising anti-human CEACAM1 antibodies, compositions comprising antibodies capable of inhibiting or blocking the interaction between PD-1 and its ligands, and methods for their combined use in treating cancer. Patents have been granted in the United States, Europe, Canada, China, Japan, Korea, Mexico, and Russia. The European patent was validated in the United Kingdom, Ireland, the Netherlands, Germany, Spain, Italy, France, Switzerland, and Poland. These patents have a maximum term of November 24, 2034. Patent applications are pending in Europe (divisional), Brazil and India.

Patent Family 5 relates to humanized antibodies, capable of specific binding to human CEACAM1 molecules containing human-to-murine back-mutations in non-CDR variable regions, and their encoding polynucleotide sequences. Patents have been granted in the United States, Europe, Canada, China, Eurasia (validated in Russia), Israel, Japan Korea, and Mexico with a maximum term of April 26, 2035. The European patent was validated in United Kingdom, Ireland, the Netherlands, Germany, Spain, Italy, France, Switzerland, and Poland. Divisional applications are pending in the United States and Mexico and national phase applications are pending in Brazil, Canada, India, and Korea.

License Agreement with Tel HaShomer

On April 16, 2012, cCAM Biotherapeutics Ltd. (cCAM), a subsidiary of Merck Sharp and Dohme Corp. (MSD) entered into a license agreement with THM and Ramot at Tel Aviv University Ltd. (‘Ramot’), which was effective as of May 25, 2010, pursuant to which THM and Ramot granted cCAM a worldwide, royalty-bearing, exclusive license to develop, manufacture, produce, market and sell any biopharmaceutical product and/or diagnostic product using patents and inventions owned by THM and Ramot in connection with uses of the glycoprotein CEACAM1 (the ‘THM License Agreement’). The THM License Agreement was subsequently amended in 2013 and in 2015.

NT219

TyrNovo Ltd.’s (TyrNovo’s), majority owned subsidiary of the company, patent and patent application portfolio, covering NT219 and other compounds, includes six patent families, covering compounds that modulate protein kinase signaling and their use in the treatment of protein kinase related disorders, including cancer and neurodegenerative disorders.

Patent Family 1 relates to compounds modulating the insulin-like growth factor receptor signaling and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer. Patents were granted in Europe and the United States, and have a maximum term of December 4, 2027, April 2, 2028, respectively. The European patent was validated in France, Germany, Switzerland and the United Kingdom.

Patent Family 2 also relates to compounds modulating the insulin-like growth factor receptor signaling and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer, and specifically discloses and claims NT219. Patents were granted in Europe and Israel, and have a maximum term of June 7, 2029, and in the United States, with a maximum term of April 2, 2028. The European patent was validated in France, Germany, Italy, the Netherlands, Spain, Switzerland, and the United Kingdom.

Patent Family 3 relates to compounds having a benzo[e][1,3]thiazin-7-one core and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer. Patents were granted in Europe and the United States, with a maximum term of December 27, 2031, and April 9, 2032, respectively. The European patent was validated in France, Germany, Italy, the Netherlands, Spain, Switzerland, and the United Kingdom.

Patent Family 4 relates to combinations of the compounds disclosed in Patent Families 1-3, acting as dual modulators of Insulin Receptor Substrate (IRS) and signal transducer and activator of transcription 3 (STAT3), with various targeted drug classes (inhibitors of Epidermal Growth Factor Receptor (EGFR), mTOR; mitogen-activated protein kinase (MEK) or mutated B-Raf), as well as chemotherapeutic agents (Gemcitabine, 5-FU, Irinotecan and Oxaliplatin), and use of such combinations for the treatment of cancer. Patents were granted in Australia, China, Europe, and Israel; and have a maximum term of February 4, 2036, and in the United States, with a maximum term of August 12, 2036. Patent applications are pending in Brazil, Canada, China, Europe, Japan, Korea, and the United States. The European patent was validated in Switzerland, Germany, Spain, France, Great Britain, Ireland, Italy, and the Netherlands.

Patent Family 5 relates to specific combinations of the compounds disclosed in Patent Families 1-3, with various antibodies against programmed cell death 1 (PD-1) protein and/or anti-programmed cell death protein 1 ligand (PD-L1). Patent applications are pending in Brazil, Canada, China, Europe, Israel, Japan, Korea, Mexico, Russia and the United States. Any patent issuing from these applications will have a maximum patent term of November 16, 2037.

Patent Family 6 relates to an isolated substantially pure trans isomer of NT219, methods for its preparation and use thereof in treating cancer. An international PCT patent application is pending, as well as a Chinese patent application. Any patent issued based on the PCT application will have a maximum patent term of October 3, 2042. Any patent issued based on the Chinese patent application will have a maximum patent term of February 17, 2042.

Exclusive License Agreement with Yissum

In August 2013, TyrNovo entered into a license agreement with Yissum, which was subsequently amended in April 2014 and March 2017, pursuant to which Yissum has granted TyrNovo an exclusive license (with the right to sublicense) for the development, use, manufacturing and commercialization of products using certain patents and know-how owned by Yissum and patent applications filed by Yissum in connection with unique inhibitors of the IGF-1R Pathway (the ‘Yissum License Agreement’).

IM1240

Patent Family 1 relates to conditionally activated tri-specific antibodies that engage T cells, NK cells, and tumor cells, including the antibody clone identified as IM1240, compositions thereof, and methods of use thereof for treating cancer in a subject in need. The tri-specific antibodies further include a cleavable capping technology for regulating the binding/activation of T cells to within a tumor microenvironment and for extending the half-life of the antibodies. National Phase applications have been entered and are pending in Australia, Brazil, Canada, China, Europe, Israel, India, Japan, the Republic of Korea, Mexico, and the United States. The expected term of any granted national phase application is May 4, 2041, not including patent term extension.

In addition, the company owns four additional patent families related to conditionally activated tri-specific antibodies that engage T cells, NK cells and tumor cells, including different TAAs with their respective CDRs and compositions thereof, and methods of use thereof for treating cancer, as well as GvHD, viral or bacterial infections in a subject in need.

Collaboration Agreement with Mor Research Applications

In September 2022, the company entered into a research collaboration agreement with Mor Research Applications (‘Mor’), the technology transfer subsidiary of Clalit Healthcare Services, which is Israel’s largest health maintenance organization (HMO), covering approximately half the population of Israel (52%) (approximately 4.8 million members) and operates 14 hospitals. Pursuant to the collaboration agreement, Mor agreed to provide the company, during the term of the agreement, with first access to early-stage projects in the field of oncology, developed by Mor and available for licensing by Mor, that promote innovative technological ideas in the oncology field.

Other

The company recently purchased three patent families covering uses of a monoclonal antibody, which the company is evaluating for their potential for further development, for the purpose of treating cancer and infectious diseases, based on these patents.

Government Regulations

In the U.S., the company must follow the rules and regulations established by the FDA requiring the presentation of data indicating that the company’s products are safe and efficacious and are manufactured in accordance with Current Good Manufacturing Practice regulations.

Research and Development

The company’s research and development expenses were $16.3 million for the year ended December 31, 2022.

History

The company was formerly known as Kitov Pharmaceuticals Holdings Ltd. and changed its name to Kitov Pharma Ltd in 2018. Further, the company changed its name to Purple Biotech Ltd. in 2020.