On September 17, 2020 NOXXON Pharma N.V. (Euronext Growth Paris: ALNOX), a biotechnology company focused on improving cancer treatments by targeting the tumor microenvironment (TME), reported a poster with the final clinical results from the Phase 1/2 study with CXCL12 inhibitor, NOX-A12, and pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020 (Press release, NOXXON, SEP 17, 2020, View Source [SID1234565301]). The enhanced immune response and long survival times for certain late-stage patients combined with the good overall safety profile confirmed in the final data support further development of the combinations containing NOX-A12 plus pembrolizumab and established standard of care regimens in earlier lines of therapy. The poster presentation is complemented by a video presentation with remarks highlighting the trial’s most significant data provided by Dr. Niels Halama from the National Center for Tumor Diseases (NCT) in Heidelberg, Germany, the first author of the poster presentation and the principal investigator of the trial.

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"In this trial, we observed a number of patients – 25% of the total – who experienced disease stabilization and many with prolonged survival also during the follow-up period, which is particularly noteworthy in patients at such a late-stage of disease progression. In fact, we saw multiple cases of 4th line pancreatic cancer patients, who did not respond at all to their prior therapy, surviving for more than one year," commented Dr. Niels Halama.

"The patients in this study were, on average, receiving their 6th line of therapy in colorectal cancer and their 4th line of therapy in pancreatic cancer. In addition, all patients had liver metastases and, in 95% of cases, were completely non-responsive to their last therapy before entering this study. As such, the data from this study provide signals that support a beneficial impact of the combination of NOX-A12 with pembrolizumab for patients with extremely limited options. Thus, we are planning to advance NOX-A12 into the next stage of clinical development in at least one of these indications," added Dr. Jarl Ulf Jungnelius, Senior Medical Advisor of NOXXON.

The trial called for all patients to have a baseline biopsy of tumor tissue, two weeks of NOX-A12 monotherapy and then a second biopsy to assess changes induced in the tumor microenvironment by NOX-A12. After the second biopsy, it was planned to move all patients to a combination therapy of NOX-A12 plus pembrolizumab (MSD’s anti-PD-1 antibody) and continue combination therapy until tumor progression or safety issues. CXCL12, the target of NOX-A12 which is thought to exclude immune cells from the tumor microenvironment, was found to be abundantly present in all tumor samples at baseline.

NOX-A12 penetrated cancer tissue in both pancreatic and colorectal cancer patients where it neutralized its target, CXCL12. NOX-A12 monotherapy resulted in induction of a Th1-like immune response in patients when baseline biopsies were compared to post-NOX-A12 monotherapy samples. The extent of CXCL12 neutralization in tumor tissue correlates with a Th1 immune response and disease stabilization and based on the obtained results, an optimized dosing strategy for NOX-A12 will be used for future studies. As would be expected if the immune system were better coordinating a response against the cancer, T cells in the cancer both moved together (aggregation) and moved towards the tumor cells in responding tissues.

The combination of NOX-A12 plus pembrolizumab resulted in stable disease in 25% of patients, and prolonged time on treatment vs. prior therapy for 35% of patients. Overall survival was 39% at 6 months and 20% at 12 months. Three of the stable disease patients (15% of the starting study population) survived for more than a year. In addition, the combination of NOX-A12 with pembrolizumab appears to be safe and this allows exploration of further combination approaches in earlier line patients combining an optimized dose with standard of care.

Taken together, these data thus support a role of CXCL12 in resistance to immunotherapy and suggest that NOX-A12 may be able to counter this effect by boosting the immune response in tumor tissue. Further studies of NOX-A12 in combination regimens are warranted and currently the company is exploring strategies with external experts to combine NOX-A12 with anti-PD1 agents and established standard of care regimens in earlier lines of therapy than those explored in this clinical trial.

The poster presentation #1537P is available for registered delegates to view on demand on the ESMO (Free ESMO Whitepaper) Virtual Congress 2020 program page starting today from 09.00 a.m. CEST until 08.00 p.m. CEST on September 21, 2020. Additionally, Dr. Halama’s video presentation as well as the poster have been published on the NOXXON website. The poster abstract is openly available on the Congress platform.

On September 17, 2020 Provectus (OTCQB: PVCT) reported that preliminary response, safety, and immune correlative data from the Company’s Phase 1b/2 study of small molecule autolytic cancer immunotherapy PV-10, an injectable formulation of Provectus’ proprietary rose bengal disodium (RBD), in combination with KEYTRUDA (pembrolizumab) for the treatment of advanced cutaneous melanoma in patients refractory to immune checkpoint blockade (CB) will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020, held online from September 19-21, 2020 (Press release, Provectus Pharmaceuticals, SEP 17, 2020, View Source [SID1234565300]).

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This combination therapy study first enrolled and treated CB-naïve patients in its main cohort (CB-Naïve Cohort). A subsequent expansion cohort, the subject of the abovementioned ESMO (Free ESMO Whitepaper) poster presentation, enrolled and treated CB-refractory patients (CB-Refractory Cohort).

Intralesional (IL) (aka intratumoral) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death and induce tumor-specific reactivity in circulating T cells.1-3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with CB.4 In CB-refractory advanced cutaneous melanoma, IL PV-10 may restore disease-specific T cell function, which may also be prognostic of clinical response.

Summary CB-Refractory Cohort Data from the ESMO (Free ESMO Whitepaper) 2020 Presentation:

Baseline characteristic: median age of 74 years (range 28-90)
Disease characteristics: 60% Stage IV M1b-d; patients were refractory to single- and dual-agent CB treatment (YERVOY, KEYTRUDA, or OPDIVO+YERVOY)
Safety (15 patients): Consistent with the established patterns for the single-agent use of each drug; principally grades 1 and 2 injection-site reactions for PV-10; principally grades 1 to 3 immune-mediated reactions for KEYTRUDA
Overall patient efficacy (11 patients; RECIST 1.1): 9% complete response (CR), 36% overall response rate (ORR), and 64% disease control rate (DCR)
Immune correlative analytes from the combination therapy, including damage-associated molecular pattern (DAMP) high mobility group box protein 1 (HMGB1) and tumor specific functional T cell activity, exhibited systemic release similar to that previously shown in CB-naïve patients receiving single-agent PV-10.2
Two-year landmark survival data from the CB-Naïve Cohort were also presented at the ESMO (Free ESMO Whitepaper) Virtual Congress 2020. These data included 62% overall survival (OS) and median OS not reached; 10% CR and 67% ORR (RECIST 1.1), including 82% ORR for Stage M1b-c patients; and a stable, non-overlapping safety profile equivalent to that of the CB-Refractory Cohort.

Provectus’ current Good Manufacturing Practices (cGMP) RBD is a proprietary pharmaceutical-grade drug substance produced by the Company’s quality-by-design (QbD) manufacturing process to exacting regulatory standards that avoids the formation of uncontrolled impurities currently present in commercial-grade rose bengal. Provectus’ RBD and cGMP RBD manufacturing process are protected by composition of matter and manufacturing patents as well as trade secrets.

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors said, "Refractory metastatic melanoma is a high unmet medical need that is growing, with low response and survival rates as well as limited patient treatment options. These preliminary data of PV-10 in combination with immune checkpoint blockade for patients who previously failed checkpoint blockade treatment show that the necessary upfront tumor destruction by PV-10 directly against injected disease burden can result in a PV-10-induced, tumor-specific, functional T cell response. Thus, these data demonstrate that PV-10 is capable of restoring T cell function in checkpoint-refractory melanoma, an immunologically-cold disease setting."

A copy of the poster presentation is available on Provectus’ website at View Source

About the Phase 1b/2 Combination Therapy Trial (NCT02557321)

A first expansion cohort of the Phase 1b portion of the study began enrolling patients with metastatic cutaneous melanoma who were CB-refractory in December 2018. This CB-Refractory Cohort extended an exploratory group of refractory patients enrolled into the study’s main cohort, which primarily enrolled CB-naïve patients. Patients with at least one injectable lesion and who were candidates for KEYTRUDA were eligible. Eligible subjects received the combination treatment of PV-10 and KEYTRUDA every three weeks for up to five cycles (i.e., over a period of up to 12 weeks, with no further PV-10 administered after week 12), followed by only KEYTRUDA every three weeks for up to 24 months. The primary endpoint for the Phase 1b trial was safety and tolerability. ORR and progression-free survival were key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).

About Rose Bengal Disodium

RBD is 4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. The Company manufactures cGMP RBD using a patented process designed to meet stringent modern global quality requirements for pharmaceuticals and pharmaceutical ingredients.

An IL formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor cancers. By targeting tumor cell lysosomes, RBD treatment may yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells, including a T cell mediated immune response against treatment refractory and immunologically cold tumors.1-3 Adaptive immunity can be enhanced by combining CB with RBD.4 IL PV-10 is undergoing clinical study for relapsed and refractory adult solid tumor cancers, such skin and liver cancers.

IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.5,6

A topical formulation of cGMP RBD drug substance, PH-10, is being developed as a clinical-stage immuno-dermatology drug product for inflammatory dermatoses, such as atopic dermatitis and psoriasis. RBD can modulate multiple interleukin and interferon pathways and key cytokine disease drivers.7

Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia.8,9

Oral formulations of cGMP RBD are also undergoing preclinical study as prophylactic and therapeutic treatments for high-risk adult solid tumor cancers, such as head and neck, breast, pancreatic, liver, and colorectal cancers.

Different formulations of cGMP RBD are undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Tumor Cell Lysosomes as the Seminal Cancer Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Building on the Discovery, Exploration, and Characterization of Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.10 Cancer progression and metastasis are associated with lysosomal compartment changes11,12, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance13.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,14, external collaborators5, and other researchers15,16,17 have independently shown that RBD triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via RBD: RBD-induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine hepatocellular carcinoma (HCC) cells can be viewed in this Provectus video of the process (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames, with a duration of approximately one hour). Exposure to RBD triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video of the process, with a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators in neuroblastoma cells to show that lysosomes are disrupted upon exposure to RBD.5

Tumor Autolytic Death via RBD: RBD causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens; release of these signaling factors may initiate an immunologic cascade where local response by the innate immune system may facilitate systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Mediated immune signaling pathways may include an effect on STING, which plays an important role in innate immunity.9

Orphan Drug Designations (ODDs)

ODD status has been granted to RBD by the U.S. Food and Drug Administration for metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Intellectual Property (IP)

Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which cGMP RBD and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial-grade rose bengal in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of RBD and CB (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035; US patent application numbers include 20200138942.

On September 17, 2020 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported preclinical proof-of-concept data for BLU-945, an investigational precision therapy for patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) (Press release, Blueprint Medicines, SEP 17, 2020, View Source [SID1234565299]). The new preclinical data showed BLU-945 potently and selectively inhibited triple-mutant EGFR harboring the most common on-target resistance mutations to standard treatments for EGFRm NSCLC, resulting in robust anti-tumor activity in multiple lung cancer models. The data were made available today in a poster presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020.

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Currently, there are no approved therapies for patients with osimertinib-resistant EGFRm NSCLC, and there is an urgent need for new therapies to address tumor resistance. BLU-945 was designed to potently inhibit triple-mutant EGFR harboring either the activating L858R or exon 19 deletion mutations combined with the acquired T790M and C797S mutations, the most common on-target resistance to standard EGFR inhibitors. In addition, BLU-945 was designed to be wild-type EGFR and kinome selective with the potential for improved tolerability and combination strategies.

"Our scientists at Blueprint Medicines specifically engineered BLU-945 to tackle treatment resistance in patients with EGFR-mutated lung cancer, and the preclinical proof-of-concept data we’re reporting today highlight the potential of BLU-945 to offer clinical benefit to patients along with a safety profile that enables combinations with other EGFR-targeted therapies across multiple treatment lines," said Marion Dorsch, Ph.D., Chief Scientific Officer of Blueprint Medicines. "The recent FDA approval of GAVRETO (pralsetinib) combined with our rapidly advancing EGFR research program highlight our broad commitment to patients with lung cancer, as well as the potential of our research platform to address the evolution of cancer and enable durable patient outcomes."

In preclinical data presented at the ESMO (Free ESMO Whitepaper) congress, BLU-945 inhibited triple mutant EGFR with sub-nanomolar potency and demonstrated greater than 900-fold selectivity over wild-type EGFR along with excellent overall kinome selectivity. In a triple mutant EGFR cell-line, BLU-945 potently inhibited the EGFR pathway, while osimertinib demonstrated limited activity. BLU-945 monotherapy resulted in robust anti-tumor activity in multiple cell line-derived and patient-derived xenograft (PDX) models of triple mutant EGFR NSCLC. In addition, BLU-945 treatment in combination with osimertinib or gefitinib resulted in tumor regression in a triple mutant EGFR NSCLC PDX model derived from a patient with progressive disease following five lines of prior therapy. BLU-945 was also highly active in an intracranial disease model.

Based on these preclinical proof-of-concept data, Blueprint Medicines plans to develop BLU-945 as a monotherapy and in combination with other agents for the treatment of patients with osimertinib-resistant EGFR NSCLC. The company plans to initiate an international Phase 1 dose-escalation trial of BLU-945 in the first half of 2021.

In addition, Blueprint Medicines expects to nominate a brain-penetrant development candidate targeting double mutant EGFR harboring the activating L858R or exon 19 deletion mutations and the acquired C797S mutation, the most common on-target resistance profile following first-line osimertinib, in the fourth quarter of 2020. The company plans to develop this candidate as both a monotherapy and in combination with BLU-945.

About EGFRm NSCLC

Lung cancer is the leading cause of cancer death worldwide. Among the 80 to 85 percent of lung cancers classified as NSCLC, about 10 to 15 percent of cases in the US and Europe and about 40 to 50 percent of cases in Asia are caused by activating EGFR mutations. In recent years, the introduction of EGFR targeted therapies including osimertinib has dramatically improved outcomes in patients with EGFRm NSCLC. However, the emergence of tumor resistance represents an urgent medical need and there are no approved therapies for osimertinib-resistant EGFRm NSCLC.

About BLU-945

Derived from Blueprint Medicines’ proprietary research platform, BLU-945 is designed to treat patients with osimertinib-resistant EGFRm NSCLC. In preclinical studies, BLU-945 potently inhibited triple-mutant EGFR harboring either the activating L858R or exon 19 deletion mutations combined with the acquired T790M and C797S mutations, the most common on-target resistance to first-generation EGFR inhibitors and the third-generation EGFR inhibitor osimertinib, respectively. In addition, BLU-945 demonstrated excellent selectivity for triple-mutant EGFR over wild-type EGFR and other clinically relevant kinases, potentially enabling well-tolerated combinations with other EGFR inhibitors. Blueprint Medicines owns worldwide development and commercialization rights for BLU-945.

On September 17, 2020 Provectus (OTCQB: PVCT) reported that 2-year landmark survival, response, and safety data from the Company’s Phase 1b/2 study of small molecule autolytic cancer immunotherapy PV-10, an injectable formulation of Provectus’ proprietary rose bengal disodium (RBD), in combination with KEYTRUDA (pembrolizumab) for the treatment of advanced cutaneous melanoma in patients naïve to immune checkpoint blockade (CB) will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020, held online from September 19-21, 2020 (Press release, Provectus Biopharmaceuticals, SEP 17, 2020, View Source [SID1234565298]).

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Intralesional (IL) (aka intratumoral) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death and induce tumor-specific reactivity in circulating T cells.1-3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with CB.4

ESMO 2020 Presentation Summary Data of this CB-Naïve Cohort:

2-year Survival Analysis
62% overall survival (OS) (55% for KEYTRUDAa alone)
Median OS not reached (median OS not reached for KEYTRUDAa alone)
65% disease-specific survival (DSS); median DSS for all patients not reached; 23.5-month median DSS for Stage IV M1c patients
Safety
Consistent with the established patterns for single-agent use of each drug; principally grades 1 and 2 injection site reactions for PV-10; principally grades 1 to 3 immune-mediated reactions for KEYTRUDA
Synergy of approved and investigational first-line cutaneous melanoma combination therapies: Schmidt et al. (JAMA Netw Open 2020b) have proposed a Bliss independent activity model to analyze observed combination therapy overall response rates (ORRs) and a Z score to measure the difference between observed and calculated ORRs. The higher the Z score, the greater the contribution of the combination therapy. Provectus calculated a Z score of 25% for the PV-10+KEYTRUDA combination. Other first-line (i.e., CB-naïve) advanced cutaneous melanoma combination therapy Z scores include:b

15.5% for OPDIVO+YERVOY, 23.4% for KEYTRUDA+YERVOY,
-0.8% for KEYTRUDA+epacadostat (IDO-1), 30% OPDIVO+epacadostat,
13.5% for KEYTRUDA+IMLYGIC (oncolytic virus), and
13% for OPDIVO+bempegaldesleukin (interleukin-2)c.
Provectus’ current Good Manufacturing Practices (cGMP) RBD is a proprietary pharmaceutical-grade drug substance produced by the Company’s quality-by-design (QbD) manufacturing process to exacting regulatory standards that avoids the formation of uncontrolled impurities currently present in commercial-grade rose bengal. Provectus’ RBD and cGMP RBD manufacturing process are protected by composition of matter and manufacturing patents as well as trade secrets.

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors said, "These two-year survival landmark data support the clinical value of PV-10 in combination with immune checkpoint blockade in a predominantly Stage IV melanoma patient population, including those with extensive visceral disease. These data illustrate a stable, non-overlapping safety profile over time; highlight substantial, efficient, upfront tumor destruction by PV-10 directly against injected disease burden; and appear to be the result of a strong, PV-10-induced, tumor-specific, functional T cell response.2 Taken together,PV-10’s clinical and mechanistic attributes may better leverage the strengths of checkpoint blockade for the durable treatment benefit of melanoma patients."

A copy of the poster presentation is available on Provectus’ website at View Source

About the Phase 1b/2 Combination Therapy Trial (NCT02557321)

The Phase 1b portion of the study completed enrollment of 23 patients with metastatic cutaneous melanoma in April 2018 at clinical sites in the U.S.; of these patients, 21 were naïve to checkpoint inhibition treatment. Patients with at least one injectable lesion and who were candidates for KEYTRUDA were eligible. Eligible subjects received the combination treatment of PV-10 and KEYTRUDA every three weeks for up to five cycles (i.e., over a period of up to 12 weeks, with no further PV-10 administered after week 12), followed by only KEYTRUDA every three weeks for up to 24 months. The primary endpoint for the Phase 1b trial was safety and tolerability. Overall response rate and progression-free survival were key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).

About Rose Bengal Disodium

RBD is 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. The Company manufactures cGMP RBD using a patented process designed to meet stringent modern global quality requirements for pharmaceuticals and pharmaceutical ingredients.

An IL formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor cancers. By targeting tumor cell lysosomes, RBD treatment may yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells, including a T cell mediated immune response against treatment refractory and immunologically cold tumors.1-3 Adaptive immunity can be enhanced by combining CB with RBD.4 IL PV-10 is undergoing clinical study for relapsed and refractory adult solid tumor cancers, such skin and liver cancers.

IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.5,6

A topical formulation of cGMP RBD drug substance, PH-10, is being developed as a clinical-stage immuno-dermatology drug product for inflammatory dermatoses, such as atopic dermatitis and psoriasis. RBD can modulate multiple interleukin and interferon pathways and key cytokine disease drivers.7

Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia.8,9

Oral formulations of cGMP RBD are also undergoing preclinical study as prophylactic and therapeutic treatments for high-risk adult solid tumor cancers, such as head and neck, breast, pancreatic, liver, and colorectal cancers.

Different formulations of cGMP RBD are undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Tumor Cell Lysosomes as the Seminal Cancer Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Building on the Discovery, Exploration, and Characterization of Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.10 Cancer progression and metastasis are associated with lysosomal compartment changes11,12, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance13.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,14, external collaborators5, and other researchers15,16,17 have independently shown that RBD triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via RBD: RBD-induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine hepatocellular carcinoma (HCC) cells can be viewed in this Provectus video of the process (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames, with a duration of approximately one hour). Exposure to RBD triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video of the process, with a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators in neuroblastoma cells to show that lysosomes are disrupted upon exposure to RBD.5

Tumor Autolytic Death via RBD: RBD causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens; release of these signaling factors may initiate an immunologic cascade where local response by the innate immune system may facilitate systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Mediated immune signaling pathways may include an effect on STING, which plays an important role in innate immunity.9

Orphan Drug Designations (ODDs)

ODD status has been granted to RBD by the U.S. Food and Drug Administration for metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Intellectual Property (IP)

Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which cGMP RBD and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial-grade rose bengal in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of RBD and CB (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035; US patent application numbers include 20200138942.

On September 17, 2020 Bayer reorted that Updated clinical data for Vitrakvi (larotrectinib) reinforce the consistent, long-term efficacy and established safety profile in an integrated dataset of 175 adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion cancer (Press release, Bayer, SEP 17, 2020, View Source [SID1234565297]).1 In addition, new tumor type specific sub-analyses in lung and thyroid cancer patients further emphasize these durable responses with no new safety signals reported.2,3 These results are being presented at the ESMO (Free ESMO Whitepaper) Virtual Congress 2020, to be held between September 19-21, 2020.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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Vitrakvi is approved in the U.S., Canada, Brazil and the European Union (EU). In the U.S., Vitrakvi is approved for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Additional filings in other regions are underway or planned.

Adult and Pediatric Integrated Data Set

In an expanded data set with a longer follow-up (cut-off July 15, 2019) of 175 patients (116 adult and 59 pediatric) with non-primary central nervous system (CNS) TRK fusion cancer, Vitrakvi demonstrated a durable, investigator-assessed overall response rate (ORR) of 78% (95% CI 71-84; n=136/175), with 19% (n=33) complete responses (CRs), 59% (n=103) partial responses (PRs) and 13% (n=23) with stable disease. The ORR in 14 patients with CNS metastases was 71% (95% CI 42-92; n=10/14; all responses were partial responses).1

"The consistent and durable responses as well as the safety profile from the larotrectinib data are supportive in determining the appropriate treatment option for my patients with TRK fusion cancer," said Professor Ray McDermott, St. Vincent University Hospital and Tallaght Hospital, Ireland. "These clinically meaningful responses underscore the urgency for widespread NTRK testing."

The median duration of response (DoR) was not estimable at a median follow-up of 13.5 months, with a 12-month DoR rate of 81% (95% CI 73-89). After a median follow-up of 13.8 months, the median progression-free survival (PFS) was 36.8 months (95% CI 25.7- NE). Median overall survival (OS) was not reached after 15.3 months of follow-up; 12-month estimated median OS rate was 90% (95% CI 85-95) and 24-month estimated OS rate was 83% (95% CI 75-90). At the time of data cut-off, 100 patients (57%) were still on treatment.1

In the expanded safety population of 279 patients, with 34 patients being treated with Vitrakvi for more than 24 months, adverse events (AEs) were primarily grade 1 and 2, and no new safety signals were reported. Serious AEs related to Vitrakvi were reported in 5% (15/279) of patients; the most common serious grade 3 and 4 events were increased alanine aminotransferase, increased aspartate aminotransferase and nausea (n=2 each).1

In the primary data set at the time of FDA approval, Vitrakvi demonstrated an ORR of 75% (n=55) (95% CI, 61-85), including 22% CRs and 53% PRs assessed by independent review committee and the median DoR was not yet reached (range 1.6+ to 33.2+) (n=44).

"Designed specifically to treat TRK fusion cancer, Vitrakvi is a meaningful advancement in the treatment of both adult and pediatric patients with TRK fusion cancer and represents a true paradigm shift in cancer care — where treatment is based on the oncogenic driver and not the tumor location," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer’s Pharmaceutical Division. "These data affirm Vitrakvi’s robust clinical profile with the largest dataset and longest follow-up of any TRK inhibitor and reinforce our longstanding commitment to developing innovative treatments for patients."

Vitrakvi in Lung and Thyroid Cancers

In a sub-analysis of 14 adult heavily pre-treated patients with metastatic lung cancer harboring an NTRK gene fusion, the demonstrated ORR was 71% (95% CI 42-92; n=10/14) with an additional year of follow-up, with 7% (n=1) CRs, 64% (n=9) PRs and 21% (n=3) with stable diseases. For patients with CNS metastases, the ORR was 57% (95% CI 18-90; no patients with CR, n=4/7 with PRs). At a median follow-up of 12.9 months, median DoR was not estimable (NE) (95% CI 5.6-NE months). The estimated DoR at 12 months was 88%. At a median follow-up of 14.6 months, the median PFS had not been reached (95% CI 7.2-NE) and the estimated rate of PFS at 12 months or more was 69%. The median OS was not reached (95% CI 17.2-NE) at a median follow-up of 12.6 months and 91% of patients were alive at 12 months. Duration of treatment ranged from 2.1 to 39.6+ months with three of seven patients with CNS metastases still on treatment at the time of data cut-off. Treatment-emergent AEs were primarily grade 1 and 2, supporting Vitrakvi’s long-term safety profile.2

In a separate subset analysis of 28 adults and children with locally advanced or metastatic TRK fusion thyroid cancer, the ORR was 75% (95% CI 55-89; n=21/28), with 7% (n=2) CRs and 68% (n=19) PRs. The ORR was 29% (no CR, 29% PR [95% CI 4-71; n=2/7]) for patients with anaplastic disease, a rare, aggressive subtype of thyroid cancer. The ORR was 90% (95% CI 70-99; n=19/21) for differentiated histology. All four patients with CNS metastases at baseline had a PR, three of which are continuing treatment. While median DoR was not estimable (95% CI 14.8-NE months) at a median follow-up of 10.2 months, the estimated DoR at 12 months was 95% (95% CI 85-100). Median PFS was not estimable (95% CI 16.6-NE months) at a median follow up of 12.8 months; estimated PFS was 81% (95% CI 67–96) at 12 months and 70% (95% CI 45–94) at 18 months. The median OS was 27.8 months (95% CI 16.7-NE) with an estimated OS at 12 months of 92% (95% CI 82-100) and a median OS of 14.1 months (95% CI 2.6-NE) for patients with anaplastic thyroid cancer; not reached for differentiated thyroid cancer. The safety profile was consistent with that of the overall safety population previously reported, with AEs mostly grade 1 and 2.3

Vitrakvi Growth Modulation Index Analysis

122 patients who had been treated with Vitrakvi and followed up for at least 6 months (or discontinued early) and had at least one prior line of systemic therapy in the advanced setting were eligible for retrospective growth modulation index (GMI) analysis. GMI is calculated as a ratio of PFS with Vitrakvi to the time to progression or time to treatment failure (TTPF) on the most recent prior line of therapy. In the analysis of 122 adult and pediatric patients with metastatic and locally advanced disease treated with Vitrakvi, the median GMI was 3.35 (range 0.00-337). 69% (n=84/122) of patients had a GMI of ≥ 1.33. The median TTPF on prior line of therapy was 2.7 months (95% CI 2.0–3.1) and median PFS on Vitrakvi was 33.4 months (95% CI 13.8–[NE]; hazard ratio [HR] 0.20 [95% CI 0.14–0.29]).4

Data for the integrated dataset and GMI analysis were pooled from three larotrectinib clinical trials (NCT02122913, NCT02576431 and NCT02637687) in adult and pediatric patients with TRK fusion cancer.1,4 Data from the lung and thyroid cancer subsets were pooled from two larotrectinib clinical trials (NCT02122913 and NCT02576431).2,3

About Vitrakvi (larotrectinib)5

Vitrakvi (larotrectinib) is indicated for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are either metastatic or where surgical resection will likely result in severe morbidity and have no satisfactory alternative treatments or that have progressed following treatment.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information for Vitrakvi (larotrectinib)

Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurologic adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.

Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily.

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).

Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.

Please see the full Prescribing Information for VITRAKVI (larotrectinib).

About TRK Fusion Cancer

TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless to where it originates in the body. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. We have the passion and determination to develop innovative medicines to help extend the lives of people living with cancer. The oncology franchise at Bayer includes six marketed products across various indications and several compounds in different stages of clinical development. A key area of focus is prostate cancer, where we have several treatments on the market or in development. Another key focus at Bayer is on shifting oncology treatment, with an approved TRK inhibitor exclusively designed to treat solid tumors that have an NTRK gene fusion, a key oncogenic driver, and another TRK inhibitor advancing through the pipeline. The company’s approach to research prioritizes targets and pathways with the potential to impact the way that cancer is treated.