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 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi reported the presentation of positive results from the pivotal Phase 2 trial for the PD-1 inhibitor Libtayo (cemiplimab) in patients with locally advanced basal cell carcinoma (BCC) who had progressed on or were intolerant to hedgehog inhibitor (HHI) therapy (Press release, Regeneron, SEP 17, 2020, View Source [SID1234565318]). The data were shared in a late-breaking presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020, and form the basis of regulatory submissions, including in the U.S. and European Union.

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"Advanced basal cell carcinoma can be an unrelenting, highly disfiguring disease, and there are no approved treatment options once a patient progresses on or becomes intolerant to hedgehog inhibitors," said Alexander Stratigos, M.D., Professor of Dermatology at the University of Athens Medical School at Andreas Sygros Hospital and a trial investigator. "This is the first time a prospective trial of an investigational medicine has shown a clinical benefit in this patient population, and the Libtayo data provide hope for this difficult-to-treat cancer."

Per independent central review, the objective response rate (ORR) was 31% among Libtayo-treated patients (n=84; 95% confidence interval [CI]: 21-42%), with a median follow-up of 15 months (range: 1-25 months). This included a 6% (n=5) complete and 25% (n=21) partial response rate. This is an increase from the ORR shared in May and includes two responses that were confirmed after the initial data analysis. Responses were seen regardless of baseline PD-L1 expression in tumor cells.

As of data cut-off, the median duration of response and median overall survival had not yet been reached. At one-year, 85% of responses were ongoing (95% CI; 61-95%), the probability of progression-free survival was 57% (95% CI: 44-67%), and the probability of overall survival was 92% (95% CI: 84-97%), according to Kaplan-Meier estimates.

No new Libtayo safety signals were observed. The most common treatment-related adverse events (AEs) were fatigue (25%, n=21), pruritus (14%, n=12) and asthenia (14%, n=12). Grade 3 or higher treatment-related AEs that occurred in at least 2 patients were colitis (5%, n=4), fatigue and adrenal insufficiency (2%, n=2 each). Fourteen patients (17%) discontinued treatment due to treatment-emergent AEs.

Libtayo was invented using Regeneron’s VelocImmune technology that utilizes a proprietary genetically-engineered mouse platform endowed with a genetically-humanized immune system to produce optimized fully-human antibodies. VelocImmune technology has been used to create multiple antibodies including Dupixent (dupilumab), Praluent (alirocumab) and Kevzara (sarilumab), which are approved in multiple countries around the world. Regeneron previously used these technologies to rapidly develop a treatment for Ebola virus infection, which is currently under review by the FDA, and to create REGN-COV2, a potentially preventative and therapeutic medicine for COVID-19.

Libtayo is being jointly developed by Regeneron and Sanofi under a global collaboration agreement. The use of Libtayo to treat advanced BCC is investigational and has not been fully evaluated by any regulatory authority.

About the Pivotal BCC Trial
In this ongoing, global Phase 2 trial, two cohorts of patients were studied: locally advanced BCC and metastatic BCC. All patients received Libtayo 350 mg intravenously every three weeks for up to 93 weeks or until disease progression. The primary endpoint is ORR, and key secondary endpoints include overall survival, progression free survival, duration of response, safety and tolerability. The median duration of response and median overall survival were estimated using Kaplan-Meier analyses. Detailed interim metastatic BCC data are planned for presentation at an upcoming medical meeting.

About BCC
BCC is a common type of non-melanoma skin cancer. While the vast majority of BCCs are caught early and easily cured with surgery and radiation, a small proportion of tumors can become advanced and penetrate deeper into surrounding tissues (locally advanced) or spread to other parts of the body (metastatic), which is more difficult to treat. In the U.S. alone, approximately 2 million new cases of BCC will be diagnosed every year, 20,000 U.S. patients will have advanced BCC and 3,000 patients will die of this disease.

About Libtayo
Libtayo is a fully-human monoclonal antibody targeting the immune checkpoint receptor PD-1 on T-cells. By binding to PD-1, Libtayo has been shown to block cancer cells from using the PD-1 pathway to suppress T-cell activation.

Libtayo is the first immunotherapy approved in the U.S., EU and other countries for adults with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. In the U.S., the generic name for Libtayo in its approved indication is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration. Outside of the U.S., the generic name for Libtayo in its approved indication is cemiplimab.

The extensive clinical program for Libtayo is focused on difficult-to-treat cancers. In skin cancer, this includes trials in adjuvant and neoadjuvant CSCC in addition to the pivotal trial in advanced BCC. Libtayo is also being investigated in pivotal trials in NSCLC and cervical cancer, as well as in trials combining Libtayo with either conventional or novel therapeutic approaches for both solid tumors and blood cancers. These potential uses are investigational, and their safety and efficacy have not been evaluated by any regulatory authority.

IMPORTANT SAFETY INFORMATION AND INDICATION FOR U.S. PATIENTS

What is Libtayo?
Libtayo is a prescription medicine used to treat people with a type of skin cancer called cutaneous squamous cell carcinoma (CSCC) that has spread or cannot be cured by surgery or radiation.

It is not known if Libtayo is safe and effective in children.

What is the most important information I should know about Libtayo?
Libtayo is a medicine that may treat a type of skin cancer by working with your immune system. Libtayo can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one problem at the same time. These problems may happen anytime during treatment or even after your treatment has ended.

Call or see your healthcare provider right away if you develop any symptoms of the following problems or these symptoms get worse:

Lung problems (pneumonitis). Signs and symptoms of pneumonitis may include new or worsening cough, shortness of breath, and chest pain.
Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include diarrhea (loose stools) or more frequent bowel movements than usual; stools that are black, tarry, sticky or that have blood or mucus; and severe stomach-area (abdomen) pain or tenderness.
Liver problems (hepatitis). Signs and symptoms of hepatitis may include yellowing of your skin or the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach area (abdomen), drowsiness, dark urine (tea colored), bleeding or bruising more easily than normal, and feeling less hungry than usual.
Hormone gland problems (especially the adrenal glands, pituitary, thyroid and pancreas). Signs and symptoms that your hormone glands are not working properly may include headaches that will not go away or unusual headaches, rapid heartbeat, increased sweating, extreme tiredness, weight gain or weight loss, dizziness or fainting, feeling more hungry or thirsty than usual, hair loss, feeling cold, constipation, deeper voice, very low blood pressure, urinating more often than usual, nausea or vomiting, stomach-area (abdomen) pain, and changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness.
Kidney problems, including nephritis and kidney failure. Signs of these problems may include decrease in your amount of urine, blood in your urine, swelling in your ankles, and loss of appetite.
Skin problems. Signs of these problems may include rash, itching, skin blistering, and painful sores or ulcers in the mouth, nose, throat, or genital area.
Problems in other organs. Signs of these problems may include headache, tiredness or weakness, sleepiness, changes in heartbeat (such as beating fast, seeming to skip a beat, or a pounding sensation), confusion, fever, muscle weakness, balance problems, nausea, vomiting, stiff neck, memory problems, seizures (encephalitis), swollen lymph nodes, rash or tender lumps on skin, cough, shortness of breath, vision changes, or eye pain (sarcoidosis), seeing or hearing things that are not there (hallucinations), severe or persistent muscle pain, severe muscle weakness, low red blood cells (anemia), bruises on the skin or bleeding, and changes in eyesight.
Rejection of a transplanted organ. Your doctor should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.
Infusion (IV) reactions that can sometimes be severe and life-threatening. Signs of these problems may include chills or shaking, itching or rash, flushing, shortness of breath or wheezing, dizziness, fever, feeling of passing out, back or neck pain, and facial swelling.
Getting medical treatment right away may help keep these problems from becoming more serious.

Your healthcare provider will check you for these problems during your treatment with Libtayo. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may delay or completely stop treatment if you have severe side effects.

Before you receive Libtayo, tell your healthcare provider about all your medical conditions, including if you:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus;
have had an organ transplant;
have lung or breathing problems;
have liver or kidney problems;
have diabetes;
are pregnant or plan to become pregnant; Libtayo can harm your unborn baby
Females who are able to become pregnant:
Your healthcare provider will give you a pregnancy test before you start treatment.
You should use an effective method of birth control during your treatment and for at least 4 months after your last dose of Libtayo. Talk with your healthcare provider about birth control methods that you can use during this time.
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Libtayo.
are breastfeeding or plan to breastfeed. It is not known if Libtayo passes into your breast milk. Do not breastfeed during treatment and for at least 4 months after the last dose of Libtayo.
Tell your healthcare provider about all the medicines you take, including prescription and over- the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Libtayo include tiredness, rash, diarrhea, muscle or bone pain, and nausea. These are not all the possible side effects of Libtayo. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Regeneron Pharmaceuticals and Sanofi at 1-877-542-8296.

On September 17, 2020 Polaris Group reported that the first patient has been dosed in a phase 1B trial of ADI‑PEG 20 in combination with Radiotherapy and Temozolomide for the treatment of Newly Diagnosed Glioblastoma Multiforme (GBM) (Press release, Polaris Pharmaceuticals, SEP 17, 2020, View Source [SID1234568214]). The Lead Investigator is Dr. Wei from Linkou Chang Gung Memorial Hospital. There will be 26 patients enrolled in this phase 1B trial.

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On September 17, 2020 Boehringer Ingelheim and Mirati Therapeutics, Inc. (NASDAQ: MRTX) reported a clinical collaboration to evaluate the combination of BI 1701963, a SOS1::pan-KRAS inhibitor blocking KRAS independent of mutation type, and MRTX849, a KRAS G12C selective inhibitor in patients with solid tumors that harbor the KRAS G12C mutation (Press release, Boehringer Ingelheim, SEP 17, 2020, View Source [SID1234565282]). The collaboration will investigate the potential of this combination to provide more effective and durable responses for patients with lung and colorectal cancers who currently have limited treatment options.

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Preclinical data suggest that the combination of a KRAS G12C inhibitor with a SOS1::pan-KRAS inhibitor results in increased anti-tumor activity based on the complementary mechanisms of these targeted oncology agents. By shifting the equilibrium from active KRAS(ON) towards the inactive KRAS(OFF) form, SOS1::pan-KRAS inhibitors have the potential to sensitize KRAS G12C mutant tumors to covalent KRAS G12C inhibitors that bind to KRAS(OFF).

"We look forward to collaborating with Boehringer Ingelheim to test this combination in clinical trials," said Joseph Leveque, M.D., Executive Vice President and Chief Medical Officer of Mirati Therapeutics, Inc. "This collaboration is aligned with the broad and aggressive development strategy we have for MRTX849 and brings the potential for another therapeutic option to patients with KRAS G12C mutations."

"We are excited to partner with Mirati in our ambition to make a difference for people living with KRAS-driven cancers. Combining our SOS1::pan-KRAS inhibitor with the mutation specific G12C inhibitor could be a win-win approach enhancing the response to therapy," said Victoria Zazulina, M.D., Global Medical Head for Oncology at Boehringer Ingelheim. "We have a comprehensive KRAS program including the first SOS1::pan-KRAS inhibitor in the clinic, BI 1701963, for which we are exploring several combinations to optimize its therapeutic benefit in broad patient populations."

Under the terms of the non-exclusive collaboration, Mirati will be the sponsor of the trial and Boehringer Ingelheim and Mirati will jointly share the costs of and oversee clinical development for the combined therapy.

About MRTX849
MRTX849 is an investigational, orally available small molecule that is designed to potently and selectively inhibit a form of KRAS, which harbors a substitution mutation (G12C). KRAS G12C mutations are present in approximately 14% of non-small cell lung cancer (NSCLC) adenocarcinoma patients, in 3-4% of colorectal cancer patients, and in subsets of other types of cancer. Tumors characterized by KRAS G12C mutations are commonly associated with poor prognosis and resistance to therapy, and patients with these mutations have few treatment options. MRTX849 is being evaluated in a Phase 1/2 trial treating patients with molecularly identified, KRAS G12C-positive advanced solid tumors and in the first quarter of 2020, enrollment began in the registration enabling cohort in monotherapy NSCLC, colorectal cancer and pancreatic cancer.

About BI 1701963
BI 1701963 is an investigational, orally available small molecule, that is designed to bind to the catalytic domain of SOS1 preventing the interaction with KRAS(OFF) and simultaneously blocking SOS1 driven feedback. This reduces the formation of KRAS(ON) and in consequence inhibits MAPK pathway signaling in KRAS-dependent cancers. The selective inhibition of SOS1 is a therapeutic concept that could allow KRAS blockade irrespective of KRAS mutation type (pan-KRAS approach). SOS1::KRAS inhibitors exhibit activity on a broad spectrum of KRAS alleles, including all major G12D/V/C and G13D oncoproteins, as recently published by Hofmann MH, et al. in Cancer Discovery, a journal of the American Association of Cancer Research (AACR) (Free AACR Whitepaper). BI 1701963 is currently being evaluated in a Phase I clinical trial in patients with advanced KRAS-mutated cancers to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and preliminary efficacy of BI 1701963 alone and in combination with MEK inhibitors.

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.