On June 24, 2021 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported that a first patient has been enrolled in a randomized, controlled Phase II study evaluating the combination of TG4001 with avelumab versus avelumab monotherapy in patients with HPV16-positive anogenital tumors (NCT: 03260023) (Press release, Transgene, JUN 24, 2021, View Source [SID1234584330]).

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TG4001 IS AN INVESTIGATIONAL THERAPEUTIC VACCINE TARGETING HPV-POSITIVE TUMORS, including cervical, anal, and other anogenital cancers. It is based on a Vaccinia vector (MVA), which is engineered to express HPV16 E6 and E7 antigens and interleukin 2 (IL-2). TG4001 is designed to alert the immune system specifically to cells presenting these HPV antigens (that can be found on HPV-related tumors) and to induce a specific cellular immune response against these cancer cells.

Based on promising data obtained in the Phase Ib/II part of the trial, Transgene is progressing the development of TG4001 in combination with avelumab, through a randomized Phase II trial and an extended collaboration with the alliance of Merck KGaA, Darmstadt, Germany, and Pfizer, which is supplying avelumab.

PHASE II TRIAL AIMS TO SHOW THE SUPERIORITY OF TG4001 + AVELUMAB OVER AVELUMAB MONOTHERAPY

The randomized Phase II trial is focusing on patients with recurrent or metastatic HPV16-positive anogenital cancer, including cervical, vulvar, vaginal, penile, and anal cancer, without liver metastases. In the Phase Ib/II part of the study, very encouraging clinical outcome was observed in patients without liver metastases [1,2].

Patients will be randomized to either receive the combination regimen of the therapeutic vaccine TG4001 and avelumab or avelumab alone. The trial will be enrolling patients in the USA and in Europe (France and Spain).

The primary endpoint of the trial is progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and a series of immunological parameters.

An interim analysis will be performed after the enrollment of approximately 50 patients. Transgene expects to communicate interim analysis data around the end of 2022.

Dr. Maud Brandely, MD, PhD, Chief Medical Officer of Transgene, added: "We are confident that the combination regimen of TG4001 and avelumab has the potential to deliver improved progression-free survival for patients with advanced/recurrent HPV16-positive anogenital cancer without liver metastases. This confidence is based on the very encouraging results from the initial Phase Ib/II study, which showed important clinical benefits in this patient population in terms of response rate and progression-free survival. This earlier study part also showed that patients had vaccine-induced reactive T cells against E6, E7 or both. This randomized trial has been designed to further demonstrate that the addition of TG4001 to an immune checkpoint inhibitor can improve the clinical outcome for patients with HPV16-positive anogenital cancer without liver metastases. We are looking forward to announcing the interim results from this expanded study which could be a key milestone in bringing TG4001 to patients in need of improved treatment options."

About the trial
The multi-center, open label, randomized Phase II trial (NCT03260023) is designed to compare the efficacy of the combination of TG4001 and avelumab versus avelumab alone in patients with HPV16-positive anogenital cancers who have disease progression after a maximum of one line of systemic treatment for recurrent/metastatic disease, or who are not eligible for first-line chemotherapy.

Prof. Christophe Le Tourneau, M.D., PhD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, is the Principal Investigator of the study. The trial is being conducted in collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer Inc. (NYSE: PFE), which are providing avelumab for the trial. Avelumab is co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc. Transgene will continue to be the sponsor of the trial and conduct the trial.

Patients will receive TG4001 at the dose of 5×107 plaque-forming units (pfu), subcutaneously (SC), weekly for 6 weeks, every 2 weeks up to six months, and every 12 weeks thereafter, in combination with avelumab or avelumab alone at 800 mg, intravenously (IV) every two weeks, until disease progression. The primary endpoint of the trial is progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and other immunological parameters. The trial could enroll approximately 150 patients until the final analysis.

Patients with liver metastases will be followed in an ancillary arm and will not be included in the primary analyses.

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About the data presented at SITC (Free SITC Whitepaper) 2020 and ESMO (Free ESMO Whitepaper) IO 2020 [1,2]
The results from the Phase Ib/II parts of the trial combining TG4001 with avelumab in HPV16-positive recurrent and/or metastatic malignancies were presented at SITC (Free SITC Whitepaper) 2020 [1] and ESMO (Free ESMO Whitepaper) IO 2020[2].

The combination of TG4001 and avelumab demonstrated anti-tumor activity (23.5% ORR) in patients with previously treated recurrent and/or metastatic HPV-related cancers (including patients with oropharyngeal cancers and anogenital cancers). Presence of liver metastases had a profound impact on the outcome in terms of ORR and PFS. In patients without liver metastases, an ORR of 34.8% and a median PFS of 5.6 months were achieved. The treatment induced HPV-specific T-cell responses and was associated with increased levels of immune cell infiltration in the tumors and expression of genes associated with activation of the immune system.

About TG4001
TG4001 is an investigational therapeutic vaccine based on a non-propagative, highly attenuated Vaccinia vector (MVA), which is engineered to express HPV16 antigens (E6 & E7) and an adjuvant (IL-2). TG4001 is designed to have a two-pronged antiviral approach: to alert the immune system specifically to cells presenting the HPV16 E6 and E7 antigens, that can be found in HPV16-related tumors, and to further stimulate the infection-clearing activity of the immune system through interleukin 2 (IL-2). TG4001 has been administered to more than 300 individuals, demonstrating good safety and promising efficacy results [1, 2]. Its mechanism of action and good safety profile make TG4001 an excellent candidate for combinations with other therapies in HPV-mediated solid tumors.

On June 24, 2021 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a biotechnology company focused on developing cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box , reported the efforts being undertaken by the Company to have the U.S. Food and Drug Administration (FDA) clinical hold lifted (Press release, PharmaCyte Biotech, JUN 24, 2021, View Source [SID1234584329]). These efforts are necessary so that PharmaCyte may proceed with its planned clinical trial in locally advanced, inoperable, pancreatic cancer (LAPC).

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The Company’s Chief Executive Officer, Kenneth L. Waggoner, discussed the background of the clinical hold stating, "On September 1, 2020, the Company submitted an Investigational New Drug Application (IND) to the FDA for our planned Phase 2b clinical trial in LAPC. On October 1, 2020, the Company received notice from the FDA that it had placed our IND on clinical hold. And on October 30, 2020, the FDA sent a letter to us setting forth the reasons for the clinical hold and specific guidance on what we must do to have the clinical hold lifted."

For the purpose of addressing the clinical hold, the Company has assembled a team of regulatory and scientific experts to respond to the items requested by the FDA. That team has been actively working to complete the list of items requested by the FDA. Those items can be found on pages 28 and 29 of PharmaCyte’s latest Form 10-Q for the period ending January 31, 2021.

Mr. Waggoner then explained, "The Company is in varying stages of addressing the studies and acquiring the information requested by the FDA to have the clinical hold lifted. Thus far:

The Company has successfully completed a 3, 6, 9, and 12-month product stability study on the Company’s clinical trial product (CypCaps), including container closure integrity testing for certain timepoints; the next time point in this ongoing study will be at 18 months of product stability.
The Company has designed and commenced various additional studies recommended by the FDA, including a stability study on the cells from the Master Cell Bank (MCB) used to make the CypCaps, which are already at the 3-year stability timepoint, and further sequence analysis of the DNA encoding of the Cyp2B1 gene in the encapsulated cells in the CypCaps. It has also collated existing information on the reproducibility and quality of the filling of the MCB cells into vials ready for CypCaps manufacturing as requested by the FDA.
The Company has designed and commenced biocompatibility studies such as (i) a Subchronic and Chronic Toxicity study; (ii) a Skin Sensitization study; (iii) an Acute Systematic Toxicity study; (iv) an Ames test [Genotoxicity Bacteria and Reverse Mutation tests]; (v) an Intracutaneous test; (vi) a Complement Activation test; (vii) a Hemolysis test; (viii) an In Vitro Cytotoxicity test; and (ix) an In Vivo Micronucleus assay. To enable these tests to be performed, the Company has already manufactured and delivered an additional 400 syringes of empty capsules. Some of the data being generated will also be used to demonstrate comparability with the CypCaps successfully used—in two earlier German clinical trials for pancreatic cancer.
The Company has designed and commenced studies designed to show that CypCaps are not in any way adversely affected by the catheters used by interventional radiologists to deliver them, nor by the contract media used to visualize the blood vessels during implantation of the CypCaps. Further, the studies are designed to demonstrate how robust the CypCaps are during delivery and use as well as to document that the syringes used to deliver the CypCaps will allow delivery consistently, smoothly and safely.
Austrianova is providing additional detailed confidential information to the FDA on the manufacturing process, including information on the improvements made to the product since the last clinical trials with respect to reproducibility and safety, but that have not changed the overall physical characteristics of the CypCaps. The Company is supporting Austrianova in this work.
The Company is in the process of updating its documentation to include (i) more pre-clinical data as discussed above, (ii) some additional parameters for release of the CypCaps, (iii) specifically recommending the catheters and contrast used to deliver the CypCaps as well as (iv) extending its discussion on immunology.
Finally, the Company has designed an abbreviated study in pigs to address biocompatibility and long-term implantation of the capsules. This animal study will complement the positive data already available from the previous human clinical trials showing the safety of CypCaps implantation for up to two years in humans.
The Company feels that the carcinogenicity data obtained to date, together with the long-term data from the two previous German trials, show that CypCaps are unlikely to cause any long-term cancer. Furthermore, the patients who will be treated with CypCaps are already suffering with inoperable, late-stage pancreatic cancer, and chemotherapeutics, like ifosfamide, (the drug given at low concentrations with the CypCaps), are approved for treatment of cancer even through it is known to have a carcinogenic potential. Indeed, virtually all anti-cancer treatments used today by their very nature have an inherent potential to cause cancer. Moreover, the cells within the CypCaps are primed by ifosfamide to commit cell suicide if they try to divide."
Mr. Waggoner continued, "The list of items that we have been addressing is lengthy, time consuming and costly. Some of the studies required by the FDA caused us to find suitable partners and Contract Research Organizations to assist us in the work. But our team has been working tirelessly on every item and will continue to do so until we have done all that we can to satisfy the FDA requests. In addition, we plan to request a meeting with the FDA for further guidance and to update them on the progress that we have made.

"As we continue to reach milestones on the requested studies, we will strive to report on the material developments that we believe will allow us to get the clinical hold lifted."

To learn more about PharmaCyte’s pancreatic cancer therapy and how it works inside the body to treat locally advanced inoperable pancreatic cancer, we encourage you to watch PharmaCyte’s documentary video complete with medical animations at: View Source

On June 24, 2021 Prothena Corporation plc (NASDAQ:PRTA), a late-stage clinical company with a robust pipeline of novel investigational therapeutics built on protein dysregulation expertise, reported that Bristol Myers Squibb exercised its option under the global neuroscience research and development collaboration to enter into an exclusive U.S. license for PRX005 and will pay Prothena $80 million (Press release, Prothena, JUN 24, 2021, View Source [SID1234584328]). PRX005 is designed to be a best-in-class anti-tau antibody by specifically targeting an area within the microtubule binding region (MTBR) for the potential treatment of Alzheimer’s disease (AD). Phase 1 study with PRX005 has initiated.

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"Our continued collaboration with Bristol Myers Squibb on PRX005 allows us to further leverage our combined expertise to accelerate the development of therapies with the potential to transform the lives of those affected by neurodegeneration," said Gene Kinney, PhD, President and Chief Executive Officer of Prothena. "Mounting scientific evidence suggests the MTBR of tau is most closely associated with the pathogenic spread of tau. The presence of MTBR fragments in cerebrospinal fluid have also been shown to correlate with dementia stages in Alzheimer’s disease to a higher degree than fragments of other tau regions. These recent biological understandings support the further development of PRX005, which uniquely targets a key region within the MTBR of the tau protein. In our studies, we have found that targeting specific regions within the MTBR reduce pathogenic tau uptake into neurons, an attribute that was not achievable with antibodies targeting other regions of tau."

"We are pleased that our collaboration with Prothena has successfully identified and developed PRX005, a novel, differentiated anti-tau antibody that we believe has the potential to provide a meaningful disease modifying treatment option for the millions of patients that suffer from Alzheimer’s disease," said Richard Hargreaves, Senior Vice President and Head of Bristol Myers Squibb’s Neuroscience Thematic Research Center. "We look forward to our continued partnership with Prothena."

Tau is a microtubule associated protein, which aggregates and hyper-phospohrylates in the brains of individuals with AD to form pathological neurofibrillary tangles. Tau tangles, along with amyloid beta plaques represent the pathological hallmarks of AD. The presence of tau pathology strongly correlates with neurodegeneration and cognitive impairment in AD and its pattern of progression throughout the brain suggests that tau pathology spreads through anatomically connected pathways via cell-to-cell transmission, a hypothesis supported by multiple preclinical studies. This propagation of pathology is thought to be mediated by tau "seeds" containing the MTBR of tau. PRX005 has demonstrated superior ability to bind, intercept and block cellular internalization of pathogenic tau, and mitigate downstream neurotoxicity compared to other anti-tau antibodies in multiple preclinical studies.

About the Global Neuroscience Research and Development Collaboration

This global neuroscience research and development collaboration is focused on three proteins implicated in the pathogenesis of several neurodegenerative diseases, including tau, TDP-43 and an undisclosed target. PRX005 is designed to be a best-in-class anti-tau, MTBR-specific antibody for the potential treatment of Alzheimer’s disease and is the first program to advance to the clinic from this collaboration, where the Phase 1 study has initiated. With this payment, Prothena will have received a total of $230 million pursuant to the collaboration, and is eligible to receive up to an additional $160 million for U.S. rights, up to $165 million for global rights, and up to $1.7 billion for regulatory and commercial milestone payments for a total of up to $2.2 billion plus potential tiered commercial sales royalties across multiple programs.

About PRX005 for Alzheimer’s Disease

PRX005 is designed to be a best-in-class anti-tau antibody that specifically targets a key region within the microtubule binding region (MTBR), which has been shown in preclinical studies to be involved in the pathological spread of tau. Neurofibrillary tangles composed of misfolded tau proteins, along with amyloid beta plaques, are pathological hallmarks of Alzheimer’s disease (AD). Cell-to-cell transmission of pathogenic extracellular tau and the accumulation of pathogenic tau also correlate with the progression of symptomatology and clinical decline in patients with AD. Recent publications suggest that during the course of AD progression, tau appears to spread throughout the brain via synaptically-connected pathways; this propagation of pathology is thought to be mediated by tau "seeds" containing the MTBR of tau. Additionally, it has been recently reported that the presence of MTBR fragments in cerebrospinal fluid correlate with dementia stages in AD to a higher degree than fragments of other tau regions. In preclinical research, antibodies targeting this region of tau were superior in blocking tau uptake and neurotoxicity, which has been associated with efficacy in AD animal models. In these preclinical models, PRX005 demonstrated significant inhibition of cell-to-cell transmission and neuronal internalization in vitro and in vivo and slowed pathological progression in a tau transgenic mouse model.

About Alzheimer’s Disease

Alzheimer’s disease is a type of dementia that can cause increasingly serious symptoms, including confusion, disorientation, mood and behavioral changes, difficulty speaking, swallowing, and walking. Approximately 6.2 million Americans age 65 and older are currently estimated to be living with Alzheimer’s disease, making it the most common neurodegenerative disorder. It is also the sixth leading cause of death among adults in the United States. There is an urgent need for therapies that slow the progression and ultimately prevent Alzheimer’s disease to address this global healthcare crisis. Prothena’s Alzheimer’s disease portfolio spans next generation antibody immunotherapy, small molecule and vaccine approaches, geared toward building upon first generation treatments to advance the treatment paradigm.

On June 24, 2021 Starpharma (ASX: SPL, OTCQX: SPHRY) reported that a presentation by Dr Jackie Fairley, CEO, reported that it will be broadcast on Thursday 24 June 2021 (US ET) as part of OTCQX’s Virtual Life Sciences Investor Forum (Press release, Starpharma, JUN 24, 2021, View Source;mc_eid=bf52dd3418 [SID1234584327]). The Life Sciences Investor Forum is a leading investor conference that is attended by tens of thousands of investors, primarily US-based retail investors, as well as advisors.

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Details of the forum are found via this link: Virtual Life Sciences Investor Forum. Starpharma’s pre-recorded presentation features a company overview, including the latest updates on the VIRALEZE Antiviral Nasal Spray which has shown potent antiviral activity against multiple variants of coronavirus/SARS-CoV-2 in laboratory studies, and has been registered in Europe (launched) and India. The presentation will also include an overview of Starpharma’s DEP clinical-stage and preclinical assets, and corporate partnerships for its DEP drug delivery platform, including with Merck & Co., Inc (MSD) and AstraZeneca, as well as its VivaGel products, which are approved in more than 45 countries. The presentation is attached and also available on Starpharma’s website.

On June 24, 2021 Sirnaomics, Inc., a biopharmaceutical company engaged in the discovery and development of RNAi therapeutics against cancer and fibrotic diseases, reported that dose administration for the first patient in a Phase 1 U.S. clinical study for liver cancer treatment, with the company’s siRNA (small interfering RNA) drug candidate, STP705 (Press release, Sirnaomics, JUN 24, 2021, View Source [SID1234584326]). STP705 takes advantage of a dual-targeted inhibitory property and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expression.

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This Phase 1 trial is a multicenter, open-Label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of STP705, with an intratumoral administration. In this "basket study" of up to 50 subjects suffering from cholangiocarcinoma, hepatocellular carcinoma, or liver metastases from colorectal cancer, the patients with advanced/metastatic or surgically unresectable solid tumors and are refractory to standard therapy will be treated with STP705. This therapeutic regimen is designed to take advantage of a dual-targeted inhibitory property of siRNAs and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expressions. Early pre-clinical and clinical studies using STP705 have shown an increase of active T cell infiltration into the tumor microenvironment. In addition, knocking down TGF-β1 and COX-2 gene expressions in animal fibrosis tissue can activate fibroblast apoptosis with significant antifibrotic efficacy.

"Advancing STP705 from skin cancer to liver cancer is a major milestone for Sirnaomics’ clinical programs, especially with a basket study design that consists of multiple tumor types. We are particularly interested in learning whether the mechanism of action validated in the skin cancer clinical study can be further verified in this liver cancer study," said Patrick Lu, Ph.D., founder, President and Chief Executive Officer of Sirnaomics. "We are expecting that the combination of anti-fibrotic effects and enhanced tumor immunity will provide a novel approach for the treatment of cholangiocarcinoma and hepatocellular carcinoma using our novel siRNA therapeutics. Sirnaomics is committed to advancing our polypeptide nanoparticle delivery system for innovative RNAi-based cancer therapy."

"Liver cancer is a devastating disease for patients with high mortality and high unmet medical need," stated Michael Molyneaux, MD, Chief Medical Officer of Sirnaomics. "The company is excited to announce first dosing, as we hope to gain important insight into the potential safety and efficacy of STP705 in this Phase 1 trial and build on the data from this study to expand into other oncology indications."

Sirnaomics expects to report initial clinical data from the Phase 1 trial in the second half of 2021. Additional information about this clinical trial is available at clinicaltrials.gov using the identifier: NCT04676633

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About Liver Cancer

Liver cancer is a global health problem, with liver neoplasms representing the second-most frequent cause of cancer-related death. There are many different types of liver cancers including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), liver angiosarcoma, hepatoblastoma and others. Additionally, liver is a highly metastasis-permissive organ. It is the most frequently afflicted organ by metastasis and liver metastases are much more common than primary hepatic tumors. The distinctive biology of the liver renders it intrinsically susceptible to metastases. The true prevalence of liver metastasis is unknown, but between 30% and 70% of patients dying of cancer have liver metastases and most patients with liver metastases will die of their disease.

STP705 and Liver Cancer

Over expressions of TGF-β1 and COX-2 have been well-characterized as playing key regulatory roles in tumorigenesis. TGF-β is produced by different liver cells and is demonstrated to induce tumor cell migration and survival. TGF-β has been found to be overexpressed in metastatic HCC tissues. Overexpression of TGF-β is generally accepted to be associated with metastasis and poor prognosis. COX-2 is reported to be highly expressed in cancer stem cells and promotes cell migration in HCC cell lines. Additionally, inhibition of COX-2 suppresses cell migration and induces apoptosis. As such TGF-β1 and COX-2 are excellent therapeutic targets for treatment of liver cancer.

STP705 is composed of two siRNA oligonucleotides targeting TGF-β1 and COX-2 mRNA respectively and formulated in nanoparticles with a proprietary Histidine-Lysine Co-Polymer (HKP) peptide. Each individual siRNA has demonstrated the ability to inhibit the expression of their target mRNA and combining the two siRNAs produces a synergistic effect that diminishes pro-fibrogenic, pro-inflammatory, and pro-tumorigenic factors. Sirnaomics has completed several pre-clinical studies that demonstrate that inhibition of TGF-β1 and COX-2 is expected to result in the inhibition of tumor growth and provide an alternative approach for the treatment of various liver cancers. Molecular analyses of the effects of administering the combination demonstrated that the inhibition of these targets had effects on downstream gene products associated with numerous oncology targets.

Additional immunohistochemistry and image analyses of the liver and tumor tissues demonstrated that animals treated with STP705 resulted in increased CD4+ and CD8+ T cell infiltration within the tumor microenvironment. Using STP705 for treatments of hepatocellular carcinoma and cholangiocarcinoma have been designated as Orphan Drug indications by U.S. FDA. STP705 has also been evaluated in a Phase 2a clinical trial for treatment of Non-melanoma skin cancer.