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Ascendis Pharma A/S Announces Filing of Investigational New Drug Application to Initiate TransCon™ TLR7/8 Agonist Clinical Program

On December 30, 2020 Ascendis Pharma A/S (Nasdaq: ASND), a biopharmaceutical company that utilizes its innovative TransCon technologies to create product candidates that address unmet medical needs, reported the filing of an investigational new drug (IND) application with the U.S. Food and Drug Administration to initiate the clinical program of TransCon TLR7/8 Agonist (Press release, Ascendis Pharma, DEC 30, 2020, View Source [SID1234573331]).

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TransCon TLR7/8 Agonist is a long-acting prodrug of resiquimod, a small molecule agonist of Toll-like receptors (TLR) 7 and 8. Administered as an intratumoral injection, TransCon TLR7/8 Agonist is designed to provide sustained activation of intratumoral antigen presenting cells driving tumor antigen presentation and induction of immune stimulatory cytokines in the tumor.

"The filing of our first oncology IND for TransCon TLR7/8 Agonist – which is designed to provide intratumoral, sustained release of resiquimod over several weeks from a single administration with minimal systemic exposure and potent immune response against cancer cells – is a major milestone for Ascendis," said Juha Punnonen, M.D., Ph.D., Senior Vice President and Head of Oncology at Ascendis Pharma. "We believe TransCon TLR7/8 Agonist represents a potential paradigm shift in the treatment of cancer through sustained release of an immunostimulatory molecule over several weeks inside the tumor, thereby employing the patients’ own immune systems to destroy cancer cells with reduced risk of systemic adverse events."

About TransCon Technology

TransCon refers to "transient conjugation." The proprietary TransCon platform is an innovative technology to create new therapies that are designed to optimize therapeutic effect, including efficacy and safety and through dosing frequency. TransCon molecules have three components: an unmodified parent drug, an inert carrier that protects it, and a linker that temporarily binds the two. When bound, the carrier inactivates and shields the parent drug from clearance. When injected into the body, physiologic conditions (e.g., pH and temperature) initiate the release of the active, unmodified parent drug in a predictable manner. Because the parent drug is unmodified, its original mode of action is expected to be maintained. TransCon technology can be applied broadly to proteins, peptides or small molecules in multiple therapeutic areas, and can be designed for systemic or localized release.

TRACON Pharmaceuticals Announces Acceptance of the Envafolimab (KN035) NDA by the NMPA in China that was Submitted by its Corporate Partners Alphamab Oncology and 3D Medicines

On December 30, 2020 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted cancer therapeutics and utilizing a cost efficient, CRO-independent product development platform to partner with ex-U.S. companies to develop and commercialize innovative products in the U.S., reported its corporate partners, Alphamab Oncology and 3D Medicines, received notification that the Chinese National Medical Products Administration (NMPA) accepted for review the new drug application (NDA) for envafolimab (KN035) in the indication of MSI-H/dMMR cancer (Press release, Tracon Pharmaceuticals, DEC 30, 2020, View Source [SID1234573330]).

"We congratulate our partners on acceptance of the initial regulatory submission in China for approval of envafolimab in MSI-H/dMMR advanced solid tumors including colorectal and gastric cancer, which marks another important milestone in the development and potential commercialization of the program," said Charles Theuer, M.D., Ph.D., TRACON Chief Executive Officer. "The acceptance of the NDA for review by Chinese regulators highlights the advanced status of envafolimab product development. In addition to the registration trial in MSI-H/dMMR advanced solid tumors in China, Envafolimab is being studied in two other registration trials, a randomized Phase 3 trial in biliary tract cancer in China being conducted by 3D Medicines and Alphamab, and TRACON’s ENVASARC trial in sarcoma in the U.S., in which dosing was initiated earlier this month."

About Envafolimab (KN035)

Envafolimab (KN035), a novel, single-domain antibody against PD-L1, is the first subcutaneously injected PD-(L)1 inhibitor to be studied in registration trials. Envafolimab is currently being studied in the ENVASARC Phase 2 registration trial in the U.S. sponsored by TRACON, as well as in a Phase 2 registration trial as a single agent in MSI-H/dMMR advanced solid tumor patients and a Phase 3 registration trial in combination with gemcitabine and oxaliplatin in advanced biliary tract cancer patients in China sponsored by TRACON’s corporate partners, Alphamab Oncology and 3D Medicines. Alphamab Oncology and 3D Medicines submitted an NDA to the NMPA in China for envafolimab in MSI-H/dMMR cancer that was accepted for review in December 2020. In the Phase 2 registration trial, the confirmed objective response rate (ORR) by blinded independent central review in MSI-H/dMMR colorectal cancer (CRC) patients treated with envafolimab who failed a fluoropyrimidine, oxaliplatin and irinotecan was 32%, which was similar to the 28% confirmed ORR reported in the Opdivo package insert in MSI-H/dMMR CRC patients who failed a fluoropyrimidine, oxaliplatin, and irinotecan and the 33% confirmed ORR reported for Keytruda in MSI-H/dMMR CRC patients who failed a fluoropyrimidine, oxaliplatin and irinotecan in cohort A of KEYNOTE-164.

About ENVASARC (NCT04480502)

The ENVASARC registration trial is a multi-center, open-label, randomized, non-comparative, parallel cohort study at approximately 25 top cancer centers in the United States that began dosing in December 2020. TRACON expects the trial to enroll 160 patients with UPS or MFS who have progressed following one or two lines of prior treatment and have not received an immune checkpoint inhibitor, with 80 patients enrolled into cohort A of treatment with single agent envafolimab and 80 patients enrolled in cohort B of treatment with envafolimab and Yervoy. The primary endpoint is ORR by blinded independent central review with duration of response a key secondary endpoint.

Codiak Reports Positive Initial Phase 1 Results for exoIL-12™ Demonstrating Tolerability and Absence of Systemic IL-12 Exposure in Healthy Volunteers

On December 30, 2020 Codiak BioSciences, Inc. (NASDAQ: CDAK), a clinical-stage biopharmaceutical company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, reported that the primary objectives were met in the initial part of its Phase 1 trial, which evaluated a single ascending dose of exoIL-12 in healthy volunteers (Press release, Codiak Biosciences, DEC 30, 2020, View Source [SID1234573329]). In this randomized, placebo controlled, double-blind study, exoIL-12 demonstrated a favorable safety and tolerability profile, with no local or systemic treatment-related adverse events and no detectable systemic exposure of IL-12.

"This is an important milestone, as these results show that exoIL-12 acts in humans as we had expected, based on our preclinical evaluations. The safety and tolerability profile observed here support the target profile that we are hoping to achieve with this candidate," said Benny Sorensen, M.D., Ph.D., Senior Vice President and Head of Clinical Development, Codiak. "We’re looking forward to advancing exoIL-12 into the multi-dose part of the study in cutaneous T cell lymphoma patients and presenting the detailed results from the healthy volunteer part of this study at an upcoming medical conference."

exoIL-12 is the first engineered exosome therapeutic candidate to be evaluated in humans and one of two Codiak programs currently in clinical development. exoIL-12 was engineered using the company’s proprietary engEx Platform and designed to display functional IL-12 on the exosome surface using the exosomal protein, PTGFRN, as a scaffold, the capability of which was identified by Codiak scientists.

IL-12 is a potent anti-tumor cytokine, but prior clinical development conducted by others1 of recombinant IL-12 (rIL-12)-based therapies has generally been hindered by significant safety and tolerability concerns. To overcome these limitations, exoIL-12 was designed to facilitate dose control of IL-12 and limit systemic exposure and associated toxicity by localizing IL-12 in the tumor microenvironment (TME) in order to potentially expand the therapeutic index.

Initial Data from Healthy Volunteers

A total of five cohorts each with five subjects, randomized 3:2 active drug to placebo, were enrolled and dosed in the first part of the Phase 1 study. Each cohort received a subcutaneously administered single ascending dose of exoIL-12: 0.3 µg, 1.0 µg, 3.0 µg, 6.0 µg or 12.0 µg, respectively.

No treatment-related adverse events were observed throughout 10 days of follow-up. In particular, no chills, fever, fatigue, dizziness, myalgia, headache or back pain were reported. These symptoms have been observed in previous clinical studies of subcutaneously administered rIL-12 at comparable doses (ranging from 2 to 12 µg)1 to those used in Codiak’s study of exoIL-12.

Plasma pharmacokinetic (PK) measurements of subjects that received exoIL-12 showed no systemic exposure with levels of IL-12 below the limit of quantification. In contrast, previous rIL-12 clinical studies showed dose-dependent systemic exposure with dosages of 5 and 12 µg resulting in Cmax plasma levels of approximately 15 to 45 pg/ml within 6 to 12 hours after dosing.1

Codiak’s analyses of pharmacodynamic (PD) data from the healthy volunteer portion of the exoIL-12 trial, including skin IL-12 levels and IL-12 signaling from skin punch biopsies collected before and at 24 hours, Day 8 and Day 15 after subcutaneous administration around the injection site, are ongoing and are expected to be available in early Q1 2021. The company intends to use these results to identify an optimal pharmacological dose to carry forward into the second part of the trial, which is on track to begin in Q1 2021 and will evaluate repeat dosing of exoIL-12 in patients with early-stage cutaneous T cell lymphoma (CTCL).

exoIL-12 Development and Ongoing Phase 1 Clinical Trial

Codiak is initially focusing development of exoIL-12 on tumors that have previously shown clinical responses to IL-12 used as a monotherapy, such as CTCL. While the biological rationale for IL-12 as a cancer treatment has been validated in previous human clinical studies, its utility has been severely limited due to serious adverse events caused by systemic exposure.

Codiak has engineered exoIL-12 to display fully active IL-12 on the surface of the exosome, which is designed to facilitate potent local pharmacology at the tumor injection site with precisely quantified doses. Exosomal delivery has demonstrated limited systemic exposure to IL-12 in preclinical models and resulted in significant and prolonged PD activity and both local and systemic anti-tumor immune responses.

The Phase 1 clinical trial is designed in two parts to evaluate safety, tolerability, PK and PD of exoIL-12 after single, ascending, subcutaneous doses in healthy volunteers, followed by repeat dose exoIL-12 into the lesions of stage IA-IIB CTCL patients. Patients with CTCL will be monitored for safety, PK, and PD effects through analysis of blood and tumor biopsies, and for local and systemic anti-tumor efficacy using validated CTCL assessment criteria. Safety, biomarker and preliminary anti-tumor efficacy results from CTCL patients are anticipated in mid-2021.

About exoIL-12

exoIL-12 is Codiak’s exosome therapeutic candidate engineered to display fully active IL-12 on the surface of the exosome, using the exosomal protein, PTGFRN, as a scaffold, and designed to facilitate potent local pharmacology at the injection site with precisely quantified doses. By limiting systemic exposure of IL-12 and associated toxicity, Codiak hopes to enhance the therapeutic index with exoIL-12, delivering a more robust tumor response, dose control and an improved safety profile.

Codiak intends to focus development of exoIL-12 on tumors that have, in previous clinical testing, shown clinical responses to IL-12 used as a monotherapy. This includes cutaneous T cell lymphoma (CTCL), melanoma, Merkel cell carcinoma, Kaposi sarcoma, glioblastoma multiforme and triple negative breast cancer.

About the engEx Platform

Codiak’s proprietary engEx Platform is designed to enable the development of engineered exosome therapeutics for a wide spectrum of diseases and to manufacture them reproducibly and at scale to pharmaceutical standards. By leveraging the inherent biology, function and tolerability profile of exosomes, Codiak is developing engEx exosomes designed to carry and protect potent drug molecules, provide selective delivery and elicit the desired pharmacology at the desired tissue and cellular sites. Through its engEx Platform, Codiak seeks to direct tropism and distribution by engineering exosomes to carry on their surface specific targeting drug moieties, such as proteins, antibodies/fragments, and peptides, individually or in combination. Codiak scientists have identified two exosomal proteins that serve as surface and luminal scaffolds. By engineering the exosome surface or lumen and optimizing the route of administration, Codiak aims to deliver engEx exosomes to the desired cell and tissue to more selectively engage the drug target, potentially enhancing the therapeutic index by improving potency and reducing toxicity.

Incyte and Cellenkos Enter into Global Development Collaboration Agreement for CK0804

On December 30, 2020 Incyte (Nasdaq:INCY) and Cellenkos, Inc., a privately held, clinical stage biotech company, reported a development collaboration to investigate the combination of ruxolitinib (Jakafi) and CK0804, Cellenkos’ cryopreserved CXCR4 enriched, allogeneic, umbilical cord blood-derived T-regulatory cells, in patients with myelofibrosis (MF) (Press release, Incyte, DEC 30, 2020, View Source [SID1234573327]). In addition, Incyte has an exclusive option to acquire sole rights to develop and commercialize CK0804, and genetically-modified variants of CK0804, in benign and malignant hematology indications.

"This collaboration supports our continued commitment to developing new therapeutic options that may improve and expand treatment options for patients with MF, part of a group of rare blood cancers known as myeloproliferative neoplasms (MPNs)," said Steven Stein, M.D., Chief Medical Officer, Incyte. "We are excited to partner with Cellenkos to initiate this study as part of our LIMBER clinical development program, designed to evaluate new monotherapy and combination strategies for patients with MPNs."

"We are delighted to partner with Incyte, a global biopharmaceutical company, to further study and develop CK0804. Incyte’s investment in strong science and R&D excellence makes them an ideal partner to evaluate CK0804 in combination with ruxolitinib as a potential treatment for the many patients living with myelofibrosis, especially those who are transfusion dependent," said Tara Sadeghi, Vice President, Clinical Operations, Cellenkos, Inc. "Our innovative strategy of exploiting the CXCR4/CXCL12 axis to redirect the immune modulatory T-regulatory cells specifically to the diseased bone marrow holds the promise of resolving inflammation to allow for normal hematopoeisis resulting in clinical improvement. This collaboration is in line with our corporate strategy to partner with world-leading major pharma companies in order to maximize access to our innovative cellular medicines."

Per the terms of the agreement, the companies plan to initiate a Phase 1b single arm, open-label study evaluating ruxolitinib in combination with CK0804 in patients with MF. Incyte will fund the study, which will be operationalized by Cellenkos.

In addition, per the agreement, Incyte will have an option to acquire an exclusive global license to develop and commercialize the program. Upon exercising the global licensing option, Incyte would be responsible for all activities and costs associated with research, development and commercialization of the program. Cellenkos would be eligible to receive a $20 million licensing fee and, for each distinct product under the agreement, development, regulatory and sales milestones totaling up to $294.5 million as well as tiered royalties ranging from mid-single digit to low-double digits, if approved.

The collaboration is effective immediately.

About Myelofibrosis (MF)

MF is a rare, chronic blood cancer that is part of a group of diseases known as MPNs. In MF, scar tissue forms in the bone marrow and impairs its ability to produce normal blood cells. This can result in an enlarged spleen, and symptoms such as fatigue, itching and night sweats, which can impact a patient’s quality of life. About 16,000 to 18,500 people in the United States are living with MF.

About LIMBER

Incyte is a leader in the discovery and development of therapies for patients with myeloproliferative neoplasms (MPNs). The Leadership In MPNs BEyond Ruxolitinib (LIMBER) program is designed to evaluate multiple monotherapy and combination strategies to improve and expand treatments for patients with myeloproliferative neoplasms (MPNs). The program currently has three key areas of focus: development of a new, once-daily formulation of ruxolitinib; ruxolitinib-based combinations with new targets such as PI3Kδ, BET and ALK2; and new therapeutic options.

About Ruxolitinib (Jakafi)

Ruxolitinib (Jakafi) is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. FDA for the treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea, in adults with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF and for the treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States. Jakafi is a registered trademark of Incyte Corporation. Jakavi is a registered trademark of Novartis AG in countries outside the United States.

About CK0804

CK0804 is a novel allogenic cell therapy product consisting of T-regulatory cells that exploit the CXCR4/CXCL12 axis and are derived from clinical-grade umbilical cord blood units and manufactured using Cellenkos’ proprietary process. The product is cryopreserved and readily available off-the-shelf, without any requirement for HLA matching, and is infused intravenously. One manufacturing campaign can result in multiple doses of cryopreserved product that can be shipped to the clinical site, where it can be stored for an extended period or made available for immediate treatment, as needed.

Important Safety Information for Jakafi (ruxolitinib)

Jakafi can cause serious side effects, including:

Low blood counts: Jakafi (ruxolitinib) may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.

Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

Increases in cholesterol: You may have changes in your blood cholesterol levels. Your healthcare provider will do blood tests to check your cholesterol levels during your treatment with Jakafi.

The most common side effects of Jakafi include: for certain types of MF and PV – low platelet or low red blood cell counts, bruising, dizziness, headache, and diarrhea; and for acute GVHD – low platelet, red or white blood cell counts, infections, and fluid retention.

These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had hepatitis B, have or had liver or kidney problems, are on dialysis, have a high level of fat in your blood (high blood cholesterol or triglycerides), had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider.

Women should not take Jakafi while pregnant or planning to become pregnant. Do not breast-feed during treatment with Jakafi and for 2 weeks after the final dose.

Propanc Biopharma Advances POP1 Joint Research and Drug Discovery Program for Projected US$111.2B Global Metastatic Cancer Market

On December 30, 2020 Propanc Biopharma, Inc. (OTC: PPCB) ("Propanc" or the "Company"), a biopharmaceutical company developing novel cancer treatments for patients suffering from recurring and metastatic cancer, reported that the Proenzymes Optimization Project 1 ("POP1") joint research and drug discovery program advanced towards producing commercial scale quantities of the two proenzymes trypsinogen and chymotrypsinogen (Press release, Propanc, DEC 30, 2020, View Source [SID1234573326]). The Company’s product candidate is targeting the global metastatic cancer treatment market, projected to be worth US$111.2 Billion by 2027, according to current analysis by Emergen Research.

The program’s lead research scientist, Mr. Aitor González, synthesized and purified both proenzymes in the laboratory. Once purified, the proenzymes were lyophilized (freeze dried) and each formed a stable, dry white powder. Mr. González then determined the sequence of proteins of each proenzyme by mass spectrometry. He recently started to produce larger quantities of the proenzymes with the objective of establishing their combined anti-cancer effects against pancreatic and colorectal cancers. In addition, research activities were transferred to the MEDINA Foundation Research Center to scale up production. MEDINA is a Non-Profit Research Organization established in 2008 through a public-private alliance between the Regional Government of Andalusia, Spain, the pharmaceutical company Merck Sharp & Dohme de España S.A. (MSD), and the University of Granada. Medina’s scientific platforms support the development of multidisciplinary research programs in Microbiology, Natural Product Chemistry and Screening & Target Validation. For further information, please click on the following link: View Source

The POP1 program is designed to produce a backup clinical compound to the lead product candidate, PRP. The objective is to produce large quantities of trypsinogen and chymotrypsinogen for commercial use that exhibits minimal variation between lots and without sourcing the proenzymes from animals. Propanc is undertaking the challenging research project in collaboration with the Universities of Jaén and Granada, led by research scientist Mr. Aitor González, supported by Dr. Macarena Perán, Ph.D., representing the Universities and Propanc’s Chief Scientific Officer, Dr. Julian Kenyon, M.D.

Mr. James Nathanielsz, Propanc’s Chief Executive Officer said, "By expanding our product pipeline, our vision is to establish a new product class that provides a solution for the treatment and prevention of many recurring and spreading malignant tumors, perceived as untreatable, with less toxicity compared to standard treatments and no immune suppression. This is critical for patients who are at risk of dying from secondary infection, especially in the context of a global pandemic. Through our PRP development and POP1 drug discovery programs we are making positive steps towards achieving our vision."

"Despite a challenging year due to the global pandemic, we made significant advancements in producing synthetic recombinant versions of trypsinogen and chymotrypsinogen," said Dr. Julian Kenyon. "These two active pharmaceutical ingredients combine to form our lead product candidate, PRP, which are currently of animal origin. Our objective is to further stabilize and enhance the combined effects of the two proenzymes when administered to patients."