On March 12, 2020 Kymera Therapeutics Inc., a biotechnology company pioneering targeted protein degradation to invent breakthrough protein degrader medicines for patients, reported the closing of a $102 million Series C financing (Press release, Kymera Therapeutics, MAR 12, 2020, View Source [SID1234555448]). The round was led by Biotechnology Value Fund (BVF) and Redmile Group with participation from Wellington Management Company, Bain Capital Life Sciences, funds managed by Janus Henderson Investors and BlackRock, Rock Springs Capital and a large US-based, healthcare-focused fund. Existing investors also participated in the round.

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Kymera also received a strategic investment from The Leukemia & Lymphoma Society‘s Therapy Acceleration Program (LLS TAP) directed toward advancing the company’s work to treat blood-based cancers.

"We are very excited to be joined by a top-tier group of investors as we continue on our path to become a fully integrated biotech company," said Nello Mainolfi, PhD, co-founder, President and CEO of Kymera Therapeutics. "We are well capitalized to advance up to three programs to the clinic by next year, while we continue to enhance our best-in-class platform to unlock new biology and invent new medicines."

Kymera’s Pegasus targeted protein degradation platform harnesses the body’s natural protein recycling machinery to degrade disease-causing proteins, with a focus on un-drugged nodes in validated pathways currently inaccessible with conventional therapeutics.

Kymera‘s lead program targets IRAK4, a protein known to play a significant role in inflammation mediated by toll-like and IL-1 receptors. Kymera is planning to advance its IRAK4 degrader program in a variety of autoinflammatory and autoimmune diseases, as well as in precision-medicine targeted oncology indications. The company is also developing novel protein degrader therapies to target STAT3, an un-drugged oncogenic transcription factor as well as a driver of inflammation and fibrosis, in a range of cancers and chronic diseases.

"Targeted protein degradation is one of the most promising new therapeutic modalities, with the potential to transform medicine as we know it. Kymera is leading the way with an incredible team, a sophisticated drug discovery platform and important new protein degrader therapies designed to address the most elusive drug targets" said Bruce Booth, DPhil, co-founder, Chairman of the Board of Kymera Therapeutics and partner at Atlas Venture.

On March 12, 2020 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported high-level results from the Phase III GY004 trial, led by NRG Oncology and sponsored by the US National Cancer Institute (NCI), that examined primarily the efficacy and safety of the potential new medicine cediranib added to Lynparza (olaparib) versus platinum-based chemotherapy in patients with platinum-sensitive relapsed ovarian cancer (Press release, AstraZeneca, MAR 12, 2020, View Source [SID1234555443]). Ovarian cancer is the eighth most common cause of death from cancer in women worldwide.

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The trial did not meet the primary endpoint in the intent-to-treat (ITT) population of a statistically significant improvement in progression-free survival (PFS) with cediranib added to Lynparza versus platinum-based chemotherapy. Cediranib is an oral vascular endothelial growth factor receptor (VEGFR) inhibitor, which blocks the growth of blood vessels supporting tumour growth.

José Baselga, Executive Vice President, Oncology R&D, said: "Despite these disappointing results, we remain committed to expanding on the benefits already demonstrated with Lynparza for patients with advanced ovarian cancer. We will work closely with NRG Oncology and the NCI to review the full results to inform our ongoing research."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Ovarian cancer is one of the most difficult tumours to diagnose and treat early. AstraZeneca, MSD and our partners will continue to explore ways to help patients through our joint clinical trial development programme."

The safety and tolerability profiles observed in GY004 were generally consistent with those known for each medicine.

The NCI and NRG Oncology will present the full data at a forthcoming medical meeting.

Ovarian cancer

Ovarian cancer is the eighth most common cause of death from cancer in women worldwide.1 In 2018, there were nearly 300,000 new cases diagnosed2 and around 185,000 deaths.1 Most women are diagnosed with advanced (Stage III or IV) ovarian cancer and have a five-year survival rate of approximately 30%.3 The primary aim of treatment in relapsed ovarian cancer is to delay progression of the disease for as long as possible, therefore increasing the time to re-initiation of chemotherapy with its associated toxicities, and maintaining quality of life for these patients.4,5,6

GY004

GY004 is an open-label, randomised, multicentre, Phase III trial testing the efficacy and safety of the potential new medicine cediranib added to Lynparza, versus Lynparza monotherapy versus standard platinum-based chemotherapy in patients with recurrent platinum-sensitive ovarian cancer, fallopian tube, or primary peritoneal cancer patients, with or without a BRCA mutation.

The GY004 trial is led by NRG Oncology, a non-profit research organisation funded by the NCI, in collaboration with AstraZeneca. The NCI is part of the National Institutes of Health. AstraZeneca provided both cediranib and Lynparza to support the trial through a Cooperative Research and Development Agreement with the NCI.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair, such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in 73 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 58 countries, including the US and Japan, for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. In 2019, Lynparza was additionally approved in the US for the treatment of germline BRCA-mutated metastatic pancreatic cancer. Regulatory reviews are underway in other jurisdictions for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for the treatment of advanced ovarian cancer, metastatic breast cancer and pancreatic cancer. It has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical-trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

Cediranib

Cediranib is an oral vascular endothelial growth factor (VEGF) receptor inhibitor that has demonstrated efficacy as a monotherapy and in combination in various cancers. Cediranib has shown anti-tumour activity in many cancers, including ovarian, breast, colorectal, renal, lung, sarcoma and glioblastoma. Cediranib is being evaluated in combination with Lynparza in advanced ovarian cancer in the Phase II CONCERTO trial, Phase II/III GY005 trial (sponsored by the NCI) and Phase III ICON9 trial (sponsored by University College, London).

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On March 11, 2020, IDEAYA Biosciences, Inc. (the "Company") entered into a Clinical Trial Collaboration and Supply Agreement (the "Agreement") with Pfizer Inc. ("Pfizer"), pursuant to which the Company and Pfizer will collaborate on a portion of the Company’s Phase 1/2 study in Metastatic Uveal Melanoma (MUM) and other solid tumors harboring activating GNAQ or GNA11 hotspot mutations, in each case pertaining to the clinical evaluation of the Company’s IDE196 compound in combination with Pfizer’s MEK inhibitor, binimetinib (the "Combination Study") (Filing, 8-K, Ideaya Biosciences, MAR 11, 2020, View Source [SID1234555643]). Pursuant to the Agreement, the Company is the sponsor of the Combination Study and the Company will provide the Company’s IDE196 compound and will pay for the costs of the Combination Study. Pfizer will provide binimetinib for the Combination Study at no cost to the Company. The Company and Pfizer will jointly own clinical data from the Combination Study and all inventions relating to the combined use of IDE196 and binimetinib. The Company and Pfizer will form a joint development committee responsible for coordinating all regulatory and other activities under the Agreement.

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On March 11, 2020 Cofactor Genomics reported that Tumor-infiltrating lymphocytes (TILs) are lymphocytes that directly infiltrate the tumor microenvironment (TME) opposing or surrounding tumor cells and in some cases subsets of cancer-reactive T-cells with killing activity clonally expand and mount an anti-tumor response (Press release, Cofactor Genomics, MAR 11, 2020, View Source [SID1234555565]). The degree of TIL infiltration is measured by both the extent and density of the TIL infiltrate using standardized systems that have been defined for objective grading of the degree of infiltration.¹ Accurate TIL measurement is critical as the extent of infiltration has been associated with favorable outcomes for a variety of tumors.2,3,4 Furthermore, the revolutionary emergence of immune checkpoint inhibition to treat cancers is limited to tumors that exhibit endogenous populations of TILs at sufficient frequencies that can be sufficiently reinvigorated to recognize tumor antigens and mediate tumor killing. For tumors where the extant population of TILs is absent or fails to function, other immune modulating therapies such as adoptive T-cell transfer, engineered T-cell therapies or cancer vaccines can be used to augment the native TIL population in the anti-tumor response. Accordingly, measurement of tumor-infiltrating lymphocytes infiltration is key to informing the most effective therapeutic options and patient outcomes.

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In combination with tumor-infiltrating lymphocytes, PD-1/PD-L1 expression is also a common parameter for evaluating the tumor microenvironment (TME).5 Though the importance of PD-1/PD-L1 expression has been demonstrated in some cases (e.g., registration of pembrolizumab for non-small cell lung cancer patients with PDL1 expression in >50% of analyzed tumor cells6), its well-established variability, both temporally and spatially, limits its applicability as a predictor of response. Indeed, it is likely that PD-1/PD-L1 expression is just one of many multivariates in the TME that mediate response and it has been suggested that more relevant correlates might include the overall mutational burden of the tumor (TMB) in addition to the clonal diversity of the tumor-infiltrating lymphocytes population and to the expression of PD-1/PD-L1 on the infiltrating lymphocytes themselves.7,8 Moreover, other important attributes of the TME, such as the presence of tumor-associated macrophages (TAMs) or myeloid-derived suppressor cells (MDSCs), are currently underestimated and not included in most of the currently used classifications of immune infiltrates.9

Immune checkpoint inhibitors and T-cell-based therapies, both adoptive and engineered, have unlocked new avenues to treat cancer. Due to their novel mechanism of action, these therapies are not associated with the traditional adverse events seen with cytotoxic chemotherapy.10,11 However, inhibition of checkpoint receptors/ligands and introduction of engineered T-cells (e.g., CAR-T) can lead to excessive immune system activation with the upregulation of T-cell proinflammatory responses, cytokine release syndrome, and immune effector cell-associated neurotoxicity syndrome.10,11 This activation of the immune system can result in immune-related adverse events and the precise exact mechanism of these has not been fully elucidated, but it is hypothesized that T-cell activity, autoantibodies, and proinflammatory cytokines likely contribute to their onset. Dermatologic, gastrointestinal, endocrine, and pulmonary-related immune-related adverse events are the most common, but they can manifest in any organ system.

Accurate assessment of immune cell infiltration in the tumor microenvironment, the subtypes of immune cells present, the expression levels of immune escape genes and the overall neoantigen load of the tumor (as estimated by TMB) are emerging as predictive variables that in combination might serve to better inform immunotherapy treatment decisions. It is likely that additional variates will emerge and when combined, enable the development of multidimensional biomarker with significantly enhanced predictive accuracy for treatment type, likelihood of response and potential for adverse events.

Cofactor has built an immune-profiling solution with ImmunoPrism, that allows many of these immune features to be measured, in parallel, from two sections of FFPE. Importantly, as described above, it’s unlikely that one single measurement provides sufficient context for understanding disease and therapy response, which is what drives us to use machine-learning to build multidimensional biomarkers.

On March 11, 2020 Checkpoint Therapeutics, Inc. ("Checkpoint") (NASDAQ: CKPT), a clinical-stage, immuno-oncology biopharmaceutical company focused on the acquisition, development and commercialization of novel treatments for patients with solid tumor cancers, reported financial results and recent corporate highlights for the full-year ended December 31, 2019 (Press release, Checkpoint Therapeutics, MAR 11, 2020, View Source [SID1234555507]).

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James F. Oliviero, President and Chief Executive Officer of Checkpoint, said, "Checkpoint achieved significant progress in 2019. Notably, we continued to advance the development of our lead antibody product candidate, cosibelimab, which is in an ongoing, multicenter, registration-enabling Phase 1 clinical trial intended to support a potential Biologics License Application ("BLA") submission for the initial indication of metastatic cutaneous squamous cell carcinoma ("CSCC"). Importantly, earlier this year, we announced confirmation by the FDA of the registration submission pathway in CSCC based on the ongoing clinical trial, which we are pleased to report is now over one-third enrolled. We also successfully closed on gross proceeds of approximately $20 million in a November financing to extend our cash runway to support these efforts." Mr. Oliviero continued, "We believe cosibelimab, upon approval, has the potential to be a market disrupting product through both its differentiated two-fold mechanism of action and our plan to enter the market at a price point substantially lower than the class of PD-1 and PD-L1 agents available today that generate over $25 billion in annual sales."

2019 and Recent Corporate Highlights:

In March 2019, Checkpoint announced two new patent issuances by the U.S. Patent and Trademark Office and the European Patent Office for CK-101, our third-generation epidermal growth factor receptor ("EGFR") inhibitor in Phase 1 development as a treatment for patients with EGFR mutation-positive non-small cell lung cancer ("NSCLC"). The patents cover CK-101 in the U.S. and Europe through at least August 2034, not including any potential patent term extensions.
In June 2019, Checkpoint was added to the Russell 2000 Index.
In September 2019, positive interim results for cosibelimab were presented at the European Society for Medical Oncology ("ESMO") Congress 2019 in Barcelona, Spain. The poster presentation provided updated interim efficacy and safety results from the ongoing multicenter Phase 1 clinical trial of cosibelimab, including expansion cohorts in CSCC and NSCLC. A 50% objective response rate was observed in CSCC and a 40% objective response rate was observed in NSCLC. Cosibelimab appeared to be safe and well-tolerated with a potentially favorable safety profile as compared to the currently available anti-PD-1 therapies.
In November 2019, pharmacokinetic and target occupancy modeling data for cosibelimab were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th Annual Meeting. The poster, titled "Semi-mechanistic PK and target-occupancy modeling to support dose justification for anti-PD-L1 clinical candidate CK-301 (TG-1501) in oncology patients," compared pharmacokinetic and tumor target occupancy data at steady state under various dosing regimens of cosibelimab to those of three marketed anti-PD-L1 monoclonal antibodies: atezolizumab, durvalumab and avelumab. The results demonstrated that cosibelimab dosed at 800 mg and 1,200 mg once every two weeks or every three weeks is expected to achieve over 99% PD-L1 target occupancy throughout the dosing interval, which is comparable to atezolizumab and durvalumab and higher than avelumab at approved doses.
Also in November 2019, Checkpoint closed on gross proceeds of approximately $19.6 million in an underwritten public offering of its common stock before deducting underwriting discounts and commissions and other offering-related expenses.
In January 2020, Checkpoint announced confirmation of the registration path for cosibelimab in metastatic CSCC. U.S. Food and Drug Administration feedback supports the plan to submit a BLA based on data from the ongoing Phase 1 trial. Approximately one-third of enrollment is complete as of year-end in the cohort of patients with metastatic CSCC.
Financial Results:

Cash Position: As of December 31, 2019, Checkpoint’s cash and cash equivalents totaled $26.1 million, compared to $22.0 million at December 31, 2018, an increase of $4.1 million.
R&D Expenses: Research and development expenses for the year ended December 31, 2019, were $19.3 million, compared to $33.7 million for the year ended December 31, 2018, a decrease of $14.4 million. Research and development expenses for the year ended December 31, 2019, included $3.2 million of non-cash stock expenses, compared to $1.8 million in stock compensation expense for the year ended December 31, 2018.
G&A Expenses: General and administrative expenses for the year ended December 31, 2019, were $7.2 million, compared to $6.6 million for the year ended December 31, 2018, an increase of $0.6 million. General and administrative expenses for the year ended December 31, 2019, included $3.2 million of non-cash stock expenses, compared to $2.7 million in stock compensation expense for the year ended December 31, 2018.
Net Loss: Net loss attributable to common stockholders for the year ended December 31, 2019, was $24.7 million, or $0.70 per share, compared to a net loss of $36.4 million, or $1.27 per share, for the year ended December 31, 2018.