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On April 24, 2020 Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs, reported the pricing of the sale of 1,672,689 shares of common stock of OncoCyte Corporation at a price to buyers of $2.27 per share, representing the closing price of OncoCyte common stock on April 23, 2020 (Press release, Lineage Cell Therapeutics, APR 24, 2020, View Source [SID1234556581]). Net proceeds from the sale were approximately $3.7 million. The sale is expected to close by April 30, 2020, subject to certain closing conditions. Following the completion of the sale, Lineage will own approximately 4.3 million shares of OncoCyte. Based on the closing price of OncoCyte’s common stock on April 23, 2020, the value of Lineage’s remaining OncoCyte shares following the closing is approximately $9.7 million. Lineage has agreed not to sell additional shares of OncoCyte common stock prior to June 8, 2020 or unless the OncoCyte common stock price closes above $3.40.
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"In light of impacts to our industry from the COVID-19 pandemic, we have elected to make this sale to support our operations and maintain timelines," stated Brian M. Culley, Lineage CEO. "We believe this most recent transaction involving OncoCyte alongside our culture of focused and responsible spending will help us successfully navigate through this virus-related disruption. We are pleased that demand for OncoCyte shares was again available at market prices with no discount. Looking ahead, we look forward to providing our next OpRegen update at the upcoming 2020 ARVO Meeting, which will be hosted virtually via ARVOLearn."
On April 24, 2020 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported further positive results from the Phase III PROfound trial of Lynparza (olaparib) in men with metastatic castration-resistant prostate cancer (mCRPC) who have a homologous recombination repair gene mutation (HRRm) and have progressed on prior treatment with new hormonal agent (NHA) treatments (e.g. enzalutamide and abiraterone) (Press release, AstraZeneca, APR 24, 2020, View Source [SID1234556580]).
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Results from the trial showed a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival (OS) with Lynparza versus enzalutamide or abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations.
The Phase III PROfound trial had met its primary endpoint in August 2019, showing significantly improved radiographic progression-free survival (rPFS) in men with mutations in BRCA1/2 or ATM genes, and had met a key secondary endpoint of rPFS in the overall HRRm population.
José Baselga, Executive Vice President, Oncology R&D, said: "Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve. We are thrilled by these results for Lynparza and we are working with regulatory authorities to bring this medicine to patients as soon as possible."
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Lynparza has demonstrated significant clinical benefit across key endpoints in PROfound, including overall survival for patients with BRCA or ATM mutations, and this reinforces its potential to change the treatment standard for patients with metastatic castration-resistant prostate cancer. These data further support MSD and AstraZeneca’s commitment to uncovering the ways in which Lynparza can help patients impacted by cancer."
The safety and tolerability profile of Lynparza was generally consistent with previous trials. The data will be presented at a forthcoming medical meeting.
Lynparza was granted Priority Review in the US for patients with HRRm mCRPC in January 2020, with regulatory reviews ongoing in the EU and other jurisdictions. AstraZeneca and MSD are exploring additional trials in prostate cancer including the ongoing Phase III PROpel trial, with first data expected in 2021, testing Lynparza as a 1st-line medicine for patients with mCRPC in combination with abiraterone acetate versus abiraterone acetate alone.
Metastatic castration-resistant prostate cancer
Prostate cancer is the second-most common cancer in men, with an estimated 1.3 million new cases diagnosed worldwide in 2018, and is associated with a significant mortality rate.1 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.2 In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.2 Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.3 Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.3 Despite advances in treatment for men with mCRPC, five-year survival is low and extending survival remains a key goal for treating these men.3
HRR gene mutations
HRR mutations occur in approximately 20-30% of patients with mCRPC.4 HRR genes allow for accurate repair of damaged DNA in normal cells.5,6 HRR deficiency (HRD) means the DNA damage cannot be repaired, and can result in normal cell death.6 This is different in cancer cells, where a mutation in HRR pathways leads to abnormal cell growth and therefore
cancer.6 HRD is a well-documented target for PARP inhibitors, such as Lynparza. PARP inhibitors block a rescue DNA damage repair mechanism by trapping PARP bound to DNA single-strand breaks which leads to replication fork stalling causing their collapse and the generation of DNA double-strand breaks, which in turn lead to cancer cell death.6
PROfound
PROfound is a prospective, multicentre, randomised, open-label, Phase III trial testing the efficacy and safety of Lynparza versus enzalutamide or abiraterone in patients with mCRPC who have progressed on prior treatment with NHA treatments (abiraterone or enzalutamide) and have a qualifying tumour mutation in BRCA1/2, ATM or one of 12 other genes involved in the HRR pathway.
The trial was designed to analyse patients with HRRm genes in two cohorts: the primary endpoint was rPFS in those with mutations in BRCA1/2 or ATM genes and then, if Lynparza showed clinical benefit, a formal analysis was performed of the overall trial population of patients with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRRm genes; a key secondary endpoint).
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 a number of 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 the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. Lynparza is approved in the US and several other countries for the treatment of germline BRCA-mutated metastatic pancreatic cancer. Regulatory reviews are underway in several jurisdictions for ovarian, breast, pancreatic and prostate cancers.
Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, 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.
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 Koselugo (selumetinib), a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo 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 April 24, 2020 FUJIFILM Toyama Chemical Co., Ltd. (President: Junji Okada) reported that it has begun a phase I clinical trial of anticancer agent "FF-21101" in Japan, for the treatment of cancer patients with refractory advanced solid tumors, who have experienced a recurrence or remote metastasis (Press release, Fujifilm, APR 24, 2020, View Source [SID1234556574]). The study will evaluate the safety, tolerability, pharmacokinetics, and efficacy of FF-21101 for advanced ovarian, biliary tract, and head-and-neck solid tumor cancers.
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FUJIFILM Corporation developed FF-21101, which employs an antibody that conjugates radioisotope (RI) of yttrium (90Y)*1 (armed antibody*2). Through antigen-antibody reactions*3, FF-21101 accumulates selectively in cancer tissues that express the antigen P-cadherin*4, and specifically delivers radiation emitted by yttrium (90Y) to the cancer tissues. By targeting P-cadherin, the investigational therapy is expected to demonstrate efficacy in shrinking solid tumors.
In 2016, FUJIFILM Corporation began a U.S. clinical study of FF-21101 for the treatment of advanced solid tumors in cancer patients.
In addition to FF-21101, FUJIFILM Toyama Chemical is actively working to develop therapeutic radiopharmaceuticals such as F-1515 (lutetium [177Lu] DOTA-octreotate) for neuroendocrine tumors*5, and F-1614 (3-iodobenzylguanidine [131I]) for refractory pheochromocytoma*6, among others.
FUJIFILM Toyama Chemical is contributing to healthcare by striving to improve medicine and enhance the quality of life.
* 1 A radioisotope that emits radiation suited for treatment (beta rays). Its physical half-life is 64 hours.
* 2 An antibody that has been chemically linked with RI and toxins, it is expected to attack cancer tissues.
* 3 A phenomenon whereby antigens, such as foreign substances that have entered the body, or specific proteins that express in cancer, combine with the protein antibodies created by immune cells.
* 4 A protein that is known to express on the cell surface of numerous solid cancers and be involved in cancer’s proliferation and metastasis.
* 5 A tumor derived from neuroendocrine cells that distribute widely throughout the body. Although it develops in a variety of organs all over the body, it occurs especially frequently in the pancreas, digestive tract, and the lungs.
* 6 A neuroendocrine tumor that develops mainly from the adrenal medulla (a part of the adrenal gland located above the kidney, consisting of cells that secrete hormones).
On April 24, 2020 QIMR Berghofer Medical Research Institute reported that it has entered a research collaboration and licence agreement with Shanghai-based biopharmaceutical company EpimAb Biotherapeutics to develop bi-specific antibodies against immuno-oncology targets (Press release, QIMR Berghofer Medical Research Institute, APR 24, 2020, View Source [SID1234556536]).
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The novel targets were identified by QIMR Berghofer visiting scientist Professor Bill Dougall and the Coordinator of the Institute’s Immunology Department, Professor Mark Smyth.
Under the agreement, the researchers will test antibodies that act on two immune targets simultaneously using EpimAb’s platform Fabs-In-Tandem Immunoglobulin (FIT-Ig).
Under the terms of the agreement, EpimAb has been granted an exclusive licence to develop the bi-specific antibodies.
QIMR Berghofer’s Acting Director and CEO, Professor David Whiteman AM, welcomed the agreement.
"Professors Bill Dougall and Mark Smyth are world leaders in identifying new immune targets for cancer," he said.
"By partnering with EpimAb – a company that specialises in developing bispecific antibodies – we hope to speed up the development of much-needed new cancer immunotherapies."
Professor Smyth said the bispecifics field had opened up new potential avenues to treat cancer.
"Existing immune checkpoint therapies usually act on a single immune target," Professor Smyth said.
"By developing antibodies that target two immune checkpoints simultaneously, we hope to produce a stronger anti-cancer response.
"EpimAb’s unique platform technology will allow us to further evaluate some of our most recent discoveries."
EpimAb’s CEO and founder, Dr Chengbin Wu, said he looked forward to using the company’s technology to evaluate novel bispecific target pairs developed under the collaboration.
"QIMR Berghofer is one of the pioneering institutes in the discovery of immuno-oncology mechanisms which are playing an important role in today’s treatment of cancer," Dr Wu said.
"We are proud to collaborate with QIMR Berghofer to identify novel target combinations as EpimAb enters the next stage of growth."
The terms of the agreement are commercial-in-confidence.
Special Issue of Acta Medica Academica (AMA) focused on Genomics in Hematology and Oncology Practice A special issue of Acta Medica Academica (AMA) focused on Genomics in Hematology and Oncology Practice was recently edited by Dr. Gordan Srkalovic (Medical Director, Herbert-Herman Cancer Center, Sparrow Health System, Lansing, Michigan, USA). As a guest editor, he brought together a network of leading oncologists in the field to write on Precision Medicine in their areas of expertise. Sparrow Cancer Center is a 1stOncology Healthcare Partner and in this blog article we cover this timely resource that describes the possible boons of Genomics in Cancer Therapy. This full treasure trove of a special issue of Acta Medica Academica is available totally free at the link below so read, enjoy, and push the boundaries of science to find more therapies for cancer throughout the world!
The year of 1999 witnessed a revolution in science, because the United States National Institutes of Health (NIH), along with other institutions of the world, revealed the secret ‘blue-print’ of the genetic code of human species – the human genome. Dr. Francis Collins (Director, NIH) proudly proclaimed in his publication that this would change the that way we think of medicine, and would create new ways to diagnose, prevent, and treat diseases (1). This vision became the template for change. The years kept on flowing, but the progress in Precision Medicine did not occur as predicted, not until more than 15 years later.
Then, in 2016, then-Vice President Joe Biden started a movement out of his own personal tragedy called “The Cancer Moonshot Initiative”. This was meant to accelerate cancer research that was aimed to make various therapies available to more patients, while also improving physicians’ abilities to prevent cancer and detect it at an early age. This fell into the 21st Century Cures Act and was signed into law by President Obama. It opened up the silos between the laboratories, industries, and computer experts, and exploded the field of cancer genomics.
For clarification: Genomics is NOT the same as Genetics! In cancer genomics, the genome of the tumor (not of the person) is carefully studied, and the abnormalities in the cancer genome that cause the development and growth of cancer is analyzed to find improved methods for diagnosing and treating the disease. This tsunami of information has led to fast development of therapies and approvals of targeted therapies that are saving lives with lesser side effects. Lung cancer is a classic example of this. It is hard for us to keep track of all this information. This is where we need a reference, updated, and reliable book – a manual that summarizes the key information for each type of cancer and that can educate the readers on different types of cancer treatments in this new age.
A special issue of Acta Medica Academica (AMA) focused on Genomics in Hematology and Oncology Practice was recently edited by Dr. Gordan Srkalovic (Medical Director, Herbert-Herman Cancer Center, Sparrow Health System, Lansing, Michigan, USA). This blog article seeks to cover this timely resource that describes the possible boons of Genomics in Cancer Therapy. As a guest editor, he brought together a network of leading oncologists in the field to write on Precision Medicine in their areas of expertise. Thus, we have a confluence of knowledge available here, all for free, just for your benefit, dear readers. So read, enjoy, and push the boundaries of science to find more therapies for cancer throughout the world. Here, we have summarized below what you will find inside this treasure trove.
The journal opens with an article by Trivedi et al (2019) that looks at the use of genomics and the changing landscape of clinical practice in the modern medicine (2). The style of medical treatment has changed much over the years and there has been a massive influx of new technologies. The next step is to personalize disease management. However, there are challenges to fully make the jump from genomics to personalized treatments. Here they discuss some of these challenges and evaluate potential solutions.
This is followed by an article by Audeh et al (2019) which explains the 70 gene MammaPrint assay that was developed as the genomic assay for diagnosis of breast cancer. This test was validated with a randomized trial. It is the first US FDA cleared genomic test for breast cancer (3). The authors describe how this assay was created, and what information it can provide to women so that not everyone needs to go through chemotherapy.
Next, Madanat et al (2019) describe the recent advances in the genomics of acute myeloid leukemia (AML) and present the current state of the field (4). Authors summarized an up to date review of all the published data about genes that are commonly mutated, and the genomic pathways involved in AML. The review highlighted the use of genomics to combat AML’s future gene mutations and their interactions. Therefore, this data is important for the future therapeutic directions in the field of AML.
An article by Shi et al (2019) follows this, where the authors aim to summarize recent developments in laboratory work-up on lymphomas and discuss their clinical relevance (5). The paper goes in depth about these developments, but for our purposes, the main importance are ideas regarding research and clinical care of patients. Although there are newer and cheaper ways to test genetic abnormalities some of those are time-consuming and do not provide needed information. Not only that these options are still relatively limited, but also, widespread knowledge about advanced genetic testing is scarce, even among clinicians. Thus, they note the need for lot of basic groundwork before dwelling deeper into the field and trying to utilize it in this context.
We then move on to Castaneda et al (2019) who provide a concise review on the genetics of multiple myeloma (6). The authors describe how the multiple myeloma disease is considered incurable at present and they review the heterogeneity in its clinical presentation that can be traced to cytogenetic abnormalities in the malignant clone. They focus on emerging cytogenetics of multiple myeloma and discuss how the field of genomics in multiple myeloma has grown, as well as the current issues faced by the field. They concluded that personalized medicine is an ongoing challenge for myeloma patients because of the complexity and heterogeneity of the disease. However, they offer hope that as a result of ongoing genomic “revolution”, we could expect development of improved therapies.
Devitt et al (2019) review the current role of genomic testing in the risk, prognosis, and treatment of genitourinary malignancies (7). The authors describe how genitourinary cancers (their focus was prostate, kidney, and urothelial cancers) have not yet experienced the benefits of genomic data as much as other cancers, but the data is helpful in identifying those patients who have a high risk of getting the cancers. They also say that more therapeutic opportunities will be available for these patients in the future.
Next is an article on Lung Cancer Genomics by Parikh (2019) (8). Advanced lung cancers tend to have poor prognoses due to limited treatment options. However, with the use of genomic testing, the landscape of other treatment options is improving all of which can help these patients live longer.
A review article on Genomic-Based Therapy of Gynecologic Malignancies by Markman (2019) looks to inform about the recent advancements made in the use of targeted therapeutics in management (9). Testing of genomic abnormalities has been limited mostly to two genes in these types of cancers. However, with recent advances in precision medicine, the author anticipates that more tests and more options may become available for diagnosis and therapy of gynecological cancers.
Saadeh et al (2019) reviewed the role of precision medicine in oncologic pharmacy practice. This is unique because it talks about pharmacogenomics (PGX) (10). This concept of PGX is part of the precision medicine approach. It studies how genetic variations may influence an individual’s response to drug therapy. It is based on inherited polymorphisms in drug metabolizing enzymes or other targets. Recommendations from PGX can help prevent newer and existing drug toxicities that are common in cancer patients under treatment.
Lastly, Trivedi et. al (2019) describes the experience and outcomes from 54 cases presented to the Molecular Tumor Board (MTB) established at the Herbert-Herman Cancer Center, Sparrow Health Systems (Lansing, Michigan, USA) between 2017 and 2018. During this time, all patients under treatment considerations had different types of cancers. These cases were presented virtually by oncologists and discussed with the scientific and clinical team of Foundation Medicine company. The goal was to identify specific molecular pathways to precisely determine treatment target options or trials for each cancer patient. These patients badly needed other and newer options because their tissue analyses had not shown targetable mutations. Of these patients, 81% had one or more potentially actionable alteration and 22% received genomic-matched therapy as per MTB recommendations. The multidisciplinary approach of MTB combined with new technologies allowed for improved oncology patient care. Therefore, it was concluded that such usage and education about MTB should increase in other community centers as well, so that advances of precision medicine are brought to as many patients as possible. This is a highly novel and innovative approach because it dissolves the boundaries of different disciplines while keeping the patient’s interest at the center.
What comes next in the field? The ultimate goal of precision medicine is to become the method of choice to use for all types of patients, not just cancer patients. By developing a computer skillset that can organize massive amounts of patient data and create algorithms, we can anticipate and prevent disease in patients in any and every field of medicine beyond cancer medicine. This is exactly what the “ALL OF US” movement is doing. So, dear readers, please join in and learn, as the time is ticking away. Get on board. Otherwise, as Dr. Srkalovic says “you will be dinosaurs” and generations may watch you in the Jurassic Park series.
References
1. Collins, Francis S., et al. “A New Initiative on Precision Medicine: NEJM.” New England Journal of Medicine, 17 Mar. 2020.
2. Trivedi H, Kling HM, Treece T, Audeh W, Srkalovic G. Changing Landscape of Clinical-Genomic Oncology Practice. Acta Med Acad. 2019;48(1):6-17.
3. Audeh W, Blumencranz L, Kling HM, Trivedi H, Srkalovic G. Prospective Validation of a Genomic Assay in Breast Cancer: The 70-gene Mamma-Print Assay and the MINDACT Trial. Acta Med Acad. 2019;48(1):18-34.
4. Madanat YF, Kalaycio, ME, Nazha A. Advances in Acute Myeloid Leukemia Genomics, Where Do We Stand in 2018? Acta Med Acad. 2019;48(1):35-44.
5. Shi M, Dao L, Jevremovic D. Laboratory Work-Up of Chronic B-Cell Lymphoid Malignancies– A Value-Based Approach. Acta Med Acad. 2019;48(1):45-56.
6. Castaneda O, Baz R. Multiple Myeloma Genomics – A Concise Review. Acta Med Acad. 2019;48(1):57-67.
7. Devitt ME, Dreicer R. Evolving Role of Genomics in Genitourinary Neoplasms. Acta Med Acad. 2019;48(1):68-77.
8. Parikh AR. Lung Cancer Genomics. Acta Med Acad. 2019;48(1):78-83.
9. Markman M. Genomic-Based Therapy of Gynecologic Malignancies. Acta Med Acad. 2019;48(1):84-9
10. Saadeh C, Bright D, Rustem D. Precision Medicine in Oncology Pharmacy Practice. Acta Med Acad. 2019;48(1):90-104.
11. Trivedi H, Acharya D, Chamarthy U, Hamdan M, Herman J, Srkalovic G, et al. Implementation and Outcomes of a Molecular Tumor Board at Herbert-Herman Cancer Center, Sparrow Hospital. Acta Med Acad. 2019;48(1):105-15.
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