On December 12, 2019 Gritstone Oncology, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company developing the next generation of cancer immunotherapies to fight multiple cancer types, reported that the company has presented preliminary Phase 1 GRANITE immunogenicity data demonstrating the rapid, robust and consistent induction of large numbers of CD8+ T cells against multiple neoantigens in four solid tumor patients with available IFN-g ELISpot data (up to 3,000 IFN-g spot forming units per 106 PBMCs were generated, as measured by overnight ELISpot) within the first two dosing cohorts (Press release, Gritstone Oncology, DEC 12, 2019, View Source [SID1234552355]). Importantly, these T cells were also able to produce IL-2 and Granzyme B, demonstrating that they have cytotoxic potential. In addition to priming naive CD8+ T cells against encoded neoantigens, the data demonstrate that GRANITE can also stimulate the expansion of pre-existing T-cell populations. Safety data from five patients receiving GRANITE and three patients receiving SLATE across the first two dose levels indicate that the immunotherapies were well-tolerated with no dose-limiting toxicities observed. Dose escalation continues. These results were presented today in an oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology Congress in Geneva, Switzerland.

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"We are thrilled to observe very robust, polyfunctional CD8+ T cells against predicted neoantigens even at the first dose level of our phase 1 study," said Andrew Allen, M.D., Ph.D., co-founder, president and chief executive officer of Gritstone Oncology. "We view these preliminary results as important de-risking data, demonstrating the unprecedented immunogenicity of our heterologous prime/boost vaccine platform at its lowest dose, in combination with nivolumab. Pre-clinical data have shown a clear dose response where higher doses of the self-amplifying RNA boost vaccination, as well as the addition of anti-CTLA-4, further increase the number and function of CD8+ T cells. Notably, the starting dose of self-amplifying RNA was conservative since this is the first in-human study with this therapeutic approach. Therefore, we look forward to presenting mature data at higher doses with additional patients receiving the full immunotherapy regimen in several months."

In the GRANITE Phase 1 GO-004 study, the first dosing cohort consisted of three advanced cancer patients, including two gastroesophageal adenocarcinoma patients and one non-small cell lung cancer patient who had previously progressed on prior anti-PD-L1 therapy. From the second GRANITE dosing cohort, early ELISpot data was available from one microsatellite-stable

colorectal cancer patient. Most common adverse events in the GO-004 study were grade 1/2 fever and skin rash, consistent with an inflammatory immune reaction. In the SLATE Phase 1 GO-005 study, patients are still early in their course of treatment, and treatment-related adverse events have been limited to one injection site reaction and one case of grade 1/2 pruritus.

About GRANITE and SLATE Ongoing Phase 1/2 Clinical Studies

Gritstone’s GRANITE personalized immunotherapy delivers a cassette of 20 TSNA identified by the company using its proprietary Gritstone EDGETM artificial intelligence platform and tumor HLA peptide sequencing, representing tumor-specific neoantigens that are derived from the patient’s own tumor. GRANITE is being evaluated in combination with immune checkpoint blockade in a Phase 1/2 clinical study, referred to as GO-004, for the treatment of patients with advanced solid tumors, including microsatellite-stable colorectal cancer (MSS CRC), gastroesophageal cancer, metastatic non-small cell lung cancer, and bladder cancer. In the Phase 1 study, all patients receive a fixed dose of intramuscular adenovirus-based prime with three escalating doses (30, 100 and 300 µg) of intramuscular RNA-based boost vaccinations in combination with intravenous anti-PD-1 therapy. Following dose escalation of the RNA-based boost vaccine to 100 µg, subcutaneous anti-CTLA-4 is added to the treatment regimen in the third dosing cohort. GRANITE was granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of MSS CRC.

Gritstone’s SLATE "off-the-shelf" immunotherapy delivers a cassette of 20 TSNA identified by the company using its proprietary EDGE artificial intelligence platform and tumor HLA peptide sequencing, representing mutated gene sequences that are shared across patients (such as K-RAS mutations). SLATE is being evaluated in combination with immune checkpoint blockade in a Phase 1/2 clinical study called GO-005 for the treatment of patients with advanced solid tumors, including metastatic non-small cell lung cancer, pancreatic ductal adenocarcinoma and microsatellite-stable colorectal cancer, as well as in patients with other solid tumor types who have relevant mutation/HLA (human leukocyte antigen) combinations. In the Phase 1 study, all patients receive a fixed dose of intramuscular adenovirus-based prime with three escalating doses (30, 100 and 300 µg) of intramuscular RNA-based boost vaccinations in combination with intravenous anti-PD-1 therapy. Following dose escalation of the RNA-based boost vaccine to 30 µg, subcutaneous anti-CTLA-4 is added to the treatment regimen in the second dosing cohort.

Investor Teleconference and Webcast

The company will host a conference call today, December 12, 2019 at 8:00 am ET to review its clinical programs, including the clinical data presented at ESMO (Free ESMO Whitepaper)-IO. The conference call can be accessed by dialing (866) 866-1333 or (404) 260-1421 and referencing conference ID number 49260042. A webcast of the call and accompanying slides will be available within the Investors & Media section of the Gritstone Oncology website at View Source An archived replay will be accessible for 30 days following the event.

On December 12, 2019 SPL Medical reported that the first patient has been successfully diagnosed with suspected lymph node metastases of prostate cancer with Ferrotran (Ferumoxtran) at the University Hospital Zurich (Press release, SPL Medical, DEC 12, 2019, View Source [SID1234552339]). This follows approval (Sonderbewilligung acc. to Swiss AMBV) by Swissmedic to Universitätsspital Zurich, Institut für Diagnostische und Interventionelle Radiologie, for restricted use of Ferrotran under a compassionate use program. Ferrotran (Ferumoxtran) is a novel contrast agent for use in MRI (magnetic resonance imaging) developed for the detection of lymph node metastases of prostate cancer. It is the first contrast agent for the use in MRI that is able to identify metastases as small as 1.5 mm. The rise of prostate specific antigen (PSA) is often the first symptom of suspected recurrent lymph node metastases. Being able to detect small metastases in prostate cancer early enough should enable a better chance of successful treatment.

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SPL Medical is the manufacturer of Ferrotran and responsible for the worldwide commercialization. The company is about to start a large multicenter trial of Ferrotran that will be conducted in 10 top radiology centers in Germany, Switzerland and the Netherlands, enrolling a total of 180 patients with prostatic cancer.

The development of Ferrotran was initially enabled and accelerated by Prof. Jelle Barentsz of the Radboud university medical center in Nijmegen, the Netherlands. He discovered the unique features of Ferrotran for the early detection of lymph node metastases when he used it as contrast agent for prostate cancer patients. So far, he has diagnosed metastases in more than 1,500 patients using this agent.

"We have built a vast experience with Ferrotran and have started to train radiologists from participating clinical centers to bring them up to speed with the latest use of the product and interpretation of the imaging results," said Prof. Barentsz.

"Ferrotran represents a major opportunity to improve the diagnosis of lymph node metastases from prostate cancer, with patients subsequently having potentially better treatment outcomes and fewer side-effects," stated Dr. Jürgen Feuerstein, Chief Executive Officer of SPL Medical. "The compassionate use program at the University Hospital Zurich provides vital access for prostate cancer patients to this game-changing product. Meanwhile, at SPL Medical, we will continue advancing our clinical development plan to enable potential registration of Ferrotran."

b.e.imaging GmbH, a shareholder of SPL Medical, is the distributor of Ferrotran in Germany, Austria and Switzerland.

About Ferrotran:
Ferrotran belongs to the group of USPIO’s (Ultrasmall Superparamagnetic Particles of Iron Oxide) and is the only contrast agent that can detect lymph node metastases as small as 1.5mm. Standard MRI, CT or PET scan are normally not able to detect metastatic nodes smaller than 7 – 8 mm. Since most prostate cancer patients are dying due to metastases, a precise diagnosis is of utmost importance. The detection of small metastases, combined with a very clear and contrast rich MRI image with the administration of Ferrotran, and excellent visualization of vessels enables an earlier and more precise treatment.

On December 12, 2019 Nordic Nanovector ASA (OSE: NANO) reported an update on its LYMRIT 37-05 Phase 1 trial of Betalutin in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are not eligible for autologous stem cell transplantation (SCT) (Press release, Nordic Nanovector, DEC 12, 2019, View Source [SID1234552337]). DLBCL is an aggressive form of non-Hodgkin’s lymphoma (NHL) and accounts for up to 43% of all cases, making it the most common type of NHL.

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This open-label, dose-escalation safety trial is designed to assess the safety, tolerability, pharmacokinetic profile and preliminary anti-tumour activity of Betalutin in up to 24 patients. The primary goal of the trial is to identify the maximally tolerated dose of Betalutin which will then be further evaluated for safety and anti-tumour activity in an expansion cohort in order to select the recommended dose for phase 2. Three additional patients are currently being enrolled for further evaluation of the final dose cohort as one patient has experienced a reversible DLT (dose limiting toxicity).

On the three completed cohorts, no safety issues were identified. Evidence of disease control has been noted in some of the enrolled patients. We expect to complete the data read-out for the dose-escalation phase and submit the data to an international congress in 1H 2020.

Eduardo Bravo, Nordic Nanovector’s Chief Executive Officer, commented: "Patients with relapsed/refractory DLBCL who are not eligible for stem cell transplantation have very limited treatment options and a poor prognosis. As the safety profile of Betalutin will guide its potential for combination regimens as well as single agent consolidation therapy, we look forward to completing this part of the trial and proceeding with the expansion cohort."

On December 12, 2019 CStone Pharmaceuticals ("CStone" or the "Company", HKEX: 2616) reported that the Company has recently received the approval from the Human Research Ethics Committee (HREC) in Australia, and the acknowledgement from Australia’s Therapeutic Goods Administration (TGA) on the Phase I clinical trial of CS3005 (Press release, CStone Pharmaceauticals, DEC 12, 2019, View Source [SID1234552336]). This Phase I trial is an open-label, multicenter, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of CS3005 in patients with advanced solid tumors.

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The tumor microenvironment (TME) is a cellular space in which the tumor dynamically interacts with the surrounding blood vessels, immune cells, stromal components, signaling molecules, and the extracellular matrix. Studies showed that multiple compensatory immunosuppressive mechanisms exist in the TME not only contribute to the development of tumors but also affect the response to immunotherapies. The adenosine signaling pathway plays a critical role in immune modulation and is an important compensatory resistance mechanism against immune checkpoint inhibitors.

Discovered by CStone, CS3005 is an adenosine A2a receptor antagonist that modulates the tumor immune microenvironment. CS3005 could potentially activate antitumor immunity and improve the response to immune checkpoint inhibitors by blocking the binding of adenosine with adenosine A2a receptors and thereby reversing the immunosuppressive mechanism. At present, no adenosine A2a receptor antagonist has been approved for cancer treatment anywhere in the world.

"I am pleased that the clinical trial of CS3005 has been approved in Australia. This drug candidate is the Company’s first tumor immune microenvironment modulator entering clinical development as we have begun to roll out CStone’s Pipeline 2.0," said Dr. Frank Jiang, Chairman and CEO of CStone. "Immuno-oncology therapy has brought new hope to cancer patients in recent years, yet many patients fail to respond to those treatments. We are hopeful that the research and development of tumor microenvironment modulators will allow immunotherapies to benefit more patients."

CStone’s Chief Scientific Officer, Dr. Jon Wang, noted: "Early studies on adenosine A2a receptor antagonists have shown good safety profiles and antitumor activities, either as monotherapies or in combination with immune checkpoint inhibitors, in patients with advanced solid tumors. Interestingly, adenosine A2a receptor antagonists have also demonstrated antitumor activities in patients with low PD-L1 expressing tumors or who are resistant/refractory to anti-PD-(L)1. These observations implicate possible benefits to patients with solid tumors. CS3005 also adds to the depth and flexibility of CStone’s strategy in immuno-oncology combination therapy."

On December 12, 2019 Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) ("Ionis") reported that it has entered into privately negotiated exchange and/or subscription agreements, with certain holders of its outstanding 1.00% Convertible Senior Notes due 2021 (the "2021 Notes") and certain new investors pursuant to which Ionis will issue $398.0 million principal amount of 0.125% Convertible Senior Notes due 2024 (the "New Notes") in exchange for $340.2 principal amount of the 2021 Notes (the "Exchange Transactions") and issue $109.5 million principal amount of New Notes for cash (the "Subscription Transactions") (Press release, Ionis Pharmaceuticals, DEC 12, 2019, View Source;300973802.html [SID1234552335]). Following the closing of the Exchange Transactions, $344.8 million in aggregate principal amount of 2021 Notes will remain outstanding with terms unchanged. The Exchange Transactions and the Subscription Transactions are expected to close concurrently on or about December 19, 2019, subject to customary closing conditions.

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The New Notes will represent senior unsecured obligations of Ionis and will pay interest semi-annually in arrears on each June 15 and December 15, commencing on June 15, 2020, at a rate of 0.125% per annum. The New Notes will mature on December 15, 2024, unless earlier converted or repurchased. The New Notes will be convertible at the option of the holders in certain circumstances into cash, shares of Ionis’ common stock or a combination of cash and Ionis’ common stock, at Ionis’ election. The initial conversion rate is 12.0075 shares of Ionis’ common stock per $1,000 principal amount of New Notes, which is equivalent to an initial conversion price of approximately $83.28 per share, and will be subject to customary anti-dilution adjustments. Ionis may not redeem the New Notes prior to the maturity date.

Ionis will not receive any cash proceeds from the Exchange Transactions. In exchange for issuing the New Notes pursuant to the Exchange Transactions, Ionis will receive and cancel the exchanged 2021 Notes. Ionis estimates that net cash proceeds from the Subscription Transactions will be approximately $99.2 million after deducting estimated offering expenses for both the Exchange Transactions and the Subscription Transactions. Ionis intends to use net cash proceeds from the Subscription Transactions to pay the cost of the convertible note hedge transaction described below and for general corporate purposes.

In connection with the exchange and/or subscription agreements, Ionis entered into convertible note hedge and warrant transactions with several financial institutions. These transactions may decrease or increase dilution of Ionis’ stock based on several factors that are outlined in further detail in the Company’s 8-K filing, which was filed contemporaneously with this press release.

The New Notes and any shares of common stock issuable upon conversion of the New Notes have not been registered under the Securities Act or under any state securities laws and may not be offered or sold without registration under, or an applicable exemption from, the registration requirements. This announcement does not constitute an offer to sell, nor is it a solicitation of an offer to buy, these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any state or any jurisdiction.