On October 17, 2022 BridgeBio Pharma, Inc. (Nasdaq: BBIO) ("BridgeBio" or the "Company"), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, reported that preclinical data for its two lead RAS programs – a next-generation KRASG12C dual inhibitor program and a novel PI3Kα:RAS breaker program – in an oral presentation at the Fourth RAS Initiative Symposium in Frederick, MD (Press release, BridgeBio, OCT 17, 2022, View Source [SID1234622062]). BridgeBio will also be hosting an investor call at 1:30 ET today to discuss the data.

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KRAS G12C dual inhibitor:
BridgeBio has selected a next-generation KRASG12C dual inhibitor development candidate, BBO-8520, and plans to enter the clinic in 2023. BBO-8520 is the first-known small molecule that directly binds and inhibits KRASG12C in both its active (GTP bound) and inactive (GDP bound) conformations. BridgeBio believes this could lead to differentiated activity in cancer patients with KRASG12C driven disease, as all other known clinical stage direct KRASG12C inhibitors do not inhibit the active oncogenic form of the protein (GTP-bound KRASG12C).

Presentation highlights:
The KRASG12C GTP/GDP dual inhibitor development candidate

Using mass spectrometry, BBO-8520 was shown to completely modify both GTP (active) and GDP (inactive) forms of KRASG12C
BBO-8520 shows exceptional potency and selectivity – significantly greater potency than first-generation KRASG12C GDP-only inhibitors across multiple in vitro and in vivo assays including KRASG12C:RAF1 effector binding
Targeting KRASG12C GTP allows BBO-8520 to overcome growth factor override that is an important source of resistance for 1st-generation KRASG12C GDP-only inhibitors
BBO-8520 shows strong efficacy in KRASG12C models, including deep regressions in an NSCLC model and differentiated activity vs a first-generation KRASG12C GDP-only inhibitor in a patient-derived xenograft model
PI3Kα:RAS breaker:
BridgeBio is also pursuing PI3Kα:RAS breakers, small molecules that block RAS driven PI3Kα activation. Inhibiting PI3Kα activity by preventing its interaction with RAS can provide a "tumor selective" mechanism that spares glucose metabolism. This novel approach could, if successful, potentially have broad utility against oncogene-driven tumors (including RAS mutant tumors, PI3Kα mutant tumors, and tumors driven by RTK activation of RAS signaling) as both a monotherapy and in combination with other agents.

Presentation highlights:
PI3Kα:RAS breakers

Exhibited potent inhibition of AKT activation in KRAS G12X, PIK3CA helical mutation and HER family driven populations
Showed potent efficacy in multiple models without hyperglycemia, a common dose-limiting adverse reaction among PI3Kα kinase inhibitors
"We are excited about our next-generation KRASG12C GTP/GDP dual inhibitor development candidate and are hopeful that it has the opportunity to deliver improved outcomes for patients given the considerable unmet need remaining in the KRAS-driven cancer space," said Eli Wallace, Chief Scientific Officer, Oncology at BridgeBio. "We also think that the progress of our novel PI3Kα:RAS breaker program is very compelling, especially its in vivo demonstration of efficacy without hyperglycemia, which has proven a challenge for standard PI3Ka inhibitor treatments. We look forward to developing both programs further and hope to be able to serve the patients impacted by these two common oncogenes who are in need of innovative treatments."

Webcast Information
BridgeBio will host an investor call and simultaneous webcast to discuss preclinical data from both lead RAS programs and the selection of the KRASG12C dual inhibitor development candidate today, October 17, 2022, at 1:30 pm ET. To access this call via phone, participants will need to register using the following link where they will be provided a phone number and access code: (https://register.vevent.com/register/BIbd4d7a752dcc4ade970571556d4060e5). The webcast and presentation slides can be viewed during the time of the call via a link on the event calendar page of BridgeBio’s website at View Source A replay of the conference call and webcast will be archived on the Company’s website and will be available for at least 30 days following the event.

On October 17, 2022 The board of directors of Eli Lilly and Company (NYSE: LLY) reported that it has declared a dividend for the fourth quarter of 2022 of $0.98 per share on outstanding common stock (Press release, Eli Lilly, OCT 17, 2022, View Source [SID1234622061]).

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The dividend is payable on Dec. 9, 2022 to shareholders of record at the close of business on Nov. 15, 2022.

On October 17, 2022 Novo Nordisk reported that initiated a share repurchase programme in accordance with Article 5 of Regulation No 596/2014 of the European Parliament and Council of 16 April 2014 (MAR) and the Commission Delegated Regulation (EU) 2016/1052 of 8 March 2016 (the "Safe Harbour Rules") (Press release, Novo Nordisk, OCT 17, 2022, View Source [SID1234622060]). This programme is part of the overall share repurchase programme of up to DKK 24 billion to be executed during a 12-month period beginning 2 February 2022.

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Under the programme initiated 3 August 2022, Novo Nordisk will repurchase B shares for an amount up to DKK 4.4 billion in the period from 4 August 2022 to 31 October 2022.

Since the announcement 10 October, the following transactions have been made:

The details for each transaction made under the share repurchase programme are published on novonordisk.com.

With the transactions stated above, Novo Nordisk owns a total of 22,265,511 B shares of DKK 0.20 as treasury shares, corresponding to 1.0% of the share capital. The total amount of A and B shares in the company is 2,280,000,000 including treasury shares.

Novo Nordisk expects to repurchase B shares for an amount up to DKK 24 billion during a 12- month period beginning 2 February 2022. As of 14 October 2022, Novo Nordisk has since 2 February 2022 repurchased a total of 20,554,732 B shares at an average share price of DKK 769.54 per B share equal to a transaction value of DKK 15,817,641,061.

On October 17, 2022 SHINE Technologies, a next-generation fusion technology company, and SHINE Europe reported that the Dutch government has approved a substantial grant proposal to develop a plan to produce a variety of terbium isotopes for use in nuclear medicine (Press release, Shine Medical Technologies, OCT 17, 2022, View Source [SID1234622059]).

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Within this project, SHINE Europe, together with the University Medical Center Groningen (UMCG) and Delft University of Technology (TU Delft), aims to develop and realize all the technologies and facilities needed to secure the entire supply chain for terbium-based nuclear medicine. This will also involve increased cooperation with partners in the European Union. "Previous collaborations with UMCG and TU Delft have been very fruitful," said Harrie Buurlage, general manager of SHINE Europe. "We therefore view our collaboration within the project with great confidence."

Research shows that terbium isotopes are a potentially effective method for diagnosing and treating cancer and other diseases. But a lack of essential raw materials and complex processing technology are among the current barriers to terbium production. These obstacles can be solved by SHINE’s innovative production methods. These enable SHINE to have a vertically integrated supply chain, from raw material production through cGMP product purification.

SHINE, a world leader in new high-tech ways to produce medicine, currently produces lutetium-177 in Janesville, Wisconsin (U.S.). It is building the world’s largest fully specialized medical isotope production facility at its Janesville campus, which will add the capability to produce molybdenum-99, a diagnostic medicine used in millions of procedures to detect heart disease and cancer. The facility is expected to start up in 2023 and will be able to produce the suite of fission-based radioisotopes as well as key neutron-capture based isotopes. SHINE Europe is planning a similar production site in Veendam, the Netherlands, to come online in the next five years.

"The development of a new supply system for terbium-based drugs will be another major milestone in providing patients with access to promising new therapies to support their ongoing fight against cancer," said Harrie Buurlage, general manager of SHINE Europe. "We thank the Dutch government for their support in our terbium efforts and hope for similar support from the European Commission." The grant proposal is subject to final approval by the European Commission.

On October 17, 2022 Fennec Pharmaceuticals Inc. (NASDAQ: FENC; TSX: FRX), a commercial stage specialty pharmaceutical company, reported the U.S. commercial launch and availability of PEDMARK (sodium thiosulfate injection) to reduce the risk of ototoxicity associated with cisplatin in pediatric patients one month of age and older with localized, non-metastatic solid tumors (Press release, Fennec Pharmaceuticals, OCT 17, 2022, View Source [SID1234622058]).

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"We are proud to announce that PEDMARK is now available to pediatric patients and their physicians who are in need of options to help reduce the risk of cisplatin-induced hearing loss," said Rosty Raykov, chief executive officer of Fennec Pharmaceuticals. "Children who get platinum-based chemotherapy, such as cisplatin, are at risk for permanent hearing loss, a condition that previously could only be managed with cochlear implants and hearing aids. PEDMARK provides the first and only FDA-approved treatment specifically designed to help protect hearing in children and young adults after receiving cisplatin. We look forward to engaging with healthcare providers and supporting patient access to this breakthrough therapy with our assistance program, Fennec HEARS."

The Company has established Fennec HEARS, a comprehensive single source program designed to connect PEDMARK patients to both patient financial and product access support. The program offers assistance and resources, regardless of insurance type, that can address co-pays or lack of coverage when certain eligibility requirements are met. Fennec HEARS also provides access to care coordinators that can answer insurance questions about coverage for PEDMARK and provide tips and resources for managing treatment. For more information about product availability and patient support, please contact the Fennec HEARS program at 1-833-7PEDMARK (1-833-773-3627).

PEDMARK was approved by the U.S. Food and Drug Administration (FDA) in September 2022 based upon safety and efficacy data from two pivotal open-label, randomized Phase 3 trials (Clinical Oncology Group [COG] Protocol ACCL0431 and SIOPEL 6), which compared PEDMARK plus cisplatin-based regimen to cisplatin-based regimens alone for the reduction of cisplatin-induced hearing loss in pediatric patients.

Advances in chemotherapy-based treatment approaches for pediatric patients with localized, solid tumors have improved, resulting in an 85 percent or higher five-year survival rate for these patients.1 However, use of platinum-based chemotherapy, still the treatment of choice in many cases, can be toxic to the ears and cisplatin treatment frequently causes permanent and irreversible bilateral (affecting both ears) hearing loss. Permanent hearing loss can be seen in approximately 60 percent of children treated with cisplatin and can be as high as 90 percent.1,2 Until now, interventions with management strategies such as cochlear implants and hearing aids only occurred after hearing loss had been detected and these interventions do not return normal hearing.3

The Marketing Authorization Application (MAA) for sodium thiosulfate (tradename PEDMARQSI) is currently under evaluation by the European Medicines Agency (EMA). Prior to its approval in the U.S., the FDA granted PEDMARK Priority Review designation in 2020 and Orphan Drug designation in 2004.

About Cisplatin-Induced Ototoxicity
Cisplatin and other platinum compounds are essential chemotherapeutic agents for the treatment of many pediatric malignancies. Unfortunately, platinum-based therapies can cause ototoxicity, or hearing loss, which is permanent, irreversible, and particularly harmful to the survivors of pediatric cancer.4

The incidence of ototoxicity depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids or cochlear implants, which can be helpful for some, but do not reverse the hearing loss and can be costly over time.5 Infants and young children that are affected by ototoxicity at critical stages of development lack speech and language development and literacy, and older children and adolescents often lack social-emotional development and educational achievement.6

PEDMARK (sodium thiosulfate injection)
PEDMARK is the first and only U.S. Food and Drug Administration (FDA) approved therapy indicated to reduce the risk of ototoxicity associated with cisplatin treatment in pediatric patients with localized, non-metastatic, solid tumors. It is a unique formulation of sodium thiosulfate in single-dose, ready-to-use vials for intravenous use in pediatric patients.7 PEDMARK is also the only therapeutic agent with proven efficacy and safety data with an established dosing paradigm, across two open-label, randomized Phase 3 clinical studies, the Clinical Oncology Group (COG) Protocol ACCL0431 and SIOPEL 6.

In the U.S. and Europe, it is estimated that, annually, more than 10,000 children may receive platinum-based chemotherapy. The incidence of ototoxicity depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids. There is currently no established preventive agent for this hearing loss and only expensive, technically difficult, and sub-optimal cochlear (inner ear) implants have been shown to provide some benefit. Infants and young children that suffer ototoxicity at critical stages of development lack speech language development and literacy, and older children and adolescents lack social-emotional development and educational achievement.

PEDMARK has been studied by co-operative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, COG ACCL0431 and SIOPEL 6. Both studies have been completed. The COG ACCL0431 protocol enrolled childhood cancers typically treated with intensive cisplatin therapy for localized and disseminated disease, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, medulloblastoma, and other solid tumors. SIOPEL 6 enrolled only hepatoblastoma patients with localized tumors.

Indications and Usage
PEDMARK (sodium thiosulfate injection) is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors.

Limitations of Use
The safety and efficacy of PEDMARK have not been established when administered following cisplatin infusions longer than 6 hours. PEDMARK may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.

Important Safety Information
PEDMARK is contraindicated in patients with history of a severe hypersensitivity to sodium thiosulfate or any of its components.

Hypersensitivity reactions occurred in 8% to 13% of patients in clinical trials. Monitor patients for hypersensitivity reactions. Immediately discontinue PEDMARK and institute appropriate care if a hypersensitivity reaction occurs. Administer antihistamines or glucocorticoids (if appropriate) before each subsequent administration of PEDMARK. PEDMARK may contain sodium sulfite; patients with sulfite sensitivity may have hypersensitivity reactions, including anaphylactic symptoms and life-threatening or severe asthma episodes. Sulfite sensitivity is seen more frequently in people with asthma.

PEDMARK is not indicated for use in pediatric patients less than 1 month of age due to the increased risk of hypernatremia or in pediatric patients with metastatic cancers.

Hypernatremia occurred in 12% to 26% of patients in clinical trials, including a single Grade 3 case. Hypokalemia occurred in 15% to 27% of patients in clinical trials, with Grade 3 or 4 occurring in 9% to 27% of patients. Monitor serum sodium and potassium levels at baseline and as clinically indicated. Withhold PEDMARK in patients with baseline serum sodium greater than 145 mmol/L.

Monitor for signs and symptoms of hypernatremia and hypokalemia more closely if the glomerular filtration rate (GFR) falls below 60 mL/min/1.73m2.

Administer antiemetics prior to each PEDMARK administration. Provide additional antiemetics and supportive care as appropriate.

The most common adverse reactions (≥25% with difference between arms of >5% compared to cisplatin alone) in SIOPEL 6 were vomiting, nausea, decreased hemoglobin, and hypernatremia. The most common adverse reaction (≥25% with difference between arms of >5% compared to cisplatin alone) in COG ACCL0431 was hypokalemia.