On September 11, 2023 Day One Biopharmaceuticals (Nasdaq: DAWN) ("Day One" or the "Company"), a clinical-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for people of all ages with life-threatening diseases, reported the recently completed submission of the rolling New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tovorafenib as a monotherapy in relapsed or progressive pediatric low-grade glioma (pLGG) (Press release, Day One, SEP 11, 2023, View Source [SID1234635063]). The Company anticipates the FDA will file the rolling NDA by mid-November 2023.

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pLGG is the most common brain tumor diagnosed in children, with patients suffering profound tumor and treatment-associated morbidities that can impact their life trajectory over the long term. For the majority of patients in the relapsed setting, there is no standard of care and no approved therapies.

"We believe that tovorafenib, if approved, could change the treatment landscape for children living with this chronic and relentless disease," said Jeremy Bender, Ph.D., chief executive officer of Day One. "The NDA submission of tovorafenib is a significant milestone for Day One and an important step towards bringing a potential new targeted therapy to children with brain cancer."

The Company initiated the rolling submission of the NDA in May 2023 based on data from the FIREFLY-1 trial with a data cutoff as of December 22, 2022. An updated Clinical Study Report (CSR) was submitted to the FDA with an additional six months of safety and efficacy data through June 5, 2023.

FIREFLY-1 is an open-label, pivotal Phase 2 trial, which treated a total of 137 patients across two study arms. Arm 1 evaluated tovorafenib in 77 patients as a once-weekly monotherapy in patients aged 6 months to 25 years with relapsed or progressive pLGG. The primary endpoint of the trial is ORR by Response Assessment for Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria. Secondary endpoints include ORR by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG), progression-free survival (PFS), duration of response (DOR), time to response, clinical benefit rate and safety. The NDA submission also includes an exploratory analysis of ORR by Response Assessment for Neuro-Oncology Low-Grade Glioma (RANO-LGG). All data have been assessed by a blinded Independent Review Committee (IRC).

Updated FIREFLY-1 Data Demonstrate Consistent and Durable Response

New data from the FIREFLY-1 trial, with a data cutoff of June 5, 2023, are described below. Detailed data will be presented at an upcoming medical conference.

RANO-HGG (n=69 evaluable) data, the primary endpoint of the trial:

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67% ORR (complete response (CR) + partial response (PR))

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93% clinical benefit rate (CBR) (CR + PR + stable disease (SD))

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17% (n=12) CR

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49% (n=34) PR

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26% (n=18) SD

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At the time of data cutoff, the median duration of response (DOR) based on RANO-HGG criteria was 16.6 months (95% CI: 11.6, not estimable)

Among a total of 77 treated patients:

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The median duration of tovorafenib treatment was 15.8 months, with 66% (n=51) of patients on treatment at the time of data cutoff

Safety data, based on the 137 patients treated in both Arm 1 and Arm 2 of FIREFLY-1, indicated monotherapy tovorafenib to be generally well-tolerated. The vast majority of adverse events were Grade 1 or Grade 2, with most common side effects reported related to tovorafenib being change in hair color (76%), fatigue (44%), maculopapular rash (41%), dry skin (33%), and dermatitis acneiform (30%). The most commonly reported treatment-related lab abnormalities were CPK elevation, LDH elevation, anemia, hypophosphatemia and AST elevation. Nearly all of the lab abnormalities had no clinical manifestations and did not require clinical intervention or change in study treatment.

The NDA submission also included the evaluation of responses by RAPNO-LGG and RANO-LGG. Those results include:

RAPNO-LGG (n=76 evaluable) data, a key secondary endpoint of the trial:

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51% ORR (CR + PR + minor response (MR))

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82% CBR (CR+ PR + MR + SD)

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37% (n=28) PR

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14% (n=11) MR

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30% (n=23) SD

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At the time of data cutoff, the median DOR based on RAPNO-LGG criteria was 13.8 months (95% CI: 11.3, not estimable)

RANO-LGG (n=76 evaluable) data, an exploratory analysis of the trial:

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53% ORR (CR + PR + MR)

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83% CBR (CR + PR + MR + SD)

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26% (n=20) PR

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26% (n=20) MR

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30% (n=23) SD

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At the time of data cutoff, the median DOR based on RANO-LGG criteria was 14.4 months (95% CI: 11.0, not estimable)

Tovorafenib was granted Rare Pediatric Disease Designation for relapsed or progressive pLGG and, as such, may qualify for receipt of a priority review voucher, if tovorafenib is approved by the FDA in this indication. Based on Day One’s current operating plan, management believes it has sufficient capital resources to fund anticipated operations into 2026.

About Pediatric Low-Grade Glioma

Pediatric low-grade glioma (pLGG) is the most common brain tumor diagnosed in children, accounting for 30% – 50% of all central nervous systems tumors. BRAF wild-type fusions are the most common cancer-causing genomic alterations in pLGG. These genomic alterations are also found in severe adult and pediatric solid tumors.

Pediatric low-grade glioma can impact a child’s health in many ways depending on tumor size and location, including vision loss and motor dysfunction. There are no approved therapies for the vast majority of patients with pLGG, and current treatment approaches are associated with potential acute and life-long adverse effects. While most children with pLGG survive their cancer, children who do not achieve remission following surgery may face years of increasingly aggressive therapies. Due to the indolent nature of pLGG, patients generally receive multiple years of systemic therapy.

About FIREFLY-1

FIREFLY-1 is evaluating tovorafenib as once-weekly monotherapy in patients aged 6 months to 25 years with relapsed or progressive pLGG harboring a known activating BRAF alteration. The trial is being conducted in collaboration with the Pacific Pediatric Neuro-Oncology Consortium (PNOC). The primary endpoint is overall response rate (ORR), defined as the proportion of patients with confirmed response based upon RANO-HGG criteria. Secondary and exploratory endpoints include the overall response rate based on RAPNO-LGG criteria, RANO-LGG criteria and volumetric analyses, progression-free survival, safety, functional outcomes, and quality of life measures. RANO-HGG, RANO-LGG and RAPNO-LGG are assessed by blinded independent central review. Additional information about FIREFLY-1 may be found at ClinicalTrials.gov, using Identifier NCT04775485.

About the Pacific Pediatric Neuro-Oncology Consortium

The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is an international consortium with study sites within the United States, Canada, Europe and Australia dedicated to bringing new therapies to children and young adults with brain tumors.

About Tovorafenib

Tovorafenib is an investigational, oral, brain-penetrant, highly-selective type II RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway, which is being investigated in primary brain tumors or brain metastases of solid tumors. Tovorafenib has been studied in over 325 patients to date. Currently tovorafenib is under evaluation in a pivotal Phase 2 clinical trial (FIREFLY-1) among pediatric, adolescent and young adult patients with relapsed or progressive pLGG, which is an area of considerable unmet need with no approved therapies for the vast majority of patients. Tovorafenib is also being evaluated alone or as a combination therapy for adolescent and adult patient populations with recurrent or progressive solid tumors with MAPK pathway aberrations (FIRELIGHT-1).

Tovorafenib has been granted Breakthrough Therapy and Rare Pediatric Disease designations by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pLGG harboring an activating RAF alteration. Tovorafenib has also received Orphan Drug designation from the FDA for the treatment of malignant glioma, and from the European Commission (EC) for the treatment of glioma.

On September 11, 2023 CymaBay Therapeutics, Inc. (Nasdaq: CBAY), a clinical-stage biopharmaceutical company focused on developing innovative therapies for liver and other chronic diseases with high unmet medical need, reported that it has commenced an underwritten public offering of an aggregate of $150 million of its common stock and pre-funded warrants (Press release, CymaBay Therapeutics, SEP 11, 2023, View Source [SID1234635062]). All shares of common stock and pre-funded warrants to be sold in the offering will be offered by CymaBay. CymaBay intends to grant the underwriters a 30-day option to purchase up to an aggregate of an additional 15% of the shares of its common stock offered in the public offering, including shares of common stock underlying the pre-funded warrants. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering. CymaBay anticipates using the net proceeds from the offering to fund ongoing development of seladelpar, including clinical trials targeting market expansion, and for working capital and general corporate purposes.

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Piper Sandler, Raymond James, Cantor and LifeSci Capital are acting as the joint book-running managers for the offering. BTIG is acting as the lead manager for the offering.

The securities described above are being offered by CymaBay pursuant to a shelf registration statement previously filed with and declared effective by the Securities and Exchange Commission (the "SEC"). A preliminary prospectus supplement related to the offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Copies of the preliminary prospectus supplement and the accompanying prospectus relating to this offering may be obtained, when available, from: Piper Sandler & Co., Attention: Prospectus Department, 800 Nicollet Mall, J12S03, Minneapolis, Minnesota 55402, by telephone at (800) 747-3924, or by email at [email protected]; Raymond James & Associates, Inc., Attention: Equity Syndicate, 880 Carillon Parkway, St. Petersburg, Florida 33716, by telephone at (800) 248-8863, or by e-mail at [email protected]; Cantor Fitzgerald & Co., Attention: Capital Markets, 110 East 59th Street, 6th Floor, New York, New York 10022, or by e-mail at [email protected]; or LifeSci Capital LLC, Attention: Syndicate Prospectus Department, 250 West 55th Street, 34th Floor, New York, NY 10019, by email at [email protected] or by telephone at (646) 876-5059.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On September 11, 2023 Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical-stage pharmaceutical company focused on the discovery, development and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, reported that it intends to offer and sell, subject to market and other conditions, $250.0 million of shares of its common stock in an underwritten public offering (Press release, Crinetics Pharmaceuticals, SEP 11, 2023, View Source [SID1234635061]). In addition, Crinetics intends to grant the underwriters a 30-day option to purchase up to an additional $37.5 million of shares of common stock. All of the shares to be sold in the offering are to be sold by Crinetics. There can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering.

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Crinetics intends to use the net proceeds from the proposed offering to fund the development of paltusotine, CRN04894 and its other research and development programs, and for working capital and general corporate purposes.

J.P. Morgan, Morgan Stanley, Leerink Partners and Piper Sandler are acting as joint book-running managers for the offering.

The securities described above are being offered by Crinetics pursuant to a shelf registration statement that became automatically effective upon its filing with the Securities and Exchange Commission (SEC). A preliminary prospectus supplement and accompanying prospectus relating to this offering will be filed with the SEC. When available, copies of the preliminary prospectus supplement and the accompanying prospectus relating to this offering may be obtained from: J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, by telephone at (866) 803-9204 or by email at [email protected]; Morgan Stanley & Co. LLC, Attention: Prospectus Department, 180 Varick Street, 2nd Floor, New York, NY 10014 or by email at [email protected]; Leerink Partners LLC, Attention: Syndicate Department, 53 State Street, 40th Floor, Boston, MA 02109, by telephone at (800) 808-7525, ext. 6105, or by email at [email protected]; or Piper Sandler & Co., Attention: Prospectus Department, 800 Nicollet Mall, J12S03, Minneapolis, MN 55402, by telephone at (800) 747-3924 or by email at [email protected]. Electronic copies of the preliminary prospectus supplement and accompanying prospectus will also be available on the website of the SEC at www.sec.gov.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such jurisdiction.

On September 11, 2023 Avalo therapeutics presented its corporate presentation (Presentation, Avalo Therapeutics, SEP 11, 2023, View Source [SID1234635060]).

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On September 11, 2023 Bristol Myers Squibb (NYSE: BMY) reported six-year results from Part 1 of the Phase 3 CheckMate -227 trial, which continues to demonstrate long-term, durable survival benefits of Opdivo (nivolumab)plus Yervoy (ipilimumab)compared to chemotherapy in the first-line treatment of patients with metastatic non-small cell lung cancer (mNSCLC), regardless of PD-L1 expression levels (Press release, Bristol-Myers Squibb, SEP 11, 2023, View Source;227-Trial-Show-Durable-Long-Term-Survival-with-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-in-the-First-Line-Treatment-of-Patients-with-Metastatic-Non-Small-Cell-Lung-Cancer/default.aspx [SID1234635059]). Follow-up results will be featured in an oral presentation (Abstract #OA14.03) and have been selected for the official press program at the IASLC 2023 World Conference on Lung Cancer (#WCLC23) hosted by the International Association for the Study of Lung Cancer on September 11, 2023, from 2:32 a.m. to 2:42 a.m. EDT / 2:32 p.m. to 2:42 p.m. SGT.

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With a minimum follow-up of over six years (73.5 months), the longest reported for a Phase 3 trial with immunotherapy in mNSCLC:

Follow-up results of the primary endpoint population of patients with tumor PD-L1 expression ≥1% show that the six-year survival rate for Opdivo plus Yervoy was 22%, compared to 13% for chemotherapy (Hazard Ratio [HR] 0.78; 95% Confidence Interval [CI]: 0.67 to 0.91).
In an exploratory analysis of patients with PD-L1 expression <1%, more than three times as many patients treated with Opdivo plus Yervoy were alive at six years compared to those treated with chemotherapy (16% vs. 5%, respectively; HR 0.65; 95% CI: 0.52 to 0.81).
Among those who responded to treatment, greater proportions of patients had tumor burden reduction ≥80% with Opdivo plus Yervoy vs. chemotherapy in both the PD-L1 ≥1% (15% vs. 3%, respectively) and <1% (8% vs. 1%, respectively) subgroups, and six-year overall survival (OS) rates for patients with tumor burden reduction ≥80% with Opdivo plus Yervoy were higher compared to chemotherapy (59% vs. 42% for PD-L1 ≥1% and 77% vs. 0% for PD-L1 <1%, respectively).
The safety profile for the dual immunotherapy combination Opdivo plus Yervoy remained consistent with previously reported data from this trial and was manageable with established protocols, with no new safety signals identified.
"Immunotherapy has transformed the treatment of advanced lung cancer, and thankfully, a diagnosis no longer means the same thing as it used to for many patients. With these six-year results, we are seeing remarkably sustained and durable clinical survival benefits with nivolumab plus ipilimumab year-over-year," said Solange Peters, M.D., Ph.D., professor and chair of medical oncology and the thoracic malignancies program in the Department of Oncology at the University Hospital of Lausanne in Lausanne, Switzerland. "The long-term efficacy seen with the dual immunotherapy regimen in CheckMate -227 reinforce the importance of nivolumab plus ipilimumab to transform outcomes for appropriate patients with metastatic non-small cell lung cancer."

"We are ecstatic to see Opdivo plus Yervoy continue to demonstrate almost double the overall survival rates as chemotherapy after six years of follow-up – the longest-ever for a Phase 3 trial with immunotherapy in metastatic non-small cell lung cancer. Further, the Opdivo plus Yervoy regimen more than tripled survival for patients with PD-L1 expression <1%, a population that is difficult to treat and faces high unmet needs," said Abderrahim Oukessou, M.D., vice president, thoracic cancers global program lead, Bristol Myers Squibb. "Our results presented at WCLC 2023 build on our legacy of transforming survival expectations with immunotherapy combinations. Looking ahead, we are excited to expand our research into targeted and small molecule therapies, as well as additional immunotherapy combinations, in the hope of potentially finding solutions for as many people living with thoracic cancers as possible."

Opdivo plus Yervoy-based combinations have shown significant improvements in OS in six Phase 3 clinical trials in five tumors to date: metastatic NSCLC, metastatic melanoma, advanced renal cell carcinoma, malignant pleural mesothelioma and esophageal squamous cell carcinoma.

About CheckMate -227

CheckMate -227 is a multi-part open-label global randomized Phase 3 trial evaluating Opdivo-based regimens versus platinum-doublet chemotherapy in patients with first-line metastatic non-small cell lung cancer (NSCLC) across non-squamous and squamous tumor histologies.

There are two independent primary endpoints in Part 1 for Opdivo plus Yervoy (versus chemotherapy): overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and progression-free survival (PFS) in patients with tumor mutational burden (TMB) ≥10 mutations/megabase (mut/Mb) across the PD-L1 spectrum (assessed in patients enrolled across Parts 1a and 1b). Patients were treated as follows:

Part 1a: Opdivo (3 mg/kg every 2 weeks) plus Yervoy (1 mg/kg every 6 weeks), Opdivo monotherapy (240 mg every 2 weeks), or chemotherapy (every 3 weeks for up to four cycles) in patients whose tumors express PD-L1 (≥1%)
Part 1b: Opdivo plus Yervoy,Opdivo (360 mg every 3 weeks) plus chemotherapy (every 3 weeks for up to four cycles), or chemotherapy (every 3 weeks for up to four cycles) in patients whose tumors do not express PD-L1 (<1%)
Part 1 met both its independent primary endpoints of PFS with the Opdivo plus Yervoy combination versus chemotherapy in patients whose tumors have high (≥10 mut/Mb) TMB, regardless of PD-L1 expression, and OS demonstrating a superior benefit for Opdivo plus Yervoy versus chemotherapy in first-line metastatic NSCLC patients whose tumors expressed PD-L1 ≥1%.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer, representing up to 84% of diagnoses. Survival rates vary depending on the stage and type of the cancer when diagnosed.