On June 20, 2024 Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) (the "Company" or "Sonnet"), a clinical-stage company developing targeted immunotherapeutic drugs, reported the entry into a definitive agreement for the immediate exercise of certain outstanding warrants to purchase up to an aggregate of 2,828,500 shares of common stock, issued by Sonnet in October 2023 (the "Existing Warrants"), at a reduced exercise price of $1.20 per share (Press release, Sonnet BioTherapeutics, JUN 20, 2024, View Source [SID1234644455]). The shares of common stock issuable upon exercise of the Existing Warrants are registered pursuant to an effective registration statement on Form S-1 (File No. 333-274581). The closing of the offering is expected to occur on or about June 21, 2024, subject to satisfaction of customary closing conditions.

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Ladenburg Thalmann & Co. Inc. is acting as the exclusive placement agent for the offering.

In consideration for the immediate exercise of the Existing Warrants for cash, Sonnet will issue new unregistered warrants to purchase up to 5,657,000 shares of common stock (the "New Warrants"). The New Warrants will have an exercise price of $1.55 per share (priced at-the-market under the rules of the Nasdaq Stock Market), will be exercisable upon issuance, and have a term equal to five years from the date of issuance. In connection with the transaction, Sonnet also (i) reduced the exercise price of the Existing Warrants to purchase an aggregate of 2,824,000 shares of common stock for all holders not participating in the transaction to $1.20 per share for the remaining term of the Existing Warrants, (ii) reduced the exercise price of certain outstanding warrants to purchase up to an aggregate of 227,272 shares of common stock issued by Sonnet in June 2023 (the "June Warrants") to $1.55 per share and (iii) extended the term of the June Warrants to the term of the New Warrants.

The gross proceeds to Sonnet from the exercise of the Existing Warrants are expected to be approximately $3.4 million, prior to deducting placement agent fees and offering expenses. The Company intends to use the net proceeds for research and development, including clinical trials, working capital, the repayment of all or a portion of liabilities, and general corporate purposes.

The New Warrants described above were offered in a private placement pursuant to an applicable exemption from the registration requirements of the Securities Act of 1933, as amended (the "1933 Act"), and, along with the shares of common stock issuable upon exercise, have not been registered under the 1933 Act, and may not be offered or sold in the United States absent registration with the Securities and Exchange Commission ("SEC") or an applicable exemption from such registration requirements. Sonnet has agreed to file a registration statement with the SEC covering the resale of the shares of common stock issuable upon exercise of the New Warrants.

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

On June 20, 2024 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing first-in-class1 therapeutics that combine both targeted and immune-mediated mechanisms, reported new positive data from the ongoing global randomized Phase 1b/2 clinical study in which amezalpat2 (TPST-1120), Tempest’s PPAR⍺ antagonist, delivered a six-month improvement in median overall survival ("OS") advantage when combined with atezolizumab and bevacizumab in a comparison to atezolizumab and bevacizumab alone in the first-line treatment of patients with unresectable or metastatic hepatocellular carcinoma ("HCC") (Press release, Tempest Therapeutics, JUN 20, 2024, View Source [SID1234644456]).

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"We are thrilled by these new survival data that build on the already meaningful data released in the fall showing the improvement of the amezalpat arm over atezolizumab and bevacizumab control across all study endpoints," said Stephen Brady, president and chief executive officer of Tempest. "These new data come after 10 more months of follow-up since the last data analysis and show not only a strong hazard ratio of 0.65 favoring the amezalpat arm, but also a six-month improvement in the median overall survival with half the patients still in survival follow up, as well as observation of a survival advantage across key populations – results that we believe put amezalpat in a strong position for a successful pivotal Phase 3."

At the cutoff date of February 14, 2024, the new data from 40 patients randomized to the amezalpat arm and 30 patients randomized to the control arm show:

21 month median OS for the amezalpat arm versus 15 month for the control arm, a six-month survival advantage
20/40 patients remain in survival follow up in the amezalpat arm, compared to 9/30 patients in the control arm
0.65 hazard ratio ("HR") for OS, revealing a stable HR since the top-line analysis 10 months earlier when the HR was 0.59
Manageable safety profile consistent with Phase 1 data
The earlier top-line data analysis, dated April 20, 2023, had a median follow up of 9.2 and 9.9 months for the amezalpat and control arms, respectively, and showed:

Confirmed objective response rate ("cORR" or "confirmed ORR") of 30% for the amezalpat arm versus 13.3% for the control arm;
Biomarker subpopulation findings were consistent with the mechanism of action of amezalpat
Patients with b-catenin activating mutations (21% in this study (n=7)) showed a cORR of 43% and a disease control rate ("DCR") of 100% in the amezalpat arm
The amezalpat arm was consistently active across both PD-L1 positive and PD-L1 negative tumors, with a cORR of 27% in the amezalpat arm compared to 7% for the control arm in PD-L1 negative tumors
Amezalpat remains well tolerated, with safety data comparable between the two arms
The randomized arms were generally well balanced at baseline
ORR was determined by RECIST v1.1, and confirmed responses included at least two scans. Tempest retains all product rights to amezalpat.

Conference Call & Webcast Information

Tempest will host a webcast conference call today, June 20, 2024 at 8:30am ET.

To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. The live webcast and audio archive of the presentation may be accessed on the investor section of the Tempest website at View Source The webcast will be available for replay for 30 days.

About the Randomized Clinical Trial

The Phase 1b/2 global randomized HCC study is part of Roche’s Morpheus program and evaluates amezalpat in combination with atezolizumab and bevacizumab versus atezolizumab and bevacizumab, the standard of care, in patients with unresectable or metastatic HCC not previously treated with systemic therapy. The trial randomized 70 patients to receive either amezalpat with atezolizumab + bevacizumab or a contemporaneous control arm of atezolizumab + bevacizumab alone at approximately 25 sites worldwide, including in the United States, Europe, and Asia. The primary efficacy endpoint was confirmed objective response rate, and key secondary endpoints including PFS and OS. Under the terms of the clinical collaboration agreement, Roche is managing the study operations for this global, multicenter trial and Tempest retains all product rights.

About Amezalpat (TPST-1120)

Amezalpat is an oral, small molecule, selective PPAR⍺ antagonist. Tempest’s data suggest that amezalpat treats cancer by targeting tumor cells directly and by modulating immune suppressive cells and angiogenesis in the tumor microenvironment. In an ongoing global randomized phase 1b/2 study of amezalpat in combination with atezolizumab and bevacizumab in first-line patients with advanced HCC, the amezalpat arm showed clinical superiority across multiple study endpoints when compared to atezolizumab and bevacizumab alone, the standard of care. These randomized data were supported by positive results observed in the Phase 1 clinical trial in patients with heavily pretreated advanced solid tumors.

About Hepatocellular Carcinoma

HCC is an aggressive cancer with rising mortality and is projected to become the third leading cause of cancer death by 2030.3 Every year, more than 900,000 people worldwide are diagnosed with HCC.4 Incidence and mortality are highest in East Asia and are increasing in parts of Europe and the US.5 In the US, HCC represents the fastest-rising cause of cancer-related death.3

Nine out of ten cases of HCC are caused by chronic liver disease, which includes chronic hepatitis B and C infection, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related liver disease (ALD) and cirrhosis resulting from these conditions.6

Even if diagnosed in the early stage, an estimated 70-80% of people with early-stage HCC experience disease recurrence following surgery.7 Early recurrence is associated with poorer prognosis and shorter survival.5,8 Tumor size, number of tumors, and portal vein invasion are associated with an increased risk of recurrence.

On June 20, 2024 Medigene AG (Medigene, the "Company", FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported that it has selected its lead candidate for MDG2021, a T cell receptor engineered T cell (TCR-T) therapy targeting Kirsten rat sarcoma viral oncogene homologue (KRAS) G12D with human leukocyte antigen (HLA)-A*11 being developed in combination with the Company’s PD1-41BB costimulatory switch protein (CSP) technology (Press release, MediGene, JUN 20, 2024, View Source [SID1234644457]).

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With its proprietary End-to-End (E2E) Platform, the Company has successfully generated an optimal KRAS G12D-HLA-A*11 TCR that meets the Company’s selection criteria for highly specific, sensitive and safer (3S) TCRs as the lead that will now advance into the pre-clinical stage. The Company’s evaluation criteria for TCR selection included sensitive and precise tumor cell recognition combined with simultaneous display of a high safety profile demarked by lack of recognition of panels of healthy cells and tissues, matched and mismatched for HLA.

"We are delighted to announce that we have successfully generated a novel 3S TCR targeting KRAS G12D-A*11 that meets our rigorous selection criteria of high specificity, heightened sensitivity, and promising potential for enhanced safety," said Dr. Selwyn Ho, Chief Executive Officer at Medigene.

"The selection of this KRAS G12D lead-TCR expands our library of TCRs against neoantigens and cancer-testis antigens. Further, with the addition of our armoring & enhancement technology, PD1-41BB CSP to our TCR-T therapies, we are confident that our approach will yield best-in-class TCR-T therapies, providing improved outcomes for patients with to date, difficult-to-treat solid tumors such as colorectal cancer and pancreatic cancer. We are looking forward to presenting initial pre-clinical data on MDG2021 at upcoming scientific conferences in the second half of 2024."

The Company’s E2E Platform continues to generate 3S TCRs with unique and distinctive attributes that will be utilized across multiple therapeutic modalities, including TCR-T therapies, TCR-guided T cell engagers and TCR natural killer cell therapies. The new 3S TCR is designed for co-expression with Medigene’s PD1-41BB CSP to enhance the proliferation, persistence, and cytotoxic function of TCR-T cells, while simultaneously mitigating immunosuppressive effects of the tumor microenvironment.

Following the lead announcement of Medigene’s first KRAS program MDG2011 (KRAS G12V-A*11) in June 2023, MDG2021 is the latest program now in preclinical development within Medigene’s library of neoantigens that comprises multiple KRAS mutations and HLAs. The MDG20xx program is dedicated to further develop the Company’s TCR library, exploring other KRAS neoantigen mutations and HLAs.

On June 19, 2024 Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, reported that the National Medical Products Administration of China has approved golidocitinib for the treatment of adult patients with relapsed or refractory (r/r) peripheral T-Cell lymphoma (PTCL) whose disease has progressed on or were refractory to at least 1 prior systemic therapy (Press release, Dizal Pharma, JUN 19, 2024, View Source [SID1234644442]). To date, golidocitinib is the first and only approved Janus kinase 1 (JAK1) selective inhibitor for r/r PTCL patients globally.

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PTCL is a heterogeneous group of aggressive T-cell/natural killer (NK) cell non-Hodgkin lymphomas (NHL). Patients with PTCL face an extremely high risk of disease relapse even if they achieved tumor remission following first-line conventional therapy. The outcome for relapsed or refractory patients is extremely poor, with a 3-year survival rate of 23% and a median overall survival (mos.) of 5.8 months. Although couple of drugs have been granted conditional approval by regulatory agencies in the relapsed or refractory setting, their single agent activities have been modest, with objective response rates (ORRs) lower than 30%.

Golidocitinib was approved based on findings from JACKPOT8 Part B (JACKPOT8B) study, the multinational pivotal study to evaluate the efficacy and safety of golidocitinib in r/r PTCL as a monotherapy. The primary endpoint was the objective response rate (ORR), assessed by an independent review committee (IRC). Full analysis of the study was simultaneously published in The Lancet Oncology and presented in oral session at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

In JACKPOT8B study, golidocitinib demonstrated superior and durable antitumor efficacy and a favorable safety profile in r/r PTCL patients, compared with existing treatment options. At the data cut-off date August 31, 2023, the ORR was 44.3% including a complete response (CR) rate of 23.9% per IRC. Tumor responses were observed across various PTCL subtypes. The median duration of response (mDoR) was 20.7 months and 53.8% of patients were still responding.

"Golidocitinib features novel mechanism and unique molecular design, positioning it as the first oral JAK1 only inhibitor for the treatment of r/r PTCL. Multiple studies have clearly demonstrated its favorable pharmacokinetic properties and significant clinical benefit," said Jun Zhu, MD, PhD at the Department of Lymphoma, Peking University Cancer Hospital and Institute, the leading principal investigator of the JACKPOT8B study, "Golidocitinib achieved an ORR of 44.3% and a DoR of 20.7 months in r/r PTCL. It’s approval and market launch provide a much needed option for doctors to treat PTCL patients."

Dizal was the first to identify and validate targeting the JAK/STAT pathway as a promising therapeutic approach for PTCL, leading to the development of golidocitinib as the world’s first JAK1 only inhibitor. With > 200 to 400-fold selectivity over other JAK family members and ideal pharmacokinetic properties, golidocitinib exerts potent antitumor efficacy with a favorable safety profile.

"We are thrilled to bring golidocitinib, the world’s first JAK1 only inhibitor, to patients in China, marking the second approved innovative drug from Dizal," said Xiaolin Zhang, PhD, CEO of Dizal. "Golidocitinib yields good antitumor efficacy across different subtypes of PTCL, which differentiate golidocitinib from other targeted therapies. At Dizal, we aspire to discover and develop first-in-class and groundbreaking new medicines to address unmet medical needs around the world. With the US FDA Fast Track designation, we are expediting global development of golidocitinib to bring this exciting drug to patients worldwide."

With superior efficacy and safety profile, golidocitinib has been widely acknowledged at prestigious international congresses including ASCO (Free ASCO Whitepaper), EHA (Free EHA Whitepaper), ICML, and ASH (Free ASH Whitepaper), with six oral presentations over four consecutive years. The results of the multinational study JACKPOT8 were published in Annals of Oncology and The Lancet Oncology.

About golidocitinib (DZD4205)

Golidocitinib is currently the first and only Janus kinase 1 (JAK1) selective inhibitor being evaluated for the treatment of r/r PTCL. In June 2024, golidocitinib was approved by the National Medical Products Administration (NMPA) of China for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (r/r PTCL).

At the data cut-off date of August 31, 2023, golidocitinib has demonstrated robust and durable anti-tumor efficacy, with an ORR of 44.3%. More than 50% of the patients with tumor remission achieved a complete response with a CRR of 23.9%. Per IRC assessment, mDoR reached 20.7 months. Golidocitinib was granted Fast Track Designation by the U.S. FDA for the treatment of r/r PTCL in February 2022. In September 2023, the CDE accepted its NDA and granted Priority Review for the treatment of r/r PTCL. The Phase I clinical data of golidocitinib (JACKPOT8 PART A) was published in Annals of Oncology (Impact Factor: 51.8), and global pivotal trial data of golidocitinib for the treatment of r/r PTCL (JACKPOT PART B) was published in The Lancet Oncology (Impact Factor: 54.4).

On June 19, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported that China’s National Medical Products Administration (NMPA) has approved the clinical trial application for GFH375 (VS-7375) in an open-label, multi-center phase I/II study targeting advanced solid tumor patients with KRAS G12D mutation (Press release, GenFleet Therapeutics, JUN 19, 2024, View Source [SID1234644443]). G12D mutation is the most prevalent KRAS mutation detected in human cancers, and no G12D-targeted therapies have been approved yet.

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GFH375 is a highly potent and selective KRAS G12D inhibitor targeting both "ON" (GTP-bound) and "OFF" (GDP-bound) states of the protein. According to the latest preclinical findings posted at 2024 AACR (Free AACR Whitepaper) annual meeting, GFH375 demonstrated preliminary safety data, favorable oral bioavailability and potent efficacy across preclinical models; moreover, GFH375 holds the potential for treating G12D-mutant cancers with brain metastases.

GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) in 2023 to advance three oncology programs. The first program selected is GFH375, which represents a significant milestone as the GenFleet’s first product to achieve overseas out-licensing at preclinical stage and the IND approval in China, underscoring the company’s expertise in the development of RAS-targeted therapies.

The study (GFH375X1101) will be conducted at ~40 hospitals, including the prominent Shanghai Chest Hospital. In phase I, the study aims to evaluate the safety/tolerability and preliminary efficacy of GFH375 in advanced G12D-mutant solid tumor patients. Additionally, the phase I trial will determine the recommended phase II dose (RP2D). Progressing into Phase II, the study will further assess the efficacy of GFH375 for patients of advanced solid tumors including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) – three cancer types with highest prevalence of G12D mutation; the study will also investigate the underlying mechanisms of patients’ response and resistance to the treatment.

"I am excited that the clinical trial application for GFH375 has been approved. The therapeutic landscape for G12D-mutant cancers remains challenging with limited treatment options, highlighting the significant unmet medical needs in this population. The G12D mutation is one of the most prevalent KRAS mutations and the development of G12D-targeted therapies has garnered significant attention recently. We eagerly await favorable safety and efficacy outcome for GFH375 in the upcoming trial, with the hope of introducing a novel life-saving treatment for patients." stated Dr. Shun Lu, professor of Dept. of Medical Oncology, Shanghai Chest Hospital.

"We are delighted to enter in a clinical trial to assess the clinical benefits of our G12D targeted program in monotherapy setting and explore the possibilities of synergistic effects that may arise from potential combination regimen in future. GenFleet’s expertise in developing RAS-targeted therapies has been exemplified by the successful development of fulzerasib (GFH925, a KRAS G12C inhibitor) and the NDA acceptance of its monotherapy for NSCLC in China. This allows GenFleet to be well positioned to advance our second RAS pathway inhibitor GFH375 into the clinical trial, as well as other RAS-inhibiting therapies in our pipeline." stated Yu Wang, Ph.D/M.D., Chief Medical Official of GenFleet.

References:

1. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma, NPJ Precision Oncology, Feb. 2024

2. Next batter up! Targeting cancers with KRAS G12D mutations, Trends in Cancer (Cell Press), Nov. 2023

3. Pan-KRAS inhibitor disables oncogenic signaling and tumor growth, Nature, May 2023

About KRAS G12D mutation and GFH375

RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK and PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans. Among KRAS mutations, G12D, G12V, and G12C represent the top three most frequently mutated alleles. KRAS G12D mutation is commonly found in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. A large percentage of patients harboring KRAS G12D mutation are found without smoking history and with poor response to PD-1 inhibitors. Mutant-selective G12D inhibitors hold promise to benefit large segments of KRAS-driven PDAC patients since KRAS G12D alterations are the most frequently occurring somatic change in PDAC patients (about 40%) who are reported to have an overall 5-year survival rate lower than 10%.

GFH375 is an orally active, potent, highly selective small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the GTP/GDP exchange, thereby disrupting the activation of downstream pathways and effectively inhibiting tumor cell proliferation. Preclinical studies demonstrated that the inhibition of GFH375 on tumor growth is enhanced along with the increase in dosage and duration of treatment; GFH375 also demonstrated low off-target risk in kinase selectivity and safety target assays.

GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) to advance three novel oncology discovery programs related to RAS pathway-driven cancers. The risk-sharing structure of the collaboration provides Verastem Oncology a milestone-based option to license up to three compounds. The licenses would give Verastem Oncology development and commercialization rights outside of China while GenFleet would retain rights inside of the Chinese mainland, Hong Kong, Macau, and Taiwan.