On October 30, 2023 Amplia Therapeutics Limited (ASX: ATX), ("Amplia" or the "Company"), reported the completion of the Phase 1b stage of the ongoing ACCENT clinical trial in firstline patients with advanced pancreatic cancer (Press release, Amplia Therapeutics, OCT 30, 2023, View Source [SID1234636419]). A safe and well tolerated dose of narmafotinib, the company’s lead asset and best-in-class FAK inhibitor, will now be taken into the Phase 2a portion of the trial that will start imminently.

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The Phase 1b stage of the ACCENT trial was designed to test ascending doses of orally-dosed narmafotinib in patients, in combination with the standard-of-care chemotherapy regime of gemcitabine combined with Abraxane. This dose-escalation stage has identified a dose of narmafotinib that provides sufficient circulating drug levels to significantly block the activity of the FAK enzyme. Importantly, this dose has been shown to be safe and well-tolerated across the three cohorts of patients (14 in total) in the trial.

The Phase 1b study was not powered for an efficacy readout, however, all patients were assessed for the impact drug treatment had on their cancer using the international standard Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria1. The initial data obtained for the first 14 patients who completed the trial as per protocol, whilst preliminary and in some cases requiring a confirmatory scan, are positive, with 36% of patients demonstrating a partial response as their best overall response, and with a disease control rate (combined partial response and stable disease) of 93% (Table). These numbers compare very favourably with the published data of the clinical benefit of the gemcitabine and Abraxane combination in pancreatic cancer2. Across all doses, narmafotinib was shown to be generally safe and well-tolerated. All patients who completed their first 28-day cycle of treatment elected to stay on narmafotinib, with 7 patients (as of 27th October) having received narmafotinib as part of the combination for 5 months or more. As previously reported, one dose-limiting toxicity event was observed and notably, no treatment-related adverse events greater than Grade 3 were considered related to narmafotinib.

The clinical trial data has been reviewed by the ACCENT Safety Review Committee who support the dose selection and moving to the Phase 2a (Part B) stage of the trial. The Phase 2a trial will be run at the seven trial sites open in Melbourne, Sydney and Brisbane, with five additional sites in Korea expected to open by the end of this year.

Amplia’s CEO and Managing Director Dr Chris Burns commented: "Completion of the Phase 1b stage of the trial is an important milestone for the ACCENT trial. We have now identified a safe and welltolerated dose of narmafotinib to take into the Phase 2a stage of the trial and the preliminary efficacy signals we have seen to date, across three dose cohorts, are very encouraging. The team at Amplia are now focused on executing the next phase of the trial as quickly and efficiently as possible. As always, we thank the patients for participating in the trial, and the clinical trial staff and investigators for their continued involvement in the trial."

About the ACCENT Trial

The protocol for the ACCENT trial is entitled ‘A Phase 1b/2a, Multicentre, Open Label Study of the Pharmacokinetics, Safety and Efficacy of AMP945 in Combination with Nab-paclitaxel and Gemcitabine in Pancreatic Cancer Patients’.

The trial is a single-arm open label study conducted in two stages. The first, Phase 1b stage of the trial, will determine an optimal dose of AMP945 by assessing the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of AMP945 when dosed in combination with gemcitabine and Abraxane in first-line patients with advanced pancreatic cancer.

The Part B Phase 2a, stage of the trial is designed to assess efficacy in combination with gemcitabine and Abraxane. The primary endpoint being Objective Response Rate (ORR). Further endpoints will assess efficacy. Safety and tolerability will continue to be assessed.

More information about the ACCENT trial, including a list of participating sites, can be found via our website and at ClinicalTrials.gov under the identifier NCT05355298.

The Company will provide further updates on the next stage of the trial as recruitment proceeds.

On October 27, 2023, ImmuneOnco Biopharmaceuticals (Shanghai) Co., Ltd. reported that 2 drug candidates independently developed by the company, IMM2510, a bispecific antibody-receptor recombinant protein targeting PD-L1/VEGFA and IMM27M, an ADCC-enhanced CTLA-4 monoclonal antibody, are proposed to combined for the treatment of advanced solid tumors (Press release, ImmuneOnco Biopharma, OCT 27, 2023, View Source [SID1234655695]). This clinical phase I study was approved by the National Medical Products Administration (NMPA). this is another milestone achievement in the rapid development of ImmuneOnco.

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The initial results of the Phase I clinical trial of the IMM2510 have shown great safety profiles and positive efficacy, with tumor response observed in three different dose groups (3mg/kg, 10mg/kg, 20mg/kg). Among them, one PR was observed in each of 3 mg/kg and 10 mg/kg dose groups in patients with lung squamous cell carcinoma who had failed PD1 therapy, and one PR was observed in another thymic adenosquamous cell carcinoma (20 mg/kg). After discussion by the Safety Review Committee SRC, it was unanimously agreed that the RP2D dose of 20mg/kg Q2W as a single drug and proceed to Phase II for further development.

Overall data form the phase I dose escalation clinical trial of the IIMM27M for solid tumors showed that IMM27M was well tolerated, with no dose-limiting toxicities (DLTs) occurring in all subjects across the seven dose groups of 0.1 mg/kg to 7.5 mg/kg. Among them, initial positive tumor response (both obtained PR) was observed in 2 breast cancer patients after multiple lines of treatment (one case was 3 mg/kg, the other was 5 mg/kg); in addition, Tumor shrinkage exceeding 20% SD was observed in melanoma patients (2 mg/kg). After discussion by the Safety Review Committee (SRC), it was unanimously agreed that 5mg/kg Q3W should be used as a single drug RP2D dose and proceed to enter Phase II for further development.

Preclinical efficacy studies shown that IMM2510 produces stronger synergistic anti-tumor activity compared with the combination of VEGF blocking antibody and PD-L1 antibody. Repeated in vivo studies proved that IMM27M has strong anti-tumor activity and can be used in clinical studies in combination with a variety of drugs in the company’s pipeline. Dual immune combination therapy of CTLA4 combined with PD1/PD-L1 was proven to have clear clinical synergy.

Dr. Tian, Wenzhi, founder and chairman of ImmuneOnco, said:

"We are very pleased that our Phase I clinical trial application of IMM2510 combined with IMM27M in the treatment of advanced solid tumors has been approved by the NMPA. The dual immune combination therapy of CTLA4 combined with PD1/PD-L1 has proven to have clear clinical synergy, BMS’s "O+Y" The (Opdivo+Yervoy) combination has been approved by the FDA for multiple indications, covering multiple clinical indications such as melanoma, colorectal cancer, renal cell carcinoma, hepatocellular carcinoma, and non-small cell lung cancer; AZ’s "D +T" (Durvaluma+Tremelimumab) combination has been approved for liver cancer and non-small cell lung cancer indications. At the same time, Roche’s "T+A" (Tecentriq+Avastin) combination has also been approved for marketing in China and the United States as a first-line treatment for advanced liver cancer. These combination therapies all involve two targets. We believe that the triple-target treatment of IMM2510 combined with IMM27M are expected to have better clinical efficacy. We plan to carry out clinical exploratory studies in multiple advanced solid tumors (liver cancer, breast cancer, lung cancer, etc.), and looking forward to bringing good news to cancer patients.

On October 27, 2023 Specialty reported care growth, strong launch uptake of Beyfortus and ALTUVIIIO drive solid Q3 results (Press release, Sanofi, OCT 27, 2023, View Source [SID1234638477]).

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Q3 2023 sales growth of 3.2% at CER and business EPS(1) decrease of 2.1% at CER
• Specialty Care grew 13.5% driven by Dupixent (€2,847 million, +32.8%) and ALTUVIIIO more than offsetting
the impact of Aubagio generic competition in the U.S.
• Stable Vaccines sales (-0.6%) benefited from strong Beyfortus launch offsetting lower influenza vaccines sales
• General Medicines core assets grew 3.1%, non-core assets declined mainly due to Lantus (€343 million, –
32.9%)
• CHC sales grew 4.6% driven by Digestive Wellness and Allergy categories
• Business EPS(1) of €2.55, down 11.5% on a reported basis and down 2.1% at CER with Aubagio LOE
• IFRS EPS of €2.01 (up 21.1%)
Key R&D milestones and regulatory achievements in Q3
• Beyfortus U.S. approval for prevention of RSV lower respiratory tract disease in infants
• ALTUVIIIO approval for hemophilia A in Japan and Nexviazyme for the treatment of Pompe disease in China
Progress on Corporate Social Responsibility strategy in Q3
• Sanofi Global Health Unit: first deliveries of cardio-metabolic products under the Impact brand to the Republic of
Djibouti and to global non-governmental organizations
Full-year 2023 business EPS guidance reiterated
• Sanofi expects 2023 business EPS(1) to grow mid single-digit(2) at CER, barring unforeseen major adverse events.
Applying average October 2023 exchange rates, the currency impact on 2023 business EPS is estimated between
-6.0% to -7.0%. This guidance includes approximately €400 million of expected one-off COVID vaccine revenues
in the fourth quarter.
Paul Hudson, Sanofi Chief Executive Officer, commented:
"The continued impressive performance of Dupixent, the highly anticipated launch of Beyfortus for the protection
of all infants against RSV and the strong uptake of ALTUVIIIO in hemophilia were key drivers in the quarter,
exemplifying our successful strategy execution towards sustainable growth from innovative medicines. The underlying
strength of our growth drivers more than offset the expected impact from generic competition on Aubagio in U.S.
and lower sales from mature products across the General Medicines portfolio in the quarter. With our two recent
business development deals in immunology and vaccines, we are further strengthening the core of our innovative
pipeline and follow our strategic focus of transforming the practice of medicine through breakthrough science. As we
enter a compelling next chapter of our company’s Play to Win strategy, we remain confident in the outlook for the
last quarter and consequently keep our full-year earnings guidance unchanged."
Q3 2023 Change Change
at CER
9M 2023 Change Change
at CER
IFRS net sales reported €11,964m -4.1% +3.2% €32,151m -0.4% +3.9%
IFRS net income reported €2,525m +21.6% _ €5,955m +13.2% —
IFRS EPS reported €2.01 +21.1% _ €4.76 +13.3% —
Free cash flow(3) €1,853m -31.2% _ €4,982m -16.1% —
Business operating income €4,028m -10.4% -1.0% €10,087m -2.2% +4.1%
Business net income(1) €3,196m -11.4% -1.9% €8,072m -1.6% +4.8%
Business EPS(1) €2.55 -11.5% -2.1% €6.45 -1.5% +4.9%
Changes in net sales are expressed at constant exchange rates (CER) unless otherwise indicated (definition in Appendix 7). (1) In order to facilitate an
understanding of operational performance, Sanofi comments on the business net income statement. Business net income is a non-IFRS financial
measure (definition in Appendix 7). The consolidated income statement for Q3 2023 is provided in Appendix 3 and a reconciliation of reported IFRS net
income to business net income is set forth in Appendix 4; (2) 2022 business EPS was €8.26; (3) Free cash flow is a non-IFRS financial measure
(definition in Appendix 7).

On October 27, 2023 Theseus Pharmaceuticals, Inc. (the "Company") reported written notice to ARIAD Pharmaceuticals, Inc. ("ARIAD") of its termination of the License Agreement, dated June 13, 2018, between the Company and ARIAD (the "ARIAD License Agreement"), which termination will be effective in accordance with the terms of the termination for convenience clause of such agreement (Filing, 8-K, Theseus Pharmaceuticals, OCT 27, 2023, View Source [SID1234636556]).

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The Company previously announced in July 2023 that it was discontinuing enrollment in the ongoing Phase 1/2 study and terminating development of THE-630 in patients with gastrointestinal stromal tumors. THE-630 is derived from intellectual property licensed to the Company under the ARIAD License Agreement and is therefore subject to the ARIAD License Agreement. In connection with the termination of development of THE-630, the Company is terminating the ARIAD License Agreement. The Company did not use any intellectual property licensed to the Company, or any biological materials provided to the Company, under the ARIAD License Agreement to develop any of the Company’s other programs.

Under the ARIAD License Agreement, the Company acquired an exclusive, transferable (subject to certain restrictions), sublicensable (subject to certain conditions), worldwide license, under certain of ARIAD’s patent rights, know-how and compounds and a certain ARIAD chemical library, to develop, use, manufacture, market and commercialize certain compounds, and products that contain such compounds, that are therapeutically useful for the treatment of diseases and disorders in humans, including with respect to KIT.

Pursuant to the terms of the ARIAD License Agreement and related stock purchase agreements, the Company issued an aggregate of 1,615,427 shares of the Company’s Series A Preferred Stock to ARIAD (which converted to shares of common stock of the Company in connection with the Company’s initial public offering in October 2021). If the Company had commercialized a product subject to the ARIAD License Agreement, the Company would have been obligated to make tiered royalty payments to ARIAD of low- to mid-single digits of the Company’s future net sales and those of the Company’s sublicensees of each product comprising a licensed ARIAD compound in each country, beginning on the first commercial sale of such product in such country and ending on the later of (1) ten years following such first commercial sale and (2) the expiry of all patents that cover the product in such country, or the royalty term.

On October 27, 2023 Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with a strong unmet medical need, reported financial results for the quarter ended September 30, 2023 and provided a corporate update on recent developments (Press release, Oryzon, OCT 27, 2023, View Source [SID1234636420]).

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Dr Carlos Buesa, Oryzon’s Chief Executive Officer, said: "Oryzon continued with a strong path in its clinical programs in the third quarter. In CNS, we recently reported positive blinded aggregate safety data of 198 patients from our Phase IIb PORTICO trial with vafidemstat in BPD at the ECNP conference earlier this month. BPD is a highly unmet medical need and an enormous commercial opportunity with limited competition and a low risk of generification. PORTICO is now fully enrolled, and we remain on track to present top-line data early next year. The company has started a structured dialogue with corporate pharma to identify a suitable partner to move forward the asset to Phase III, pending positive results. Our Phase IIb trial with vafidemstat in schizophrenia, EVOLUTION, has also continued to enroll patients. We continue working for a future submission of an IND to initiate HOPE in 2024, the first randomized Phase I/II personalized medicine trial with an LSD1 inhibitor, in Kabuki Syndrome patients."

Dr Buesa continued: "In oncology, we also continued to make progress this quarter, with both iadademstat’s ongoing clinical trials, the FRIDA trial in combination with gilteritinib in relapsed/refractory FLT3-mutant AML patients, where a new cohort has been initiated, and the collaborative trial with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in neuroendocrine tumors, which is actively recruiting patients. In addition, and broadening our epigenetic pipeline, we reported positive preclinical efficacy data of ORY-4001, our selective HDAC-6 inhibitor recently nominated as a clinical development candidate, in Charcot-Marie-Tooth (CMT) at the Third Annual Global CMT Research Convention in Cambridge, U.S., and the medical team participated in several round tables."

Third Quarter and Recent Highlights

Vafidemstat in large multifactorial CNS indications:

Positive preliminary blinded aggregate safety data from PORTICO, vafidemstat’s Phase IIb clinical trial in BPD, reported at the 36th European College of Neuropsychopharmacology (ECNP) congress 2023, corresponding to the initial 198 randomized patients (data cut-off, August 23rd 2023). As of September 2023, PORTICO randomized 210 participants, and 131 of the originally planned participants (N = 150) already completed the trial. Results presented at ECNP 2023 confirm that PORTICO enrolled a representative real-world BPD population allowing common comorbidities and concomitant medications that are typically exclusionary in other BPD trials, as well as allowed subjects to receive psychotherapy during the trial. The screen failure and dropout rates were lower than in the most recent BPD clinical trial. Finally, the aggregated blinded safety data on the fully enrolled sample supports that vafidemstat has been extremely safe and well-tolerated, with a low discontinuation rate (2%) due to treatment-emergent adverse events (TEAEs) and 0% due to serious TEAEs (STEAEs). Only one serious TEAE deemed severe was reported, which fully recovered/resolved during the study. Current data of PORTICO continue to support that vafidemstat is safe and well-tolerated. Positive results from PORTICO’s interim analysis, conducted by the independent DMC in Q1 2023, were previously reported, with the trial being determined to be non-futile and to be continued with the planned enrollment number. PORTICO is a multicenter, double-blind, randomized, placebo-controlled Phase IIb conducted in the U.S. and EU to evaluate the efficacy and safety of vafidemstat in BPD patients. The trial has two independent primary objectives: reduction of aggression/agitation and overall BPD improvement. The trial is fully recruited and last patient out is expected before the end of 2023. Topline results are expected in Q1 2024, followed by a full data presentation at a psychiatric conference, as well as in a peerreviewed journal publication.
The EVOLUTION Phase IIb clinical trial with vafidemstat in patients with schizophrenia continues to enroll patients. This Phase IIb study aims to evaluate the efficacy of vafidemstat on negative symptoms and cognitive impairment in patients with schizophrenia. This project is partially financed with public funds from the Spanish Ministry of Science and Innovation and is being carried out in various Spanish hospitals.
Vafidemstat in monogenic CNS indications:

We continue the preparations of a new precision medicine trial in Kabuki Syndrome (KS). The company is in a dialogue with the regulatory agencies to refine the final design of this trial and expects to submit an IND for HOPE to the U.S. Food and Drug Administration (FDA) in 2024.
Iadademstat in oncology:

FRIDA, an open-label, multicenter Phase Ib clinical trial of iadademstat in combination with gilteritinib in patients with relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) harboring a FMS-like tyrosine kinase mutation (FLT3mut+), continues to enroll patients. The primary objectives of the trial are to evaluate the safety and tolerability of iadademstat in combination with gilteritinib in patients with FLT3mut+ R/R AML and to establish the Recommended Phase 2 Dose (RP2D) for this combination. Secondary objectives include the evaluation of the treatment efficacy, measured as the rate of complete remission and complete remission with partial hematological recovery (CR/CRh), the Duration of Responses (DoR), and the assessment of Measurable Residual Disease (MRD). The study is being conducted in the U.S. and will accrue up to approximately 45 patients. If successful, Oryzon and the FDA have agreed to hold a meeting to discuss the best plan to further develop this combination in this much-in-need AML population.
The collaborative Phase II basket trial of iadademstat in combination with paclitaxel in platinum R/R small cell lung cancer (SCLC) and extrapulmonary high-grade neuroendocrine tumors (NET trial) continues to enroll patients. This trial is being conducted in the U.S. under a collaborative clinical research agreement with the FCCC, under which the FCCC will be conducting different collaborative combination clinical trials with iadademstat, with Oryzon providing funding, the drug, and technical expertise.
Preparations for the STELLAR trial, a randomized, multicenter Phase Ib/II study of iadademstat plus a checkpoint inhibitor in first-line extensive-stage SCLC, are ongoing. The company believes that STELLAR could potentially support an application for accelerated approval.
Earlier stage programs:

Positive preclinical efficacy data in CMT with ORY-4001, a selective histone deacetylase 6 (HDAC-6) inhibitor, was presented at the Third Annual Global CMT Research Convention held in September. ORY-4001 treatment was able to reverse disease progression symptoms in a CMT mice model which reliably recapitulates many of the symptoms of this condition in humans, improving myelination and restoring axon integrity in the sciatic nerve, and improving compound muscle action potential and nerve conduction in comparison with untreated animals. The results presented are fruit of a collaboration entered in 2022 between Oryzon and the CMT Research Foundation (CMTRF), a U.S.-based patient-led, non-profit organization focused on delivering treatments and cures for CMT. ORY-4001 was recently nominated as a clinical development candidate for the treatment of certain neurological diseases as CMT, Amyotrophic Lateral Sclerosis (ALS) and others, and the compound will now enter into IND enabling studies to prepare it for clinical studies. HDAC6 inhibitors have been previously proposed as potentially effective treatments for CMT, ALS and other neurological disorders that lack effective treatments.
Financial Update: Third Quarter 2023 Financial Results

Research and development (R&D) expenses were $3.8 and $12.2 million for the quarter and nine months ended September 30, 2023, respectively, compared to $4.3 and $11.9 million for the quarter and nine months ended September 30, 2022.

General and administrative expenses were $0.7 and $2.9 million for the quarter and nine months ended September 30, 2023, respectively, compared to $0.7 and $3.3 million for the quarter and nine months ended September 30, 2022.

Net losses were $0.8 and $3.4 million for the quarter and nine months ended September 30, 2023, respectively, compared to $0.7 and $3.9 million for the quarter and nine months ended September 30, 2022. The result is as expected, given the biotechnology business model where companies in the development phase typically have a long-term maturation period for products, and do not have recurrent income.

Negative net result was $1.7 million (–$0.03 per share) for the nine months ended September 30, 2023, compared to a negative net result of $1.9 million (–$0.04 per share) for the nine months ended September 30, 2022.

Cash, cash equivalents and marketable securities totaled $8.8 million as of September 30, 2023.