On October 23, 2023 Ayala Pharmaceuticals, Inc. (OTCQX: ADXS), a clinical-stage oncology company, reported that new data from the RINGSIDE study evaluating its lead investigational candidate AL102 for the treatment of desmoid tumors (DT) reported presentation at the European Society for Molecular Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023, taking place October 20th to 24th in Madrid, Spain (Press release, Ayala Pharmaceuticals, OCT 23, 2023, View Source [SID1234636237]). The data are from Phase 2 (Part A) of the study and from the Open Label Extension (OLE). The results are featured in a poster being presented by Professor Robin Jones, Team Leader in Sarcoma Clinical Trials at The Institute of Cancer Research and Consultant Medical Oncologist at The Royal Marsden, UK.

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"The RINGSIDE results continue to improve over time, with more patients in this latest Phase 2 and OLE data cut demonstrating responses to treatment with AL102," said Kenneth Berlin, President and CEO of Ayala. "We are seeing impressive anti-tumor activity across multiple parameters and are particularly encouraged by the high response rates, including 83% in the 1.2 mg once daily arm, the dose being used in our Phase 3 study, and 64% across all three doses combined. Furthermore, in two other important efficacy parameters, patients receiving 1.2 mg daily dose experienced an 88% reduction in tumor volume and 85% reduction in T2W signal intensity in median best change from baseline. We are pleased to note that 29 of the 42 patients who participated in Phase 2 of RINGSIDE entered the OLE and that we are seeing new responses in some of the patients who were receiving dosing twice a week and are now receiving 1.2 mg once daily. The Phase 3 registration segment (Part B) of RINGSIDE continues to enroll patients globally at a good pace with greater than 70% of the 154 patients we aim to enroll already dosed. These latest results from Phase 2 and OLE reinforce our belief that AL102 has the potential to be a best-in-class gamma secretase inhibitor and may offer a promising new treatment option to patients with unresectable, recurrent or progressive desmoid tumors."

Professor Robin Jones commented, "The outlook for patients with desmoid tumors appears to be improving, with one gamma secretase inhibitor already in registration with FDA, as an important new class of agents. These latest results on AL102 are unprecedented, showing meaningful clinical benefits across three key efficacy measures in a large proportion of treated patients as well as a manageable safety profile."

Andres Gutierrez MD PhD., Executive VP and Chief Medical Officer of Ayala, added, "The data from the Phase 2 segment of RINGSIDE continue to show efficacy across all dose cohorts with the earliest and deepest responses observed in the 1.2 mg once daily arm, the dose being evaluated in the ongoing Phase 3 segment. The large reductions in T2 signal intensity, as measured by MRI, are noteworthy as they have been correlated with loss of tumor cellularity and symptom control in patients undergoing treatment for DT. AL102 continues to be generally well tolerated and has a manageable safety profile as seen in all three dose arms. The safety results appear consistent with the GSI class."

RINGSIDE Study Phase 2 and OLE Highlights

The ongoing Phase 2/3 RINGSIDE clinical trial is a randomized, global multi-center study evaluating AL102 in patients with progressing desmoid tumors. The study consists of two parts: Phase 2 (Part A) is an open-label, dose regimen finding study, and Phase 3 (Part B) is a double blind, placebo-controlled study and Open Label Extension utilizing the 1.2 mg once daily dose regimen selected based on data from Phase 2. Patients in Phase 2 were randomized to one of three dose regimens of AL102 (n=14 each), including 1.2 mg once daily (QD), 4 mg twice a week (BIW) or 2 mg BIW. Patients in the intermittent dosing arms were allowed to rollover to the Open Label Extension to receive 1.2 mg once daily after evaluations were completed in the Phase 2 part.

The results presented at ESMO (Free ESMO Whitepaper) reflect a cut-off date as of July 5, 2023.

Efficacy Results

1.2 mg once daily achieved ORR of 83% per RECIST in the evaluable population as assessed by MRI BICR (Blinded Independent Central Review)
ORR per RECIST was 64% in evaluable patients across the 3 dose arms (n=36)
Efficacy results continue to demonstrate a dose-response pattern favoring the 1.2 mg once daily arm
First Partial Responses (PRs) observed at 16 weeks and 21 additional PRs and 1 Complete Response across all dose arms
Early and deep volume (-52%) and T2 signal intensity (-58%) reductions within 16 weeks after starting 1.2 mg once daily
Best overall median reductions of 88% and 85% in volume and T2 signal intensity, respectively, in the 1.2 mg once daily arm at 16.6 months of median time on treatment
Reductions in volume and T2 signal intensity were also observed across biweekly dose arms
29 patients rolled over to the OLE between Oct 2022 and May 2023, with 27 still on study
Three patients from the 4 mg BIW arm achieved PR after rolling over to the OLE where they received 1.2 mg once daily
Best overall responses for the three dose arms in the evaluable population of Part A and OLE, as determined by blinded independent central review (BICR), are summarized in the table below:

Evaluable population

1.2 mg QD 4 mg BIW 2 mg BIW All
(n=12) (n=13) (n=11) (n=36)
ORR (CR + PR), n (%) 10 (83) 8 (62) 5 (45) 23 (64)
Complete Response (CR) 0 0 1 (9) 1 (3)
Partial Response (PR) 10 (83) 8 (62) 4 (36) 22 (61)
Stable Disease (SD) 2 (17) 5 (38) 5 (45) 12 (33)
Progressive Disease (PD) 0 0 1 (9) 1 (3)
Disease Control Rate 100% 100% 91% 97%
Time to objective response (months), median (range)

8.1 12 9.2 9.4
(3.8-15) (9.0-18) (6.4-9.2) (3.8-18)
The second table shows tumor responses as measured by volume reduction, T2W signal intensity and RECIST:

Best median change from baseline across all dose groups as measured on MRI by BICR

1.2 mg QD 4 mg BIW 2 mg BIW Overall
(n=12) (n=13) (n=11) (n=36)
Tumor Volume -88 -70 -481 -832
T2W Signal Intensity (cellularity) -85 -77 -53 -76
Central RECIST v1.1 -54 -36 -29 -38
1 n=10 for tumor volume in the 2 mg BIW arm
2 n=35 for tumor volume in the overall population

Safety

AL102 was generally well tolerated with a manageable safety profile across all dose arms
Adverse events (AEs) were consistent with gamma secretase inhibitors’ (GSI) mechanism of action. The most frequent treatment-related AEs with 1.2 mg once daily included diarrhea (92.8%), nausea (57.1%), fatigue (50%), dry skin (50%), alopecia (50%), stomatitis (50%), dermatitis acneiform (42.9%), dry mouth (42.9%), hypophosphatemia (42.9%), rash maculopapular (37.7%) and aspartate aminotransferase increased (28.6%)
Regardless of dose regimen, AEs were Grade 1 or Grade 2 in >95% of the cases
There was one Grade 4 unrelated AE and no Grade 5 AEs. There were no treatment-related serious AEs
Ovarian dysfunction was reported in 56% of pre-menopausal women in the 1.2 mg once daily arm and 61% of pre-menopausal women across all dose arms
The registration-enabling Phase 3 segment of RINGSIDE is now enrolling patients globally. Patients are receiving AL102 1.2mg once daily or placebo. For more information on RINGSIDE, please visit ClinicalTrials.gov and reference Identifier NCT04871282 (RINGSIDE).

A copy of the poster will be available on the Ayala corporate website, following the ESMO (Free ESMO Whitepaper) congress.

About Desmoid Tumors

Desmoid tumors, also called aggressive fibromatosis or desmoid-type fibromatosis, are rare connective tissue tumors that typically arise in the upper and lower extremities, abdominal wall, head and neck area, mesenteric root, and chest wall, or other parts of the body. Desmoid tumors do not metastasize, but often aggressively infiltrate neurovascular structures and vital organs. People living with desmoid tumors are often limited in their daily life due to chronic pain, functional deficits, general decrease in their quality of life and organ dysfunction. Desmoid tumors have an annual incidence of approximately 1,700 patients in the United States and typically occur in patients between the ages of 15 and 60 years. They are most commonly diagnosed in young adults between 30-40 years of age and are more prevalent in females. Today, surgery is no longer regarded as the cornerstone treatment of desmoid tumors due to surgical morbidity and a high rate of recurrence post-surgery. There are currently no FDA-approved systemic therapies for the treatment of unresectable, recurrent or progressive desmoid tumors.

About AL102

AL102 is an investigational small molecule Gamma Secretase Inhibitor (GSI) that is designed to potently and selectively inhibit Notch 1, 2, 3 and 4, and is currently being evaluated in the Phase 2/3 RINGSIDE clinical studies in patients with progressing desmoid tumors. AL102 is designed to inhibit the expression of Notch gene targets by blocking the final cleavage step by the gamma secretase required for Notch activation. Ayala obtained an exclusive, worldwide license to develop and commercialize AL102 from Bristol-Myers Squibb Company in November 2017. AL102 was granted U.S. FDA Fast Track Designation for the treatment of DT.

On October 23, 2023 Artios Pharma Limited (Artios), a clinical-stage biotech company led by pioneers of DNA damage response ("DDR") drug development, reported promising monotherapy data from the Phase 1/1b portion of the ongoing Phase 1/2a study (NCT04657068) of its ataxia telangiectasia and Rad-3 related ("ATR") kinase inhibitor ART0380 in advanced or metastatic solid tumors as part of a poster presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (ESMO) (Free ESMO Whitepaper) 2023 (Press release, Artios Pharma, OCT 23, 2023, View Source [SID1234636236]). ART0380 is a clinically advanced, oral, highly potent, and selective ATR inhibitor with best-in-class potential. The Phase 1/1b portion of the trial presented at ESMO (Free ESMO Whitepaper) assessed the safety and tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of ART0380 monotherapy in patients with advanced or metastatic solid tumors. The patient population was enriched for cancers harboring DNA damage response deficiencies as identified by the Artios DcoDeR platform (n = 49).

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Dr. Niall Martin, Chief Executive Officer at Artios, said: "As a master regulator of replication stress, ATR inhibition can increase DNA damage and powerfully suppress tumor growth across broad cancer types harboring genetic defects. However, durability and long-term use with first-generation ATR inhibitors has been limited by challenges with toxicity and tolerability. Our next-generation ATR inhibitor ART0380 has demonstrated highly encouraging molecular and clinical responses as a monotherapy particularly in patients with DDR deficiency and high replication stress alterations. We believe the predictable and manageable safety profile and reliable pharmacokinetics of ART0380 offers combination flexibility as well as continuous and intermittent dosing regimen options. We look forward to further evaluating the therapeutic potential of ART0380 alone and in combination with chemotherapies in patients with selected cancer biologies as part of the ongoing Phase 2 trial. We expect initial Phase 2 combination data with gemcitabine in patients with platinum resistant ovarian cancer in the first half of 2025, and with irinotecan in ATM deficient cancers in the second half of 2024."

Key Phase 1/1b efficacy data support ART0380 is active across tumor types:

Molecular responses and reduction in tumor size observed in multiple cancer types, including those harboring molecular alterations or biology consistent with high replication stress
Molecular responses were associated with longer progression free survival (PFS)
Durable confirmed responses in all enrolled patients with high grade endometrial cancer
Potent tumor-specific DNA damage detected by selective increases in γH2Ax in circulating tumor cells but not normal cells in DDR deficient tumors predicted through Artios’ DcoDeR platform
Key Phase 1/1b safety and PK data demonstrate ART0380 is well-tolerated and predictable:

Safe and well tolerated at intermittent and continuous doses
Predictable, manageable, and reversible on-target anemia
Dose proportional increases in exposure with rapid absorption and relatively rapid elimination and low variability
The global, open-label, multi-center, Phase 1/2a study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ART0380 as a monotherapy or in combination with gemcitabine or irinotecan in patients with advanced or metastatic solid cancers. In the Phase 1/1b portion of the trial, patients with advanced solid cancers receiving escalating doses of ART0380 on a continuous daily (QD) or intermittent (3 days on, 4 days off) schedule will be evaluated. Patient enrollment was enriched for those with cancers harboring DNA damage response deficiencies as identified by the Artios DcoDeR platform. The Phase 2 portion will evaluate intermittent dosing of ART0380 in combination with gemcitabine in patients with platinum-resistant high grade serious ovarian, primary peritoneal or fallopian tube carcinoma, and in combination with irinotecan in ATM deficient cancers. Up to 250 patients are expected to be enrolled in the Phase 1/2a study which will be conducted at multiple oncology centers across the United States and Europe.

ART0380 is being developed as an oral anti-cancer agent for the treatment of cancers that harbor defects in DNA repair and in combination with agents including those that cause DNA damage. ART0380 was originally in-licensed by Artios from The University of Texas MD Anderson Cancer Center and ShangPharma Innovation in 2019. The molecule was jointly developed as part of a collaboration between ShangPharma and MD Anderson’s Therapeutics Discovery Division.

On October 23, 2023 Artios Pharma Limited (Artios), a clinical-stage biotech company led by pioneers of DNA damage response ("DDR") drug development, reported promising monotherapy data from the Phase 1/1b portion of the ongoing Phase 1/2a study (NCT04657068) of its ataxia telangiectasia and Rad-3 related ("ATR") kinase inhibitor ART0380 in advanced or metastatic solid tumors as part of a poster presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (ESMO) (Free ESMO Whitepaper) 2023 (Press release, Artios Pharma, OCT 23, 2023, View Source [SID1234636236]). ART0380 is a clinically advanced, oral, highly potent, and selective ATR inhibitor with best-in-class potential. The Phase 1/1b portion of the trial presented at ESMO (Free ESMO Whitepaper) assessed the safety and tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of ART0380 monotherapy in patients with advanced or metastatic solid tumors. The patient population was enriched for cancers harboring DNA damage response deficiencies as identified by the Artios DcoDeR platform (n = 49).

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Dr. Niall Martin, Chief Executive Officer at Artios, said: "As a master regulator of replication stress, ATR inhibition can increase DNA damage and powerfully suppress tumor growth across broad cancer types harboring genetic defects. However, durability and long-term use with first-generation ATR inhibitors has been limited by challenges with toxicity and tolerability. Our next-generation ATR inhibitor ART0380 has demonstrated highly encouraging molecular and clinical responses as a monotherapy particularly in patients with DDR deficiency and high replication stress alterations. We believe the predictable and manageable safety profile and reliable pharmacokinetics of ART0380 offers combination flexibility as well as continuous and intermittent dosing regimen options. We look forward to further evaluating the therapeutic potential of ART0380 alone and in combination with chemotherapies in patients with selected cancer biologies as part of the ongoing Phase 2 trial. We expect initial Phase 2 combination data with gemcitabine in patients with platinum resistant ovarian cancer in the first half of 2025, and with irinotecan in ATM deficient cancers in the second half of 2024."

Key Phase 1/1b efficacy data support ART0380 is active across tumor types:

Molecular responses and reduction in tumor size observed in multiple cancer types, including those harboring molecular alterations or biology consistent with high replication stress
Molecular responses were associated with longer progression free survival (PFS)
Durable confirmed responses in all enrolled patients with high grade endometrial cancer
Potent tumor-specific DNA damage detected by selective increases in γH2Ax in circulating tumor cells but not normal cells in DDR deficient tumors predicted through Artios’ DcoDeR platform
Key Phase 1/1b safety and PK data demonstrate ART0380 is well-tolerated and predictable:

Safe and well tolerated at intermittent and continuous doses
Predictable, manageable, and reversible on-target anemia
Dose proportional increases in exposure with rapid absorption and relatively rapid elimination and low variability
The global, open-label, multi-center, Phase 1/2a study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ART0380 as a monotherapy or in combination with gemcitabine or irinotecan in patients with advanced or metastatic solid cancers. In the Phase 1/1b portion of the trial, patients with advanced solid cancers receiving escalating doses of ART0380 on a continuous daily (QD) or intermittent (3 days on, 4 days off) schedule will be evaluated. Patient enrollment was enriched for those with cancers harboring DNA damage response deficiencies as identified by the Artios DcoDeR platform. The Phase 2 portion will evaluate intermittent dosing of ART0380 in combination with gemcitabine in patients with platinum-resistant high grade serious ovarian, primary peritoneal or fallopian tube carcinoma, and in combination with irinotecan in ATM deficient cancers. Up to 250 patients are expected to be enrolled in the Phase 1/2a study which will be conducted at multiple oncology centers across the United States and Europe.

ART0380 is being developed as an oral anti-cancer agent for the treatment of cancers that harbor defects in DNA repair and in combination with agents including those that cause DNA damage. ART0380 was originally in-licensed by Artios from The University of Texas MD Anderson Cancer Center and ShangPharma Innovation in 2019. The molecule was jointly developed as part of a collaboration between ShangPharma and MD Anderson’s Therapeutics Discovery Division.

On October 23, 2023 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated oral kinase inhibitors to treat hematologic malignancies, reported that the Company will provide a clinical update on Monday, October 30, 2023 at 8:30 AM Eastern Time, in conjunction with poster presentations at the European School of Haematology (ESH) 6th International Conference: Acute Myeloid Leukemia "Molecular and Translational": Advances in Biology and Treatment, being held October 29-31, 2023, in Estoril, Portugal (Press release, Aptose Biosciences, OCT 23, 2023, View Source [SID1234636235]).

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The webcast event will include a comprehensive review of up-to-date clinical data for Aptose’s lead compound tuspetinib and will feature Naval Daver, MD, Professor, Director Leukemia Research Alliance Program, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX. Dr. Daver is the lead investigator on Aptose’s APTIVATE trial and is recognized for significant achievements in the development of novel AML treatments, including several combination therapies.

Tuspetinib (TUS), a once-daily oral tablet, is a precision targeted myeloid kinase inhibitor that suppresses a select handful of kinases known to drive the proliferation of acute myeloid leukemia (AML) but avoids other kinases that can compromise safety. Tuspetinib as a single agent was well-tolerated and highly active among relapsed or refractory (R/R) AML patients with a diversity of adverse genotypes and delivered a 42% CR/CRh across evaluable venetoclax (VEN) naïve patients at the 80mg daily RP2D. Tuspetinib also is being studied in combination with venetoclax (VEN) in the APTIVATE international Phase 1/2 expansion trial in R/R AML patients. The TUS/VEN doublet has been well tolerated and achieved multiple responses in patients who previously failed venetoclax (Prior-VEN failure AML), including Prior-VEN failure patients who also previously failed FLT3 inhibitors, all of whom represent emerging populations of high unmet medical need. Notably, tuspetinib targets venetoclax resistance mechanisms that may re-sensitize Prior-VEN failure patients to venetoclax.

Aptose Clinical Update Details

Date & Time: Monday, October 30, 2023, 8:30 AM ET

Participant Webcast Link: here (View Source)

The slides will be available on Aptose’s website here and the webcast of the presentation will be archived shortly after the conclusion of the event.

Poster Presentations

As announced prior, the Aptose poster presentations at ESH are listed below. Note that the poster presentations will include additional data not found in the abstracts. The posters accepted for presentation are listed below and can be viewed beginning October 29, 2023, on site at the ESH poster exhibit hall and online on the Aptose website here.

Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy as Monotherapy and Combined with Venetoclax in Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

Tuspetinib Oral Myeloid Kinase Inhibitor Creates Synthetic Lethal Vulnerability to Venetoclax

On October 23, 2023 Aligos Therapeutics, Inc. (Nasdaq: ALGS), a clinical stage biopharmaceutical company focused on developing novel therapeutics to address unmet medical needs in liver and viral diseases, reported that it has entered into a securities purchase agreement for a private placement that is expected to result in gross proceeds of approximately $92 million, before deducting placement agent fees and other expenses, to advance its portfolio of drug candidates (Press release, Aligos Therapeutics, OCT 23, 2023, View Source [SID1234636234]).

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The private placement is being led by a life sciences dedicated investment firm with participation from other new and existing institutional investors including Armistice Capital, Deep Track Capital, EcoR1 Capital and Roche Venture Fund, among others. Also participating in the private placement are certain members of the company’s Board of Directors, including Lawrence M. Blatt, Ph.D., M.B.A, the company’s Chairman and Chief Executive Officer.

Aligos currently expects to use the net proceeds from the private placement, together with its existing cash, cash equivalents and investments, to fund the continued advancement of its Phase 2a NASH, ALG-055009 study evaluating its thyroid hormone receptor beta agonist, its CAM-E candidate, ALG-000184, as well as to fund discovery and research to broaden its pipeline of drug candidates, and for other general corporate purposes.

Aligos believes its cash, cash equivalents and investments, including the expected net proceeds from the private placement, will provide sufficient funding of planned operations through the end of 2025.

In the private placement, Aligos is selling 31,429,266 shares of common stock, pre-funded warrants to purchase up to 81,054,686 shares of common stock and accompanying warrants to purchase up to 56,241,973 shares of common stock, at a combined price of $0.8193 per share of common stock and accompanying warrant and $0.8192 per pre-funded warrant and accompanying warrant. Each pre-funded warrant will have a nominal exercise price of $0.0001 per share of common stock, will be immediately exercisable and will be exercisable until exercised in full. The accompanying warrants will have an exercise price of $0.7568 per share of common stock, will be immediately exercisable and will expire on October 25, 2030. The private placement is expected to close on October 25, 2023, subject to the satisfaction of customary closing conditions.

Piper Sandler is acting as sole placement agent for the private placement.

The securities sold in this private placement have not been registered under the Securities Act of 1933, as amended, or applicable state securities laws, and may not be offered or sold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements. Aligos has agreed to file a registration statement with the Securities and Exchange Commission registering the resale of the shares of common stock issued in the private placement and the shares of common stock issuable upon exercise of the pre-funded warrants and the common warrants issued in the private placement.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy any securities described herein, 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 the registration or qualification under the securities laws of any such state or jurisdiction.