On July 5, 2023 Ayala Pharmaceuticals, Inc. (OTCQX: ADXS), a clinical-stage oncology company, reported that it has concluded an instructive and successful End-of-Phase-2 (EOP2) meeting with the U.S. Food and Drug Administration (FDA). As a result of the meeting, the company confirms that it is in agreement with the FDA on key elements of the randomized Phase 3 segment of RINGSIDE (Press release, Ayala Pharmaceuticals, JUL 5, 2023, View Source [SID1234633048]). The Agency accepted the Company’s selection of the 1.2 mg once daily dose being evaluated in the currently-enrolling Phase 3 and the completed and proposed clinical pharmacology plan. As previously agreed with the FDA on a seamless Phase 2/3 design, enrollment in the Phase 3 segment of RINGSIDE commenced in November 2022, and is continuing globally as planned, with target enrollment of 156 patients.

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"We are grateful for the FDA’s continued support and guidance, and very pleased to have reached agreement with the Agency on these items," said Ken Berlin, President and Chief Executive Officer of Ayala. "Supported by the clinical data generated from studies to date, we believe 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. There are currently no approved therapies for these rare tumors. Current standards of care, which include off-label chemotherapy, radiation and tyrosine kinase inhibitors, are often poorly tolerated and offer inconsistent efficacy. We look forward to completing enrollment of the Phase 3 segment of this important study."

The Phase 3 segment of the RINGSIDE study is a double-blind, multi-center trial enrolling up to 156 patients with progressive disease, randomized between AL102 1.2mg dosed once daily or placebo. The primary endpoint is progression-free survival (PFS) with secondary endpoints including objective response rate (ORR), duration of response (DOR), and patient-reported Quality of Life (QOL) measures.

AL102 received Fast Track designation from the U.S. FDA for the treatment of progressing desmoid tumors, a rare disease with no currently approved treatments.

About RINGSIDE

The RINGSIDE pivotal Phase 2/3 study is a randomized global multi-center trial, with a seamless design, allowing Ayala to continue to Phase 3 without concluding the Phase 2 segment. The Phase 2 segment of the study (Part A) evaluated the efficacy, safety, tolerability, and tumor volume by MRI after 16 weeks of AL102 in patients with desmoid tumors. It enrolled 42 patients and evaluated 3 doses of AL102. Phase 3 of RINGSIDE (Part B) is a double-blind, placebo-controlled, clinical trial enrolling up to 156 patients with progressive disease, comparing AL102 at 1.2 mg once-daily to placebo. For more information on the RINGSIDE Phase 2/3 study of AL102 for the treatment of desmoid tumors, please visit ClinicalTrials.gov and reference Identifier NCT04871282 (RINGSIDE).

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 July 4, 2023 pHion Therapeutics reported a joint Innovate UK award with Queen’s University Belfast (Press release, pHion Therapeutics, JUL 4, 2023, View Source [SID1234638968]). The £1million grant will fund a 24-month project to develop a multi-antigenic therapeutic vaccine for prostate cancer. This next generation vaccine is possible because of pHion’s innovative technology which delivers the mRNA into antigen-presenting cells in stealth mode. The company’s proprietary RALA platform uses a peptide as the ‘taxi’ to deliver the mRNA cargo, and because the peptide is not recognised as foreign, no adverse response is triggered, and the mRNA trains the immune cells to attack the cancer.

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The project is a collaboration between founder and CEO of pHion Therapeutics, Professor Helen McCarthy, and Dr Niamh Buckley, both from the School of Pharmacy at Queen’s. The £1million grant was awarded in the recent Innovate UK Biomedical Catalyst 2022 Round 2: Industry-led Research & Development funding competition.

Prostate Cancer accounts for 7.3% of all cancers worldwide (1.4 million cases) and 27.8% of all cancers in the UK. The 5-year survival rate for the most aggressive form, metastatic Castrate Resistant Prostate Cancer (CRPC), is only 28.9% in the UK; and the incidence is also set to rise by a further 12% by 2035. Worldwide, a recent Global Cancer Observatory (GCO) study has predicted a 60% increase to ~2.3 million new cases and 740,000 deaths by 2040.

As Professor Helen McCarthy explains: ‘Given the likely trajectory for this aggressive disease, there is an urgent need to develop a next generation vaccine that can reduce mortality rates. Our vision is to begin large-scale toxicology studies by the end of the project and, from there, to progress to clinical trials."

"The investment from Innovate UK will support growth in the global use of pHion’s unique technology, and further strengthen the UK’s position in the emerging gene therapy market."

On July 4, 2023 OSE Immunotherapeutics SA (ISIN: FR0012127173; Mnemo: OSE) reported that the United States Patent and Trademark Office has granted a new patent protecting Tedopi, a therapeutic cancer vaccine treating HLA-A2 positive patients after secondary resistance to PD-1/PD-L1 immune checkpoint inhibitor treatment (Press release, OSE Immunotherapeutics, JUL 4, 2023, View Source [SID1234633043]). The new patent further improves the unique value proposition of Tedopi and provides protection until year 2037 in the US.

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This US patent recognises the innovation of a multiepitope combination (all peptides included in Tedopi) administered after failure to PD-1/PD-L1 immune checkpoint inhibitor in HLA-A2 positive non-small cell lung cancer (NSCLC) patients. This further protection for Tedopi, OSE Immunotherapeutics’ most advanced late-stage asset, adds significant value to the Company’s product portfolio.

Nicolas Poirier, CEO of OSE Immunotherapeutics, said: "We are very pleased to expand our patent portfolio internationally with this new US patent strengthening the protection rights for Tedopi in the significant US market. This patent represents an additional milestone in the product’s clinical development based on the first Phase 3 positive results in non-small cell lung cancer after checkpoint inhibitor escape in secondary resistance. These data show a significant overall survival benefit, an improved quality of life and a better safety profile versus chemotherapy. The next confirmatory Phase 3 trial under preparation in second line treatment will address the same high unmet medical need. Tedopi presents a differentiated mechanism of action activating tumor specific T cells after acquired resistance of immune checkpoint inhibitor."

This patent family, focused on the same targeted population, has been filed internationally in other territories and has already been granted previously in Japan.

This population in second line treatment after failure to PD-1/PD-L1 inhibitor treatment, targeted with Tedopi, is estimated to be up to 100,000 patients per year in 7 major markets across the US, Europe, China and Japan. This estimate is based on HLA-A2-positive patients accounting for about 45% of all NSCLC patients, as well as the large and growing use of anti-PD-1/PD-L1 therapies and their failure rate.

On July 4, 2023 Taiho Oncology Europe GmbH and Taiho Pharmaceutical Co., Ltd., reported that the European Commission has granted conditional marketing authorization for LYTGOBI (futibatinib) monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma (CCA) with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy (Press release, Taiho, JUL 4, 2023, View Source [SID1234633042]).

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CCA is an aggressive cancer of the bile ducts of the liver. While rare – in Europe, approximately 6.000-8.000 people are diagnosed with CCA1 – this disease is associated with poor outcomes and is growing in prevalence worldwide2, underscoring the need for new treatment options.

"Today is an important day for current and future patients with CCA as well as the healthcare providers who treat them," said Peter Foertig, MD, Vice President, Medical Affairs, Taiho Oncology Europe. "LYTGOBI is an oral molecularly targeted medication that may provide clinically meaningful outcomes for patients undergoing treatment for CCA."

Added John Bridgewater, MD, PhD, Investigator and Senior Author of the recently published FOENIX*-CCA2 pivotal trial in the New England Journal of Medicine: "FGFR2 fusions/rearrangements are one of the most frequent actionable alterations in CCA. As an irreversibly binding FGFR inhibitor, LYTGOBI targets FGFR in a unique way and offers new hope in a disease that, for me, has been among the most challenging to treat in my career." Professor Bridgewater is a Clinical Researcher and Medical Oncologist at University College London Cancer Institute and University College London Hospitals NHS Foundation Trust.

The European Commission’s conditional marketing authorization for LYTGOBI is based on data from the aforementioned FOENIX-CCA2 trial, a global open label trial evaluating 103 patients with unresectable, locally advanced or metastatic intrahepatic (inside the bile ducts of the liver) CCA harboring FGFR2 gene rearrangements, including fusions.

In this trial, patients received LYTGOBI orally once daily at a dose of 20mg until disease progression or unacceptable toxicity. Within Europe, patients were enrolled from France, Germany, Italy, the Netherlands, Spain and the United Kingdom.

Results of FOENIX-CCA2 trial showed:

LYTGOBI demonstrated an objective response rate (ORR) of 42% as assessed by independent review (primary endpoint met).3
LYTGOBI demonstrated a median duration of response (DOR) – a key secondary endpoint – of 9.7 months. A total of 72% of the responses lasted >6 months.3
"I believe that LYTGOBI may be part of a new era in the treatment of CCA, one in which the power of personalised medicine may touch the lives of patients in ways we haven’t seen before with traditional chemotherapy," said Helen Morement, CEO of the AAMF – The Cholangiocarcinoma Charity and the UK’s only charity dedicated to this cause.

"We thank the many patients and healthcare professionals who participated in the FOENIX-CCA2 trial," said Atsushi Azuma, Managing Director of Taiho Pharmaceutical and Chairman of Taiho Oncology Europe. "Patients with CCA are often diagnosed at an advanced stage when surgery is not an option. We are pleased that LYTGOBI now will be a new treatment option for patients with CCA."

A conditional marketing authorization in Europe is granted for medicines that fulfill an unmet medical need to treat serious diseases, and the benefits of having them available earlier outweighs any risks associated with using the medicines while waiting for further evidence. Under the specific obligation to complete post-authorization measures for the conditional marketing authorization, Taiho has until October 2027 to provide additional clinical data on LYTGOBI.

Safety Information From the EU Summary of Product Characteristics (SmPC)3

LYTGOBI may cause serious adverse reactions. The most common serious adverse reactions were intestinal obstruction and migraine.

The most common adverse reactions were hyperphosphatemia, nail disorders, constipation, alopecia, diarrhoea, dry mouth, fatigue, nausea, dry skin, increased AST, abdominal pain, stomatitis, vomiting, palmar-plantar erythrodysaesthesia syndrome, arthralgia, and decreased appetite.

Prolonged hyperphosphatemia may cause soft tissue mineralization, including cutaneous calcification, vascular calcification, and myocardial calcification, anaemia, hyperparathyroidism, and hypocalcemia that may cause muscle cramps, QT interval prolongation, and arrythmias. Hyperphosphatemia is a pharmacodynamic effect expected with LYTGOBI administration. Recommendations for management of hyperphosphatemia include dietary phosphate restriction, administration of phosphate-lowering therapy, and dose modification when required.

LYTGOBI can cause serous retinal detachment, which may present with symptoms such as blurred vision, visual floaters or photopsia. Ophthalmological examination should be performed prior to initiation of therapy, 6 weeks thereafter, and urgently at any time for visual symptoms. For serous retinal detachment reactions, the dose modification guidelines should be followed.

LYTGOBI should not be used during pregnancy unless the clinical condition of the women requires treatment with LYTGOBI.

On July 4, 2023 Jacobio Pharma (1167.HK), a clinical-stage oncology company drugging the undruggable targets, reported its novel KRAS G12C inhibitor glecirasib’s pivotal study for pancreatic cancer has been approved from CDE (Center for Drug Evaluation), which became the first global pancreatic cancer registrational clinical study for KRAS G12C (Press release, Jacobio Pharmaceuticals, JUL 4, 2023, View Source [SID1234633041]).

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The pivotal clinical trial approved in China will evaluate the efficacy and safety of Glecirasib as a single agent for the second line treatment or above of Pancreatic Cancer patients with a KRAS G12C mutation. This is a multi-center, single-arm, open-label study. The study results will be used to submit NDA (New Drug Application) for pancreatic cancer.

"The pivotal study of pancreatic cancer is the second approved registrational study after non-small cell lung cancer", said gastrointestinal oncology expert Dr. Andrea Wang-Gillam, the Chief Medical Officer of Jacobio, "We hope to work with clinical study investigators to jointly advance the clinical trials and strive to bring more treatment options to cancer patients with KRAS G12C-mutated as soon as possible."

Pancreatic cancer is a malignant tumor and there is a lack of effective treatment currently. The five-year overall survival rate is only 5%. About 90% of pancreatic cancer patients have different types of KRAS mutations. Besides KRAS G12C inhibitor glecirasib, Jacobio is developing KRASmulti, KRAS G12D and other projects, which are expected to benefit more pancreatic cancer patients.

About Glecirasib
Glecirasib is Jacobio’s novel KRAS G12C inhibitor. Jacobio has initiated a number of Phase I/II clinical trials in China, the United States and Europe for patients with advanced solid tumors harbouring KRAS G12C mutation, including a pivotal clinical trial int NSCLC in China; a monotherapy study for STK11 co-mutated NSCLC in the front-line setting; combination therapy trials with SHP2 inhibitor JAB-3312, anti-PD-1 antibody and Cetuximab.