On July 13, 2021 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM: HCM; HKEX: 13) reported the first commercial sale in China of ORPATHYS (savolitinib), HUTCHMED’s oral, potent, and highly selective small molecule inhibitor of MET, a receptor tyrosine kinase, which occurred on July 12, 2021 (Press release, Hutchison China MediTech, JUL 13, 2021, https://www.hutch-med.com/first-commercial-sale-of-orpathys-milestone-payment/ [SID1234586916]).

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This follows less than three weeks after the June 22, 2021 approval of ORPATHYS in China for the treatment of patients with locally advanced or metastatic non-small cell lung cancer ("NSCLC") with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy.

Under the terms of the license and collaboration agreement between HUTCHMED and AstraZeneca ("AstraZeneca") (LSE/STO/Nasdaq: AZN), a US$25 million non-creditable and non-refundable milestone payment is triggered by the first commercial sales of ORPATHYS in China. HUTCHMED is responsible for the clinical development, marketing authorization, manufacturing and supply of ORPATHYS in China, while AstraZeneca is responsible for its commercialization for which it will pay HUTCHMED fixed royalties of 30% based on all China sales.

More than a third of the world’s lung cancer patients are in China and, among those with NSCLC, approximately 2-3% have tumors with MET exon 14 skipping alterations, a targetable mutation in the MET gene.[i],[ii],[iii] This mutation is more common (13-22%) among patients with pulmonary sarcomatoid carcinoma (PSC), a rare and aggressive subtype of NSCLC usually resistant to chemotherapy.[i],[iv]

About ORPATHYS
ORPATHYS is an oral, potent, and highly selective MET tyrosine kinase inhibitor ("TKI") that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations) or gene amplification.

ORPATHYS is marketed in China for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. It is currently under clinical development for multiple tumor types, including lung, kidney, and gastric cancers, as a single treatment and in combination with other medicines.

ORPATHYS development in NSCLC
Phase II study of ORPATHYS monotherapy in MET Exon 14 skipping alteration NSCLC (NCT02897479) – In June 2021, ORPATHYS was granted drug registration conditional approval by the National Medical Products Administration of China (NMPA) for MET Exon 14 skipping alteration NSCLC. The approval was based on the results of a Phase II study in China; results of this study were presented during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program in May 2020, and updated results were published in The Lancet Respiratory Medicine in June 2021. At a median follow up of 17.6 months, ORPATHYS demonstrated an objective response rate ("ORR") of 42.9% (95% confidence interval [CI] 31.1-55.3) and median progression-free survival ("PFS") of 6.8 months (95% CI 4.2-9.6) in the overall trial population. PFS was clinically meaningful across subgroups, and ORR results were consistent regardless of prior treatment or tumor histology, including in patients with the PSC subtype (40.0%, 95% CI 21.1-61.3) and patients with other NSCLC subtypes (44.4%, 95% CI 29.6-60.0). Disease control rate ("DCR") in the overall trial population was 82.9% (95% CI 72.0-90.8). The safety and tolerability profile of ORPATHYS was consistent with previous trials, and no new safety signals were identified.

SAVANNAH Phase II study of ORPATHYS in combination with TAGRISSO in patients who have progressed following TAGRISSO due to MET amplification or overexpression (NCT03778229) – This is a single-arm, open-label, global study in epidermal growth factor receptor ("EGFR") mutation positive NSCLC patients with MET amplified/overexpressed tumors following progression after treatment with TAGRISSO, an EGFR TKI owned by AstraZeneca.

Phase III study of ORPATHYS in combination with TAGRISSO in patients who have progressed following EGFR TKI treatment due to MET amplification (in planning) – This is a randomized, open-label study in China in EGFR mutation positive NSCLC patients with MET amplified tumors following progression after treatment with any EGFR TKI.

Phase III study of ORPATHYS in combination with TAGRISSO in treatment naïve patients with EGFR mutant positive NSCLC with MET overexpression (in planning) – This is a randomized, blinded study in China in untreated, unresectable or metastatic patients with EGFR mutation positive NSCLC with MET positive tumors.

ORPATHYS development in kidney cancer
SAVOIR randomized, controlled study of ORPATHYS monotherapy in MET-driven papillary renal cell carcinoma ("RCC") (NCT03091192) – In May 2020, data from 60 patients in this global study of ORPATHYS monotherapy compared with sunitinib monotherapy in MET-driven papillary RCC was presented at the ASCO (Free ASCO Whitepaper) 2020 Program and published simultaneously in JAMA Oncology. ORPATHYS demonstrated encouraging activity, including an ORR of 27% versus 7% for sunitinib, with no ORPATHYS responding patients experiencing disease progression at data cut-off, and an encouraging overall survival ("OS") hazard ratio of 0.51 (95% CI: 0.21–1.17; p=0.110) with median not reached at data cut-off.

CALYPSO Phase I/II study of ORPATHYS in combination with IMFINZI PD-L1 inhibitor in RCC (NCT02819596) – The CALYPSO study is an investigator initiated open-label Phase I/II study of ORPATHYS in combination with IMFINZI, a PD-L1 antibody owned by AstraZeneca. The study is evaluating the safety and efficacy of the ORPATHYS/IMFINZI combination in patients with papillary RCC and clear cell RCC. An analysis of 41 patients enrolled in the PRCC cohort of in this study was presented at the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting, showing a confirmed response rate in 14 MET-driven patients of 57%, with a median duration of response ("DoR") of 9.4 months, median PFS of 10.5 months and median OS of 27.4 months. No new safety signals were seen.

Phase III in combination with IMFINZI PD-L1 inhibitor in MET-driven, unresectable and locally advanced or metastatic PRCC (in planning) – Based on the encouraging results of the SAVOIR and CALYPSO studies, we intend to initiate a global Phase III, open-label, randomized, controlled study of ORPATHYS plus IMFINZI versus sunitinib monotherapy versus IMFINZI monotherapy in patients with MET-driven, unresectable and locally advanced or metastatic PRCC.

ORPATHYS development in other cancer indications
Phase II study of ORPATHYS monotherapy in advanced or metastatic MET amplified gastric cancer ("GC") or adenocarcinoma of the gastroesophageal junction ("GEJ") (NCT04923932) – This Phase II trial is an open-label, two-cohort, multi-center study to evaluate the efficacy, safety and pharmacokinetics ("PK") of ORPATHYS in locally advanced or metastatic GC or GEJ patients whose disease progressed after at least one line of standard therapy. The primary endpoint is ORR as assessed by an independent review committee. Other endpoints include 12-week and 6-month PFS rates, median PFS, DoR, DCR, median OS, safety, PK and quality of life.

This trial follows multiple Phase II studies that have been conducted in Asia to study ORPATHYS in MET-driven gastric cancer patients, including VIKTORY.[v] VIKTORY is an investigator initiated Phase II umbrella study in gastric cancer in South Korea in which a total of 715 patients were successfully sequenced into molecular-driven patient groups, including those with MET amplified gastric cancer. Patients whose tumors harbor MET amplification were treated with ORPATHYS monotherapy, reporting an ORR of 50% (10/20, 95% CI: 28.0, 71.9).

ORPATHYS opportunities are also continuing to be explored in multiple other MET-driven tumor settings via investigator-initiated studies including non-small cell lung cancer, gastric cancer and colorectal cancer.

On July 13, 2021 Sanofi’s ongoing efforts to simplify its Consumer Healthcare portfolio and accelerate its growth trajectory, reported that the company has signed an agreement with HYPERA S.A. ("Hypera Pharma") for the divestiture of eight products commercialized in Latin America (Press release, Sanofi, JUL 13, 2021, View Source [SID1234584867]). The agreement also includes four prescription products from the General Medicine portfolio.

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"As discussed during our Capital Markets Day in February, simplifying the CHC product portfolio is an important part of our strategy to focus our resources and efforts where we can bring the most value, especially to consumers. We are pleased these products will continue to be available for consumers as we focus on becoming a fully integrated standalone business" said Julie Van Ongevalle, Executive Vice-President, Sanofi and Head of Sanofi Consumer Healthcare.

Sanofi does not anticipate any impact of this divestiture to its Latin American-based workforce.

The transaction is expected to close at the end of 2021, subject to approval of relevant regulatory authorities and other customary closing conditions.

On July 13, 2021 Cyclacel Pharmaceuticals, Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; "Cyclacel" or the "Company"), a biopharmaceutical company developing innovative medicines based on cancer cell biology, reported that dosing of the first patient in the Company’s multi-cohort Phase 1/2 study of oral fadraciclib in patients with advanced solid tumors (Press release, Cyclacel, JUL 13, 2021, View Source [SID1234584817]).

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"Advancing oral fadraciclib, our lead candidate, into this Phase 1/2 trial, represents a key clinical milestone and corporate objective for our team," said Spiro Rombotis, Cyclacel’s President and Chief Executive Officer. "This is the first of four streamlined Phase 1/2 studies we plan to open over the coming months as we expand our clinical programs to evaluate the potential of fadraciclib and CYC140, our oral PLK1 inhibitor, first in solid tumors and lymphomas and then in leukemias. We look forward to providing periodic updates on our clinical progress and data from these open-label studies."

"We are pleased to have dosed the first patient in this study and are delighted by the enthusiasm and strong interest from current and prospective investigators," said Mark Kirschbaum M.D., Senior Vice President & Chief Medical Officer of Cyclacel. "The study has initially opened at City of Hope and MD Anderson Cancer Center with more sites to join later on. We are building an excellent network of participating institutions both in terms of clinical and scientific expertise. In previous studies with single agent, intravenous fadraciclib we have observed durable suppression of MCL1 and other mechanistically-related proteins, including cyclin E and MYC, at tolerated doses. In addition, a patient with MCL1 amplified, advanced endometrial cancer experienced deep PR and 100% shrinkage of her target tumor lesions on single agent fadraciclib treatment. We are excited to begin mid-stage development of fadraciclib with the objective of registration-enabling outcomes and offering a new treatment option for patients with advanced solid tumors or lymphomas."

"Based upon prior clinical activity shown to date, further exploration of this novel CDK2/9 inhibitor is warranted across a number of solid tumor histologies," said Miguel Villalona-Calero, M.D., co-leader of the Developmental Cancer Therapeutics Program and Professor, Department of Medical Oncology & Therapeutics Research at the City of Hope, a world-renowned, independent research and treatment center for cancer, diabetes and other life-threatening diseases. "We look forward to enrolling patients in this trial and evaluating the potential treatment benefit of this experimental therapy both as a single agent and in combinations."

The Phase 1/2 registration-directed trial (CYC065-101) uses a streamlined design and will first determine the recommended Phase 2 dose (RP2D) for single-agent, oral fadraciclib. Once RP2D has been established, the trial will immediately enter into proof-of-concept, cohort stage, using a Simon 2-stage design, where single agent fadraciclib will be administered to patients in up to eight cohorts defined by histology thought to be sensitive to the drug’s mechanism of action and informed by the clinical activity of fadraciclib in previous studies. The cohorts will include patients with breast cancer (selected for metastatic, hormone receptor positive, HER-2 negative, post-CDK4/6 inhibitor; HER-2 refractory; or triple negative), colorectal (including KRAS mutant), endometrial, hepatocellular and ovarian cancers, as well as certain lymphomas. An additional basket cohort will enroll patients with biomarkers relevant to the drug’s mechanism, including MCL1, MYC and cyclin E, regardless of histology. The protocol allows for expansion of a cohort based on response which may allow acceleration of the clinical development and registration plan for fadraciclib.

About Cyclin-Dependent Kinases and Fadraciclib

Cyclin-dependent kinases (CDKs) are critical for cell cycle control and transcriptional regulation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased cancer cell survival. Fadraciclib, a next generation CDK inhibitor, is a highly selective, potent, orally and intravenously available, inhibitor of CDK2 and CDK9. CDK2 drives cell cycle transitions and CDK9 regulates transcription of genes through phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II (RNAP II). By inhibiting CDK2 and CDK9 fadraciclib causes apoptotic death of cancer cells at sub-micromolar concentrations.

Preclinical data suggest that fadraciclib may benefit patients with certain cyclin E-addicted or MYC-amplified solid tumors, including certain forms of breast cancer, neuroblastoma, ovarian cancer, uterine serous carcinoma and adult and pediatric hematological malignancies, such as ALL, AML, B-cell lymphoma, CLL, and multiple myeloma. Similarly to FDA-approved CDK4/6 inhibitors, fadraciclib may be useful in combination with other anticancer drugs, including HER2 inhibitors, such as trastuzumab, or BCL2 inhibitors, such as venetoclax.

In a prior Phase 1 open-label trial (CYC065-01), patients with high copy CCNE (cyclin E), MYC or MCL1 showed sensitivity to intravenously-administered, single-agent fadraciclib. A heavily pretreated patient with MCL1 amplified endometrial cancer achieved a radiographically confirmed partial response (PR) after a month and a half on fadraciclib. This patient continues on therapy for almost two years and reduction in her target tumor lesions has reached 100%. An additional patient with cyclin E amplified ovarian cancer achieved stable disease with 29% shrinkage in her target tumor lesions.

On July 13, 2021 Evrys Bio, a biotech company developing Next Gen Antivirals, reported the company was awarded a $34.3 million contract from the Department of Defense (DOD) to develop a drug, simultaneously effective against multiple high-risk viral agents (Press release, Evrys Bio, JUL 13, 2021, View Source [SID1234644911]). The proposed drug intends to improve disease survival after exposure to one or more viruses from three families: alphaviruses, arenaviruses and filoviruses. Evrys Bio’s broad-spectrum antiviral technology is based on the discovery that certain human proteins, called sirtuins, normally defend the human (host) cell from being invaded by pathogens. The novel drug will target the human SIRT-2 protein.

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The DOD’s Defense Threat Reduction Agency’s Chem Bio Technologies, Vaccines and Therapeutics Division executed an Other Transaction Authority (OTA) agreement with Evrys for this effort. The milestone-based agreement anticipates five years of development from drug-prototype identification to proof-of-concept and regulatory filings.

"EVRYS stands for the Company’s vision to ultimately address every virus," said Lillian Chiang, PhD, CEO, Evrys Bio. "This DTRA collaboration addresses highly lethal viral infection and extends our pipeline that already includes developing products to treat pan-respiratory, pan-hepatic, and pan-opportunistic viral infections."

On July 13, 2021 ISA reported the closing of a EUR 26 million funding round with participation from new investors including Invest-NL and existing investors including Regeneron (Press release, ISA Pharmaceuticals, JUL 13, 2021, View Source [SID1234584799]). The proceeds of this round will be used to advance the lead product ISA101b towards first marketing authorization as well as to broaden the clinical pipeline of immunotherapies based on the Synthetic Long Peptide (SLP) platform technology.

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Gerben Moolhuizen, CEO of ISA Pharmaceuticals, said, "We are very happy with the continued support of our existing partners and shareholders. Invest-NL’s support underlines the innovation at ISA Pharma and potential impact of our SLP immunotherapies for the treatment of serious diseases."

SLP immunotherapies act through the specific activation of the patient’s own immune system. Lead product ISA101b targets cancers caused by human papilloma virus type 16 (HPV16). It is in late stage clinical development in three trials for the treatment of advanced stages of HPV16-positive head and neck cancer and cervical cancer in combination with Libtayo (cemiplimab, anti-PD1 immunotherapy), which is being co-developed by Regeneron and Sanofi.

Leo Holwerda, Director Capital at Invest-NL, notes: "Our investment in ISA Pharmaceuticals is a good example of how our TOPSS program can help promising Dutch start-ups and innovative companies which were affected by COVID-19. Invest-NL is happy to support ISA Pharmaceuticals to accelerate its clinical studies and we are confident that the company will succeed in bringing its lead therapy for patients with HPV16-positive head & neck cancer and cervical cancer to the market. This innovative and impactful therapy will strengthen the prospects of many patients."

Persistent HPV16 infection can cause head & neck, cervical and anogenital cancers. These cancers can be severe and life-threatening with low overall survival rates once these cancers progress to advanced stages. HPV16 is a major cause of head & neck cancer with over 25,000 new cases and 11,000 deaths in Europe (source) and 46,000 new cases and 9,000 deaths in the US (source).
HPV16 is also responsible for about 50% of cervical cancer cases. Cervical cancer is the 2nd most common cancer in women aged 15 to 44 years in Europe, with over 60,000 new diagnoses and 25,000 deaths each year in Europe. Globally there are more than 500,000 new patients and 300,000 deaths (source).

The SLP technology platform is at the basis of several ISA pipeline products that are scheduled to proceed into clinical trials over the next few years. Three promising products are in the final stages of pre-clinical development. ISA104 targets the hepatitis B virus (HBV) in chronically infected patients. Chronic HBV is a major cause of liver cirrhosis and liver cancer and affects over 250 million people worldwide (source). ISA103 is aimed at tumours that express PRAME, a protein closely associated with the malignant behaviour of cells in numerous types of cancers. ISA106 is a potential treatment for high risk COVID-19 infected patients.