On May 2, 2022 HUTCHMED (China) Limited ("HUTCHMED" or the "Company") (Nasdaq/AIM:HCM; HKEX:13) reported that the U.S. Food and Drug Administration ("FDA" or the "Agency") has issued a Complete Response Letter ("CRL") regarding the New Drug Application ("NDA") for surufatinib for the treatment of pancreatic ("pNETs") and extra-pancreatic (non-pancreatic, "epNETs") neuroendocrine tumors ("NETs") (Press release, Hutchison China MediTech, MAY 2, 2022, View Source [SID1234613300]). FDA determined that the current data package, based on two positive Phase III trials in China and one bridging study in the United States (U.S.), does not support an approval in the U.S. at this time. The CRL indicated that a multi-regional clinical trial ("MRCT") is required for U.S. approval.

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The safety and efficacy of surufatinib, an oral inhibitor of angiogenesis and immune modulation, was demonstrated in the SANET-p and SANET-ep studies, two randomized double-blind Phase III trials in patients with advanced pNETs and epNETs conducted in China. Results of a HUTCHMED sponsored bridging study conducted in the U.S. suggest similar safety and efficacy to the SANET study population in China. Surufatinib was approved in China for the treatment of pNETs and epNETs in June 2021 and December 2020, respectively.

Surufatinib received U.S. FDA Fast Track Designations in April 2020 for the treatment of pNETs and epNETs. Orphan Drug Designation for pNETs was granted in November 2019. In a May 2020 pre-NDA meeting, HUTCHMED reached an agreement with the FDA that the two positive Phase III studies of surufatinib in patients with pNETs and epNETs in China, along with the bridging trial in the U.S. could form the basis to support a U.S. NDA submission. The FDA accepted the filing of the NDA on June 30, 2021.

The FDA evaluated the applicability of the SANET studies data generated in one country to U.S. patients and U.S. medical practice. The CRL stated that the FDA will require a MRCT that includes subjects more representative of the US patient population and aligned to current U.S. medical practice. In addition, pandemic-related issues concerning inspection scheduling and access contributed to the FDA action. This action by the FDA is not related to any safety issues with surufatinib. HUTCHMED is working with the FDA to evaluate next steps.

Dr Weiguo Su, Chief Executive Officer and Chief Scientific Officer of HUTCHMED, commented: "Although this decision from the FDA is disappointing, we remain confident about the clinical value of surufatinib for NET patients and committed to making surufatinib available to patients globally. We look forward to working with the Agency to evaluate its feedback. Throughout the duration of the U.S. review process, we have been transparent and collaborative with the FDA. There are very few treatments approved and used in these rare diseases, and patients and physicians would benefit from more options to address the unmet medical need. We look forward to continued engagement with the FDA on developing a plan to bring surufatinib to patients in the U.S."

HUTCHMED International, headquartered in Florham Park, New Jersey, drives clinical and regulatory development in the US, Europe and Japan. Dr Marek Kania, Executive Vice President, Managing Director and Chief Medical Officer of HUTCHMED International, commented: "Our global development strategy remains unchanged. Outside of the U.S. and China, we remain committed to engaging with regulators in Europe, where our Marketing Authorization Application ("MAA") submission for surufatinib is under review, and in Japan where we have an ongoing Japanese bridging study. Furthermore, our foundational approach is to conduct multi-regional registration trials, such as our 14-country, 691-patient FRESCO-2 Phase III trial for fruquintinib for patients with metastatic colorectal cancer which is expected to read-out in the second half of this year."

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About Surufatinib
Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects.

HUTCHMED currently retains all rights to surufatinib worldwide.

About Surufatinib Development
epNETs in China: On December 29, 2020, surufatinib was granted drug registration approval in China for the treatment of epNET. Surufatinib is marketed in China under the brand name SULANDA. The approval was based on results from the SANET-ep study, a Phase III trial (clinicaltrials.gov identifier: NCT02588170) in patients with advanced epNETs conducted in China. The study met the pre-defined primary endpoint of PFS at a preplanned interim analysis, and was published in The Lancet Oncology[1]. Median PFS was significantly longer for patients treated with surufatinib at 9.2 months, compared to 3.8 months for patients in the placebo group (HR 0.334; 95% CI: 0.223-0.499; p<0.0001). Surufatinib had an acceptable safety profile, with the most common treatment related adverse events of grade 3 or worse being hypertension (36% of surufatinib patients vs. 13% of placebo patients), proteinuria (19% vs. 0%) and anemia (5% vs. 3%).

pNETs in China: On June 16, 2021, surufatinib was granted drug registration approval in China for the treatment of pNET. The approval was based on results from the SANET-p study, a Phase III trial (clinicaltrials.gov identifier: NCT02589821) in patients with advanced pNET in China. The pre-defined primary endpoint of PFS was met at a preplanned interim analysis and was published in The Lancet Oncology[2], demonstrating that surufatinib reduces the risk of disease progression or death by 51% in patients, with a median PFS of 10.9 months compared to 3.7 months on placebo (HR 0.491; 95% CI: 0.391-0.755; p=0.0011). The safety profile of surufatinib was manageable and consistent with observations in prior studies.

Immunotherapy combinations: HUTCHMED entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-PD-1 monoclonal antibodies, including with tislelizumab (BGB-A317) and TUOYI (toripalimab), which are approved as monotherapies in China.

NETs in Europe: An MAA submission to the EMA was validated in July 2021, which includes data from a U.S. Phase I/II study, as well as the completed Phase III SANET-ep and SANET-p studies used to support marketing authorization in China.

NETs in Japan: A Japan registration-enabling bridging study was initiated in September 2021. Based on dialogue with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), it was agreed that a Japanese NDA include results from a pivotal study to be conducted in Japan.

The surufatinib Expanded Access Protocol (EAP) in the U.S. will no longer allow new patients to enroll in the study.

On May 2, 2022 Exact Sciences Corp. (NASDAQ: EXAS), a leader in advanced cancer diagnostics, reported that company management will participate in the following conference and invited investors to participate by webcast (Press release, Exact Sciences, MAY 2, 2022, View Source [SID1234613299]).

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BofA Securities Healthcare Conference, Las Vegas
Fireside Chat on Wednesday, May 11, 2022 at 5:00 p.m. ET
The webcast can be accessed in the investor relations section of Exact Sciences’ website at www.exactsciences.com.

On May 2, 2022 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 recent publications of preclinical data for luxeptinib (CG-806) in three peer-reviewed scientific journals (Press release, Aptose Biosciences, MAY 2, 2022, View Source [SID1234613298]). Luxeptinib, Aptose’s oral, dual lymphoid and myeloid kinome inhibitor, is an investigational drug currently in two Phase 1 a/b trials: one in patients with relapsed or refractory B cell malignancies, and separately in patients with relapsed or refractory acute myeloid leukemias (AML) or high-risk myelodysplastic syndromes (MDS) .

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Recent Journal Articles:

Luxeptinib disables NLRP3 inflammasome-mediated IL-1β release and pathways required for secretion of inflammatory cytokines IL-6 and TNFα Biochemical Pharmacology (2022)195 114861 (link)

Luxeptinib is an orally bioavailable kinase inhibitor with potency against select kinases including BTK. Aberrant activation of inflammasomes act as drivers of pathological complications observed during autoimmune and inflammatory disorders, metabolic syndromes, and cancer; and inhibiting the inflammasome-induced activation of pro-inflammatory cytokines has shown beneficial effects in human disease models. BTK and certain other kinases serve as an integral components or influence functions of the NLRP3 inflammasome complex. The aim of this study was to determine if luxeptinib interferes with the release of IL-1β, IL-6 and TNFα from THP-1 monocytes and bone marrow-derived macrophages following endotoxin exposure and priming of the NLRP3 inflammasome.

Key findings:

Luxeptinib inhibits NLRP3 inflammasome function in THP-1 monocytes and bone marrow-derived macrophages.
Mechanistically, luxeptinib prevents the release of cleaved IL-1β from THP-1 cells by inhibiting the ability of the NLRP3 inflammasome to proteolytically cleave caspase-1 to its active form.
Luxeptinib does not impede the assembly of the NLRP3-ASC complex but does potently inhibit three kinases phosphorylated in response to endotoxin. Phosphorylation and nuclear translocation of transcription factor NF-κBp65 was inhibited by luxeptinib.
Luxeptinib also inhibits the release of TNFα and IL-6 in response to activation of the TLR pathway without affecting the TLR/IRAK/MyD88 proteins.
These studies provide novel insights into the mechanisms by which luxeptinib interferes with the NLRP3 inflammasome and endotoxin-induced inflammatory signaling pathways, along with its protective effects against inflammation-induced toxicity in murine models.
The ability of luxeptinib to inhibit inflammatory pathways at concentrations which are well-tolerated in patients makes it a potential clinical candidate for the treatment of inflammatory diseases and inflammation-associated resistance in cancer.
Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma Cell Death & Disease – Nature (2022)13:246 (link)

Small molecules BTK inhibitors like ibrutinib are approved for the treatment of mantle cell lymphoma, or MCL, a rare subtype of non-Hodgkin’s lymphoma (NHL). Nevertheless, median duration of response is less than two years, and MCL patients who develop therapeutic resistance have poor outcomes. Resistance to BTK inhibitors is not clearly understood and a number of alternative mechanisms have been implicated. Luxeptinib, previously known as CG-806, inhibits LYN, SYK, and BTK activation, potently inhibiting both wildtype and C481S mutant BTK, and is expected to have activity in settings where resistance to BTK inhibitors is driven by these mutations. In a Phase 1 trial in patient with chronic lymphocytic leukemia (CLL) and NHL, treatment with luxeptinib resulted in decreased phosphorylation of SYK and BTK in the circulating malignant cells within eight hours of administration. This current pre-clinical study investigates mechanism and efficacy of luxeptinib in MCL.

Key findings:

Luxeptinib induced apoptosis in ibrutinib-resistant MCL cell lines, and in primary MCL cells luxeptinib downmodulated anti-apoptotic proteins Mcl-1 and Bcl-xL and reversed stromal cell survival effects.
Luxeptinib, but not ibrutinib, blocked SYK and BTK signaling and inhibited ERK phosphorylation in MCL cell lines and primary MCL cells.
Dual suppression of BTK/SYK activation with luxeptinib demonstrated efficacy in a PDX MCL model, where efficacy was accompanied by downmodulation of Bcl-2 family proteins and NFκB.
Luxeptinib induced metabolic reprogramming toward a glycolytic shift in MCL cells, accompanied by mitochondrial depolarization and induction of mitophagy that eliminates dysfunctional mitochondria and leads to cell death.
Luxeptinib Inhibits BTK/SYK/ERK signaling and is a potentially promising new therapy in MCL and NHL.
Luxeptinib (CG-806) targets FLT3 and clusters of kinases operative in acute myeloid leukemia Molecular Cancer Therapeutics (2022), Mol. Cancer Ther. molcanther.0832.2021 (link)

AML cells survive via dysregulation of multiple pathways, including FLT3 mutations that occur in approximately 30% of AML patients and are associated with increased risk of relapse and poor survival. Luxeptinib, currently in a Phase 1a/b clinical trial for the treatment of AML, potently inhibits both FLT3 and many of the kinases that participate in rescue pathways that contribute to relapsed and refractory disease. In this study, researchers investigated the range of kinases it inhibits, its antiproliferative landscape ex vivo with AML patient samples, and its in vivo efficacy in xenograft models.

Key findings:

Luxeptinib, an oral non-covalent kinase inhibitor, potently suppresses wild type and mutant forms of FLT3 and select clusters of kinases that can participate in rescue pathways.
Oral luxeptinib demonstrated strong antitumor activity in preclinical in vivo AML xenograft models but no myelosuppression or evidence of tissue damage in acute toxicology studies.
Importantly, luxeptinib does not inhibit the TEC, EGFR, or ERBB2 kinases that can be associated with cardiac, skin and bleeding adverse events.
Ex vivo profiling of luxeptinib against 186 AML fresh patient samples demonstrated greater potency relative to other FLT3 inhibitors, including cases with mutations in FLT3, IDH1/2, ASXL1, NPM1, SRSF2, TP53 or RAS.
A combination of venetoclax and luxeptinib enhanced cell killing of the majority of AML samples relative to either drug alone.
Luxeptinib retained activity against FLT3 mutants that render cells resistant to quizartinib, gilteritinib, and crenolanib FLT3 inhibitors.
"These publications contribute to the wealth of preclinical data demonstrating luxeptinib’ s unique activity as a lymphoid and myeloid kinome inhibitor, and now as an inflammation kinome inhibitor, and support its continued clinical development in several therapeutic areas," said William G. Rice, Ph.D., Chairman, President, and Chief Executive Officer. "Luxeptinib is a clinical-stage compound, currently in Phase 1 a/b studies in AML and B-cell malignancies. We look forward to reporting on our progress in the upcoming months."

On May 2, 2022 DBV Technologies (Euronext: DBV – ISIN: FR0010417345 – Nasdaq Global Select Market: DBVT) (the "Company"), a clinical-stage biotechnological company, reported that it has filed a prospectus supplement with the U.S. Securities and Exchange Commission ("SEC") relating to an At-The-Market offering (the "ATM Program") (Press release, DBV Technologies, MAY 2, 2022, View Source [SID1234613297]). Pursuant to this new financing program, the Company may offer and sell, including with unsolicited investors who have expressed an interest, a total gross amount of up to $100 million of American Depositary Shares ("ADS"), each ADS representing one-half of one ordinary share of DBV Technologies, from time to time in sales deemed to be an "at the market offering" pursuant to the terms of a sales agreement (the "Sales Agreement") with Jefferies LLC ("Jefferies"), acting as sales agent, subject to French regulatory limits. The timing of any sales will depend on a variety of factors. The ATM Program is presently intended to be effective through the expiration of the Company’s existing registration statement registering the ADSs to be issued under the ATM Program, i.e. until July 16, 2024, unless terminated prior to such date in accordance with the sales agreement or the maximum amount of the program has been reached.

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The Company currently intends to use the net proceeds (after deduction of fees and expenses related to the financing), if any, of sales of ADSs issued under the program, together with its existing cash and cash equivalents, primarily for activities associated with potential approval and launch of Viaskin Peanut, as well as to advance the development of the Company’s product candidates using its Viaskin Platform and for working capital and other general corporate purposes, at the Company’s discretion.

Jefferies, as sales agent, will use commercially reasonable efforts to arrange on the Company’s behalf for the sale of all ADSs requested to be sold by the Company to eligible investors requesting it, consistent with Jefferies’ normal sales and trading practices. Sales prices may vary based on market prices and other factors. Only eligible investors (as described in greater detail below) may purchase ADSs under the ATM Program.

The ADSs and the underlying ordinary shares will be issued through one or more share capital increases without shareholders’ preferential subscription rights under the provisions of Article L. 225-138 of the French Commercial Code (Code de commerce) and pursuant to the 28th resolution adopted by the Annual General Meeting of Shareholders held on May 19, 2021 (the "2021 Annual General Meeting") (or any substitute resolutions, adopted from time to time), within the limit of a maximum number of 16,528,961 ordinary shares (being the maximum authorized by the shareholders for such resolution), representing a maximum potential dilution of approximately 30% based on the existing share capital of the Company, it being specified that the number of underlying ordinary shares to be admitted on the regulated market of Euronext in Paris ("Euronext Paris") shall represent, over a period of 12 months,

less than 20% of the ordinary shares already admitted to trading on said market without a French listing prospectus.

The new ordinary shares to be sold in the form of ADSs would be issued in one or more offerings at market prices of the ADSs at the time of pricing of the considered capital increase.

The ATM Program may only be issued to the categories of investors defined in the 28th resolution adopted by the 2021 Annual General Meeting (or any similar resolutions that may be substituted for it in the future), comprising (i) any natural person(s) or legal entity(ies), including companies, trusts, investment funds or other investment vehicle(s), regardless of their form, under French or foreign law, investing on a regular basis in the pharmaceutical, biotechnological or medical technology sector, and/or (ii) French or foreign companies, institutions or entities of any form, carrying out a significant portion of their business in these sectors or in the cosmetics or chemical sector or in the field of medical devices or research in these areas. The new ordinary shares will be admitted to trading on the regulated market of Euronext in Paris and the issued ADSs will trade on the Nasdaq Global Select Market ("Nasdaq").

On an illustrative basis, assuming the issuance of the full amount of $100 million (or €92.7 million (all convenience translations in this press release are based on the noon buying rate of the Federal Reserve Bank of New York in effect as of April 25, 2022, of €1.00 = $1.08) of ADSs under the ATM Program at an assumed offering price of $1.29 (or €1.20), the last reported sale price of the ADSs on Nasdaq on April 29, 2022, a holder of 1.0% of the outstanding Company’s share capital as of the date of this press release, would hold 0.60% of the outstanding Company’s share capital after the completion of the transaction (calculated on the basis of the number of outstanding shares on the date of publication of this press release), it being specified that, in any event, the
number of underlying ordinary shares shall not exceed the limit set forth in the 28th resolution adopted by the 2021 Annual General Meeting (or any substitute resolutions, adopted from time to time, including the 18th resolution presented to the shareholders vote at the Annual General Meeting to be held on May 12, 2022) and shall represent, over a period of 12 months, less than 20% of the ordinary shares already admitted to trading on said market without a listing prospectus.

During the term of the ATM Program, the Company will include in the publication of its quarterly results information about its use of the program during the preceding quarter and will also provide an update after each capital increase on a dedicated location on its corporate website in order to inform investors about the main features of each issue that may be completed under the ATM Program from time to time.

A shelf registration statement on Form S-3 (including a prospectus) relating to DBV Technologies’ securities, including the ADSs, was filed with the SEC and has been declared effective. Before purchasing ADSs in the offering, prospective investors should read the prospectus supplement and the

accompanying prospectus, together with the documents incorporated by reference therein. Prospective investors may obtain these documents for free by visiting EDGAR on the SEC’s website at www.sec.gov. Alternatively, a copy of the prospectus supplement (and accompanying prospectus) relating to the offering may be obtained from Jefferies LLC, 520 Madison Avenue, New York, NY 10022 or by telephone at (877) 821-7388 or by email at [email protected]. No prospectus will be subject to the approval of the French Financial Markets Authority (the Autorité des Marchés Financiers or the "AMF") pursuant to Regulation (EU) 2017/1129 of the European Parliament and of the Council dated June 14, 2017, as amended (the "Prospectus Regulation") since the contemplated share capital increase(s) (for the issuance of the ordinary shares underlying the ADSs) would be offered to qualified investors (as such term is defined in Article 2(e) of the Prospectus Regulation) and fall under the exemption provided for in Article 1(5)(a) of the Prospectus Regulation which states that the obligation to publish a prospectus shall not apply to admission to trading on a regulated market of securities fungible with securities already admitted to trading on the same regulated market, provided that they represent, over a period of 12 months, less than 20% of the number of securities already admitted to trading on the same regulated market.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, 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 registration or qualification under the securities laws of any such state or jurisdiction. In particular, no public offering of the ADSs will be made in Europe.

Information available to the public

Detailed information concerning the Company, in particular with regard to its business, results, forecasts and corresponding risk factors, is provided in the Company’s Annual Report on Form 10-K (the "Annual Report"), filed with the U.S. SEC on March 9, 2022, its 2021 universal registration document (the "URD"), filed with the AMF on March 9, 2022 and under number D.22-0081, as well as in the half-yearly financial report (containing an update of the main information on the Company, its development and its projects) (the "Half-Year Report"), and documents filed with the U.S. SEC from time-to-time (the "SEC Filings"). The Annual Report and SEC Filings are available on the SEC’s website (www.sec.gov). The URD as well as other regulated information are available on the AMF website (www.amf-france.org). All of the foregoing documents are available on the Company’s website and are available free of charge on request at the Company’s registered office at 177-181 avenue Pierre-Brossolette, 92120 Montrouge, France.

On May 2, 2022 Supernus Pharmaceuticals, Inc. (Nasdaq: SUPN), a biopharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases, reported that the Company expects to report financial and business results for the first quarter of 2022 after the market closes on Monday, May 9, 2022 (Press release, Supernus, MAY 2, 2022, View Source [SID1234613296]).

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Jack Khattar, President and CEO, and Tim Dec, Senior Vice President and CFO, will host a conference call to present the first quarter 2022 financial and business results on Monday, May 9, 2022 at 4:30 p.m. ET. Following management’s prepared remarks and discussion of business results, the call will be open for questions.

A live webcast will be available in the Events & Presentations section of the Supernus website at www.supernus.com.

Please refer to the information below for conference call dial-in information. Callers should dial in approximately 10 minutes prior to the start of the call.

Conference Call Name: Supernus Pharmaceuticals First Quarter 2022 Results Conference Call
Following the live call, a replay will be available on the Company’s website, www.supernus.com, in the Investor Relations section. The webcast will be available on the Company’s website for 60 days following the live call.