On December 11, 2020 Bristol Myers Squibb (NYSE: BMY) reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of Inrebic (fedratinib) for the treatment of disease-related splenomegaly (enlarged spleen) or symptoms in adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis, who are Janus Associated Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib (Press release, Bristol-Myers Squibb, DEC 11, 2020, View Source [SID1234572694]). The CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). If approved, Inrebic will be the first, once-daily oral therapy to significantly reduce spleen volume and symptom burden for patients with myelofibrosis where treatment with ruxolitinib has failed or who are JAK inhibitor naïve.

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The CHMP adopted a positive opinion based on results from the JAKARTA and JAKARTA2 studies. The pivotal JAKARTA study evaluated the efficacy of once-daily oral doses of Inrebic compared with placebo in 289 patients with intermediate-2 or high-risk primary or secondary myelofibrosis with splenomegaly.1 The JAKARTA2 study evaluated the efficacy of once-daily oral doses of Inrebic in 97 patients with intermediate or high-risk primary or secondary myelofibrosis with splenomegaly previously treated with ruxolitinib.2

"For nearly a decade, patients with myelofibrosis who have progressed on ruxolitinib have had no treatment options for this rare bone marrow disorder, characterized by debilitating symptoms and an enlarged spleen," said Diane McDowell, M.D., vice president, Hematology Global Medical Affairs, Bristol Myers Squibb. "The positive CHMP opinion for Inrebic reinforces our commitment to improving on standards of care for patients living with hard-to-treat blood diseases and we look forward to the European Commission’s decision."

The EC is expected to deliver its final decision within 67 days of receipt of the CHMP opinion. The decision will be applicable to all EU member states and Iceland, Norway and Liechtenstein.

Inrebic is approved in the United States for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.1 In Canada, Inrebic is approved for the treatment of splenomegaly and/or disease related symptoms in adult patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, including patients who have been previously exposed to ruxolitinib.3

In the clinical development program of Inrebic, which included 608 patients, serious and fatal cases of encephalopathy, including Wernicke’s, occurred in Inrebic-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with Inrebic in clinical trials and 0.16% (1/608) of cases were fatal.

About JAKARTA and JAKARTA2

The Inrebic development program consisted of multiple studies (including JAKARTA and JAKARTA2) in 608 patients who received more than one dose (ranging from 30 mg to 800 mg), of whom 459 had myelofibrosis, including 97 previously treated with ruxolitinib.3 JAKARTA was a pivotal Phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy of once-daily oral doses of Inrebic compared with placebo in patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with splenomegaly and a platelet count of ≥50 x 109/L who were previously untreated with a JAK inhibitor. The study included 289 patients randomized to receive either Inrebic 500 mg (n=97) or 400 mg (n=96) or placebo (n=96)1 across 94 sites in 24 countries.1 JAKARTA2 was a Phase 2, open-label, single arm study of Inrebic in myelofibrosis patients previously treated with ruxolitinib with a diagnosis of intermediate-1 with symptoms, intermediate-2 or high-risk myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis with splenomegaly and platelet count ≥50 x 109/L. The study included 97 patients who started Inrebic at 400 mg once daily across 10 countries.2

The primary endpoint of JAKARTA and JAKARTA2 was spleen response rate, defined as the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 as measured by magnetic resonance imaging (MRI) or computerized tomography (CT) with a follow-up scan 4 weeks later. Secondary endpoints of the studies included symptom response rate, defined as the proportion of patients with a 50% or greater reduction in Total Symptom Score when assessed from baseline to the end of cycle 6 as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary2 (night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, bone or muscle pain).1,2

About Myelofibrosis

Myelofibrosis is a serious and rare bone marrow disorder that disrupts the body’s normal production of blood cells. Bone marrow is gradually replaced with fibrous scar tissue, which limits the ability of the bone marrow to make blood cells. The disorder can lead to anemia, weakness, fatigue and enlargement of the spleen and liver, among other symptoms.4 Myelofibrosis is classified as a myeloproliferative neoplasm, a group of rare blood cancers that are derived from blood-forming stem cells.5 In the EU, approximately 1 of every 100,000 people will be diagnosed with myelofibrosis each year.6 Both men and women are affected, and while the disease can affect people of all ages, the median age at diagnosis ranges from 60 to 67 years.7,8

About Inrebic

Inrebic (fedratinib) is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Inrebic is a JAK2-selective inhibitor with higher potency for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2 or FLT3, Inrebic reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2V617F-driven myeloproliferative disease, Inrebic blocked phosphorylation of STAT3/5, increased survival and improved disease-associated symptoms, including reduction of white blood cells, hematocrit, splenomegaly and fibrosis.1

U.S. INDICATION

INREBIC (fedratinib) is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

U.S. IMPORTANT SAFETY INFORMATION

WARNING: ENCEPHALOPATHY INCLUDING WERNICKE’S
Serious and fatal encephalopathy, including Wernicke’s, has occurred in patients treated with INREBIC. Wernicke’s encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

WARNINGS AND PRECAUTIONS

Encephalopathy, including Wernicke’s: Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in INREBIC-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with INREBIC in clinical trials and 0.16% (1/608) of cases were fatal.

Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including Wernicke’s, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Anemia: New or worsening Grade 3 anemia occurred in 34% of INREBIC-treated patients. The median time to onset of the first Grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks with partial recovery and stabilization after 16 weeks. Red blood cell transfusions were received by 51% of INREBIC-treated patients and permanent discontinuation of INREBIC occurred due to anemia in 1% of patients. Consider dose reduction for patients who become red blood cell transfusion dependent.

Thrombocytopenia: New or worsening Grade ≥3 thrombocytopenia during the randomized treatment period occurred in 12% of INREBIC-treated patients. The median time to onset of the first Grade 3 thrombocytopenia was approximately 1 month; with 75% of cases occurring within 4 months. Platelet transfusions were received by 3.1% of INREBIC-treated patients. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention both occurred in 2.1% of INREBIC-treated patients. Obtain a complete blood count (CBC) at baseline, periodically during treatment, and as clinically indicated. For Grade 3 thrombocytopenia with active bleeding or Grade 4 thrombocytopenia, interrupt INREBIC until resolved to less than or equal to Grade 2 or baseline. Restart dose at 100 mg daily below the last given dose and monitor platelets as clinically indicated.

Gastrointestinal Toxicity: Gastrointestinal toxicities are the most frequent adverse reactions in INREBIC-treated patients. During the randomized treatment period, diarrhea occurred in 66% of patients, nausea in 62% of patients, and vomiting in 39% of patients. Grade 3 diarrhea 5% and vomiting 3.1% occurred. The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment. Consider providing appropriate prophylactic anti-emetic therapy (e.g., 5-HT3 receptor antagonists) during INREBIC treatment. Treat diarrhea with anti-diarrheal medications promptly at the first onset of symptoms. Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours, interrupt INREBIC until resolved to Grade 1 or less or baseline. Restart dose at 100 mg daily below the last given dose. Monitor thiamine levels and replete as needed.

Hepatic Toxicity: Elevations of ALT and AST (all grades) during the randomized treatment period occurred in 43% and 40%, respectively, with Grade 3 or 4 in 1% and 0%, respectively, of INREBIC-treated patients. The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months. Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher ALT and/or AST elevations (greater than 5 × ULN), interrupt INREBIC dose until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. If re-occurrence of a Grade 3 or higher elevation of ALT/AST, discontinue treatment with INREBIC.

Amylase and Lipase Elevation: Grade 3 or higher amylase 2% and/or lipase 10% elevations developed in INREBIC-treated patients. The median time to onset of any grade amylase or lipase elevation was 15 days, with 75% of cases occurring within 1 month of starting treatment. One patient developed pancreatitis in the fedratinib clinical development program (n=608) and pancreatitis resolved with treatment discontinuation. Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher amylase and/or lipase elevations, interrupt INREBIC until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose.

ADVERSE REACTIONS:

The most common adverse reactions for INREBIC treated vs. placebo were diarrhea (66% vs. 16%), nausea (62% vs. 15%), anemia (40% vs. 14%), and vomiting (39% vs. 5%). Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received INREBIC. Adverse reactions requiring dosage interruption in >3% of patients who received INREBIC included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received INREBIC. Adverse reactions requiring dosage reduction in >2% of patients who received INREBIC included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

DRUG INTERACTIONS:

Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure. Increased exposure may increase the risk of adverse reactions. Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce the dose of INREBIC when administering with a strong CYP3A4 inhibitor. Avoid INREBIC with strong and moderate CYP3A4 inducers. Avoid INREBIC with dual CYP3A4 and CYP2C19 inhibitor. Coadministration of INREBIC with drugs that are CYP3A4 substrates, CYP2C19 substrates, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs. Monitor for adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 substrates as necessary when coadministered with INREBIC.

PREGNANCY/LACTATION: Consider the benefits and risks of INREBIC for the mother and possible risks to the fetus when prescribing INREBIC to a pregnant woman. Due to the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with INREBIC, and for at least 1 month after the last dose.

RENAL IMPAIRMENT: Reduce INREBIC dose when administered to patients with severe renal impairment. No modification of the starting dose is recommended for patients with mild to moderate renal impairment. Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions.

HEPATIC IMPAIRMENT: Avoid use of INREBIC in patients with severe hepatic impairment.

Please see full Prescribing Information, including Boxed WARNING.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming people’s lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

On December 11, 2020 PureTech Health plc (LSE: PRTC, Nasdaq: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company dedicated to discovering, developing and commercializing highly differentiated medicines for devastating diseases, reported the initiation of its Phase 1 clinical trial of LYT-200 for the potential treatment of metastatic solid tumors that are difficult to treat and have poor survival rates (Press release, PureTech Health, DEC 11, 2020, View Source [SID1234572693]). LYT-200 is one of several novel therapeutic opportunities within PureTech’s Wholly Owned Pipeline that will be discussed today at its virtual R&D Day.

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"Each year, hundreds of thousands of people are diagnosed with solid tumors, and many will present with metastatic disease that do not respond to existing immunotherapy agents," said Zev Wainberg, M.D., co-director of the UCLA GI Oncology Program, associate professor of medicine at UCLA and the principal investigator on PureTech’s LYT-200 trial. "By targeting galectin-9, LYT-200 is designed to block foundational immunosuppressive mechanisms that shut down the body’s natural ability to fight a number of cancers. The unique mechanism of LYT-200 holds potential across a number of solid tumor types and may enable LYT-200 to be used as a single agent, as well as in combination with checkpoint inhibitors and other anti-cancer treatments."

LYT-200 is a clinical stage, fully human, monoclonal antibody (mAb), that is designed to target galectin-9, an immunosuppressive protein that simultaneously activates multiple immunosuppressive pathways in the tumor microenvironment and is prominently expressed in multiple difficult-to-treat cancers, including breast cancer, pancreatic and cholangiocarcinoma. It is currently being evaluated in the first stage of an adaptive Phase 1/2 trial. The primary objective of the Phase 1 portion of the trial is to assess the safety and tolerability of escalating doses of LYT-200 in order to identify a dose to carry forward into a subsequent Phase 2 trial. The Phase 1 will also assess LYT-200’s pharmacokinetic and pharmacodynamic profiles. Following the topline results, which are expected in the fourth quarter of 2021, PureTech intends to initiate the Phase 2 expansion cohort portion of the trial, which will further assess the recommended Phase 2 dose as a single agent or in combination with chemotherapy and anti-PD-1 therapy in multiple solid tumor types, including pancreatic cancer and cholangiocarcinoma.

"We are pleased to have initiated the Phase 1 part of our LYT-200 clinical trial, which is a dose-finding portion designed to assess safety and tolerability and explore preliminary signals of efficacy for LYT-200," said Aleksandra Filipovic, M.D. PhD, head of oncology at PureTech. "We have generated compelling preclinical data to date, which we believe support the potential of LYT-200 as a new anti-cancer therapy targeting galectin-9, both as a single agent and in combination with other anti-cancer therapies."

Dr. Zev Wainberg and Dr. Siddhartha Mukherjee, clinician and researcher at Columbia University and Pulitzer Prize-winning author of The Emperor of All Maladies and The Gene, will discuss their perspectives on the field of immuno-oncology during today’s virtual R&D Day, which will be available on the Investors section of the corporate website under Events & Presentations. To register, please sign up here.

About LYT-200

LYT-200 is a monoclonal antibody targeting a foundational immunosuppressive protein, galectin-9, for the potential treatment of solid tumors, including pancreatic ductal adenocarcinoma, colorectal cancer and cholangiocarcinoma, that are difficult to treat and have poor survival rates. PureTech has presented preclinical data demonstrating high expression of galectin-9 across breast cancer, pancreatic and cholangiocarcinoma samples and found that the highest levels of galectin-9 correlated with shorter time to disease relapse and poor survival. These data suggest that galectin-9 could be significant both as a therapeutic target for a range of cancers and as a cancer biomarker. Preclinical animal and patient-derived organoid tumor models also showed the potential efficacy of LYT-200 and the importance of galectin-9 as a target. LYT-200 is currently being evaluated in a Phase 1/2 adaptive design trial, and results from the Phase 1 portion are expected in the fourth quarter of 2021.

About PureTech’s Virtual R&D Day

The virtual R&D Day will showcase PureTech’s scientific leadership in lymphatics and related immune pathways and detail PureTech’s Wholly Owned Pipeline. Product candidates within this pipeline include LYT-100, a clinical-stage, anti-fibrotic and anti-inflammatory small molecule being advanced for the potential treatment of interstitial lung diseases and lymphedema, LYT-200, a clinical-stage monoclonal antibody targeting foundational immunosuppressive mechanisms for the potential treatment of solid tumors, and LYT-300, an oral form of allopregnanolone that is being advanced into IND-enabling studies for a range of neurological conditions. Additionally, the R&D Day will detail PureTech’s discovery platforms, including the Glyph technology platform, which is designed to target therapeutics to the lymphatic system and potentially enabling oral administration of natural bioactive molecules such as neurosteroids and cannabinoids, and the Orasome technology platform, which is designed to enable the oral administration of biotherapeutics, such as antisense oligonucleotides, short interfering RNA, mRNA, modular expression systems for therapeutic proteins, peptides and nanoparticles.

On December 11, 2020 Bristol Myers Squibb (NYSE: BMY) reported that its wholly owned subsidiary, Celgene, and Cipla Limited (Cipla) have settled their litigation related to patents for REVLIMID (lenalidomide) (Press release, Bristol-Myers Squibb, DEC 11, 2020, View Source [SID1234572692]).

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As part of the settlement, the parties will file Consent Judgments with the United States District Court for the District of New Jersey that enjoin Cipla from marketing generic lenalidomide before the expiration of the patents-in-suit, except as provided for in the settlement, as described below.

In settlement of all outstanding claims in the litigation, Celgene has agreed to provide Cipla with a license to Celgene’s patents required to manufacture and sell certain volume-limited amounts of generic lenalidomide in the United States beginning on a confidential date that is some time after March 2022. For each consecutive twelve-month period (or part thereof), following the volume-limited entry date until January 31, 2026, the volume of generic lenalidomide sold by Cipla cannot exceed certain agreed-upon percentages. The specific volume-limited license date and percentages are confidential. In addition, Celgene has agreed to provide Cipla with a license to Celgene’s patents required to manufacture and sell an unlimited quantity of generic lenalidomide in the United States beginning no earlier than January 31, 2026.

Cipla’s ability to market lenalidomide in the U.S. will be contingent on its obtaining approval of an Abbreviated New Drug Application.

On December 11, 2020 NANOBIOTIX (Paris:NANO) (Euronext: NANO – ISIN : FR0011341205 – the ‘‘Company’’), a clinical-stage nanomedicine company pioneering new approaches to the treatment of cancer, reported the pricing of its initial public offering on the Nasdaq Global Select Market by way of a capital increase of 7,300,000 new ordinary shares (the "New Shares"), consisting of a public offering of 5,445,000 ordinary shares in the form of American Depositary Shares ("ADSs"), each representing the right to receive one ordinary share, in the United States (the "U.S. Offering") and a concurrent offering of 1,855,000 ordinary shares in certain jurisdictions outside of the United States to certain investors (the "European Offering" and together with the U.S. Offering, the "Global Offering") (Press release, Nanobiotix, DEC 11, 2020, View Source [SID1234572690]). The offering price was set at $13.50 per ADS in the U.S. Offering and a corresponding offering price of €11.14 per New Share based on an exchange rate of €1.00 = $1.2115 as published by the European Central Bank on December 10, 2020. The aggregate gross proceeds are expected to be approximately $98.6 million, equivalent to approximately €81.3 million, before deduction of underwriting commissions and estimated expenses payable by the Company. The Global Offering is expected to close on December 15, 2020, subject to the satisfaction of customary closing conditions.

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All the securities sold in the Global Offering will be issued by the Company. The ADSs have been approved for listing on the Nasdaq Global Select Market and are expected to begin trading on December 11, 2020 under the ticker symbol "NBTX." The Company’s ordinary shares are listed on the regulated market of Euronext Paris under the ticker symbol "NANO."

The New Shares (some of which are represented by ADSs) sold in the Global Offering will be subject to an application for admission to trading on the regulated market of Euronext in Paris (Compartment B) on the same trading line as the existing shares under the same ISIN code FR0011341205 and are expected to be admitted to trading on December 15, 2020.

Jefferies LLC is acting as global coordinator and joint book-running manager for the Global Offering, and Evercore Group, L.L.C. and UBS Securities LLC are acting as joint book-running managers for the U.S. Offering. Gilbert Dupont is acting as manager for the European Offering (together, the "Underwriters").

Type of Offering

The New Shares will be issued through a capital increase without shareholders’ preferential subscription rights by way of a public offering and under the provisions of Article L.225-136 of the French Commercial Code (Code de commerce) and pursuant to the 2nd and 7th resolutions of the Company’s extraordinary general shareholders’ meeting held on November 30, 2020.

The offering price per New Share in euros is equal to the volume weighted average price of the Company’s ordinary shares on the regulated market of Euronext in Paris over the last three trading days preceding the start of the offering (i.e., December 7, 8 and 9, 2020), minus a discount of 9.80%, and has been determined by the Company pursuant to the 2nd resolution of the Company’s extraordinary general shareholders’ meeting held on November 30, 2020.

Option to Purchase Additional Shares

The Company has granted the Underwriters an option to purchase (the "Underwriters’ Option"), for a 30-day period (until January 9, 2021), up to 1,095,000 additional ADSs, which represents 15% of the aggregate amount of the New Shares to be issued in the Global Offering, at the same offering price.

Stabilization

In connection with the Global Offering, Jefferies LLC, acting as stabilization agent, may over-allot the securities or effect transactions with a view to supporting, stabilizing, or maintaining the market price of the securities at a level higher than which might otherwise prevail in the open market. However, there is no assurance that the stabilization agent will take any stabilization action and, if begun, may be ended at any time without prior notice. Any stabilization action or over-allotment shall be carried out in accordance with all applicable rules and regulations and may be undertaken on the regulated market of Euronext in Paris and on the Nasdaq Global Select Market.

Dilution

The 7,300,000 New Shares to be issued in the Global Offering (5,445,000 of which are ordinary shares represented by ADSs) will result in a dilution of approximately 28% of the Company’s outstanding share capital on a non-diluted basis excluding the exercise of the Underwriters’ Option, and approximately 32% of the Company’s outstanding share capital on a non-diluted basis, in the case of a full exercise of the Underwriters’ Option.

Estimated Proceeds from the Global Offering

The gross proceeds of the issuance of the New Shares are expected to be approximately $98.6 million (€81.3 million), assuming no exercise of the Underwriters’ Option.

The Company estimates that the net proceeds of the Global Offering will be approximately $86.7 million (€71.5 million), after deducting approximately $6.9 million (€5.7 million) in underwriting commissions and approximately $5.0 million (€4.1 million) in estimated offering expenses.

The Company expects to use the net proceeds from the Global Offering to advance the overall development of NBTXR3, prioritizing the treatment of locally advanced head and neck cancers, as follows (assuming an exchange rate of €1.00 = $1.2115, the exchange rate on December 10, 2020):

approximately $48.5 million (€40 million) to advance its clinical trial of NBTXR3 in the United States and Europe for the treatment of locally advanced head and neck cancers through an interim analysis of efficacy data,
approximately $18.2 million (€15 million) to advance the development of its other clinical and pre-clinical programs, and
the remainder for working capital funding and other general corporate purposes.
As of September 30, 2020, the Company had cash and cash equivalents of €42.4 million (non audited). The Company believes that the net proceeds from the Global Offering, together with its cash and cash equivalents, will be sufficient to fund its operations through the first quarter of 2023.

Underwriting

The Global Offering is subject to an underwriting agreement entered into on December 10, 2020. The underwriting agreement does not constitute a "garantie de bonne fin" within the meaning of Article L. 225-145 of the French Commercial Code (Code de commerce).

Documentation

The Company has filed a registration statement, including a prospectus, relating to these securities with the U.S. Securities and Exchange Commission ("SEC"), which was declared effective by the SEC on December 10, 2020. The securities referred to in this press release will be offered only by means of a prospectus in the United States. Copies of the final prospectus relating to and describing the terms of the Global Offering can be obtained, when available, from Jefferies LLC, 520 Madison Avenue New York, NY 10022, or by telephone at 877-547-6340 or 877-821-7388, or by email at [email protected]; or from Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, New York 10055, or by telephone at 888-474-0200, or by email at [email protected]; or from UBS Securities LLC, Attention: Prospectus Department, 1285 Avenue of the Americas, New York, New York 10019, or by telephone at 888-827-7275, or by email at [email protected].

Application will be made to list the New Shares on the regulated market of Euronext in Paris pursuant to a listing prospectus subject to an approval from the French Autorité des Marchés Financiers ("AMF") and comprising the 2019 Universal Registration Document (Document d’Enregistrement Universel) of the Company filed with the AMF on May 12, 2020 under number R.20-010, as completed by a first amendment to such Universal Registration Document filed with the AMF on November 20, 2020 under number D.20-0339-A01 and a second amendment to such Registration Document, which will be filed on December 11, 2020 as well as a Securities Note (Note d’opération), including a summary of the prospectus. Following the filing of the second amendment to the 2019 Universal Registration Document, copies of the 2019 Universal Registration Document, as amended, will be available free of charge at the Company’s head office located at 60 rue de Wattignies, 75012 Paris, France, on the Company’s website (www.nanobiotix.com) and on the AMF’s website (www.amf-france.org).

The final prospectus will also be available at www.sec.gov. 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.

Risk Factors

Investors should carefully consider the risk factors likely to affect the Company’s business as described in Section 1.5 "Risk Factors" in the 2019 Universal Registration Document, in Section 3 "Risk Factors" of the first amendment to the 2019 universal registration document and in Section 4 "Risk Factors" of the second amendment to the 2019 universal registration document expected to be filed with the AMF on December 11, 2020 before making an investment decision. If any of these risks are realized, the Company’s business, financial condition, operating results and prospects could be materially and adversely affected. In addition, other risks, not identified or considered significant by the Company, could have the same adverse effect and investors could lose all or part of their investment.

Allocation of the Share Capital

The following table presents the expected allocation of the Company’s share capital following the settlement and delivery of the New Shares (5,445,000 of which are ordinary shares represented by ADSs):

On December 11, 2020 Odonate Therapeutics, Inc. (NASDAQ: ODT), a pharmaceutical company dedicated to the development of best‑in‑class therapeutics that improve and extend the lives of patients with cancer, reported that positive results from CONTESSA, a Phase 3 study of tesetaxel in patients with metastatic breast cancer (MBC), were presented in an oral presentation at the 2020 San Antonio Breast Cancer Symposium (SABCS) (Press release, Odonate Therapeutics, DEC 11, 2020, View Source [SID1234572689]). The results were presented by Joyce O’Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, Texas Oncology and Chair, Breast Cancer Research, US Oncology, and Co‑Principal Investigator of CONTESSA (please click here for slides).

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CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with MBC. CONTESSA is comparing tesetaxel dosed orally at 27 mg/m2 on the first day of each 21‑day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21‑day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day dosed orally for 14 days of each 21‑day cycle) in 685 patients randomized 1:1 with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Capecitabine is an oral chemotherapy agent that is considered a standard‑of‑care treatment in MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin‑dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is progression‑free survival (PFS) as assessed by the Independent Radiologic Review Committee (IRC). The secondary efficacy endpoints are overall survival (OS), objective response rate (ORR) as assessed by the IRC and disease control rate (DCR) as assessed by the IRC. CONTESSA is being conducted at 180 investigational sites in 18 countries in North America, Europe and Asia.

CONTESSA met the primary endpoint of improved PFS as assessed by the IRC. Median PFS was 9.8 months for tesetaxel plus a reduced dose of capecitabine versus 6.9 months for the approved dose of capecitabine alone, an improvement of 2.9 months. The risk of disease progression or death was reduced by 28.4% [hazard ratio=0.716 (95% confidence interval: 0.573-0.895); p=0.003] for tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone.

The ORR as assessed by the IRC was 57% for tesetaxel plus a reduced dose of capecitabine versus 41% for the approved dose of capecitabine alone (p=0.0002). The DCR as assessed by the IRC was 67% for tesetaxel plus a reduced dose of capecitabine versus 50% for the approved dose of capecitabine alone (p<0.0001). While OS data are immature, a recent interim analysis indicated the absence of an adverse effect on OS with tesetaxel plus a reduced dose of capecitabine. A protocol‑specified final analysis of OS is expected to occur in 2022.

Tesetaxel plus capecitabine was associated with a manageable side effect profile consistent with findings from previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients were: neutropenia (70.9% for tesetaxel plus capecitabine vs. 8.3% for capecitabine alone); diarrhea (13.1% for tesetaxel plus capecitabine vs. 8.9% for capecitabine alone); hand‑foot syndrome (6.8% for tesetaxel plus capecitabine vs. 12.2% for capecitabine alone); febrile neutropenia (13.1% for tesetaxel plus capecitabine vs. 1.2% for capecitabine alone); fatigue (8.6% for tesetaxel plus capecitabine vs. 4.5% for capecitabine alone); hypokalemia (8.6% for tesetaxel plus capecitabine vs. 2.7% for capecitabine alone); leukopenia (9.8% for tesetaxel plus capecitabine vs. 0.9% for capecitabine alone); and anemia (8.0% for tesetaxel plus capecitabine vs. 2.4% for capecitabine alone).

Adverse events resulting in treatment discontinuation in ≥1% of patients were: neutropenia or febrile neutropenia (4.2% for tesetaxel plus capecitabine vs. 1.5% for capecitabine alone); neuropathy (3.6% for tesetaxel plus capecitabine vs. 0.3% for capecitabine alone); sepsis or septic shock (1.8% for tesetaxel plus capecitabine vs. 0.6% for capecitabine alone); diarrhea (0.9% for tesetaxel plus capecitabine vs. 1.5% for capecitabine alone); and hand-foot syndrome (0.6% for tesetaxel plus capecitabine vs. 2.1% for capecitabine alone). Treatment discontinuation due to any adverse event occurred in 23.1% of patients treated with tesetaxel plus capecitabine versus 11.9% of patients treated with capecitabine alone.

Tesetaxel dose reductions occurred in 76% of patients treated with tesetaxel plus capecitabine, primarily due to neutropenia. Dose reductions occurred in 61% of patients treated with capecitabine alone, primarily due to hand-foot syndrome. The relative delivered dose intensity, which accounts for not only the frequency, but also the magnitude of reductions and treatment adherence, was higher in patients treated with tesetaxel plus capecitabine. Specifically, 81% of the intended dose of tesetaxel through cycle 12 was delivered in patients treated with tesetaxel plus capecitabine versus 76% of the intended dose of capecitabine through cycle 12 in patients treated with capecitabine alone.

Grade 2 alopecia (hair loss) occurred in 8.0% of patients treated with tesetaxel plus capecitabine versus 0.3% of patients treated with capecitabine alone. Grade ≥3 neuropathy occurred in 5.9% of patients treated with tesetaxel plus capecitabine versus 0.9% of patients treated with capecitabine alone. There were no treatment-related hypersensitivity reactions.

"Tesetaxel represents a potential important clinical advance for patients with metastatic breast cancer," said Joyce O’Shaughnessy, M.D. "There remains a significant unmet medical need for novel therapies that offer quality‑of‑life advantages for patients with metastatic breast cancer."

"The PFS improvement observed in CONTESSA, along with once‑every‑three‑weeks oral dosing and low rates of clinically significant hair loss and neuropathy, could make tesetaxel an important new treatment option for patients with metastatic breast cancer," said Andrew Seidman, M.D., Medical Director, Bobst International Center, Memorial Sloan Kettering Cancer Center and Professor of Medicine, Weill Cornell Medical College, and Co‑Principal Investigator of CONTESSA.

"We would like to thank all of the investigators, study team personnel, and especially the patients and their caregivers who made CONTESSA possible," said Kevin Tang, Chief Executive Officer of Odonate. "We look forward to working closely with global regulatory authorities to make tesetaxel available to patients with metastatic breast cancer. We plan to submit a New Drug Application for tesetaxel to the FDA in mid‑2021."

The Company will host a Virtual Investor and Analyst Event today at 1:00 p.m. CT / 2:00 p.m. ET.

Virtual Investor and Analyst Event Information

Date: December 11, 2020
Time: 1:00 p.m. CT / 2:00 p.m. ET
Webcast Link: Please click here
Dial-in (domestic): (866) 300-4090
Dial-in (international): (636) 812‑6660
Conference ID: 8698553

About Tesetaxel

Tesetaxel is an investigational, orally administered chemotherapy agent that belongs to a class of drugs known as taxanes, which are widely used in the treatment of cancer. Tesetaxel has several pharmacologic properties that make it unique among taxanes, including: oral administration with a low pill burden; a long (~8-day) terminal plasma half-life in humans, enabling the maintenance of adequate drug levels with relatively infrequent dosing; no history of hypersensitivity (allergic) reactions; and significant activity against chemotherapy-resistant tumors. In patients with metastatic breast cancer, tesetaxel was shown to have significant, single-agent antitumor activity in two multicenter, Phase 2 studies. Tesetaxel currently is the subject of three studies in breast cancer, including a multinational, multicenter, randomized, Phase 3 study in patients with metastatic breast cancer, known as CONTESSA. Positive results of CONTESSA were recently presented at the 2020 San Antonio Breast Cancer Symposium.

About CONTESSA

CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with metastatic breast cancer (MBC). CONTESSA is comparing tesetaxel dosed orally at 27 mg/m2 on the first day of each 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day dosed orally for 14 days of each 21-day cycle) in 685 patients randomized 1:1 with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)‑negative MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is progression-free survival (PFS) as assessed by an Independent Radiologic Review Committee (IRC). The secondary efficacy endpoints are overall survival (OS), objective response rate (ORR) as assessed by the IRC and disease control rate (DCR) as assessed by the IRC.