On June 24, 2019 Medtronic plc (the "Company") (NYSE:MDT) reported the commencement of two cash tender offers by its wholly-owned indirect subsidiaries, Medtronic, Inc. ("Medtronic, Inc."), Medtronic Global Holdings S.C.A. ("MGH") and Covidien International Finance S.A. ("CIFSA" and, together with Medtronic, Inc. and MGH, the "Offerors") (Press release, Medtronic, JUN 24, 2019, View Source;p=RssLanding&cat=news&id=2402104 [SID1234537226]). The first tender offer (the "Any and All Tender Offer") is for any and all of $1.175 billion total aggregate principal amount of the outstanding senior notes listed in Table 1 below (the "Any and All Notes"), which were issued by Medtronic, Inc. The second tender offer (the "Maximum Tender Offer" and, together with the Any and All Tender Offer, the "Tender Offers") is for up to $3.0 billion (the "Aggregate Maximum Purchase Price") combined aggregate purchase price (excluding accrued and unpaid interest to, but not including, the applicable settlement date and excluding fees and expenses related to the Tender Offers) of the outstanding senior notes listed in Table 2 below (the "Maximum Tender Offer Notes" and, collectively with the Any and All Notes, the "Notes").

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The tables below summarize certain information regarding the Notes and the Tender Offers, including the order of priority set forth in Table 2, subject to the Series Tender Caps, if applicable, and the Aggregate Maximum Purchase Price for the Maximum Tender Offer Notes. The Any and All Notes are not subject to a cap on the aggregate purchase price.

Table 1: Any and All Notes

Title of Security

CUSIP
Numbers

Issuer/Offeror

Principal Amount
Outstanding

U.S. Treasury
Reference
Security

Bloomberg
Reference Page

Fixed Spread(1)

Early Tender Payment
(2) (3)

4.125% Senior Notes due 2021 585055AV8 Medtronic, Inc. $500,000,000 2.375% U.S.T. due 3/15/2021 PX4 15 $30
3.125% Senior Notes due 2022 585055AX4 Medtronic, Inc. $675,000,000 2.375% U.S.T. due 3/15/2022 PX5 15 $30
Table 2: Maximum Tender Offer Notes

Title of Security

CUSIP
Numbers

Issuer/Offeror

Principal Amount
Outstanding

Acceptance
Priority
Level (4)

Series Tender Cap

U.S. Treasury
Reference
Security

Bloomberg
Reference Page

Fixed Spread

Early Tender Payment (2) (3)

6.500% Senior Notes due 2039 585055AQ9 Medtronic, Inc. $182,949,000 1 N/A 3.000% U.S.T. due 2/15/2049 PX1 85 $30
5.550% Senior Notes due 2040 585055AT3 Medtronic, Inc. $305,910,000 2 N/A 3.000% U.S.T. due 2/15/2049 PX1 75 $30
4.625% Senior Notes due 2045 585055BU9 Medtronic, Inc. $1,963,341,000 3 $100,000,000 3.000% U.S.T. due 2/15/2049 PX1 70 $30
4.625% Senior Notes due 2044 585055BD7 Medtronic, Inc. $176,594,000 4 N/A 3.000% U.S.T. due 2/15/2049 PX1 75 $30
4.500% Senior Notes due 2042 585055AW6 Medtronic, Inc. $128,650,000 5 N/A 3.000% U.S.T. due 2/15/2049 PX1 75 $30
4.375% Senior Notes due 2035 585055BT2 Medtronic, Inc. $2,381,619,000 6 $200,000,000 3.000% U.S.T. due 2/15/2049 PX1 50 $30
4.000% Senior Notes due 2043 585055AY2 Medtronic, Inc. $325,024,000 7 N/A 3.000% U.S.T. due 2/15/2049 PX1 75 $30
3.500% Senior Notes due 2025 585055BS4 Medtronic, Inc. $4,000,000,000 8 $1,300,000,000 2.000% U.S.T. due 5/31/2024 PX1 40 $30
3.625% Senior Notes due 2024 585055BC9 Medtronic, Inc. $850,000,000 9 N/A 2.000% U.S.T. due 5/31/2024 PX1 35 $30
6.550% Senior Notes due 2037 22303QAH3 Covidien International Finance S.A. $283,536,000 10 N/A 3.000% U.S.T. due 2/15/2049 PX1 75 $30
3.350% Senior Notes due 2027 58507LAC3 Medtronic Global Holdings S.C.A. $850,000,000 11 N/A 2.375% U.S.T. due 5/15/2029 PX1 30 $30
3.150% Senior Notes due 2022 585055BR6 Medtronic, Inc. $2,500,000,000 12 N/A 1.750% U.S.T. due 6/15/2022 PX1 25 $30
3.200% Senior Notes due 2022 22303QAN0 Covidien International Finance S.A. $650,000,000 13 N/A 1.750% U.S.T. due 6/15/2022 PX1 25 $30
2.950% Senior Notes due 2023 22303QAP5 Covidien International Finance S.A. $309,516,000 14 N/A 2.000% U.S.T. due 5/31/2024 PX1 25 $30
(1) If the Total Consideration (as defined below) based on the applicable Fixed Spread (as defined below) would have been below $1,000, then it will be equal to $1,000 per $1,000 principal amount.

(2) Per $1,000 principal amount.

(3) The Total Consideration for Notes validly tendered prior to or at the applicable Early Tender Date (as defined below) and accepted for purchase is calculated using the applicable Fixed Spread and is inclusive of the applicable Early Tender Payment (as defined below). The Total Consideration will be determined by taking into account the applicable par call date for each series of Notes, if any.

(4) The offers with respect to the Maximum Tender Offer Notes are subject to the Aggregate Maximum Purchase Price of $3.0 billion in aggregate purchase price and the Series Tender Caps. All references to the aggregate purchase price for the Maximum Tender Offer Notes include the applicable Total Consideration or Tender Offer Consideration (as defined below) and exclude applicable accrued interest and fees and expenses related to the Tender Offers. The Offerors will purchase an aggregate principal amount of Maximum Tender Offer Notes having an aggregate purchase price up to the Aggregate Maximum Purchase Price, subject to the Acceptance Priority Level and the Series Tender Caps as set forth in the table above. The Offerors reserve the right, but are under no obligation, to increase the Aggregate Maximum Purchase Price and/or any Series Tender Cap at any time, including on or after July 10, 2019, subject to applicable law, which could result in the Offerors purchasing an aggregate principal amount of Maximum Tender Offer Notes having a greater aggregate purchase price in the Maximum Tender Offers and/or purchasing an aggregate principal amount of such series of Capped Notes (as defined below) above the applicable sublimit set forth herein.

The Tender Offers are being made pursuant to an Offer to Purchase, dated June 24, 2019 (the "Offer to Purchase"), which sets forth the terms and conditions of the Tender Offers. The Tender Offers will expire at 12:00 midnight, New York City time, on July 24, 2019 (one minute after 11:59 p.m., New York City time, on July 24, 2019), or any other date and time to which such Tender Offer is extended (such date and time, as it may be extended with respect to a Tender Offer, the "Expiration Date"), unless earlier terminated. Holders of Notes must validly tender and not validly withdraw their Notes prior to 5:00 p.m., New York City time, on July 9, 2019, (such date and time, as it may be extended with respect to a Tender Offer, the "Early Tender Date"), to be eligible to receive the Total Consideration (as defined below), which is inclusive of the applicable cash amount set forth in the above tables under the heading "Early Tender Payment" (the "Early Tender Payment"). Holders of Notes who validly tender their Notes after the Early Tender Date but prior to the applicable Expiration Date will only be eligible to receive the applicable Tender Offer Consideration.

All holders of Notes accepted for purchase will also receive accrued and unpaid interest on Notes validly tendered and accepted for purchase from the applicable last interest payment date up to, but not including, the applicable settlement date.

The applicable consideration (the "Total Consideration") offered per $1,000 principal amount of Notes of each series validly tendered and accepted for purchase pursuant to the applicable Tender Offer will be determined in the manner described in the Offer to Purchase by reference to the applicable "Fixed Spread" for such Notes specified in the tables above plus the applicable yield to maturity based on the bid-side price of the applicable "U.S. Treasury Reference Security" specified in the tables above as quoted on the applicable page on the Bloomberg Bond Trader at 11:00 a.m., New York City time, on the first business day following the Early Tender Date which is expected to be July 10, 2019. The "Tender Offer Consideration" is equal to the Total Consideration minus the Early Tender Payment.

Maximum Tender Offer Notes tendered prior to or at the Early Tender Date and accepted for purchase will be accepted based on the acceptance priority levels noted on the front cover hereof, with 1 being the highest Acceptance Priority Level and 14 being the lowest Acceptance Priority Level (the "Acceptance Priority Levels") and will have priority over Maximum Tender Offer Notes tendered after the Early Tender Date, regardless of the Acceptance Priority Levels of the Maximum Tender Offer Notes tendered after the Early Tender Date. Maximum Tender Offer Notes of a series may be subject to proration if the aggregate principal amount of the Maximum Tender Offer Notes of such series validly tendered and not validly withdrawn would cause the Aggregate Maximum Purchase Price to be exceeded, or, in the case of each of the 4.625% Senior Notes due 2045, the 4.375% Senior Notes due 2035 and the 3.500% Senior Notes due 2025 (each a "Capped Note"), if the aggregate principal amount of the Capped Note validly tendered and not validly withdrawn is greater than applicable Series Tender Cap.

The Tender Offers will expire on the applicable Expiration Date. The settlement date for the Notes that are validly tendered on or prior to the Early Tender Date is expected to be July 12, 2019, the third business day following the Early Tender Date, assuming the conditions to the satisfaction of the applicable Tender Offer are satisfied. The settlement date for Notes that are validly tendered following the Early Tender Date but on or prior to the applicable Expiration Date is expected to be July 26, 2019, the second business day following the Expiration Date.

Notes that are validly tendered may be validly withdrawn at any time prior to 5:00 p.m., New York City time, on July 9, 2019 (unless extended, the "Withdrawal Deadline"). After such time Notes may not be withdrawn unless the applicable Offeror extends the Withdrawal Deadline.

In accordance with the indentures governing the Any and All Notes, and subject to available funding, Medtronic, Inc. may give notice of redemption for the redemption of any remaining 4.125% Senior Notes due 2021 or 3.125% Senior Notes due 2022 that are not validly tendered and accepted for purchase in the Any and All Tender Offers. Any such notice of redemption may be given as early as July 10, 2019. The Offerors, the Company or their affiliates may also from time to time, after completion of the applicable Tender Offer, purchase additional Notes in the open market, in privately negotiated transactions, through tender or exchange offers or otherwise, or the applicable Offeror may redeem Notes that are redeemable pursuant to their terms.

The Offerors’ obligation to accept for payment and to pay for the Notes validly tendered in the Tender Offers is not subject to any minimum tender condition but is subject to the satisfaction or waiver of the conditions described in the Offer to Purchase, including the financing condition that the Offerors shall have closed one or more debt financings resulting in net proceeds in an amount not less than the amount required, upon the terms and subject to the conditions of the applicable Tender Offer, to purchase all the Notes validly tendered and accepted for purchase in the Tender Offers and to pay accrued interest thereon and fees and expenses associated therewith. Following the Tender Offers, the Company does not intend to pursue any additional opportunistic refinancing in the Euro market for the next year. The Offerors reserve the right, subject to applicable law, to: (i) waive any and all conditions to the Tender Offers; (ii) extend or terminate the Tender Offers; (iii) increase or decrease the Aggregate Maximum Purchase Price and Series Tender Caps; or (iv) otherwise amend any of the Tender Offers in any respect.

Information Relating to the Tender Offers
Barclays Capital Inc., BofA Merrill Lynch and Goldman Sachs & Co. LLC are acting as the dealer managers (the "Dealer Managers") for the Tender Offers. The information agent and tender agent is Global Bondholder Services Corporation ("Global Bondholder"). Copies of the Offer to Purchase and related offering materials are available by contacting Global Bondholder at +1-866-470-4200 (U.S. toll-free) or +1-212-430-3774 (banks and brokers). Questions regarding the Tender Offer should be directed to Barclays Capital Inc., Liability Management Group at +1-212-528-7581 (collect) or +1-800-438-3242 (toll free), BofA Merrill Lynch, Liability Management Group, at +1-980-387-3907 (collect) or +1-888-292-0070 (toll-free) or Goldman Sachs & Co. LLC at +1-212-357-0215 (collect) or +1-800-828-3182 (toll-free).

None of the Offerors, the Company or their affiliates, their respective boards of directors or managing members, the Dealer Managers, Global Bondholder or the trustee with respect to any series of Notes is making any recommendation as to whether holders of Notes should tender any Notes in response to any of the Tender Offers, and neither the Offerors nor any such other person has authorized any person to make any such recommendation. Holders of Notes must make their own decision as to whether to tender any of their Notes, and, if so, the principal amount of Notes to tender.

This press release shall not constitute an offer to sell, a solicitation to buy or an offer to purchase or sell any securities. The Tender Offers are being made only pursuant to the Offer to Purchase and only in such jurisdictions as is permitted under applicable law.

The full details of the Tender Offers, including complete instruction on how to tender Notes, are included in the Offer to Purchase. The Offer to Purchase contains important information that should be read by holders of Notes before making a decision to tender any Notes. The Offer to Purchase may be downloaded from Global Bondholder’s website at View Source or obtained from Global Bondholder, free of charge, by calling toll-free at +1-866-470-4200 (bankers and brokers can call collect at +1-212-430-3774).

On June 24, 2019 ArQule, Inc. (Nasdaq: ARQL) reported that it has commenced an underwritten public offering, subject to market and other conditions, to issue and sell shares of its common stock (Press release, ArQule, JUN 24, 2019, View Source [SID1234537225]). In connection with the offering, ArQule expects to grant the underwriters a 30-day option to purchase up to an additional 15% of the shares of its common stock offered in the public offering. There can be no assurances as to whether or when the offering may be completed, or as to the actual size or terms of the offering. All of the shares in the offering are to be sold by ArQule.

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The Company intends to use the net proceeds of the offering to fund its core clinical programs and for general corporate purposes.

SVB Leerink and RBC Capital Markets are acting as joint bookrunning managers for the offering.

The securities described above are being offered by ArQule pursuant to a shelf registration statement on Form S-3, including a base prospectus, that was filed by ArQule with the Securities and Exchange Commission ("SEC") and automatically became effective on June 24, 2019. The offering is being made only by means of a written prospectus and prospectus supplement that form a part of the registration statement. A preliminary prospectus supplement and accompanying prospectus relating to the offering will be filed with the SEC and will be available on the SEC’s website located at www.sec.gov. Copies of the preliminary prospectus supplement and the accompanying prospectus relating to the offering, when available, may also be obtained from SVB Leerink LLC, Attention: Syndicate Department, One Federal Street, 37th Floor, Boston, MA 02110, by telephone at (800) 808-7525, ext. 6132, or by email at [email protected]; or from RBC Capital Markets, LLC, Attention: Equity Syndicate, 200 Vesey Street, 8th Floor, New York, NY 10281, by telephone at (877) 822-4089.

This press release does not constitute an offer to sell or a solicitation of an offer to buy, nor will there be any sales of these securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of such jurisdiction.

On June 24, 2019 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold placed on CANOVA (M13-494), a Phase 3 trial evaluating venetoclax (VENCLEXTA OR VENCLYXTO) for the investigational treatment of relapsed/refractory multiple myeloma (Press release, AbbVie, JUN 24, 2019, View Source [SID1234537224]). The CANOVA trial evaluates venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone in patients with relapsed/refractory multiple myeloma positive for the translocation (11;14) abnormality. The t(11;14) genetic biomarker is among the most common and routinely tested genetic abnormalities in patients with multiple myeloma.1

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The FDA removed the partial clinical hold based upon agreement on revisions to the CANOVA study protocol, including new risk mitigation measures, protocol-specified guidelines and updated futility criteria. Enrollment in the CANOVA trial may resume as determined by each participant site based on the approved protocol.

All other clinical trials evaluating venetoclax in patients with multiple myeloma remain on partial clinical hold while next steps continue to be evaluated with the agency. The partial clinical hold does not impact any of the approved indications for venetoclax, such as chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML). AbbVie remains confident in the benefit/risk profile of venetoclax in those approved indications.

"We are pleased to move forward with the CANOVA study which, with the t(11;14) biomarker test, can help identify patients who may respond better to treatment and add clarity for physicians when choosing a therapy, if approved," said Mohamed Zaki, M.D., Ph.D., global head of hematology development, AbbVie. "We are working closely with regulatory authorities worldwide to continue our efforts to understand the potential of venetoclax for patients with multiple myeloma while continuing to advance research in patients with the t(11;14) genetic abnormality."

Results from the Phase 3 BELLINI trial evaluating patients with relapsed/refractory multiple myeloma were presented at the 24th European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress during the late-breaking oral presentation session on Sunday, June 16. Additional data will be presented at a future congress or published in a medical journal.2

In March 2019, AbbVie announced the FDA placed a partial clinical hold on all trials evaluating venetoclax for the investigational treatment of multiple myeloma, following a review of data from the Phase 3 BELLINI trial of venetoclax with bortezomib and dexamethasone (Ven + Vd) versus placebo (placebo + Vd) in patients with relapsed/refractory multiple myeloma, in which a higher proportion of deaths (41/194 (21%)) was observed in the venetoclax arm compared to the control arm of the trial (11/97 (11%) — overall survival hazard ratio (HR) 2.027, 95% confidence interval (CI): [1.042, 3.945]). Progressive disease was the most common cause (45%) of death. The rates of serious adverse events (AEs) (48% vs 50%) and serious infections (28% vs 27%) were comparable between arms.2

Venetoclax is not approved by any regulatory authority, in any country for the treatment of multiple myeloma.

Despite the availability of multiple myeloma therapies, there is no optimal treatment sequence.3 Nearly all multiple myeloma patients eventually relapse, which is associated with poor outcomes, and each remission is typically shorter than the previous one.4 Patients with multiple myeloma have an average life expectancy of approximately five to six years after diagnosis.5 It is the second most common blood cancer with nearly 140,000 cases expected to be diagnosed worldwide this year.6,7

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About CANOVA
CANOVA is a Phase 3, multicenter, randomized, open label study of either venetoclax or pomalidomide in combination with dexamethasone in patients with t(11;14)-positive relapsed/refractory multiple myeloma.8

About BELLINI
BELLINI is a multicenter, randomized, double blind study of either venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma who have received 1 to 3 prior lines of therapy and are sensitive or naïve to proteasome inhibitors. The study included 291 patients with 194 in the venetoclax arm and 97 in the placebo arm.9

The BELLINI trial met its primary endpoint of improved progression-free survival (PFS) (22.4 months vs. 11.5 months, [hazard ratio=0.63, p=0.01]), with a median follow-up of 18.7 months, and demonstrated statistically significant improvement in overall response rate (ORR) (82% vs. 68%, p<0.01) and very good partial or better response (59% vs. 36%, p<0.01) in the venetoclax arm compared to the control arm. Median overall survival was not reached (HR 2.027, 95% CI (1.042, 3.945)).2

Safety analyses showed the majority of deaths in the venetoclax arm were related to infection and progressive disease. There were 52 deaths in the study population, 41 (21%) in the venetoclax arm and 11 (12%) in the placebo arm, with progressive disease the most common cause (45%). The rates of serious AEs (48% vs 50%) and serious infections (28% vs 27%) were comparable between arms.2

About VENCLEXTA/VENCLYXTO (venetoclax)
VENCLEXTA/VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLEXTA/VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.10

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers.

VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S. Venetoclax is not approved by any regulatory authority, in any country for the treatment of multiple myeloma. AbbVie, in collaboration with Roche, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Uses and Important VENCLEXTA (venetoclax) U.S. Safety Information10

Uses

VENCLEXTA is a prescription medicine used:

to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior treatment.
in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
are 75 years of age or older, or
have other medical conditions that prevent the use of standard chemotherapy.
It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA.

It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS.
Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

have kidney problems.
have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
have a history of high uric acid levels in your blood or gout.
are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA.
Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.
Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet.

The most common side effects of VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include low white blood cell counts; nausea; diarrhea; low platelet counts; constipation; fever with low white blood cell counts; low red blood cell counts; infection in blood; rash; dizziness; low blood pressure; fever; swelling of your arms, legs, hands, and feet; vomiting; tiredness; shortness of breath; bleeding; infection in lung; stomach (abdominal) pain; pain in muscles or back; cough; and sore throat.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit View Source or call 1-800-FDA-1088.

If you cannot afford your medication, contact: www.pparx.org for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here. Globally, prescribing information varies; refer to the individual country product label for complete information.

Use and Important VENCLYXTO (venetoclax) EU Safety Information11

VENCLYXTO (venetoclax) Indication

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with chronic lymphocytic leukaemia(CLL) who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemo immunotherapy and a B-cell receptor pathway inhibitor.
Important VENCLYXTO (venetoclax) EU Safety Information

Contraindications
Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use
Tumor lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period. Serious infections including events of sepsis with fatal outcome have been reported. Supportive measures including antimicrobials for any signs of infection should be considered.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination study with rituximab were neutropenia, diarrhea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with rituximab or as monotherapy were pneumonia, febrile neutropenia and TLS.

Discontinuation due to adverse reactions occurred in 16% of patients receiving venetoclax plus rituximab and 9% receiving venetoclax monotherapy. Dosage adjustments due to adverse reactions occurred in 15% of patients receiving venetoclax plus rituximab and 2% receiving venetoclax monotherapy. Dose interruptions occurred in 71% of patients treated with the combination of venetoclax and rituximab.

Specific Populations
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined. VENCLYXTO should be administered to patients with severe renal impairment only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we strive to discover and develop medicines that deliver transformational improvements in cancer treatment by uniquely combining our deep knowledge in core areas of biology with cutting-edge technologies, and by working together with our partners – scientists, clinical experts, industry peers, advocates, and patients. We remain focused on delivering these transformative advances in treatment across some of the most debilitating and widespread cancers. We are also committed to exploring solutions to help patients obtain access to our cancer medicines. With the acquisitions of Pharmacyclics in 2015 and Stemcentrx in 2016, our research and development efforts, and through collaborations, AbbVie’s oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 200 clinical trials and more than 20 different tumor types. For more information, please visit View Source

On June 24, 2019 Athenex, Inc. (Nasdaq: ATNX), a global biopharmaceutical company dedicated to the discovery, development and commercialization of novel therapies for the treatment of cancer, reported that the U.S. Food and Drug Administration (FDA) has allowed the Company’s Investigational New Drug (IND) application for the clinical investigation of PT01 (Pegtomarginase) for the treatment of patients with advanced malignancies (Press release, Athenex, JUN 24, 2019, View Source;p=RssLanding&cat=news&id=2402115 [SID1234537223]). The allowance is contingent upon formal submission of agreed upon updates to the IND. Pegtomarginase is a biologic product candidate in Athenex’s pipeline that is designed to provide a metabolic approach to the treatment of cancer through arginine deprivation therapy.

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Pegtomarginase is a PEGylated genetically modified human arginase that targets cancer growth and survival by removing the supply of an amino acid, arginine. A significant proportion of cancer types lack the ability to synthesize arginine due to deficient expression of certain metabolic enzymes of the urea cycle, including argininosuccinate synthetase 1 (ASS1), argininosuccinate lyase (ASL) or ornithine transcarbamylase (OTC). By depleting circulating arginine, growth of cancers with a disrupted urea cycle can be halted and cell death can be induced. Healthy cells capable of producing sufficient arginine would be largely unaffected. Previous arginine depleting therapies employed enzymes that were derived from non-human origin, which can trigger the development of neutralizing antibodies, or had multiple PEGylation sites with multiple positional isomers in the product. Athenex believes that its therapeutic Pegtomarginase, initially developed by The Hong Kong Polytechnic University (PolyU) and Avalon Biomedical (Management) Limited (Avalon Biomedical), possesses many promising attributes, notably the human-derived origin and recombinant modification that has enabled site-specific PEGylation. The resulting single isomer has a predictable and extended duration of action as demonstrated by durable arginine depletion in preclinical studies.

"We are excited to further explore this innovative approach to treating a broad range of cancers using this biologic product," stated Dr. Michael Smolinski, Senior Director, Preclinical Operations of Athenex. "We were encouraged by Pegtomarginase’s compelling profile, specifically the defined site-directed PEGylation and the resulting high activity at well-tolerated doses observed in preclinical studies. We are pleased to advance this program into the clinic and believe it offers a step forward for metabolic therapies in oncology."

Dr. Johnson Lau, Chairman and Chief Executive Officer of Athenex, added, "This will be the Company’s ninth IND candidate allowed by the FDA, demonstrating the strong execution capabilities of our research and development team. Advancing this program is in line with our strategy to expand the types of therapeutic options for cancer patients. We believe Pegtomarginase has significant potential not only as a monotherapy, but also in combination with other oncology therapeutics, including those in Athenex’s pipeline. In addition, we believe this paves the way for the use of metabolic therapeutics to condition the tumor microenvironment in order to enhance the anti-tumor activity of different therapies in combination."

Ir Professor Alexander Wai, Vice President (Research Development) of PolyU, commented, "We are delighted by this significant milestone achieved for Pegtomarginase, which was initially developed by the research team led by Professors Thomas Leung and Thomas Lo in the Department of Applied Biology and Chemical Technology and Lo Ka Chung Research Center for Natural Anti-Cancer Drug Development at PolyU. We have learned a lot through the collaboration with Avalon Biomedical and Athenex, which has also been extremely rewarding. We are deeply impressed by the strong execution capabilities at Athenex and the team’s commitment to commercializing novel technologies for the treatment of a wide range of cancers."

Athenex recently presented preclinical study results of Pegtomarginase in a poster session at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The biologic agent demonstrated high enzymatic activity, predictable pharmacokinetic-pharmacodynamic profiles, and cytotoxicity in vitro. Mouse xenograft models showed good tumor growth inhibition activity at tolerable doses with only transient weight loss during therapy.

Athenex licensed the worldwide rights to develop and commercialize Pegtomarginase from Avalon PolyTom (HK) Limited, a subsidiary of Avalon Biomedical. Pegtomarginase was initially developed by PolyU and subsequently licensed to Avalon PolyTom during the initial phase of preclinical development.

Arginine Deprivation Therapy:
Arginine is an essential amino acid to many tumor types for survival and growth. Many cancers have deficient expression of certain metabolic enzymes such as argininosuccinate synthetase 1 (ASS1), argininosuccinate lyase (ASL) or ornithine transcarbamylase (OTC), which are needed to synthesize arginine. Such cancers, also known as arginine-auxotrophic cancers, depend on external sources of arginine, making arginine deprivation therapy a potentially viable strategy for tumor treatment.

On June 24, 2019 Crescendo Biologics Ltd (Crescendo), the drug developer of novel, targeted T-cell enhancing therapeutics, reported that it will be giving a talk and presenting a poster at the Cell Engager Therapeutics Summit in Boston, US, held from 25-27 June 2019 (Press release, Crescendo Biologics, JUN 24, 2019, View Source [SID1234537222]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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Crescendo’s Chief Medical Officer, Dr Pavel Pisa’s, talk entitled ‘Humabody VH as T-cell Enhancing Therapeutics for Immuno-Oncology’ is focused on the beneficial attributes and planned clinical application of CB307. CB307 is a novel CD137-PSMA-HSA tri-specific that enables tumour selective T-cell activation, while minimising systemic toxicity.

‘Humabody VH as T-cell Enhancing Therapeutics for Immuno-Oncology’ – talk by Dr Pavel Pisa 26 June, 12:00pm.

Crescendo will also present a poster at the Summit, entitled ‘CB307: A novel T-cell costimulatory Humabody VH therapeutic for PSMA-positive tumours’. The poster will show preclinical data obtained on Crescendo’s lead programme, CB307. The poster will illustrate the generation, functional characterisation and potential therapeutic application of CB307 in PSMA-positive solid tumours.