On December 3, 2018 GlaxoSmithKline plc (LSE/NYSE: GSK) and TESARO Inc (NASDAQ: TSRO) reported that the Companies have entered into a definitive agreement pursuant to which GSK will acquire TESARO, an oncology-focused company based in Waltham, Massachusetts, for an aggregate cash consideration of approximately $5.1 billion (£4.0 billion) (Press release, TESARO, DEC 3, 2018, View Source [SID1234531813]). The proposed transaction significantly strengthens GSK’s pharmaceutical business, accelerating the build of GSK’s pipeline and commercial capability in oncology.

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TESARO is a commercial-stage biopharmaceutical company, with a major marketed product, Zejula (niraparib), an oral poly ADP ribose polymerase (PARP) inhibitor currently approved for use in ovarian cancer. PARP inhibitors are transforming the treatment of ovarian cancer, notably demonstrating marked clinical benefit in patients with and without germline mutations in a BRCA gene (gBRCA). Zejula is currently approved in the US and Europe as a treatment for adult patients with recurrent ovarian cancer who are in response to platinum-based chemotherapy, regardless of BRCA mutation or biomarker status.

Clinical trials to assess the use of Zejula in "all-comers" patient populations, as a monotherapy and in combinations, for the significantly larger opportunity of first line maintenance treatment of ovarian cancer are also underway. These ongoing trials are evaluating the potential benefit of Zejula in patients who carry gBRCA mutations as well as the larger population of patients without gBRCA mutations whose tumours are HRD-positive and HRD-negative. Results from the first of these studies, PRIMA, are expected to be available in the second half of 2019.

GSK also believes PARP inhibitors offer significant opportunities for use in the treatment of multiple cancer types. In addition to ovarian cancer, Zejula is currently being investigated for use as a possible treatment in lung, breast and prostate cancer, both as a monotherapy and in combination with other medicines, including with TESARO’s own anti-PD-1 antibody (dostarlimab, formerly known as TSR-042).

In addition to Zejula, TESARO has several oncology assets in its pipeline including antibodies directed against PD-1, TIM-3 and LAG-3 targets.

Emma Walmsley, Chief Executive Officer, GSK, said: "The acquisition of TESARO will strengthen our pharmaceuticals business by accelerating the build of our oncology pipeline and commercial footprint, along with providing access to new scientific capabilities. This combination will support our aim to deliver long-term sustainable growth and is consistent with our capital allocation priorities. We look forward to working with TESARO’s talented team to bring valuable new medicines to patients."

Hal Barron, Chief Scientific Officer and President, R&D, GSK, said: "Our strong belief is that PARP inhibitors are important medicines that have been under appreciated in terms of the impact they can have on cancer patients. We are optimistic that Zejula will demonstrate benefit in patients with ovarian cancer beyond those who are BRCA-positive as front-line treatment. We are also very excited that through this transaction, we will have the opportunity to work with an outstanding Boston-based oncology group with deep clinical development expertise and together we will explore Zejula’s efficacy beyond ovarian cancer into multiple tumour types to help many more patients."

Lonnie Moulder, Chief Executive Officer, TESARO, said: "This transaction marks the beginning of a new global partnership that will accelerate our oncology business and allow our mission of delivering transformative products to individuals living with cancer to endure. Our Board and Management team are very pleased to announce this transaction, and we are grateful to the management team at GSK for their tremendous vision and the opportunity to preserve and build upon the impact we have had in the cancer community to date."

Mary Lynne Hedley, President and Chief Operating Officer, TESARO, said: "This partnership marks an evolution in the way we live out the TESARO mission and will allow us to more rapidly deliver on our commitment to patients. I am excited to be partnering with our new colleagues at GSK as together we advance innovative scientific and drug development strategies that ultimately enable us to provide more time for more patients."

Financial highlights
The acquisition price of $75 per share in cash represents a 110% premium to TESARO’s 30 day Volume Weighted Average Price of $35.67 and an aggregate consideration of approximately $5.1 billion (£4.0 billion) including the assumption of TESARO’s net debt.

Zejula’s revenues in its current approved indication as second-line maintenance treatment for ovarian cancer were $166 million for the 9 months ended 30 September 2018.

GSK expects the acquisition of TESARO and associated R&D and commercial investments will impact Adjusted EPS for the first two years by mid to high single digit percentages, reducing thereafter with the acquisition expected to start to be accretive to Adjusted EPS by 2022.

GSK’s guidance for full-year 2018 Adjusted EPS growth remains unchanged at 8 to 10% at CER. GSK continues to expect to deliver on its previously published Group Outlooks to 2020, but following the acquisition of TESARO now expects Adjusted EPS growth at CER for the period 2016-2020 to be at the bottom end of the mid to high single digit percentage CAGR range.

Guidance and Group Outlooks are given on the bases set out on pages 37 and 38 of GSK’s Q3 2018 results, including definitions of CER growth and Adjusted results.

GSK confirms no change to its current dividend policy and continues to expect to pay 80p in dividends for 2018.

GSK expects to fund the acquisition from cash resources and drawing under a new acquisition facility.

Structure and Terms of the Transaction
Under the terms of the merger agreement between GSK and TESARO, unanimously approved by TESARO’s Board of Directors, a subsidiary of GSK will commence a tender offer within the next 10 business days to acquire all of the issued and outstanding shares of TESARO common stock for a price of $75 per share in cash upon completion of the offer. The transaction is expected to complete in the first quarter of 2019, subject to satisfaction of customary closing conditions, including the tender by TESARO stockholders of at least one share more than 50% of the issued and outstanding shares of TESARO and required regulatory approvals, including clearance by the US Federal Trade Commission. Following closing of the tender offer, GSK will acquire any shares of TESARO that are not tendered in the tender offer through a second-step merger under Delaware law at the tender offer price.

The value of the gross assets of TESARO to be acquired (as at 30 September 2018) is $711 million (£555 million at the rate of £1 = $1.28, being the 30 November spot rate). The net losses of the business were $466 million for the 9 months ended 30 September 2018 (£345 million, at the rate of £1 = $1.35, being the average rate for the 9 months ended 30 September 2018).

GSK is in discussions with several key executives of TESARO to ensure their continued employment with the company.

Additional information and where to find it
This press announcement is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer or a recommendation to sell securities, nor is it a substitute for the tender offer materials that GSK and its indirect subsidiary will file with the Securities and Exchange Commission (the "SEC"). The tender offer for the outstanding shares of TESARO’s common stock described in this press announcement has not commenced. At the time the tender offer is commenced, GSK and Adriatic Acquisition Corporation will file, or will cause to be filed, a Schedule TO Tender Offer Statement with the Securities and Exchange Commission (the "SEC"), and thereafter TESARO will file a Schedule 14D-9 Solicitation/Recommendation Statement with the SEC, in each case with respect to the tender offer. The Schedule TO Tender Offer Statement (including an offer to purchase, a related letter of transmittal and other offer documents) and the Schedule 14D-9 Solicitation/Recommendation Statement will contain important information that should be read carefully before any decision is made with respect to the tender offer. Those materials (once they become available) will be made available to TESARO’s stockholders at no expense to them by the information agent for the tender offer, which will be announced. In addition, those materials and all other documents filed by or caused to be filed by TESARO or GSK with the SEC will be available at no charge on the SEC’s website at www.sec.gov. In addition to the Schedule 14D-9 Solicitation/Recommendation Statement and Schedule TO Offer Statement (once each becomes available), TESARO and GSK file or furnish, as applicable, annual, quarterly and current reports and other information with the SEC. You may read and copy any reports or other information filed by TESARO at the SEC public reference room at 100 F Street, N.E., Washington, D.C. 20549. Please call the SEC at 1-800-0330 for further information on the public reference room. TESARO’s and GSK’s filings with the SEC are also available to the public from commercial document-retrieval services and at the SEC’s website at www.sec.gov

This announcement contains inside information for the purposes of Article 7 of EU Regulation 596/2014. The person responsible for arranging the release of this announcement on behalf of GSK is V.A. Whyte, Company Secretary.

Analyst conference call details
14:00 UK / 09:00 EST Monday 3 December

UK Direct: 01296 480 100
UK freephone: 0800 783 0906

US Direct: +1 718 354 1175
US freephone: + 1866 804 8688

Passcode: 177 245 38

Rest of world dial in numbers:
View Source

TESARO portfolio and pipeline
Zejula is an orally active and potent poly ADP-ribose polymerase (PARP) inhibitor. PARP is a family of proteins involved in many functions in a cell, including DNA repair, gene expression, cell cycle control, intracellular trafficking and energy metabolism. PARP proteins play key roles in single strand break repair through the base excision repair pathway. PARP inhibitors have shown activity as a monotherapy against tumours with existing DNA repair defects, such as BRCA1 and BRCA2, and as a combination therapy when administered together with anti- cancer agents that induce DNA damage or activate the immune system.

TESARO’s development pipeline also has a number of novel oncology candidates that modulate the function of the immune system via different mechanisms. By blocking the interaction of PD-1, TIM-3 and LAG-3 with their respective ligands, antibodies to these targets aim to restore immune anti-cancer function in patients across a variety of tumour types.

Compound Indication Phase
Niraparib Ovarian cancer maintenance (PRIMA) Phase 3
Niraparib + dostarlimab (anti-PD-1 mAb) First-line ovarian cancer treatment (FIRST) Phase 3
Niraparib + anti-PD-1 mAb Advanced NSCLC, squamous cell carcinoma of the lung Phase 2
Niraparib + bevacizumab First-line ovarian cancer maintenance (OVARIO) Phase 2
Niraparib + bevacizumab Recurrent ovarian cancer (AVANOVA) (in collaboration with ENGOT, the European Network for Gynaecological Oncological Trial groups) Phase 2
Niraparib + pembrolizumab Triple negative breast or ovarian cancer (TOPACIO) Phase 2
Dostarlimab (anti-PD-1 mAb) MSI-H tumours including metastatic endometrial cancer (GARNET) Phase 1
Niraparib + chemotherapy Ewing’s sarcoma (in collaboration with SARC, the Sarcoma Alliance for Research through Collaboration) Phase 1
Dostarlimab (anti-PD-1 mAb) Various tumour types Phase 1
Dostarlimab +/- bevacizumab + niraparib or carboplatin-paclitaxel Advanced or metastatic cancer Phase 1
TSR-022 (anti-TIM-3 mAb) Various tumour types (AMBER) Phase 1
TSR-033 (anti-LAG-3 mAb Various tumour types (CITRINO) Phase 1
Anti-LAG-3/PD-1 bispecific antibody Various tumour types Discovery
Undisclosed small molecule and antibody I-O candidates Various tumour types Discovery

Advisors
GSK is being advised by PJT Partners and additionally by Bank of America Merrill Lynch, who is also acting as corporate broker. Legal advice is being provided by Shearman & Sterling LLP, with Slaughter and May advising on the acquisition facility.

Citi is serving as TESARO’s lead financial advisor, with Centerview Partners also providing financial advice. Legal advice is being provided by Ropes & Gray LLP, and Hogan Lovells.

On December 3, 2018 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or "the Company"), reported that updated data from its Phase 2 trial of Actimab-A was highlighted in a poster presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Actinium Pharmaceuticals, DEC 3, 2018, View Source [SID1234531829]). The Actimab-A Phase 2 trial studied the ARC or Antibody Radiation Conjugate Actinium-225 – lintuzumab, which delivers potent alpha particle radiation to CD33 expressing cells, in patients with untreated AML over the age of 60 that are unfit for induction chemotherapy. Patients received fractionated doses of Ac-225 – lintuzumab on days 1 and day 8. The poster presented at ASH (Free ASH Whitepaper) highlighted data from a second cohort of 27 patients that received 1.5 µCi/kg/fraction.

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Dr. Mark Berger, Actinium’s Chief Medical Officer said, "In this difficult to treat patient population, we are pleased to have observed this level of single-agent activity from Actimab-A with the benefit of minimal extramedullary toxicities. These results strongly support continued development and we have prioritized highly attractive areas that can leverage the strengths of our ARC approach. A major initiative is our Actimab-MDS trial where we have a clear pathway to a pivotal trial established with the FDA for high-risk patients with myelodysplastic syndromes. Another exciting opportunity is via combination trials with agents like venetoclax in the relapsed, refractory AML setting where the apparent synergy of mechanisms can translate to a therapeutic advantage. In addition, we are pursuing other highly-differentiated opportunities for Actimab-A as a single-agent in patients with high unmet needs where the extremely high-potency of an ARC can be used safely at low doses. An example is our novel trial in AML patients with minimal residual disease post-remission."

Overall response rate in this dosing cohort was 22% (6/27) with 3 CRps and 3 CRis. Among responding patients, 2 had adverse cytogenetics and 1 had previous MDS. This data is in addition to previously reported data from 13 patients that were treated at an original dose cohort of 2.0 µCi/kg/fraction where a 69% overall response rate was reported. The dose was lowered to 1.5 µCi/kg/fraction due to myelosuppression lasting longer than 6 weeks, which resulted in a reduction in the incidence of prolonged thrombocytopenia from 46% to 30%.

The median age of patients in this cohort of the Phase 2 trial was 75 (60 -87) with 81% of patients having ECOG performance status of 1 (13/27) or 2 (9/27). Although patients had untreated acute myeloid leukemia (AML), 52% (14/27) of patients had prior hematologic disease with 79% (11/14) having myelodysplastic syndrome (MDS), 14% (2/14) having chromic myelomonocytic leukemia (CMML) and 7% (1/14) having myelofibrosis. A majority of patients had unfavorable cytogenetics with 56% (15/27) having intermediate-risk and 26% (7/27) having high-risk cytogenetics. In addition, patients were evaluated for CD33 splicing polymorphism and responses occurred irrespective of cytogenetic risk category or splicing genotype.

Actinium also highlighted that preliminary preclinical data from its Iomab-ACT program was highlighted in the ASH (Free ASH Whitepaper) supplemental edition of blood. Actinium’s preclinical studies showed a considerable reduction in both lymphocyte and myeloid cell counts, inclusive of immune suppressive regulatory T cells and myeloid derived suppressor cells. Further, the cytoreduction by CD45-RIT was shown to induce the expression of immune homeostatic cytokines including IL-15.The abstract can be accessed he View Source

Sandesh Seth, Actinium’s Chairman and CEO said, "Given the recent and increasing competition in AML, we believe the future development pathways selected by our team strategically differentiate Actinium’s CD33 program in a manner that can maximize value creation. We have done this by focusing on an area with limited or no competition via Actimab-MDS in targeted conditioning. We have also leveraged our AWE or Antibody Radiation Conjugate technology platform to add a different modality, namely targeted radiation, to other areas of unmet or underserved needs as evidenced by our Actimab-A plus Venetoclax combinations and Actimab-A MRD trials. With our lead asset, Iomab-B progressing well in its pivotal trial, the near-pivotal Actimab-MDS program and the Iomab-ACT program for lymphodepletion prior to CAR-T, our multi-asset pipeline will enable our company to build a franchise opportunity in targeted conditioning which is almost singular in the industry."

On December 3, 2018 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported new data from the Venclexta (venetoclax) clinical development program, including longer-term results from the Phase III MURANO study in people with previously treated chronic lymphocytic leukemia (CLL) and updated data from two Phase Ib/II studies in people with previously untreated acute myeloid leukemia (AML) ineligible for intensive chemotherapy due to coexisting medical conditions (Press release, Genentech, DEC 3, 2018, View Source [SID1234531846]). Data from the Venclexta clinical development program that ranges across multiple blood cancers, including CLL, AML, non-Hodgkin’s lymphoma and multiple myeloma, will be featured in more than 30 abstracts, including 12 oral presentations, at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting.

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"We’re excited by the versatility of Venclexta in treating a range of distinct types of blood cancer, including difficult-to-treat forms with limited options," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "These data support our broad clinical development program through which we hope to discover more ways Venclexta can be used alone or in combination with other medicines to treat additional types of cancer."

Updated Data in CLL

Two new analyses of the Phase III MURANO study in relapsed or refractory (R/R) CLL demonstrated the continued clinical benefit of Venclexta plus Rituxan (rituximab) was sustained after patients completed the chemotherapy-free, two-year fixed-duration course of therapy.

An analysis showed the combination reduced the risk of disease progression or death (progression-free survival; PFS, as assessed by investigator) by 84 percent (HR=0.16; 95 percent CI: 0.12-0.23; p<0.0001) compared to standard of care bendamustine plus Rituxan (BR) after a median three-year follow-up. At three years, 71 percent of patients in the Venclexta plus Rituxan arm had not experienced disease progression, compared to 15 percent of patients in the BR arm (median PFS: not reached vs. 17.0 months, respectively). A clinically meaningful benefit in overall survival was also observed in the Venclexta arm compared to the BR arm (88 percent vs. 80 percent, HR=0.50; 95 percent CI: 0.30-0.85). Consistent benefit was observed in all patient subgroups for Venclexta plus Rituxan compared to BR, including high-risk and low-risk groups. Data were presented in an oral session on Saturday, December 1, at 2:45 P.M. PST (Abstract #184).
A separate analysis showed higher rates of minimal residual disease (MRD)-negativity observed with Venclexta plus Rituxan compared to BR were sustained after patients completed treatment (62 percent vs. 13 percent). MRD-negativity means no cancer can be detected using a specific, highly sensitive test, and was defined as less than 1 CLL cell in 10,000 leukocytes. Importantly, these results were observed in the majority of patients in the Venclexta arm, including patients in high-risk subgroups and were consistent with the maintained PFS benefit seen with longer follow-up. These data support the utility of MRD in peripheral blood as a predictive marker of clinical outcome. No new safety signals were observed with the treatment combination of Venclexta plus Rituxan. These data will be presented in an oral session on Monday, December 3, at 11:30 A.M. PST (Abstract #695).
Updated Data in AML

Updated data from the Phase Ib M14-358 and Phase I/II M14-387 studies evaluating Venclexta in combination with a hypomethylating agent or low-dose cytarabine (LDAC) in people with previously untreated AML who are ineligible for intensive chemotherapy will also be presented. These results showed that among patients who were dependent upon blood transfusions at baseline, about half were able to achieve transfusion independence (the absence of transfusions during any consecutive 56 days during the study treatment period). No unexpected safety signals were observed with Venclexta in combination with hypomethylating agents or LDAC.

The M14-358 study showed high rates of complete remission (with at least partial blood count recovery, CR+CRh) of 67 percent for those who received Venclexta plus azacitidine and 71 percent for those who received Venclexta plus decitabine. For people taking Venclexta and azacitadine or decitabine who were dependent on blood transfusions at baseline, 50 percent and 52 percent achieved red blood cell transfusion independence, respectively; and 58 percent or 60 percent achieved platelet transfusion independence, respectively.
The M14-387 study showed rates of complete remission (with or without full recovery of normal blood cell count, CR+CRi) of 54 percent in people who received Venclexta in combination with LDAC and a median duration of remission of 8.1 months. For people taking Venclexta with LDAC, 48 percent achieved red blood cell transfusion independence and 60 percent achieved platelet transfusion independence.
Results from the two studies were presented in an oral session on Sunday, December 2 at 7:45 A.M. PST and 8:00 A.M. PST, respectively (Abstract #284 and #285).

Based on earlier results from the M14-358 and M14-387 studies, Venclexta was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of people with newly-diagnosed AML who are age 75 years or older, or for those ineligible for intensive induction chemotherapy due to coexisting medical conditions. A robust clinical development program for Venclexta in AML is ongoing, including two ongoing Phase III studies evaluating Venclexta in combination with azacitidine or with LDAC for people with previously untreated AML who are ineligible for intensive chemotherapy based on results from the M14-358 and M14-387 studies.

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

About the MURANO study

MURANO (NCT02005471) is a Phase III open-label, international, multicenter, randomized study evaluating the efficacy and safety of Venclexta in combination with Rituxan compared to bendamustine in combination with Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta, patients on the Venclexta plus Rituxan arm received six cycles of Venclexta plus Rituxan followed by Venclexta monotherapy for up to two years total. Patients on the BR arm received six cycles of BR. The study included 389 patients with chronic lymphocytic leukemia (CLL) who had been previously treated with at least one line of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta plus Rituxan or BR. The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR) and complete response rate (with or without complete blood count recovery, CR/CRi).

About the M14-358 study

The M14-358 study (NCT02203773) is an open-label, non-randomized, Phase Ib dose escalation and expansion study evaluating the safety and efficacy of Venclexta in combination with hypomethylating agents, azacitidine or decitabine, in 115 newly-diagnosed people with AML who were 60 years or older, or ineligible to receive intensive induction chemotherapy due to coexisting medical conditions. Study endpoints included complete remission rates, transfusion independence, overall survival and safety.

About the M14-387 study

The M14-387 study (NCT02287233) is an open-label, single-arm, Phase I/II dose escalation and expansion study evaluating the safety and efficacy of Venclexta in combination with LDAC in 82 newly-diagnosed people with AML who were 60 years or older, or ineligible to receive intensive induction chemotherapy due to coexisting medical conditions. Study endpoints included complete remission rates, transfusion independence, overall survival and safety.

About CLL

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, and in 2018, it is estimated there will be more than 20,000 new cases of CLL diagnosed in the United States. Although signs of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of cancerous cells.

About AML

Acute myeloid leukemia (AML) is the most common type of aggressive leukemia in adults, which has the lowest survival rate for all types of leukemia. In 2018, it is estimated there will be nearly 20,000 new cases of AML diagnosed in the United States. Many AML patients older than age 60 are unable to tolerate standard intensive chemotherapy treatment.

About Venclexta

Venclexta is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumors, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the U.S. and commercialized by AbbVie outside of the U.S. Together, the companies are committed to research with Venclexta, which is currently being studied in clinical trials across several types of blood and other cancers.

In the U.S., Venclexta has been granted four Breakthrough Therapy Designations by the FDA: in combination with Rituxan for people with relapsed or refractory chronic lymphocytic leukemia (CLL); as a monotherapy for people with relapsed or refractory CLL with 17p deletion; in combination with hypomethylating agents (azacitidine or decitabine) for people with untreated acute myeloid leukemia (AML) ineligible for intensive chemotherapy; and in combination with low-dose cytarabine for people with untreated AML ineligible for intensive chemotherapy.

Venclexta Indications

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 1 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

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. The patient’s doctor will do tests to check their risk of getting TLS before they start taking Venclexta. The patient will receive other medicines before starting and during treatment with Venclexta to help reduce the risk of TLS. The patient may also need to receive intravenous (IV) fluids through their vein.

The patient’s doctor will do blood tests to check for TLS when the patient first starts treatment and during treatment with Venclexta. It is important for patients to keep appointments for blood tests. Patients should tell their doctor right away if they 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.

Patients should drink plenty of water during treatment with Venclexta to help reduce the risk of getting TLS.

Patients should drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before the first dose, on the day of the first dose of Venclexta, and each time a dose is increased.

The patient’s doctor may delay, decrease the dose, or stop treatment with Venclexta if the patient has side effects.

Certain medicines must not be taken when the patient first starts taking Venclexta and while the dose is being slowly increased because of the risk of increased tumor lysis syndrome.

Patients must tell their doctor about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Venclexta and other medicines may affect each other, causing serious side effects.
Patients must not start new medicines during treatment with Venclexta without first talking with their doctor.
Before taking Venclexta, patients must tell their doctor about all of their medical conditions, including if they:

Have kidney problems.
Have problems with body salts or electrolytes, such as potassium, phosphorus, or calcium.
Have a history of high uric acid levels in the blood or gout.
Are scheduled to receive a vaccine. The patient should not receive a "live vaccine" before, during, or after treatment with Venclexta, until the patient’s doctor tells them it is okay. If the patient is not sure about the type of immunization or vaccine, the patient should ask their doctor. 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 an unborn baby. If the patient is able to become pregnant, the patient’s doctor should do a pregnancy test before the patient starts treatment with Venclexta, and the patient should use effective birth control during treatment and for at least 30 days after the last dose of Venclexta. If the patient becomes pregnant or thinks they are pregnant, the patient should tell their doctor right away.
Are breastfeeding or plan to breastfeed. It is not known if Venclexta passes into the patient’s breast milk. Patients should not breastfeed during treatment with Venclexta.
What to avoid while taking Venclexta:

Patients should not drink grapefruit juice, eat grapefruit, Seville oranges (often used in marmalades), or starfruit while they are taking Venclexta. These products may increase the amount of Venclexta in the patient’s blood.

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. The patient’s doctor will do blood tests to check their blood counts during treatment with Venclexta. Patients should tell their doctor right away if they 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 rituximab in people with CLL include low white blood cell counts; diarrhea; upper respiratory tract infection; cough; tiredness; and nausea.

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

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 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 the ability to father a child. Patients should talk to their doctor if they have concerns about fertility.

These are not all the possible side effects of Venclexta. Patients should tell their doctor about any side effect that bothers them or that does not go away.

Report side effects to the FDA at 1-800-FDA-1088 or View Source Report side effects to Genentech at 1-888-835-2555.

Please visit View Source for the Venclexta full Prescribing Information, including Patient Information, for additional Important Safety Information.

Rituxan Indications

Rituxan (rituximab) injection, for intravenous use, is indicated for the treatment of:

Low-grade or follicular CD20-positive non-Hodgkin’s lymphoma as a single-agent therapy in patients whose disease recurred or did not respond to initial treatment
Follicular CD20-positive non-Hodgkin’s lymphoma as an initial treatment with chemotherapy, and in patients whose initial treatment was successful, as a single-agent follow-up therapy
Low-grade CD20-positive non-Hodgkin’s lymphoma as a single-agent follow-up therapy for patients who did not progress on initial treatment with CVP chemotherapy
CD20-positive diffuse large B-cell non-Hodgkin’s lymphoma as an initial treatment in combination with CHOP chemotherapy
CD20-positive chronic lymphocytic leukemia in combination with FC chemotherapy as an initial treatment or as a treatment after disease has recurred
It is not known if Rituxan is safe and effective in children.

Important Safety Information:

Rituxan can cause serious side effects that can lead to death, including:

Infusion Reactions: Infusion reactions are very common side effects of Rituxan treatment. Serious infusion reactions can happen during the patient’s infusion or within 24 hours after the patient’s infusion of Rituxan. The patient’s doctor should give the patient medicines before infusion of Rituxan to decrease the chance of having a severe infusion reaction.

Patients must tell their doctor or get medical help right away about any of these symptoms during or after an infusion of Rituxan:
Hives (red itchy welts) or rash
Itching
Swelling of the lips, tongue, throat, or face
Sudden cough
Shortness of breath, difficulty breathing, or wheezing
Weakness
Dizziness or feel faint
Palpitations (feel like the heart is racing or fluttering)
Chest pain
Severe Skin and Mouth Reactions: Patients must tell their doctor or get medical help right away about any of these symptoms at any time during treatment with Rituxan:
Painful sores or ulcers on the skin, lips, or in the mouth
Blisters
Peeling skin
Rash
Pustules
Hepatitis B Virus (HBV) Reactivation: Before receiving Rituxan treatment, the patient’s doctor will do blood tests to check for HBV infection. If the patient has had hepatitis B or is a carrier of hepatitis B virus, receiving Rituxan could cause the virus to become an active infection again. Hepatitis B reactivation may cause serious liver problems, including liver failure, and death. The patient’s doctor will monitor for hepatitis B infection during and for several months after the patient stops receiving Rituxan.

Patients must tell their doctor right away about worsening tiredness, or yellowing of the skin or white part of the eyes during treatment with Rituxan.
Progressive Multifocal Leukoencephalopathy (PML): PML is a rare, serious brain infection caused by a virus that can happen in people who receive Rituxan. People with weakened immune systems can get PML. PML can result in death or severe disability. There is no known treatment, prevention, or cure for PML.

Patients must tell their doctor right away about new or worsening symptoms or if anyone close to the patient notices these symptoms:
Confusion
Dizziness or loss of balance
Difficulty walking or talking
Decreased strength or weakness on one side of the body
Vision problems, such as blurred vision or loss of vision
What should patients tell their doctor before receiving Rituxan?

Before receiving Rituxan, patients should tell their doctor if they:

Have had a severe reaction to Rituxan or a rituximab product
Have a history of heart problems, irregular heartbeat, or chest pain
Have lung or kidney problems
Have had an infection, currently have an infection, or have a weakened immune system
Have or have had any severe infections including:
Hepatitis B virus (HBV)
Hepatitis C virus (HCV)
Cytomegalovirus (CMV)
Herpes simplex virus (HSV)
Parvovirus B19
Varicella zoster virus (chickenpox or shingles)
West Nile Virus
Have had a recent vaccination or are scheduled to receive vaccinations. Patients should not receive certain vaccines before or during treatment with Rituxan
Have any other medical conditions
Are pregnant or plan to become pregnant. Patients must talk to their doctor about the risks to the patient’s unborn baby if receiving Rituxan during pregnancy. Females who are able to become pregnant should use effective birth control (contraception) during treatment with Rituxan and for 12 months after the last dose of Rituxan. Patients should talk to their doctor about effective birth control. Patients should tell their doctor right away if they become pregnant or think that they are pregnant during treatment with Rituxan
Are breastfeeding or plan to breastfeed. It is not known if Rituxan passes into the breast milk. Do not breastfeed during treatment and for at least 6 months after the last dose of Rituxan
Are taking any medications, including prescription and over-the-counter medicines, vitamins, and herbal supplements
What are the possible side effects of Rituxan?

Rituxan can cause serious side effects, including:

Tumor Lysis Syndrome (TLS): TLS is caused by the fast breakdown of cancer cells. TLS can cause the patient to have:
Kidney failure and the need for dialysis treatment
Abnormal heart rhythm
TLS can happen within 12 to 24 hours after an infusion of Rituxan. The patient’s doctor may do blood tests to check for TLS. The patient’s doctor may give medicine to help prevent TLS. Patients must tell their doctor right away if they have any of the following signs or symptoms of TLS:
Nausea
Vomiting
Diarrhea
Lack of energy
Serious Infections: Serious infections can happen during and after treatment with Rituxan, and can lead to death. Rituxan can increase the patient’s risk of getting infections and can lower the ability of the patient’s immune system to fight infections. Types of serious infections that can happen with Rituxan include bacterial, fungal, and viral infections. After receiving Rituxan, some people have developed low levels of certain antibodies in their blood for a long period of time (longer than 11 months). Some of these patients with low antibody levels developed infections. People with serious infections should not receive Rituxan. Patients must tell their doctor right away if they have any symptoms of infection:
Fever
Cold symptoms, such as runny nose or sore throat that do not go away
Flu symptoms, such as cough, tiredness, and body aches
Earache or headache
Pain during urination
Cold sores in the mouth or throat
Cuts, scrapes, or incisions that are red, warm, swollen, or painful
Heart Problems: Rituxan may cause chest pain, irregular heartbeats, and heart attack. The patient’s doctor may monitor the patient’s heart during and after treatment with Rituxan if they have symptoms of heart problems or have a history of heart problems. Patients must tell their doctor right away if they have chest pain or irregular heart-beats during treatment with Rituxan.
Kidney Problems: especially if the patient is receiving Rituxan for non-Hodgkin’s lymphoma. Rituxan can cause severe kidney problems that lead to death. The patient’s doctor should do blood tests to check how well their kidneys are working.
Stomach and Serious Bowel Problems That Can Sometimes Lead to Death: Bowel problems, including blockage or tears in the bowel can happen if the patient receives Rituxan with chemotherapy medicines. Patients must tell their doctor right away if they have any stomach-area (abdomen) pain or repeated vomiting during treatment with Rituxan.
The patient’s doctor will stop treatment with Rituxan if they have severe, serious, or life-threatening side effects.

What are the most common side effects during treatment with Rituxan?

Infusion-related reactions
Infections (may include fever, chills)
Body aches
Tiredness
Nausea
Other side effects include:

Aching joints during or within hours of receiving an infusion
More frequent upper respiratory tract infections
These are not all of the possible side effects with Rituxan.

Please see the Rituxan full Prescribing Information, including the Medication Guide, for additional Important Safety Information at www.Rituxan.com.

On December 3, 2018 AOP Orphan Pharmaceuticals AG (AOP Orphan) reported latest follow-up results on Ropeginterferon alfa-2b in patients with Polycythemia Vera (PV) from CONTINUATION-PV presented at ASH (Free ASH Whitepaper) 2018 (Press release, AOP Orphan Pharmaceuticals, DEC 3, 2018, View Source [SID1234531862]).

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CONTINUATION-PV is an open-label, multicenter, phase IIIb study assessing the long-term efficacy and safety of Ropeginterferon alfa-2b versus hydroxyurea (HU) or best available treatment (BAT) in patients with PV who previously participated in the PROUD-PV study.

Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon (ATC L03AB15). It is administered once every 2 weeks initially, or monthly after stabilization of hematological parameters. It is expected to be the first interferon approved for PV worldwide. AOP Orphan´s submission for marketing authorization in the EU is in the final stage of EMA review.

Clinical evidence:

Previously, at 12 months of treatment, Ropeginterferon alfa-2b was shown to be non-inferior to hydroxyurea (HU) in Complete Hematologic Response (CHR) and to have a significantly better safety and tolerability profile. . At 24 months Ropeginterferon alfa-2b achieved a significantly higher CHR of 70.5% versus 49.3% compared with HU/BAT (p=0.0101).

After 36 months of treatment Ropeginterferon alfa-2b sustained higher CHR response rates compared to HU/BAT (70.5% vs. 51.4%; p=0.0122). Further, the composite endpoint, CHR including disease symptom improvement was higher in patients treated with Ropeginterferon alfa-2b compared to HU/BAT (52.6% vs. 37.8%; p=0.0437).

Disease modification evidence:


66.0% of PV patients treated with Ropeginterferon alfa-2b, but only 27.0% having received HU/BAT showed a mutant JAK2 molecular response (p<0.0001) after 36 months. Importantly, molecular response strongly correlated with CHR, emphasizing the clinical relevance of mutant JAK2 allele burden reduction.

Analysis of additional non-JAK2 mutations, which are believed to contribute to disease progression revealed that Ropeginterferon alfa-2b, but not HU was able to reduce their respective mutant allele burden. This suggests that only Ropeginterferon alfa-2b but not HU has the ability to suppress additional clones with different mutations and modify the disease at the molecular level.

In line with molecular findings, disease or treatment related secondary malignancies occurred only in patients receiving HU/BAT, including 2 cases of acute myeloid leukemia, 1 melanoma and 2 basaliomas, whereas 3 malignancies (glioblastoma, seminoma, adrenal neoplasm) most likely unrelated to treatment were reported for patients treated with Ropeginterferon alfa-2b.

A similar number of patients experienced adverse events (89.8% for Ropeginterferon alfa-2b, 90.6% for HU) and treatment-related adverse events (74.8% for Ropeginterferon alfa-2b, 78.7% for HU). The most common (>10%) treatment-related adverse events anemia, thrombocytopenia and leukopenia occurred more frequently with HU, whereas liver enzyme increase was mainly observed with Ropeginterferon alfa-2b.

No new safety signals appeared in the third year of treatment.

Professor Heinz Gisslinger from the Medical University of Vienna, Austria presenting the results at ASH (Free ASH Whitepaper) stated, "The observed superior efficacy of Ropeginterferon alfa-2b over hydroxyurea/best-available-therapy after 36 months, is a clear proof of the long-term value of this treatment modality. Thus, Ropeginterferon alfa-2b will provide a valuable and safe new first line therapy for PV patients".

Professor Jean-Jacques Kiladjian from the Saint-Louis Hospital & Paris Diderot University in France, concluded, "The disease modification capability of Ropeginterferon alfa-2b suggested by a significant reduction of not only mutant JAK2, but also non-JAK2 allele burden and the specific targeting of the malignant clone, holds promise for improvement of progression-free survival and long-term patient benefit."

About Ropeginterferon alfa-2b


Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon (ATC L03AB15) with improved pharmacokinetic properties offering improved tolerability and convenience. It is administered once every 2 weeks, or monthly during long-term maintenance, and is expected to be the first interferon approved for PV worldwide. AOP Orphan´s submission for marketing authorization in the EU is currently under EMA review.

Ropeginterferon alfa-2b was discovered by PharmaEssentia, a long-term partner of AOP Orphan. Ropeginterferon alfa-2b has Orphan Drug designation in the European Union, Switzerland and the United States of America.


In 2009, AOP Orphan has in-licensed from PharmaEssentia Corporation the exclusive rights to develop and commercialize Ropeginterferon alfa-2b in PV, other MPNs and CML for European, Commonwealth of Independent States (CIS), and Middle Eastern markets.

About Polycythemia Vera


Polycythemia Vera (PV) is a cancer of the blood-building cells in the bone marrow resulting in a chronic increase of red blood cells, white blood cells and platelets. This condition may result in circulatory disorders such as thrombosis and embolism, as well as malignant transformation to myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2 that make the malignant clone.

On December 3, 2018 Progenics Pharmaceuticals, Inc. (NASDAQ:PGNX), an oncology company developing innovative medicines and imaging analysis technology for targeting and treating cancer, reported that the first patient has been dosed in the Company’s Phase 3 CONDOR study evaluating the diagnostic performance and clinical impact of PyL (18F-DCFPyL) in men with biochemical recurrence of prostate cancer (Press release, Progenics Pharmaceuticals, DEC 3, 2018, View Source [SID1234531895]). PyL is the Company’s PSMA-targeted small molecule PET/CT imaging agent designed to visualize prostate cancer.

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Dr. Lawrence Saperstein, Assistant Professor of Radiology and Biomedical Imaging and Chief of Nuclear Medicine at Yale Smilow Cancer Hospital, and a principle investigator of the trial said, "PyL has demonstrated excellent positive and negative predictive values in detecting the presence or absence of prostate cancer. This valuable information has the potential to provide earlier diagnoses, more informed treatment decisions, the ability to monitor responses, and ultimately improve patient outcomes."

The Phase 3 CONDOR trial is a multi-center, open label study and will enroll approximately 200 patients with biochemical recurrence of prostate cancer in 14 sites in the United States and Canada. The primary endpoint is based on positive predictive value and will assess the correct localization rate (CLR), defined as a percentage of subjects with a one-to-one correspondence between localization of at least one lesion identified by PyL and the composite truth standard. Secondary measures include the percentage of subjects with a change in intended prostate cancer treatment plans due to PyL PET/CT imaging.

"The initiation of this landmark trial marks an important milestone in the development of PSMA-targeted imaging agents which have the potential to transform the treatment landscape for recurrent prostate cancer," stated Mark Baker, CEO of Progenics. "With PyL, physicians may be able to detect very small lesions that are currently missed with conventional imaging methods, which in turn could change the treatment path. We look forward to reporting data from this trial in early 2020."

Progenics Initiates Phase 3 Trial of PyL PSMA PET Imaging Agent Page 2

In prior studies, PyL has shown strong positive predictive value to detect prostate cancer, with high sensitivity (93-99%) in reliably detecting metastatic prostate cancer lesions and high specificity (96-99%) in confirming the absence of pelvic lymph node disease.

About PyL for PET Imaging of Prostate Cancer

PyL (also known as [18F]DCFPyL) is a fluorinated PSMA-targeted Positron Emission Topography ("PET") imaging agent that enables visualization of both bone and soft tissue metastases to determine the presence or absence of recurrent and/or metastatic prostate cancer.

About Prostate Cancer

Prostate cancer is the second most common form of cancer affecting men in the United States: an estimated one in seven men will be diagnosed with prostate cancer in his lifetime. The American Cancer Society estimates that each year approximately 164,690 new cases of prostate cancer will be diagnosed and about 29,430 men will die of the disease. Approximately 2.9 million men in the U.S. currently count themselves among prostate cancer survivors