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Palbociclib (IBRANCE Capsules)

On February 19, 2016, the U. S. Food and Drug Administration approved palbociclib (IBRANCE Capsules, Pfizer, Inc.) in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
In February 2015, FDA granted accelerated approval for palbociclib in combination with letrozole for the treatment of HR-positive, HER2-negative advanced breast cancer as initial endocrine based therapy in postmenopausal women.

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Today’s approval is based on the demonstration of an improvement in progression – free survival (PFS) in an international, randomized, double-blind, parallel group, multicenter study comparing palbociclib plus fulvestrant to placebo plus fulvestrant. Women enrolled had HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy.

A total of 521 pre- and postmenopausal women were randomized (2:1) to either palbociclib plus fulvestrant or placebo plus fulvestrant until disease progression or unacceptable toxicity. Palbociclib was administered orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Fulvestrant was administered intramuscularly at a dose of 500 mg on days 1, 15, 29 and once monthly thereafter. Pre- or perimenopausal women were enrolled in the study and received the LHRH agonist, goserelin, for at least 4 weeks prior to and for the study’s duration.

Among the 521 patients, 80% were postmenopausal, all patients had received prior systemic therapy, and 75% had received a previous chemotherapy regimen. Twenty-five percent had not received prior therapy for metastatic disease, 60% had visceral metastases, and 23% had bone only disease.

The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST V1.1. The study demonstrated an improvement in PFS with a hazard ratio of 0.46 (95% CI: 0.36, 0.59; p<0.0001). The median PFS was 9.5 versus 4.6 months for patients treated in the palbociclib plus fulvestrant and placebo plus fulvestrant arms, respectively.

Safety data was evaluated in 345 patients who received palbociclib plus fulvestrant. The most common (greater than or equal to 10%) of grade 1-4 adverse reactions were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia. The most common (greater than or equal to 5%) grade 3-4 adverse reactions were neutropenia (66%) and leukopenia (31%).

The most frequently reported serious adverse reactions in patients receiving palbociclib plus fulvestrant were infections, pyrexia, neutropenia, and pulmonary embolism). Dose reductions due to an adverse reaction of any grade occurred in 36% of patients and permanent discontinuation associated with an adverse reaction occurred in 6% of patients.

The recommended dose and schedule of palbociclib is 125 mg daily for 21 consecutive days followed by 7 days off treatment in combination with fulvestrant treatment. The dose and schedule of fulvestrant is 500 mg intramuscularly on days 1, 15, 29 and once monthly thereafter.

Palbociclib is being approved prior to the Prescription Drug User Fee Act (PDUFA) goal date of April 15, 2016. This application was granted Priority Review and Breakthrough Therapy Designation. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: View Source

Full prescribing information is available at:
View Source

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at View Source, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Medtronic Announces Cash Dividend for Fourth Quarter of Fiscal Year 2016

On February 19, 2016 The board of directors of Medtronic plc (NYSE:MDT) reported that they have approved the fiscal year 2016 fourth quarter cash dividend of $0.38 per ordinary share, representing a 25 percent increase over the prior year (Press release, Medtronic, FEB 19, 2016, View Source;p=RssLanding&cat=news&id=2140914 [SID:1234509122]). This quarterly declaration is consistent with the dividend announcement made by the company in June 2015. Medtronic has increased its annual dividend payment for the past 38 consecutive years, and is a constituent of the S&P 500 Dividend Aristocrats index. The dividend is payable on April 15, 2016, to shareholders of record at the close of business on March 24, 2016. While a portion of the dividend may be treated for U.S. tax purposes as a return of capital, the company expects that potentially as early as next fiscal year, its dividend will be treated completely as a distribution of earnings for U.S. tax purposes. Additional information about the tax treatment of the dividend is available by clicking on the Investors link through the Medtronic website at www.medtronic.com.

Pfizer Receives Expanded FDA Approval For IBRANCE (palbociclib) In HR+, HER2- Metastatic Breast Cancer

On February 19, 2015 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) has approved a new indication expanding the use of IBRANCE (palbociclib) 125mg capsules, Pfizer’s metastatic breast cancer therapy (Press release, Pfizer, FEB 19, 2016, View Source [SID:1234509116]). Now IBRANCE also is approved for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer in combination with fulvestrant in women with disease progression following endocrine therapy.1 Pfizer’s supplemental New Drug Application (sNDA) for IBRANCE was reviewed and approved under the FDA’s Breakthrough Therapy designation and Priority Review programs based on results from the Phase 3 PALOMA-3 trial in pre-, peri- and post-menopausal women with HR+, HER2- metastatic breast cancer whose disease progressed on or after prior endocrine therapy in the adjuvant or metastatic setting.1

IBRANCE first was approved in February 2015 and also is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine-based therapy in postmenopausal women.1 The indication in combination with letrozole is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1 The confirmatory Phase 3 trial, PALOMA-2, is fully enrolled.

IBRANCE is the first and only cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor approved by the FDA.

"Today’s news gives more women with metastatic breast cancer the opportunity to benefit from this first-in-class medicine," said Liz Barrett, global president and general manager, Pfizer Oncology. "Since IBRANCE was approved just over one year ago, physicians across the U.S. have embraced it as a standard of care in the first-line setting. The expanded approval of IBRANCE is supported by a robust body of evidence and underscores Pfizer’s continued commitment to addressing the needs of the metastatic breast cancer community. Pfizer is proud to bring forward innovative therapies like IBRANCE that make a meaningful difference in patients’ lives."

The Phase 3 PALOMA-3 trial enrolled 521 women, regardless of menopausal status, randomized 2:1 to receive IBRANCE plus fulvestrant or placebo plus fulvestrant. This trial demonstrated that IBRANCE in combination with fulvestrant, a standard of care hormonal therapy, prolonged PFS compared with placebo plus fulvestrant in women with HR+, HER2- metastatic breast cancer whose disease progressed on or after prior endocrine therapy.1 Women in the IBRANCE plus fulvestrant arm had a median PFS of 9.5 months (95% CI: 9.2, 11.0), a substantial improvement compared with 4.6 months (95% CI: 3.5, 5.6) in the group treated with placebo plus fulvestrant [HR 0.461 (95% CI: 0.360, 0.591), p <0.0001].1 Confirmed overall response rate in patients with measurable disease as assessed by the investigator was 24.6% for the IBRANCE plus fulvestrant arm compared to 10.9% for the placebo plus fulvestrant arm.1 Duration of response was 9.3 months in the IBRANCE plus fulvestrant arm compared with 7.6 months in the placebo plus fulvestrant arm.1

The warnings and precautions of IBRANCE include neutropenia, pulmonary embolism and embryo-fetal toxicity.1 Themost common adverse reactions (≥10%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%). For more information, please see Important Safety Information for IBRANCE below.1

"There currently is no cure for metastatic breast cancer, so ongoing treatment is usually needed to control the spread of the disease," said Marisa Weiss, M.D., chief medical officer and founder, Breastcancer.org (link is external). "That’s why the availability of a first-of-its-kind treatment option like IBRANCE for women dealing with HR+, HER2- metastatic disease represents a very important advance."

Both palbociclib (IBRANCE) combination options are recommended by the National Comprehensive Cancer Network.2 Palbociclib plus letrozole is recommended (category 2A) as a first-line treatment for postmenopausal women with HR+, HER2- metastatic breast cancer.2 Palbociclib plus fulvestrant is recommended (category 1) for postmenopausal women with HR+, HER2- metastatic breast cancer who have progressed on endocrine therapy or premenopausal women receiving a luteinizing hormone-releasing hormone (LHRH) agonist.2

Pfizer believes patients should have access to the medications they need, and is committed to ensuring that patients who are prescribed IBRANCE have access to the company’s patient assistance programs. Patients in the U.S. can visit www.PfizerRxPathways.com and www.pfizercopayone.com (link is external) to learn more.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

Important Safety Information

Neutropenia was the most frequently reported adverse reaction in Study 1 (75%) and Study 2 (83%). In Study 1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In Study 2, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in Study 2. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in Study 1 (5%) and in patients treated with IBRANCE plus fulvestrant in Study 2 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in Study 1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions (≥10%) in Study 1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).

Lab abnormalities occurring in Study 1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).

The most common adverse reactions (≥10%) of any grade reported in Study 2 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

Grade 3/4 adverse reactions (≥10%) in Study 2 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Lab abnormalities occurring in Study 2 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

About IBRANCE (palbociclib) 125mg capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6,1 which are key regulators of the cell cycle that trigger cellular progression.3,4 IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.1 The indication in combination with letrozole is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1

8-K – Current report

On February 19, 2016 Heron Therapeutics, Inc. (NASDAQ: HRTX), a biotechnology company focused on improving the lives of patients by developing best-in-class medicine that address major unmet medical needs, reported fourth quarter and full year 2015 financial results and highlighted recent corporate progress (Filing, 8-K, Heron Therapeutics, FEB 19, 2016, View Source [SID:1234509115]).

Recent Corporate Progress:

In February 2016, Heron successfully demonstrated bioequivalence of HTX-019 to intravenous (IV) fosaprepitant in a study that included 100 healthy volunteers. In this study, HTX-019 demonstrated a substantially improved safety profile compared to IV fosaprepitant, which contains polysorbate 80. HTX-019, a polysorbate 80-free, IV formulation of the neurokinin-1 (NK1) receptor antagonist aprepitant, is being developed for the prevention of chemotherapy-induced nausea and vomiting (CINV).

In February 2016, Heron initiated a placebo-controlled, dose-finding, Phase 2 clinical trial of HTX-011 for the treatment of post-operative pain in approximately 100 patients undergoing abdominoplasty. HTX-011 is a long-acting formulation of the local anesthetic bupivacaine in a fixed-dose combination with the anti-inflammatory meloxicam formulated with Heron’s Biochronomer drug delivery technology.

In January 2016, the U.S. Food and Drug Administration (FDA) informed Heron that it has not yet completed its review of the New Drug Application (NDA) of SUSTOL (granisetron) Injection, extended release and was unable to take action by the Prescription Drug User Fee Act (PDUFA) goal date of January 17, 2016. The FDA stated that it is targeting taking action in late February 2016.

"While we were disappointed that the FDA was unable to complete the review of the SUSTOL NDA by the original January 2016 PDUFA goal date, we appreciate the work of the FDA and remain confident in the potential of SUSTOL as an important option for the prevention of CINV in patients with cancer," commented Barry D. Quart, Chief Executive Officer of Heron Therapeutics. "Earlier this month, we achieved important milestones for our pipeline programs. We confirmed bioequivalence for HTX-019 compared with IV fosaprepitant and showed substantially improved tolerability of HTX-019, our polysorbate 80-free, IV formulation of aprepitant. In addition, we initiated our third Phase 2 study of HTX-011, which is evaluating HTX-011 in patients undergoing abdominoplasty."

Results of Operations

As of December 31, 2015, Heron had approximately $131.2 million in cash, cash equivalents and short-term investments, compared to $72.7 million as of December 31, 2014. The net increase in cash, cash equivalents and short-term investments was primarily due to Heron’s June 2015 public equity offering that resulted in total net proceeds to us of approximately $128.2 million, partially offset by net cash used in operating activities in 2015. Based on current operating plans and projections, Heron believes that its current working capital is sufficient to fund operations through 2016.

Heron’s net cash used for operating activities for the quarter and year ended December 31, 2015 was $23.2 million and $78.5 million, respectively, compared to net cash used for operating activities of $12.9 million and $60.3 million, respectively, for the same periods in 2014.

Heron’s net loss for the quarter and year ended December 31, 2015 was $31.2 million and $97.6 million, or $0.87 per share and $2.95 per share, respectively, compared to a net loss of $20.6 million and $76.4 million, or $0.71 per share and $2.87 per share, respectively, for the same periods in 2014.

The increases in net cash used for operating activities and net loss in 2015 as compared to 2014 were primarily due to costs incurred in preparation for the commercial launch of SUSTOL, as well as clinical and manufacturing costs related to our Phase 1 and Phase 2 clinical studies for HTX-011 and costs associated with the development of HTX-019.

EFFECTOR THERAPEUTICS INCREASES ITS SERIES B FINANCING ROUND TO $56M

On February 19, 2016 eFFECTOR Therapeutics, Inc., a biopharmaceutical company developing selective translation regulators for the treatment of cancer, reported it has increased its Series B financing to a total of $56M (Press release, eFFECTOR Therapeutics, FEB 19, 2016, View Source [SID:1234509106]).

The new funding came from Sectoral Asset Management, a new investor in the syndicate, as well as existing investors. In conjunction with the increase, eFFECTOR has appointed Maha Katabi, Ph.D., CFA, partner, private equity at Sectoral Asset Management, to its board of directors. These developments further position eFFECTOR to pursue comprehensive clinical development of its lead product candidate, eFT508, a potent, highly selective, and orally bioavailable MNK1 and MNK2 inhibitor, across multiple tumor types. The funds will also be used to advance the company’s discovery pipeline addressing additional targets.

eFT508 is currently being evaluated in an open-label Phase 1/2 trial in patients with advanced solid tumors. The company expects to file a second IND for eFT508 in lymphoma in the first half of 2016 and open expansion arms in specific solid tumors as well as lymphoma. The company also plans to declare its second development candidate later this year.

"Cancer has proven to be a very difficult disease," said Steve Worland, Ph.D., president and CEO of eFFECTOR. "If we are going to bring more effective therapy to patients, we need to think strategically about new approaches to treatment. Translation regulation targets such as MNK1 and MNK2, which simultaneously regulate multiple cancer-driving and immune-signaling pathways, are an ideal way to pursue this need. With this financial backing, eFFECTOR can make significant progress developing eFT508 and the remainder of our pipeline."

Added Dr. Katabi, "Sectoral selects investments in healthcare companies developing products that can make a meaningful impact on the patients and healthcare systems they serve. Translation control is one of the most intriguing fields of research in oncology. We are very pleased to work with the experienced team of eFFECTOR to make eFT508 the first pharmacological treatment to affect the gene translation machinery, and develop a drug useful to patients with different types of cancer."