On February 23, 2018 Insmed Incorporated (Nasdaq:INSM), a global biopharmaceutical company focused on the unmet needs of patients with rare diseases, today reported financial results for the fourth quarter and full year ended December 31, 2017 and provided a business update (Press release, Insmed, FEB 23, 2018, View Source [SID1234524135]).

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"Last year proved to be pivotal for Insmed in our efforts toward building a company that will transform the lives of patients living with serious rare diseases. We are preparing for an even greater transformation in 2018 as we anticipate the launch of what would be the first approved inhaled therapy for the treatment of refractory NTM lung disease caused by MAC in the United States," said Will Lewis, President and Chief Executive Officer of Insmed. "The data reported from our ALIS program, together with our ongoing regulatory and pre-commercial activities, puts us on a trajectory to significantly help patients afflicted by this disease. We look forward to further expanding our global reach from the U.S. and Europe to include Japan. Having successfully completed a public offering in January, we are in a solid financial position to fully fund our key strategic activities, and we look forward to sharing our progress throughout the year."

Corporate Update

INS-212 and INS-312 Interim Results as of December 2017

In January, Insmed announced interim results from its INS-312 study, a 12-month extension study for patients who completed six months of treatment in the INS-212 study, but did not demonstrate culture conversion by Month 6, as well as long-term durability data from its INS-212 study evaluating ALIS + guideline-based therapy (GBT) vs. GBT alone in adult patients with nontuberculous mycobacterial (NTM) lung disease caused by Mycobacterium avium complex (MAC). Patients in either arm of the INS-212 study who did not achieve culture conversion by Month 6 had the option to enroll in INS-312 at Month 8.

Sputum culture conversion results seen through December 2017 in INS-312 for GBT non-converters who crossed over to treatment with ALIS + GBT (28%) are consistent with sputum culture conversion observed in top-line results from INS-212 (29%).
INS-312 interim descriptive data demonstrate that continued treatment with ALIS + GBT results in more patients achieving culture conversion, with 12% of prior non-converters from INS-212 ALIS + GBT achieving culture conversion by Month 6 in INS-312.
INS-212 interim data show that durability of culture conversion three months off of all treatment, which the Company believes will be the endpoint required to support full regulatory approval, is substantially higher in ALIS + GBT (61%) vs. GBT alone (0%).
Serious treatment emergent adverse events observed in INS-312 are similar to those seen in INS-212 and remain consistent with those seen with the use of inhaled antibiotics. As of December 2017, the dropout rate in INS-312 is 24%.
The Company plans to continue to monitor and evaluate patients throughout the duration of the INS-212 study and expects to report additional data in late 2018 or early 2019 when the INS-312 study has completed its full 12 months and the data has been analyzed pursuant to its statistical analysis plan as agreed with FDA.
New U.S. Patent Issued Extends ALIS Intellectual Property Protection

Earlier this week, Insmed announced that the United States Patent and Trademark Office issued U.S. Patent Number 9,895,385 concerning methods for treating NTM lung infections, including NTM lung infections caused by MAC, with ALIS. The claims of the patent relate to methods for treating MAC lung infections via administration of ALIS to non-cystic fibrosis patients by nebulization once daily for a defined treatment period. The patent extends previously existing patent coverage for ALIS by sixteen months, from January 2034 into May 2035.

Litigation Update

Insmed announces that the U.S. District Court for the District of New Jersey granted the Company’s motion to dismiss in the 2016 securities class action lawsuit brought against the Company and certain of its officers and directors. On February 15, 2018, the court dismissed the lawsuit without prejudice, meaning that the plaintiff has 30 days from the date of the order to file a second amended complaint.

Insmed Announces Key Management Promotions

Insmed also announces the promotions of Christine Pellizzari to the position of Chief Legal Officer from General Counsel and Corporate Secretary, and Nicole Schaeffer to Chief People Strategy Officer from Senior Vice President, Human Resources and Corporate Services.

Fourth Quarter Financial Results

For the fourth quarter of 2017, Insmed reported a net loss of $65.4 million, or $0.85 per share, compared with a net loss of $68.4 million, or $1.10 per share, for the fourth quarter of 2016.

Research and development expenses were $33.9 million for the fourth quarter of 2017, compared with $54.9 million for the fourth quarter of 2016. The decrease was primarily due to a one-time $30.0 million upfront payment related to INS1007 in October 2016, partially offset by an increase in expenses associated with the development of INS-1007 and higher compensation and related expenses due to an increase in headcount, as compared to the fourth quarter of 2016.

General and administrative expenses for the fourth quarter of 2017 were $31.4 million, compared with $12.2 million for the fourth quarter of 2016. The increase was primarily due to higher expenses related to our pre-commercial planning activities for ALIS, a one-time payment to reduce the royalty owed to PARI Pharma GmbH and higher compensation and related expenses due to an increase in headcount, as compared to the fourth quarter of 2016.

Balance Sheet and Cash Guidance

As of December 31, 2017, Insmed had cash and cash equivalents of approximately $381.2 million and debt of $55.0 million. These figures do not reflect the net proceeds of $435.8 million received in January 2018 from the public offering of $450 million of 1.75% senior convertible notes due in 2025. The Company’s operating expenses for the fourth quarter of 2017 were $65.4 million and $188.9 million for the full year of 2017. The cash-based operating expenses for the fourth quarter of 2017 were approximately $59.9 million and $167.9 million for the full year of 2017. The Company intends to repay the existing debt from Hercules Capital on February 28, 2018. The total payment including the backend fee and early prepayment penalty will be approximately $58 million.

The Company is investing in the following key activities in 2018: (i) the build-out of the commercial organization to support global expansion activities for ALIS, (ii) manufacturing of commercial inventory and build out of an additional third-party manufacturing facility and (iii) clinical activities for ALIS and the phase 2 development program for INS-1007, along with advancement of other pipeline programs. As a result of these activities, Insmed expects cash based operating expenses and capital and other cash investments to be in the range of $145 million to $165 million for the first half of 2018.

Conference Call

Insmed will host a conference call beginning today at 8:30 AM Eastern Time. Shareholders and other interested parties may participate in the conference call by dialing (844) 707-0669 (domestic) or (703) 639-1223 (international) and referencing conference ID number 9066979. The call will also be webcast live on the Company’s website at www.insmed.com.

A replay of the conference call will be accessible approximately two hours after its completion through March 2, 2018 by dialing (855) 859-2056 (domestic) or (404) 537-3406 (international) and referencing conference ID number 9066979. A webcast of the call will also be archived for 90 days under the Investor Relations section of the Company’s website at www.insmed.com.

Non-GAAP Financial Measures

In addition to the United States generally accepted accounting principles (GAAP) results, this earnings release includes cash-based operating expenses, a non-GAAP financial measure, which Insmed defines as total operating expenses excluding stock-based compensation expense and depreciation expense. A reconciliation of this non-GAAP financial measure to its most directly comparable GAAP financial measure is presented in the table attached to this press release.

Management believes that this non-GAAP financial measure is useful to both management and investors in analyzing our ongoing business and operating performance. Management believes that providing non-GAAP information to investors, in addition to the GAAP presentation, allows investors to view our financial results in the way that management views financial results. Management does not intend the presentation of this non-GAAP financial measure to be considered in isolation or as a substitute for results prepared in accordance with GAAP. In addition, this non-GAAP financial measure may differ from similarly named measures used by other companies.

About NTM Lung Disease

NTM lung disease is a rare and serious disorder associated with increased rates of morbidity and mortality. There is an increasing prevalence of lung disease caused by NTM, and we believe it is an emerging public health concern worldwide. Patients with NTM lung disease may experience a multitude of symptoms such as fever, weight loss, cough, lack of appetite, night sweats, blood in the sputum, and fatigue. Patients with NTM lung disease frequently require lengthy hospital stays to manage their condition. We are not aware of any approved inhaled therapies specifically indicated for refractory NTM lung disease caused by MAC in North America, Japan or Europe. Current guideline-based approaches involve use of multi-drug regimens not approved for the treatment of NTM lung disease, and treatment can be as long as two years or more.

The prevalence of human disease attributable to NTM has increased over the past two decades. In a decade long study (1997 to 2007), researchers found that the prevalence of NTM lung disease in the U.S. was increasing at approximately 8% per year and that NTM patients on Medicare over the age of 65 were 40% more likely to die over the period of the study than those who did not have the disease. In the U.S., we estimate there will be between 75,000 and 105,000 patients with diagnosed NTM lung disease in 2018, of which we expect 40,000 to 50,000 will be treated for NTM lung disease caused by MAC. We expect that between 10,000 and 15,000 of these patients will be refractory to treatment. In Japan, we estimate there will be between 125,000 and 145,000 patients with diagnosed NTM lung disease in 2018, with approximately 60,000 to 70,000 of those patients being treated for NTM lung disease caused by MAC and 15,000 to 18,000 of these treated patients being refractory to treatment. We also estimate there will be approximately 14,000 patients with diagnosed NTM lung disease in the EU5 (comprised of France, Germany, Italy, Spain and the United Kingdom) in 2018, of which we estimate approximately 4,400 will be treated for NTM lung disease caused by MAC and approximately 1,400 of these treated patients will be refractory to treatment.

About ALIS

ALIS is a novel, inhaled, once-daily formulation of amikacin that is in late-stage clinical development for adult patients with treatment-refractory NTM lung disease caused by MAC. Amikacin solution for parenteral administration is an established drug that has activity against a variety of NTM; however, its use is limited by the need to administer it intravenously and by toxicity to hearing, balance, and kidney function. Insmed’s advanced pulmonary liposome technology uses charge neutral liposomes to deliver amikacin directly to the lung where it is taken up by the lung macrophages where the NTM infection resides. This prolongs the release of amikacin in the lungs while minimizing systemic exposure thereby offering the potential for decreased systemic toxicities. ALIS’s ability to deliver high levels of amikacin directly to the lung distinguishes it from intravenous amikacin. ALIS is administered once daily using an optimized, investigational eFlow Nebulizer System manufactured by PARI Pharma GmbH (PARI), a portable aerosol delivery system.

About CONVERT (INS-212) and INS-312

CONVERT is a randomized, open-label, global Phase 3 trial designed to confirm the culture conversion results seen in Insmed’s Phase 2 clinical trial of ALIS in patients with refractory NTM lung disease caused by MAC. CONVERT is being conducted in 18 countries at more than 125 sites. The primary efficacy endpoint is the proportion of patients who achieve culture conversion at Month 6 in the ALIS plus GBT arm compared to the GBT-only arm. Patients who achieve culture conversion by Month 6 will continue in the CONVERT study for an additional 12 months of treatment following the first monthly negative sputum culture. Patients who do not culture convert have the option of enrolling in our INS-312 study. INS-312 is a single-arm open-label extension study for patients who completed six months of treatment in the INS-212 study, but did not demonstrate culture conversion by Month 6. Under the study protocol, patients in the ALIS plus GBT arm of the INS-212 study will receive an additional 12 months of ALIS plus GBT. Patients who crossed over from the GBT-only arm of the INS-212 study will receive 12 months of treatment of ALIS + GBT.

On February 23, 2018 INSYS Therapeutics, Inc. (NASDAQ:INSY), a leader in the development, manufacture and commercialization of pharmaceutical cannabinoids and spray technology, reported that it will release its fourth quarter and full year 2017 financial results on Thursday, March 8, after the U.S. financial markets close (Press release, Insys Therapeutics, FEB 23, 2018, View Source;p=RssLanding&cat=news&id=2334341 [SID1234524136]).

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Following the release, Saeed Motahari, president and chief executive officer, and Andrew Long, chief financial officer, will host a conference call at 5:00 p.m. Eastern Standard Time to discuss the results.

Interested parties can listen to the call live via the company’s website, View Source, on the Investors section Presentations & Events page; or by dialing 844-263-8304 (from inside the U.S.) or 213-358-0958 (from outside the U.S.). A webcasted replay of the call will be available on the site a few hours after the event.

On February 23, 2018 LabCorp (NYSE: LH) reported it will participate at the 39th Annual Raymond James Institutional Investors Conference. LabCorp’s presentation is scheduled for Tuesday, March 6, 2018 at 8:40 AM (ET) (Press release, LabCorp, FEB 23, 2018, View Source;p=RssLanding&cat=news&id=2334330 [SID1234524138]).

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A live audio webcast of the presentation will be available via the Company website at www.labcorp.com and archived for replay.

On February 23, 2018 Amgen (NASDAQ:AMGN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion to expand the current indication for XGEVA (denosumab) to cover skeletal-related events in patients with multiple myeloma (Press release, Amgen, FEB 23, 2018, View Source;p=RssLanding&cat=news&id=2334313 [SID1234524131]). If approved, XGEVA will be indicated for the prevention of skeletal-related events in adults with advanced malignancies involving bone. The application included new data from the Phase 3 ‘482 study, the largest international multiple myeloma trial for the prevention of skeletal-related events ever conducted.

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In the ‘482 study, XGEVA successfully met the primary endpoint, demonstrating non-inferiority to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85-1.14). The median time to first on-study skeletal-related event was 22.83 months for XGEVA and 23.98 months for zoledronic acid. The safety profile was consistent with known adverse events of XGEVA.

"More than 90 percent of patients with multiple myeloma develop bone lesions over the course of the disease. These can result in fractures and other bone complications," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "The positive opinion from the CHMP to expand XGEVA’s indication to cover skeletal-related events in patients with multiple myeloma is an important step forward in Amgen’s commitment to improving care for multiple myeloma patients at risk for developing bone complications."

Bone complications, also known as skeletal-related events, are defined as radiation to bone, pathologic fracture, surgery to bone and spinal cord compression.1

XGEVA is the first fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – a protein essential for the formation, function and survival of osteoclasts, cells which break down bone – thereby inhibiting osteoclast-mediated bone destruction. On Jan. 5, 2018, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) for XGEVA to expand the currently approved indication for the prevention of skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma. Additional regulatory applications for XGEVA for the prevention of skeletal-related events in patients with multiple myeloma are underway and have been submitted to health authorities worldwide.

Following the CHMP positive opinion, the centralized European marketing authorization of XGEVA will be expanded to cover the multiple myeloma patient population. Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions on the basis of the decision of the European Commission.

About ‘482 Study (NCT01345019)
The ‘482 study was an international, Phase 3, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function at baseline) and subcutaneous placebo every four weeks, plus investigators’ choice first-line antimyeloma therapy. Skeletal surveys using conventional radiography were obtained every 12 to 24 weeks per protocol. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). The safety and tolerability of XGEVA were also compared with zoledronic acid. An open-label extension of the study is ongoing.

About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment.2,3 It is typically characterized by osteolytic bone lesions as well as renal failure, which are both part of diagnosis (CRAB criteria).1,4 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.1

More than 90 percent of patients develop osteolytic lesions during the course of the disease.1 Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can result in significant morbidity.5 Current treatment options to prevent bone complications are limited to bisphosphonates, including zoledronic acid, which are cleared through the kidneys.6 Approximately 60 percent of all multiple myeloma patients have or will develop renal impairment over the course of the disease.7

About XGEVA (denosumab)
XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. XGEVA is also indicated for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Additionally, XGEVA is indicated in the U.S. for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

EU Important Safety Information

∇ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Calcium and Vitamin D supplementation
Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present.

Hypocalcaemia
Pre-existing hypocalcaemia must be corrected prior to initiating therapy with XGEVA. Hypocalcaemia can occur at any time during therapy with XGEVA. Monitoring of calcium levels should be conducted (i) prior to the initial dose of XGEVA, (ii) within two weeks after the initial dose, (iii) if suspected symptoms of hypocalcaemia occur. Additional monitoring of calcium level should be considered during therapy in patients with risk factors for hypocalcaemia, or if otherwise indicated based on the clinical condition of the patient.

Patients should be encouraged to report symptoms indicative of hypocalcaemia. If hypocalcaemia occurs while receiving XGEVA, additional calcium supplementation and additional monitoring may be necessary.

In the post marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported, with most cases occurring in the first weeks of initiating therapy, but can occur later.

Renal impairment
Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risk of developing hypocalcaemia and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels is especially important in these patients.

Osteonecrosis of the jaw (ONJ)
ONJ has been reported commonly in patients receiving XGEVA.

The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with XGEVA.

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:

potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
poor oral hygiene, periodontal disease, poorly fitting dentures, pre-existing dental disease, invasive dental procedures (e.g. tooth extractions).
All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with XGEVA. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to XGEVA administration.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of XGEVA treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur
Atypical femoral fractures have been reported in patients receiving XGEVA. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of XGEVA therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit risk assessment. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Patients with growing skeletons
XGEVA is not recommended in patients with growing skeletons. Clinically significant hypercalcaemia has been reported in XGEVA-treated patients with growing skeletons weeks to months following treatment discontinuation.

Others
Patients being treated with XGEVA should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications).

Patients being treated with XGEVA should not be treated concomitantly with bisphosphonates.

Malignancy in Giant Cell Tumour of Bone or progression to metastatic disease is an infrequent event and a known risk in patients with Giant Cell Tumour of Bone. Patients should be monitored for radiological signs of malignancy, new radiolucency or osteolysis. Available clinical data does not suggest an increased risk of malignancy in GCTB patients treated with XGEVA.

Warnings for excipients
XGEVA contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not use XGEVA.

This medicinal product contains less than 1 mmol sodium (23 mg) per 120 mg, i.e. essentially ‘sodium-free’.

U.S. Important Safety Information

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation in Patients with Growing Skeletons
Clinically significant hypercalcemia has been reported in XGEVA treated patients with growing skeletons, weeks to months following treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately.

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation
Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures. When XGEVA treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects.

Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

For multiple myeloma patients receiving XGEVA, the most common adverse reactions were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of XGEVA was osteonecrosis of the jaw.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Denosumab is also marketed as Prolia in other indications.

Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.

About Amgen’s Commitment to Oncology
Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen’s supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.

On February 23, 2018 AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion, recommending a marketing authorization of LYNPARZA (olaparib) tablets (300 mg twice daily) for use as a maintenance therapy for patients with platinum-sensitive relapsed high grade, epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy (Press release, Merck & Co, FEB 23, 2018, View Source [SID1234524140]). LYNPARZA is recommended for treatment in this setting regardless of patients’ BRCA mutation status.

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Sean Bohen, executive vice president, global medicines development and chief medical officer at AstraZeneca, said, "The data show that LYNPARZA provides long-term disease control, delaying the need for further chemotherapy for this broader group of women with platinum-sensitive relapsed ovarian cancer, irrespective of their BRCA status. It also offers a well-characterized safety and tolerability profile, which is critical to help enable patients to stay on treatment."

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "We welcome this positive opinion based upon data which indicate the potential impact for LYNPARZA as maintenance therapy for women with platinum-sensitive relapsed ovarian cancer. We look forward to our continued work with AstraZeneca to bring LYNPARZA to patients in the EU."

The CHMP recommendation is based on two randomized trials, SOLO-2 and Study 19, which showed LYNPARZA (olaparib) reduced the risk of disease progression or death for platinum-sensitive relapsed patients compared to placebo.

Summary of key efficacy results from randomized trials:

Analysis SOLO-2
[germline BRCA-mutated]

n=295

Study 19
[platinum-sensitive relapsed]

n=265

LYNPARZA Placebo LYNPARZA Placebo
Reduction in the risk of disease progression or death (PFS) 70%
(HR 0.30 [95% CI, 0.22-0.41], P<0.0001; median 19.1 vs 5.5 months)*

65%
(HR 0.35 [95% CI, 0.25-0.49], P<0.0001; median 8.4 vs 4.8 months)*

Reduction in the risk of death (OS) Data not yet mature 27% (HR 0.73 [95% CI, 0.55-0.95], P=0.02138**;
median 29.8 vs 27.8 months)***

PFS = progression-free survival; OS = overall survival

* By investigator-assessed analysis

** P-value considered nominal as criterion for statistical significance (P<0.0095) not met

*** Not adjusted for treatment crossover

The most frequently observed adverse reactions across clinical trials in patients receiving LYNPARZA monotherapy (≥10%) were nausea, vomiting, diarrhea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite, dizziness and anemia.

LYNPARZA, the first poly ADP-ribose polymerase (PARP) inhibitor approved, was initially licensed as a capsule formulation. The new tablet formulation will reduce dosing from eight capsules twice daily to two tablets twice daily.

LYNPARZA is available in nearly 60 countries and has treated more than 20,000 patients globally. It has the broadest clinical development program of any PARP inhibitor, and AstraZeneca and Merck are working together to bring LYNPARZA to more patients across multiple cancers. In January 2018, LYNPARZA was approved by the U.S. Food and Drug Administration for use in metastatic breast cancer, becoming the first PARP inhibitor licensed beyond ovarian cancer.

Indications for LYNPARZA (olaparib) in the U.S.

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Important Safety Information for LYNPARZA (olaparib)

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA (olaparib) if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA (olaparib) for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA (olaparib). If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Dosing and Administration

To avoid substitution errors and overdose, do not substitute LYNPARZA tablets with LYNPARZA capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Recommended tablet dose is 300 mg, taken orally twice daily, with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider dose interruption or dose reduction.

NOTES TO EDITORS

About Ovarian Cancer in Europe

Among women in Europe, ovarian cancer is the fifth most common cancer and the sixth leading cause of cancer death. The five-year survival rate for ovarian cancer in Europe is 38 percent. In 2012, there were nearly 65,000 new cases diagnosed and around 42,700 deaths. As there is no cure for relapsed ovarian cancer, the primary aim of treatment is to slow progression of the disease for as long as possible and improve or maintain the patient’s quality of life.

About SOLO-2

SOLO-2 was a phase 3, randomized, double-blinded, multicenter trial designed to determine the efficacy of LYNPARZA (olaparib) tablets compared to placebo as maintenance monotherapy in patients with platinum-sensitive relapsed or recurrent germline BRCA-mutated ovarian, fallopian tube and primary peritoneal cancer. The trial, conducted in collaboration with the European Network for Gynaecological Oncological Trial Groups (ENGOT) and Groupe d’Investigateurs National pour l’Etude des Cancers de l’Ovaire et du sein (GINECO), randomized 295 patients with documented germline BRCA1 or BRCA2 mutations who had received at least two prior lines of platinum-based chemotherapy and were in complete or partial response. Eligible patients were randomized to receive 300mg LYNPARZA tablets twice daily or placebo tablets twice daily.

About Study 19

Study 19 was a phase 2, randomized, double-blinded, placebo-controlled, multicenter trial, which evaluated the efficacy and safety of LYNPARZA compared with placebo in relapsed, high-grade serous ovarian cancer patients. The trial randomized 265 patients regardless of BRCA mutation status and who had completed at least two courses of platinum-based chemotherapy and their most recent treatment regimen. Eligible patients were randomized to receive LYNPARZA maintenance monotherapy at a dose of 400mg per day or matching placebo.

About LYNPARZA (olaparib)

LYNPARZA is a first in-class poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to potentially exploit tumor DNA damage response (DDR)-pathway deficiencies to preferentially kill cancer cells. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

LYNPARZA is being investigated in a range of DDR-deficient tumor types.