On October 23, 2018 Biogen Inc. (Nasdaq: BIIB) reported third quarter 2018 financial results, including (Press release, Biogen, OCT 23, 2018, View Source [SID1234530371]):

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Total revenues of $3.4 billion, a 12% increase versus the prior year.

Multiple sclerosis (MS) revenues were $2.3 billion, including approximately $137 million in royalties on the sales of OCREVUS, relatively stable versus the third quarter of 2017.

Revenue growth was driven in part by SPINRAZA, which contributed $468 million in global revenues.

GAAP net income and diluted earnings per share (EPS) attributable to Biogen Inc. of $1.4 billion and $7.15, respectively, compared to $1.2 billion and $5.79 in the third quarter of 2017, respectively.

Non-GAAP net income and diluted EPS attributable to Biogen Inc. of $1.5 billion and $7.40, respectively, compared to $1.3 billion and $6.31 in the third quarter of 2017, respectively

Biogen performed well against our strategic and operational priorities in the most recent quarter," said Michel Vounatsos, Biogen’s chief executive officer. "Reported revenues grew at a double-digit rate boosted by strong gains from SPINRAZA, our biosimilars business, and OCREVUS royalties versus a year ago. Net income and earnings per share both increased at double-digit rates supported by a lower tax rate and a lower share count. Our core MS business was relatively resilient during the quarter. For SPINRAZA, in the U.S. we saw increased new patient demand among adults. Outside of the U.S., SPINRAZA revenues benefitted from strong patient uptake across a number of geographies, as well as broadening approvals and solid reimbursement patterns."

"Biogen continued to advance our pipeline beyond our industry leading portfolios in MS and Alzheimer’s," Mr. Vounatsos continued. "In the third quarter, we made notable progress in stroke, progressive supranuclear palsy, and ALS. As ever, we remain focused on allocating our capital properly and efficiently with the goal of maximizing returns on behalf of our shareholders over the long-term."

In the third quarter of 2018 channel inventory levels in the U.S. were relatively stable for TECFIDERA, AVONEX, and PLEGRIDY combined. This compares to a decrease of approximately $45 million in the second quarter of 2018 and relatively stable inventory levels in the third quarter of 2017.

In the third quarter of 2018 SPINRAZA revenues comprised $224 million in sales in the U.S. and $244 million in sales outside the U.S. The number of commercial patients receiving SPINRAZA grew approximately 11% in the U.S. and approximately 29% outside the U.S. versus the second quarter of 2018. In the third quarter of 2018 Biogen recorded SPINRAZA revenues in over 30 countries.

Other Financial Highlights

In the third quarter of 2018 GAAP amortization of acquired intangibles was $282 million, including impairment charges totaling $189 million related to updates in the development status of vixotrigine (BIIB074), which are discussed below. The effects of these impairments were partially offset by a $90 million reduction in our contingent consideration liability.

In the third quarter of 2018 GAAP other net income was $115 million. This includes a gain of approximately $141 million related to changes in the fair value of certain equity investments, including shares of Ionis Pharmaceuticals, Inc., as of September 30, 2018. Non-GAAP other net expense was $26 million.

For the third quarter of 2018 the Company’s effective GAAP tax rate was 20%, and the Company’s effective non-GAAP tax rate was 21%.

In the third quarter of 2018 Biogen’s board of directors authorized a program to repurchase up to $3.5 billion of the Company’s common stock.

As of September 30, 2018, Biogen had cash, cash equivalents, and marketable securities totaling approximately $5.7 billion, and approximately $5.9 billion in notes payable.

In the third quarter of 2018 the Company generated $1.7 billion in net cash flows from operations.

For the third quarter of 2018 the Company’s weighted average diluted shares were 202 million.

Recent Events

This week Biogen will present data from its Alzheimer’s disease (AD) clinical development portfolio at the Clinical Trials on Alzheimer’s Disease (CTAD) annual meeting in Barcelona, Spain (October 24-27). Biogen will share a late-breaking oral presentation and a late-breaking poster on the efficacy of aducanumab, Biogen’s anti-amyloid beta antibody candidate for early AD, as well as cumulative safety data from the Phase 1b PRIME long-term extension study of patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild AD dementia. These results are generally consistent with previous interim analyses, and there were no changes to the risk-benefit profile of aducanumab. In addition, Samantha Budd Haeberlein, vice president, Alzheimer’s disease, dementia, and movement disorders, late stage clinical development at Biogen, will deliver a keynote address focused on lessons learned from clinical research into AD. The oral presentation, keynote address, and an investor Q&A call, will be webcast on Biogen’s website at investors.biogen.com. The poster presentations will also be available on Biogen’s website.

Wednesday, October 24, 7:15 a.m. ET / 1:15 p.m. CEST – Poster Presentations: Cumulative Aducanumab Safety Data from PRIME: A Randomized, Double-blind, Placebo-controlled, Phase 1b Study and Aducanumab 48-Month Analyses from PRIME, a Phase 1b Study in Patients with Early Alzheimer’s Disease

Thursday, October 25, 7:30-8:00 a.m. ET / 1:30-2:00 p.m. CEST – Keynote: What Have We Learned from Aducanumab?

Thursday, October 25, 4:15 p.m. ET / 10:15 p.m. CEST – Investor Q&A call with Alfred Sandrock, Jr., M.D., Ph.D., executive vice president and chief medical officer at Biogen, and Samantha Budd Haeberlein, Ph.D., vice president, Alzheimer’s disease, dementia and movement disorders, late stage clinical development at Biogen
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Friday, October 26, 9:15-9:30 a.m. ET / 3:15-3:30 p.m. CEST – Oral Presentation: Aducanumab Titration Dosing Regimen: 36-Month Analyses from PRIME, a Phase 1b Study in Patients with Early Alzheimer’s Disease

At CTAD, Biogen’s collaborator Eisai Co., Ltd. (Eisai) will also present clinical and biomarker updates from the Phase 2 study of BAN2401, an anti-amyloid beta antibody, along with safety and efficacy data for elenbecestat (development code: E2609), an investigational oral beta-amyloid cleaving enzyme (BACE) inhibitor, from the Phase 2 study in MCI to moderate AD. The BAN2401 presentation will be webcast live on Eisai’s website on Thursday, October 25, 8:30-9:30 a.m. ET / 2:30-3:30 p.m. CEST.

Today Biogen and UCB announced top-line results from a Phase 2b study evaluating the safety and efficacy of dapirolizumab pegol (DZP), an anti-CD40L pegylated Fab, in adults with moderately-to-severely active systemic lupus erythematosus (SLE) despite receiving standard-of-care treatment such as corticosteroids, anti-malarials and non-biological immunosuppressants. The primary endpoint of the study to demonstrate a dose response at 24 weeks on the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) was not met (p=0.06). The study did demonstrate consistent and potentially meaningful improvements for the majority of clinical endpoints in patients treated with DZP compared with placebo. In addition, biomarker data demonstrated evidence of proof of biology. DZP was well tolerated and demonstrated an acceptable safety profile. Biogen and UCB continue to further evaluate these data while assessing potential next steps. The companies expect to present this data at a future scientific forum.

In October 2018 Biogen and Samsung Bioepis Co. Ltd. announced the European launch of IMRALDI, an adalimumab biosimilar referencing Humira. IMRALDI is approved in Europe for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, psoriatic arthritis, psoriasis, paediatric plaque psoriasis, adult and adolescent hidradenitis suppurativa, Crohn’s disease, paediatric Crohn’s disease, ulcerative colitis, and uveitis.

In October 2018 Biogen presented data in more than 70 oral and poster presentations at the 34th Congress of the European Committee for Treatment and Research in MS (ECTRIMS) in Berlin, Germany. Key updates included clinical data and real-world evidence that further support the long-term efficacy and well-characterized safety of Biogen’s leading MS therapies, including data supporting the use of TECFIDERA and TYSABRI early within the disease course. Additional data highlighted the potential utility of serum neurofilament light (sNfL) as a biomarker of MS disease activity and updates on Biogen’s efforts to improve monitoring of cognition and other key MS outcomes through MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions).

In October 2018 Biogen presented new interim results from NURTURE, an ongoing open-label, single-arm efficacy and safety study of SPINRAZA in 25 presymptomatic infants with spinal muscular atrophy (SMA) at the Annual Congress of the World Muscle Society (WMS) held in Mendoza, Argentina. As of May 2018 all NURTURE study participants were alive and none required permanent ventilation, in contrast to the natural history of SMA. In addition, 100% of study participants achieved the motor milestone of sitting independently, 88% were able to walk with assistance, and 77% were able to walk independently. All NURTURE study participants were older than 15 months at the time of the analysis.

In October 2018 Biogen presented data from its movement disorders portfolio at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) in Hong Kong. Data presented included safety data from the Phase 1 long-term extension study of BIIB092, an anti-tau antibody, in progressive supranuclear palsy (PSP), baseline demographics from the BIIB092 Phase 2 PASSPORT study in PSP, and the design of the BIIB054 Phase 2 SPARK study in Parkinson’s disease.

In September 2018 Biogen received results from the Phase 2b study of vixotrigine (BIIB074) in painful lumbosacral radiculopathy (PLSR). The study did not meet its primary or secondary efficacy endpoints, and the Company will discontinue development in this indication. The safety data were consistent with the profile reported in previous studies. In addition, the Company has delayed the initiation of the Phase 3 studies of vixotrigine in trigeminal neuralgia as it awaits the outcome of ongoing interactions with the U.S. Food and Drug Administration regarding the design of the Phase 3 studies, a more detailed review of the Phase 2b PLSR data, and insights from the ongoing Phase 2 study in small fiber neuropathy.

In September 2018 Biogen completed enrollment in the Phase 2b AFFINITY study, evaluating opicinumab as an add-on therapy in MS patients who are adequately controlled on their anti-inflammatory disease-modifying therapy (DMT), versus the DMT alone. Opicinumab is a first-in-class human monoclonal antibody directed against LINGO-1 and is being evaluated to determine its potential for improving pre-existing disability in relapsing MS patients through remyelination.

In September 2018 Biogen enrolled the first patient in the Phase 2b study evaluating BG00011 (STX-100) in idiopathic pulmonary fibrosis.

In September 2018 Biogen completed enrollment in the Phase 2 study of BIIB092 in PSP.

In September 2018 Biogen enrolled the first patient in the Phase 1 study evaluating BIIB078 (IONIS-C9Rx), an antisense oligonucleotide drug candidate, in adults with C9ORF72-associated amyotrophic lateral sclerosis.

In August 2018 Biogen enrolled the first patient in the global Phase 3 CHARM study, designed to evaluate BIIB093 (intravenous (IV) glibenclamide) for the prevention and treatment of severe cerebral edema in large hemispheric infarction, one of the most severe types of ischemic stroke.

In July 2018 Eisai presented detailed results from the Phase 2 study (Study 201) of BAN2401, as well as detailed results from the Phase 2 study (Study 202) of elenbecestat, at the 2018 Alzheimer’s Association International Conference (AAIC) in Chicago.

Conference Call and Webcast
The Company’s earnings conference call for the third quarter will be broadcast via the internet at 8:00 a.m. ET on October 23, 2018, and will be accessible through the Investors section of Biogen’s website, www.biogen.com. Supplemental information in the form of a slide presentation is also accessible at the same location on the internet and will be subsequently available on the website for at least one month.

Note about Earnings Releases and Calls
Starting with the second quarter 2018 earnings release, Biogen has ceased publishing press releases relating to future earnings calls, earnings releases, and investor events via newswire services. The Company will post these materials on the Investors section of Biogen’s website, www.biogen.com, and issue a statement on Twitter (@biogen) when they become available.

On October 23, 2018 IDEAYA Biosciences, Inc., reported it has entered into an exclusive license agreement with Novartis to develop and commercialize Novartis’ LXS196, a Phase 1 protein kinase C (PKC) inhibitor for the treatment of cancers with GNAQ and GNA11 mutations (Press release, Ideaya Biosciences, OCT 23, 2018, View Source [SID1234535455]).

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LXS196, which will be recoded as IDE196 by IDEAYA for future development, is a potent small molecule inhibitor of PKC demonstrating early clinical activity and tolerability in an ongoing Phase 1 study of IDE196 for patients with metastatic uveal melanoma (MUM). IDE196 is active across multiple PKC isoforms and is highly selective relative to other kinases. MUM is an orphan disease of high unmet medical need, with median overall survival of approximately 10 months and no FDA approved therapies.

"There are no approved therapies for metastatic uveal melanoma, and continued development of promising clinical stage agents, such as IDE196, with a clear genetic biomarker rationale to treat patients that harbor GNAQ and GNA11 mutations through PKC are paramount," said Dr. Sophie Piperno‐Neumann, M.D., LXS196 Study Investigator and Medical Oncologist at Institute Curie, Paris, France.

IDEAYA will continue development in metastatic uveal melanoma and will also explore a tumor agnostic basket study of solid tumors with mutations of GNAQ and GNA11. Both GNAQ and GNA11 mutations are listed in multiple diagnostic panels, including the FoundationOne CDx NGS panel, FoundationOne Liquid Biopsy Panel, and the Guardant360 Liquid Biopsy panel, which provides a clear path towards identifying patients. IDEAYA is also evaluating the potential use of IDE196 to target various PKC fusion isoforms.

Novartis is conducting an ongoing Ph1 clinical trial, entitled "A Phase I, multi-center, open-label, study of LXS196, an oral protein kinase C inhibitor, in patients with metastatic uveal melanoma" (ClinicalTrials.gov Identifier: NCT02601378). In the ongoing trial, IDE196 is being studied as a single-agent and in combination therapy with HDM201, Novartis’ human double minute 2 (HDM2) inhibitor, an important negative regulator of the p53 tumor suppressor. Notably, approximately 90% of metastatic uveal melanoma patients harbor activating mutations in GNA11 or GNAQ.

"Targeting PKC, a pathway which is active in this disease, may result in improved clinical outcomes, and the data with IDE196 treatment thus far demonstrate objective responses, with tolerability that will enable ongoing and future monotherapy and combination trials," said Dr. Ellen Kapiteijn, M.D. Ph.D., LXS196 Study Investigator and Medical Oncologist at Leiden University Medical Center, Leiden, Netherlands.

Under the exclusive license, Novartis increased its equity ownership in IDEAYA, and is due future milestones and royalties, and Novartis will continue the ongoing IDE196 monotherapy and combination study with the Novartis HDM201 compound. IDEAYA has exclusive rights for further clinical development of IDE196, together with unrestricted rights to commercialize worldwide.

"IDE196 enhances our robust precision medicine pipeline, and we are ecstatic to develop this first-in-class therapy for cancer patients who harbor activating mutations of GNAQ and GNA11," said Yujiro Hata, Chief Executive Officer of IDEAYA. "Novartis has been an investor in IDEAYA since the Series A, so we are pleased to enter into this agreement and further enhance our strategic relationship."

On October 23, 2018 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported that it will report its 2018 third quarter financial results on Tuesday, November 6, 2018, after the close of the financial markets (Press release, Jazz Pharmaceuticals, OCT 23, 2018, View Source [SID1234530077]). Company management will host a live audio webcast immediately following the announcement at 4:30 p.m. EST/9:30 p.m. GMT to discuss 2018 third quarter financial results and provide a business and financial update.

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Interested parties may access the live audio webcast via the Investors section of the Jazz Pharmaceuticals website at View Source Please connect to the website prior to the start of the conference call to ensure adequate time for any software downloads that may be necessary to listen to the webcast. A replay of the webcast will be archived on the website for at least one week.

Audio webcast/conference call:
U.S. Dial-In Number: +1 855 353 7924
International Dial-In Number: +1 503 343 6056
Passcode: 8048589

A replay of the conference call will be available through November 13, 2018 and accessible through one of the following telephone numbers, using the passcode below:

Replay U.S. Dial-In Number: +1 855 859 2056
Replay International Dial-In Number: +1 404 537 3406
Passcode: 8048589

On October 23, 2018 Galera Therapeutics, Inc., a clinical-stage biotechnology company focused on the development of drugs targeting oxygen metabolic pathways with the potential to transform cancer radiotherapy, reported data from its Phase 2b clinical trial evaluating avasopasem manganese (GC4419), a highly selective and potent small molecule dismutase mimetic, in patients with locally advanced squamous cell head and neck cancer were presented today during a scientific session at the American Society for Radiation Oncology Annual Meeting in San Antonio, Texas (Press release, Galera Therapeutics, OCT 23, 2018, View Source [SID1234530124]).

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Avasopasem manganese demonstrated statistically significant reductions in the duration, incidence and severity of severe oral mucositis (SOM) in patients with head and neck cancer, its lead indication. The presentation, "A Randomized, Placebo (PBO) Controlled, Double-blind Phase 2b Trial of GC4419 (avasopasem manganese) to Reduce Severe Radiation-related Oral Mucositis (SOM) in Patients (pts) with Locally Advanced Squamous Cell Cancer of the Oral Cavity (OC) or Oropharynx (OP)," was given by trial investigator Carryn Anderson, M.D., Radiation Oncologist, University of Iowa Hospitals and Clinics.

"Approximately 70 percent of patients receiving chemoradiotherapy for head and neck cancer develop severe oral mucositis, and there is currently no drug approved to prevent or treat it. These positive Phase 2b data have been presented at multiple scientific meetings, which reinforces both the strength of the results and the urgency for a treatment to address this pervasive and unmet need," said Mel Sorensen, M.D., President and CEO of Galera. "We are pleased to have initiated our pivotal ROMAN trial of avasopasem manganese in patients with head and neck cancer earlier this month, which seeks to confirm the efficacy seen in this Phase 2b trial."

Additional non-clinical data were presented in a poster discussion, "The Radioprotector GC4419 Ameliorates Radiation Induced Lung Fibrosis While Enhancing the Response of Non-Small Cell Lung Cancer Tumors to High Dose per Fraction Radiation Exposures," by Michael Story, Ph.D., UT Southwestern Medical Center, on October 22. These data highlighted a reduction in normal organ damage and a significant increase in tumor response to radiation therapy with avasopasem managanese. Galera sponsored this research.

For more information and to view the abstracts, please visit View Source

About the Avasopasem Manganese Phase 2b Data

The 223-patient, double blind, randomized, placebo-controlled trial evaluated the safety of avasopasem manganese and its ability to reduce the duration of radiation-induced SOM in patients with locally advanced squamous cell head and neck cancer receiving seven weeks of radiation therapy plus cisplatin.

Patients in the trial were treated with either 30 mg or 90 mg of avasopasem manganese or placebo by infusion on the days they received their radiation treatment. Patients were randomized to one of the three treatment groups (1:1:1) and the trial recruited patients in both the United States and Canada. Avasopasem manganese exhibited a safety profile comparable to placebo in the two treatment groups, and was well tolerated. In the trial’s intent-to-treat population, the 90 mg dose of avasopasem manganese met the primary endpoint, demonstrating a statistically significant (p = 0.024) 92 percent reduction in the median duration of SOM from 19 days to 1.5 days.

In the 90 mg arm, avasopasem manganese also demonstrated a clinically meaningful effect in pre-specified secondary endpoints (incidence and severity of SOM). Avasopasem manganese achieved a 34 percent reduction through completion of radiation (p = 0.009), and a 36 percent reduction through 60 Gy of radiation (p = 0.010), in the overall incidence of SOM, and reduced the severity of patients’ OM by 47 percent (p = 0.045).

About Avasopasem Manganese

Avasopasem manganese (GC4419) is a highly selective and potent small molecule dismutase mimetic that closely mimics the activity of human superoxide dismutase enzymes. It works to reduce elevated levels of superoxide caused by radiation therapy by rapidly converting superoxide to hydrogen peroxide and oxygen. Left untreated, elevated superoxide can damage noncancerous tissues and lead to debilitating side effects, including oral mucositis (OM), which can limit the anti-tumor efficacy of radiation therapy. Conversion of elevated superoxide to hydrogen peroxide, which is selectively more toxic to cancer cells, can also enhance the effect of radiation on tumors, particularly with stereotactic body radiation therapy (SBRT), which produces high levels of superoxide.

Avasopasem manganese is being studied in the Phase 3 ROMAN trial of patients with head and neck cancer, its lead indication, for its ability to reduce the incidence and severity of radiation-induced severe oral mucositis. In Galera’s 223-patient, double blind, randomized, placebo-controlled Phase 2b clinical trial, avasopasem manganese demonstrated the ability to dramatically reduce the duration of SOM from 19 days to 1.5 days (92 percent), the incidence of SOM through completion of radiation by 34 percent and the severity of patients’ OM by 47 percent, while demonstrating acceptable safety when added to a standard radiotherapy regimen. Avasopasem manganese is also currently being studied in combination with SBRT for its anti-tumor effect in a Phase 1/2 trial of patients with locally advanced pancreatic cancer. In addition, in multiple preclinical studies, it demonstrated an increased tumor response to radiation therapy while preventing toxicity in normal tissue.

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy and Fast Track designations to avasopasem manganese for the reduction of SOM in patients with head and neck cancer.

About Oral Mucositis

Oral mucositis (OM) is a painful and problematic complication during cancer treatment, especially radiation therapy, caused by excessive superoxide generated during treatment that breaks down epithelial cells that line the mouth. Patients suffering from OM experience severe pain, inflammation, ulceration and bleeding of the mouth.

In the United States, more than 50 percent of patients with cancer receive radiotherapy at some time in their treatment. In patients with head and neck cancer, radiotherapy is a mainstay of treatment and approximately 70 percent of patients receiving radiotherapy develop SOM as defined by the World Health Organization as Grade 3 or 4, which is the most debilitating side effect of the radiotherapy.

SOM can adversely affect cancer treatment outcomes by causing interruptions in radiotherapy, which may compromise the otherwise good prognosis for tumor control in many of these patients. SOM may also inhibit patients’ ability to eat solid food or even drink liquids, and can cause serious infections. Further, the costs of managing these side effects are substantial, particularly when hospitalization and/or surgical placement of PEG tubes to maintain nutrition and hydration are required. There is currently no drug approved to prevent or treat SOM in patients with head and neck cancer.

On October 23, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported that Phase 3 ALTA-1L ( A LK in L ung Cancer Trial of Brig A tinib in 1 st L ine, Brig A tinib first-line treatment of lung cancer in the ALK trial of intracranial efficacy data showed anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) Among patients, ALUNBRIG (brigatinib) had better intracranial progression-free survival (PFS) and intracranial objective response rate (ORR) than crizotinib (Press release, Takeda, OCT 23, 2018, View Source [SID1234530062]). The above secondary endpoint data will be presented at the 2018 Conference of the European Congress of Oncology (ESMO) (Free ESMO Whitepaper) in Munich, Germany on October 19th (Friday) at 2:00 pm. These results further support ALUNBRIG as a promising therapeutic for ALK+ locally advanced or metastatic NSCLC adult patients who have not previously used ALK inhibitors. ALUNBRIG is currently not approved for first-line treatment of advanced ALK+ NSCLC.

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Royal Marsden Hospital Oncologist Sanjay Popat, PhD, FRCP said: "ALK+ NSCLC often spreads to the brain, so having a choice that clearly demonstrates both brain and body effectiveness is critical for doctors and their patients. The ALTA-1L trial showed that brigitinib treatment is significantly superior to crizotinib in delaying the progression of brain disease, and we look forward to sharing this clinical evidence with the medical community at ESMO (Free ESMO Whitepaper)."

The first interim analysis of the ALTA-1L trial showed that the intracranial PFS of ALUNBRIG was significantly better than crizotinib, and the risk ratio of intention to treat (ITT) population [HR]: 0.42, 95% confidence interval [CI]: 0.24−0.70; Log-rank P = 0.0006, HR with baseline brain metastasis: 0.27, 95% CI: 0.13−0.54; log-rank P <0.0001. In the population with brain metastases at baseline, the risk of intracranial progression or death in ALUNBRIG decreased by 73%. As of this first interim analysis, the timing of intracranial PFS analysis in patients without baseline brain metastasis is not yet mature.

The results also showed that the intracranial ORR of the ALUNBRIG treatment group was superior to crizotinib. Patients with measurable baseline brain metastases obtained a confirmed intracranial OR rate of 78% in the ALUNBRIG group and 29% in the crizotinib group. Patients with unrecognized baseline brain metastases obtained a confirmed intracranial OR rate of 67% in the ALUNBRIG group and 17% in the crizotinib group.

In addition, ALUNBRIG simultaneously delayed central nervous system (CNS) progression (without previous systemic progression) and systemic progression (without previous CNS progression), significantly better than crizotinib. Baseline factors associated with CNS, such as the proportion of patients with brain metastases at baseline, the average number of brain metastases, previous brain radiation therapy, and the type of patients included, the proportion of patients in both groups was balanced. The ALUNBRIG security in the ALTA-1L trial is generally consistent with the existing US version of the prescribing information.

David Kerstein, MD, global clinical director and clinical lineup strategy director for Brigatinib, said: "CNS lesions are a heavy burden for ALK+ NSCLC patients. The additional intracranial efficacy results from the ALTA-1L trial are based on previous reports of ALUNBRIG. The activity of crizotinib in patients with brain metastases highlights Takeda’s commitment to research, which aims to improve outcomes in patients with this serious disease."

The results of the above data were recently reported during the 19th World Congress of Lung Cancer Conference (WCLC) President of the International Society for the Study of Lung Cancer (IASLC). The results showed that the blinded independent review committee of the ALUNBRIG treatment group evaluated PFS better than crosazole. Tinidine, which is equivalent to a 51% lower risk of disease progression or death (HR: 0.49, 95% CI: 0.33−0.74); log-rank P = 0.0007).

The incidence of adverse events in the 3 to 5 degree treatment was 61% in the brigitinib group and 55% in the crizotinib group. The most common adverse events occurred in 3 or more degrees of treatment, brigitinib group: elevated creatine phosphokinase (16%), elevated lipase (13%), hypertension (10%), amylase High (5%); crizotinib group: alanine aminotransferase increased (9%), aspartate aminotransferase increased (6%), lipase increased (5%).

About the ALTA-1L test, the
application of ALUNBRIG in the third phase of ALTA-1L ( A LK in L ung Cancer T rial of Brig A tinib in 1 st L ine, Brig A tinib first-line treatment of ALK in lung cancer test) is ongoing. A global, multicenter, open, randomized, controlled trial enrolled 275 patients with locally advanced or metastatic ALK+ NSCLC who had not previously used ALK inhibitors. The patient received ALUNBRIG 180 mg once daily (7 days introduction period 90 mg once daily) or crizotinib 250 mg twice daily. The primary endpoint was progression-free survival (PFS) assessed by the blind independent review board (BIRC). Secondary endpoints included objective response rate (ORR) (according to RECIST v1.1), intracranial ORR, intracranial PFS, overall survival (OS), safety, and tolerability. As planned, PFS should achieve a minimum of 6 months over crizotinib, and the final endpoint analysis would require approximately 198 PFS events. The trial presupposes two primary endpoint interim analyses, one in the planned PFS event reaching approximately 50%, and the other in the planned PFS event reaching approximately 75%.

ABOUT ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, which accounts for about 85% of the world’s approximately 1.8 million newly diagnosed lung cancer cases each year, according to the World Health Organization. Genetic studies have shown that chromosomal recombination of anaplastic lymphoma kinase (ALK) is a key driver in a subset of NSCLC patients. Approximately 3 to 5% of patients with metastatic NSCLC have ALK gene rearrangements.

Takeda is committed to continuous research and development in the field of NSCLC to improve the lives of patients. About 40,000 patients worldwide are diagnosed with this serious and rare type of lung cancer every year.

About ALUNBRIG (brigatinib)

ALUNBRIG ALUNBRIG is a targeted anticancer drug discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, ALUNBRIG was recently approved by the US Food and Drug Administration (FDA) for the treatment of ALK+ metastatic NSCLC that progressed during crizotinib administration or was unable to tolerate crizotinib. The basis for the accelerated approval of this indication is the rate of tumor remission and duration of remission. The continued approval of this indication is subject to a confirmatory trial to validate and describe the clinical benefits. In July 2018, Health Canada approved ALUNBRIG for the treatment of ALK+metastatic NSCLC adult patients who progressed or were intolerant during the administration of the ALK inhibitor (cizotinib). Mainly based on FDA approved by Health Canada and is pivotal ALUNBRIG 2 ALTA ( A LK in L UNG Cancer T Rial of A P26113, A P26113 lung clinical trials A LK) test results.

ALUNBRIG has received FDA breakthrough drug certification for the treatment of crizotinib-resistant ALK+ NSCLC patients, which is also approved by the FDA orphan drug for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.

The brigatinib clinical development program further strengthens Takeda’s long-standing commitment to developing innovative therapeutics for ALK+ NSCLC patients worldwide and treating their healthcare professionals. This comprehensive program includes the following clinical trials:

Phase 1/2 trial to assess the safety, tolerability, pharmacokinetics, and initial antitumor activity of ALUNBRIG
A phase 2 pivotal ALTA trial to evaluate the efficacy and safety of the ALUNBRIG two-dose regimen in patients with ALK+ locally advanced or metastatic NSCLC who progressed during crizotinib administration
Phase 3 ALTA-1L global randomized trial comparing the efficacy and safety of ALUNBRIG with crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not previously used ALK inhibitors
A two-stage, single-group, multicenter trial of Japanese ALK+ NSCLC patients with a focus on patients who progressed during the use of alectinib
Phase 2 global single-group trial to evaluate ALUNBRIG for advanced ALK+ NSCLC patients who progressed during the use of alectinib or ceritinib
Phase 3 global randomized trial comparing the efficacy and safety of ALUNBRIG and alectinib in patients with ALK+ NSCLC who progressed during crizotinib administration
For further information on brigitinib clinical trials, please visit www.clinicaltrials.gov .

Important safety information (US)

Warnings and precautions

Interstitial lung disease (ILD)/interstitial inflammation: ALUNBRIG can cause severe, life-threatening and lethal pulmonary adverse events consistent with interstitial lung disease (ILD)/pulmonary interstitial inflammation. In the ALTA (ALTA) trial, the incidence of ILD/pulmonary interstitial inflammation was 3.7% in the 90 mg group (9 mg once daily) and 90 to 180 mg in the group (180 mg once daily, 7 days in the introduction period of 90 mg). Once a day) is 9.1%. 6.4% of patients had an adverse reaction with ILD/pulmonary interstitial inflammation in the early stage (within 9 days after ALUNBRIG was activated; median onset within 2 days), and 2.7% showed a 3 to 4 degree response. New or worsening of respiratory symptoms (eg, difficulty breathing, coughing, etc.) should be monitored, especially during the first week of ALUNBRIG activation. Once patients have new or worsening respiratory symptoms, ALUNBRIG should be suspended and other causes of ILD/pulmonary interstitial or respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia) should be assessed immediately. For 1 or 2 degrees of ILD/Pulmonary Interstitial, you can restart ALUNBRIG or permanently disable ALUNBRIG after returning to baseline. For 3 or 4 degrees ILD/pulmonary interstitial inflammation, or 1 or 2 degrees of ILD/pulmonary interstitial recurrence, ALUNBRIG should be permanently discontinued.

Hypertension: In the ALTA trial, the reported rate of hypertension was 11% in the ALUNBRIG 90 mg group and 21% in the 90→180 mg group. Overall, 5.9% of patients developed 3 degrees of hypertension. Blood pressure should be controlled before ALUNBRIG treatment. Blood pressure should be monitored after 2 weeks of ALUNBRIG treatment, at least once a month. For 3 degrees of hypertension, ALUNBRIG should be suspended even if the best antihypertensive medication is taken. After the relief of hypertension, or the severity is improved to 1 degree, ALUNBRIG can be restarted in a reduced amount. For the recurrence of 4 degrees of hypertension or 3 degrees of hypertension, consider permanently discontinuing ALUNBRIG treatment. ALUNBRIG should be used with caution in combination with antihypertensive drugs that cause bradycardia.

Bradycardia: ALUNBRIG can cause bradycardia. In the ALTA trial, heart rate was less than 50 hops per minute (bpm), 5.7% in the 90 mg group, and 7.6% in the 90→180 mg group. One patient (0.9%) in the 90 mg group developed a 2 degree bradycardia. Heart rate and blood pressure should be monitored during ALUNBRIG treatment. If it is unavoidable to combine drugs known to cause bradycardia, the frequency of monitoring should be increased. For symptomatic bradycardia, ALUNBRIG should be suspended and checked for any combination of drugs known to cause bradycardia. If a combination of drugs known to cause bradycardia is found and the dose has been discontinued or adjusted, ALUNBRIG may be restarted at the original dose after bradycardia relief; otherwise, ALUNBRIG dose should be reduced after symptomatic bradycardia relief . For life-threatening bradycardia, ALUNBRIG should be discontinued if no comorbid combination is found.

Visual impairment: In the ALTA trial, the rate of adverse reactions (including blurred vision, diplopia, and visual acuity) caused by visual impairment was 7.3% in the ALUNBRIG 90 mg treatment group and 10% in the 90→180 mg group. 3 degree macular edema and cataract occurred in 1 case in each group of 90→180 mg. Patients should be informed to report any visual symptoms. If the patient has a new or worsened visual condition of 2 degrees or more, ALUNBRIG should be suspended and an ophthalmologic assessment should be performed. If the 2 or 3 degree visual impairment returns to 1 degree or the baseline severity, ALUNBRIG can be restarted in a reduced amount. For 4 degree visual impairment, ALUNBRIG should be permanently disabled.

Increase in creatine phosphokinase (CPK): In the ALTA trial, elevated creatine phosphokinase (CPK) was 27% in the ALUNBRIG 90 mg treatment group and 48% in the 90→180 mg group. The incidence of CPK increased by 3-4 degrees, 2.8% in the 90 mg group and 12% in the 90→180 mg group. The decrease in the amount of CPK was 1.8% in the 90 mg group and 4.5% in the 90→180 mg group. Patients should be informed to report any unexplained muscle pain, tenderness or weakness. CPK levels should be monitored during ALUNBRIG treatment. For a 3 or 4 degree CPK rise, ALUNBRIG should be suspended. To be relieved or restored to 1 degree or baseline, ALUNBRIG can be restarted at the original dose or decrement.

Increased pancreatic enzyme: In the ALTA test, amylase increased by 27% in the 90 mg group and 39% in the 90→180 mg group. The increase in lipase was 21% in the 90 mg group and 45% in the 90→180 mg group. The increase in amylase at 3 or 4 degrees was 3.7% in the 90 mg group and 2.7% in the 90→180 mg group. Those with elevated 3 or 4 degrees of lipase were 4.6% in the 90 mg group and 5.5% in the 90→180 mg group. Lipase and amylase should be monitored during ALUNBRIG treatment. For 3 or 4 degrees of pancreatic enzyme elevation, ALUNBRIG should be suspended. To be relieved or restored to 1 degree or baseline, ALUNBRIG can be restarted at the original dose or decrement.

Hyperglycemia: In the ALTA trial, 43% of patients who received ALUNBRIG developed new or worsening hyperglycemia. 3.7% of patients developed 3-degree hyperglycemia (laboratory assessment based on fasting blood glucose levels). Of the 20 patients with diabetes or glucose intolerance at baseline, 2 (10%) required insulin to be activated during ALUNBRIG. Fasting blood glucose should be assessed before ALUNBRIG is enabled and should be monitored periodically. Enable or adjust hypoglycemic agents as necessary. If the optimal drug treatment does not adequately control blood glucose, ALUNBRIG should be suspended until the blood glucose is fully controlled. ALUNBRIG reduction or permanent withdrawal may also be considered.

Embryo fetal toxicity: According to its mechanism of action and animal studies, pregnant women taking ALUNBRIG can cause fetal damage. Lack of clinical data on the use of ALUNBRIG in pregnant women. The pregnant woman should be informed of the potential risk of the drug to the fetus. Women of childbearing age should be informed of effective non-hormonal contraception during ALUNBRIG treatment and at least 4 months after the last dose. Men with a female partner of childbearing age should be informed of effective contraception during treatment and at least 3 months after the last dose.

Adverse reactions

The incidence of serious adverse reactions was 38% in the 90 mg group and 40% in the 90→180 mg group. The most common serious adverse reactions were pneumonia (65% overall, 3.7% in the 90 mg group, 7.3% in the 90→180 mg group) and ILD/Pulmonary Interstitial (the overall incidence was 4.6%, 90 mg). The group incidence rate was 1.8%, and the 90→180 mg group was 7.3%). 3.7% of patients had fatal adverse reactions, including pneumonia (2 cases), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis, and urinary sepsis (1 case each).

The most common (≥25%) adverse reactions, 90 mg were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%), and 90→180 mg was nausea (40%) Diarrhea (38%), fatigue (36%), cough (34%) and headache (27%).

medicine interactions

CYP3A inhibitors : ALUNBRIG should be avoided in combination with potent CYP3A inhibitors. Grapefruit or grapefruit juice can also increase the plasma concentration of brigitinib and should be avoided. If it cannot be avoided in combination with a potent CYP3A inhibitor, ALUNBRIG should be reduced.

CYP3A inducer : ALUNBRIG should be avoided in combination with a potent CYP3A inducer.

CYP3A Substrate: The combination of ALUNBRIG and CYP3A substrate (including hormonal contraceptives) can cause a decrease in the concentration and failure of the CYP3A substrate.

Special population medication

Pregnant women: ALUNBRIG can cause fetal damage. The potential risk of the drug to the fetus should be informed to women of childbearing age.

Lactation: No data on the effect of brigitinib on breast milk secretion or on breast-fed infants or breast milk production. Breastfeeding women are advised not to breastfeed during ALUNBRIG treatment due to potential adverse effects in breastfed infants.

Men and women of childbearing age:

Contraception : Women of childbearing age should be informed of effective non-hormonal contraception during ALUNBRIG treatment and at least 4 months after the last dose.

Infertility : ALUNBRIG can cause male fertility to decline.

Pediatric Use: The safety and efficacy of ALUNBRIG in children is not established.

Geriatric Use: The ALUNBRIG clinical study did not include a sufficient number of patients aged 65 years and older to determine if their remission differed from that of younger patients. Of the 222 patients with ALTA, 19.4% were between 65-74 years old and 4.1% were 75 years or older. There were no clinically significant differences in the safety or efficacy of patients ≥65 years of age and younger patients.

Hepatic or renal dysfunction: Patients with mild liver damage or mild or moderate renal impairment are not recommended to adjust the dose. The safety of ALUNBRIG in patients with moderate or severe liver damage or severe renal impairment has not been studied.