On April 28, 2017 OncoCyte Corporation (NYSE MKT:OCX), a developer of novel, non-invasive blood based tests to aid in the early detection of cancer, reported its financial results for the quarter ended March 31, 2017(Press release, BioTime, APR 28, 2017, View Source [SID1234518721]). In addition, OncoCyte announced it will conduct an investor call on May 22, 2017 at 4:30pm ET/1:30 pm PT after its lead investigator Dr. Anil Vachani presents data from the 300 patient R&D Validation study at the American Thoracic Society 2017 International Conference (ATS) in Washington D.C.

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"We made significant progress during the first quarter towards the commercialization of our lung cancer diagnostic product, including initiating a search for a head of our sales organization as well as beginning the expansion of our sales, marketing and market access teams," commented William Annett, Chief Executive Officer. "We believe the data on our lung cancer test being presented in May demonstrates the robustness of our science and strengthens our market position."

"We plan to provide investors with an overview of the results from the 300 patient R&D Validation study on our conference call following the presentation. We believe the total addressable market for our lung cancer diagnostic test could be over $4 billion, and that we are positioned to be the first company to provide a highly accurate non-invasive confirmatory blood test to address this market. Our focus over the next few months is to complete the development process, obtain CLIA certification of our laboratory, and prepare for our anticipated commercial launch in the second half of the year."

Significant First Quarter Accomplishments

Reported the successful results of the R&D Validation study for its lung cancer diagnostic test. The results, based on the analysis of samples from approximately 300 patients, confirmed previously reported data presented by The Wistar Institute at the CHEST 2016 Annual Meeting in October. The data from the study exceed levels OncoCyte believes necessary for a commercially successful test.

Reported that it locked its prediction algorithm and intends to move to the Clinical Validation phase of development—the last phase before commercial launch.

Submitted the application for CLIA certification of OncoCyte’s laboratory where the assay will be run.

Announced that its breast cancer test is developing ahead of schedule, and began a follow-up, multi-center study to further develop and verify the results of the earlier studies.
Near-term Milestones

OncoCyte is continuing to make progress and has several upcoming events and milestones related to the development of its lung cancer diagnostic:

Poster presentation of lung cancer diagnostic R&D Validation study at the (ATS) International Conference. The data will be presented by Dr. Anil Vachani, an Associate Professor of Medicine at the Hospital of the University of Pennsylvania and the Veteran’s Administration Medical Center, at 2:15 p.m. ET on May 22, 2017.

Conference call to report on 300-patient R&D Validation study, to be held at 4:30pm ET on May 22, 2017.

Establishment of a medical advisory committee (MAC), headed by top lung cancer specialists. The MAC will advise OncoCyte on clinical unmet needs and future development strategy.

CLIA certification and California state clinical laboratory license, which OncoCyte expects to receive during the second quarter of 2017.

Clinical Validation study to confirm and replicate OncoCyte’s findings in a commercial CLIA lab setting.

Expansion of OncoCyte’s commercial capabilities in sales and marketing, revenue cycle management and reimbursement.

Launch of lung cancer test during second half of 2017 assuming successful completion of the Clinical Validation and CLIA certification.
First Quarter 2017 Financial Results

For the quarter ended March 31, 2017, OncoCyte incurred a net loss of $4.7 million, or $0.16 per share, compared to a net loss of $2.9 million, or $0.12 per share, in 2016. The $4.7 million net loss includes a $1.1 million noncash expense, or $0.04 per share, related to issuance of warrants to certain shareholders as an inducement to exercise warrants. During the first quarter OncoCyte used $3.3 million in operating activities compared to $2.2 million from the comparative prior quarter.

Research and development expenses for the quarter ended March 31, 2017 were $1.8 million compared to $1.7 million for the same period in 2016. Overall the slight increase in research and development expenses was due to increased staffing and laboratory expenses.

General and administrative expenses increased to $2.0 million from $1.0 million for the same period in 2016. Sales and marketing expenses increased to $0.7 million from $0.2 million. The increases were attributable to a $1.1 million noncash expense for the issuance of warrants as well as increased staffing for the expected commercial launch of OncoCyte’s lung cancer diagnostic during second half of 2017.

At March 31, 2017, OncoCyte had liquid assets of $13 million, including $11.4 million of cash and cash equivalents, and available-for-sale securities valued at $1.6 million.

On April 28, 2017 Bayer reported that the U.S. Food and Drug Administration (FDA) approved Stivarga (regorafenib) tablets for the second-line treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Nexavar (sorafenib) (Press release, Bayer, APR 28, 2017, View Source [SID1234518717]).

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Stivarga is the first and only treatment to demonstrate significant improvement in overall survival in second-line HCC patients. In the RESORCE trial, Stivarga was shown to provide a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo; the median OS was 10.6 [(n=379) (CI 9.1, 12.1)] vs 7.8 [(n=194) (CI 6.3, 8.8)] months, respectively (HR 0.63, 95% CI 0.50-0.79; p<0.0001). This translates to a 37% reduction in the risk of death. The number of deaths in each arm included 233 of 379 (62%) with Stivarga and 140 of 194 (72%) with placebo. Today’s FDA approval expands Bayer’s leadership in liver cancer with a treatment plan in HCC involving use of Stivarga directly after progression on Nexavar.

Stivarga is an oral inhibitor of multiple kinases involved in normal cellular functioning and in pathological processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. The FDA’s approval is based on data from the international, multicenter, placebo-controlled Phase III RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma; NCT 01774344] trial, which investigated patients with HCC whose disease had progressed during treatment with Nexavar. The most frequently observed adverse drug reactions (≥30%) in patients treated with regorafenib vs. placebo-treated patients in HCC, respectively, were: pain (55% vs. 44%), HFSR/PPE (51% vs. 7%), asthenia/fatigue (42% vs. 33%), diarrhea (41% vs. 15%), hypertension (31% vs. 6%), infection (31% vs. 18%), decreased appetite and food intake (31% vs. 15%).

"Hepatocellular carcinoma is very hard to treat, and with no new treatments in nearly a decade, options have been very limited for physicians and patients," said Dr Jordi Bruix, lead investigator for the RESORCE trial, BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Spain. "The U.S. approval of Stivarga for hepatocellular carcinoma therefore provides a significant step forward in addressing the high unmet need in this patient population."

The incidence of liver cancer is increasing worldwide and it is already the sixth most common cancer in the world and the second leading cause of cancer-related deaths globally.

"Bayer is proud to have played a significant role in the treatment of hepatocellular carcinoma," said Robert LaCaze, executive vice president and head of the Oncology Strategic Business Unit at Bayer. "We first embarked on our scientific research in this area 20 years ago. We could not have done it alone: we would like to thank the patients, caregivers and investigators for their participation and engagement in the RESORCE trial."

The approval of Stivarga in liver cancer marks the third time that this therapy has been granted FDA approval on a priority basis. The FDA granted Fast Track designation to Stivarga in HCC, which is an expedited program designed to facilitate development and review of drugs to address an unmet medical need in the treatment of a serious or life-threatening condition. The FDA also granted Orphan Drug Designation (ODD) to Stivarga in HCC. The ODD program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases and disorders. Additional regulatory filings for Stivarga in HCC are under review in countries around the world, including the EU, Japan and China. Decisions in the EU and Japan regions are expected later this year.

About Hepatocellular Carcinoma
Hepatocellular carcinoma, or HCC, is the most common form of liver cancer and represents approximately 70-85 percent of liver cancer worldwide. More than 780,000 cases of liver cancer are diagnosed worldwide each year (52,000 in the European Union, 501,000 in the Western Pacific region and 30,000 in the United States). In 2012, approximately 746,000 people died of liver cancer including approximately 48,000 in the European Union, 477,000 in the Western Pacific region and 24,000 in the United States.

About Regorafenib (Stivarga)
Regorafenib is an oral multi-kinase inhibitor that potently blocks multiple protein kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), metastasis (VEGFR3, PDGFR, FGFR) and tumor immunity (CSF1R).

Regorafenib is already approved under the brand name Stivarga in more than 90 countries worldwide, including the U.S., countries of the EU, China and Japan for the treatment of mCRC. The product is also approved in over 80 countries, including the U.S., countries of the EU, China and Japan, for the treatment of metastatic GIST. In April 2017, Stivarga was approved in the U.S. for use in patients with HCC who have been previously treated with sorafenib. In the U.S., Stivarga is already indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy. It is also indicated for the treatment of patients with locally advanced, unresectable or metastatic GIST who have been previously treated with imatinib mesylate and sunitinib malate. In the EU, Stivarga is indicated for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, as well as for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib.

Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.

On April 28, 2017 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that ALUNBRIG (brigatinib) has received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib (Press release, Ariad, APR 28, 2017, View Source [SID1234518734]). This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ALUNBRIG, which previously received Breakthrough Therapy Designation from the FDA, is a once-daily oral therapy that may be taken with or without food.

"In recent years, small molecule ALK inhibitors have revolutionized the treatment options for those with advanced ALK+ non-small cell lung cancer. Nevertheless, there is still a need for additional ALK inhibitors like brigatinib (ALUNBRIG), which have a manageable safety profile and may address mechanisms of clinical resistance to crizotinib, including progression in the central nervous system," said D. Ross Camidge, M.D., Ph.D., director of thoracic oncology at the University of Colorado. "The ALTA trial showed that brigatinib (ALUNBRIG) was highly effective post-crizotinib with the majority of patients who received 180 mg once daily with a seven-day lead in at 90 mg once daily achieving an overall response and a median duration of response greater than one year. Importantly, the extent of activity among those with brain metastases was also notable."

"For patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib, who are facing the uncertainty of disease progression and the potentially devastating impact of brain metastases, the approval of ALUNBRIG offers a new hope," said Bonnie Addario, founder and chair of the Addario Lung Cancer Foundation (ALCF).

"The rapiddevelopment of ALUNBRIG is a tribute to the dedication of many research scientists and clinicians who carefully designed and developed this new medicine to address unmet medical needs in the ALK+ NSCLC patient population. Most importantly, we would like to thank the patients and families who participated in the clinical trials," said Andy Plump, M.D., Ph.D., Takeda Chief Medical and Scientific Officer.

"Today’s FDA approval of ALUNBRIG is an important milestone in the treatment of patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib," said Christophe Bianchi, M.D., President, Takeda Oncology. "Takeda is committed to the continued development of ALUNBRIG around the globe and to bringing this important therapy to more patients in need."

About the ALTA Trial

The FDA approval of ALUNBRIG was primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial of brigatinib in adults. This ongoing, two-arm, open-label, multicenter trial enrolled 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib. Patients received either 90 mg of ALUNBRIG once daily (n=112) or 180 mg once daily following a seven-day lead-in of 90 mg once daily (n=110). The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR.

The recommended dosing regimen for ALUNBRIG is 90 mg orally once daily for the first 7 days. If 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.

With a median follow-up of 8 months (range 0.1 – 20.2), results demonstrated that of the patients who received the recommended dosing regimen (90→180 mg), 53 percent achieved a confirmed overall response (OR) as assessed by IRC and 54 percent as assessed by Investigator. At the recommended dosing regimen, the median duration of response was 13.8 months as assessed by IRC and 11.1 months by Investigator assessment. Additionally, at the recommended dosing regimen, 67 percent of patients with measurable brain metastases (n=18) achieved a confirmed intracranial OR by IRC assessment.

Efficacy data are as follows:

ALTA Efficacy Results

Efficacy parameter

IRC Assessment

Investigator Assessment

90 mg once daily
(N=112)

90→180 mg
once daily
(N=110)

90 mg once daily
(N=112)

90→180 mg
once daily
(N=110)

Overall Response Rate (95% CI)

48% (39-58)

53% (43-62)

45% (35-54)

54% (44-63)

Complete Response, n (%)

4 (3.6%)

5 (4.5%)

1 (0.9%)

4 (3.6%)

Partial Response, n (%)

50 (45%)

53 (48%)

49 (44%)

55 (50%)

Duration of Response, median in months
(95% CI)

13.8
(7.4-NE)

13.8
(9.3-NE)

13.8
(5.6-13.8)

11.1
(9.2-13.8)











CI = Confidence Interval; NE = Not Estimable

IRC assessment of intracranial efficacy is shown below:

Intracranial Overall Response in Patients with Measurable Brain Metastases in ALTA

Efficacy parameter

IRC Assessment

90 mg once daily
(N=26)

90→180 mg once daily
(N=18)

Intracranial Overall Response Rate, (95 % CI)

42% (23-63)

67% (41-87)

Complete Response, n (%)

2 (7.7%)

0

Partial Response, n (%)

9 (35%)

12 (67%)

Duration of Intracranial Response, median (months)
(range)

NE
(1.9+ – 9.2+)

5.6
(1.9+ – 9.2+)

CI = Confidence Interval; NE = Not Estimable

Among the 23 patients who exhibited an intracranial response, 78% of patients in the 90 mg arm and 68% of patients in the 90→180 mg group maintained a response for at least four months.

The warnings and precautions for ALUNBRIG are: interstitial lung disease (ILD)/pneumonitis, hypertension, bradycardia, visual disturbance, creatine phosphokinase (CPK) elevation, pancreatic enzyme elevation, hyperglycemia and embryo-fetal toxicity.

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

At the recommended dosing regimen, the most common adverse reactions (≥25%) with ALUNBRIG were nausea, diarrhea, fatigue, cough, and headache.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 222,500 new cases of lung cancer diagnosed each year in the United States, according to the American Cancer Society. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients as well. Approximately two to eight percent of patients with NSCLC have a rearrangement in the ALK gene.

The central nervous system (CNS) is a frequent site for ALK+ NSCLC progression, with up to 70 percent of patients with ALK+ NSCLC who have been treated with a first-line ALK inhibitor facing brain metastases.

About ALUNBRIG (brigatinib)

ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib, and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC. A Marketing Authorization Application (MAA) for ALUNBRIG was submitted to the European Medicines Agency (EMA) in February 2017.

The ALTA clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them. In addition to the ongoing Phase 1/2 and Phase 2 ALTA trial, brigatinib is also being studied in the Phase 3 ALTA 1L trial to assess its efficacy and safety in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor.

To learn more about ALUNBRIG, please visit www.ALUNBRIG.com or call A1Point: 1-844-A1POINT (1-844-217-6468).

For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for
life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3‑4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

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

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.
CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates: Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.

USE IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.
Lactation: Advise lactating women not to breastfeed during treatment with ALUNBRIG and for 1 week following the final dose.
Females and Males of Reproductive Potential:
Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.
Infertility: ALUNBRIG may cause reduced fertility in males.
Pediatric Use: The safety and efficacy of ALUNBRIG in pediatric patients have not been established.
Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.
Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG in patients with moderate or severe hepatic impairment or severe renal impairment has not been studied.

Please see the full Prescribing Information for ALUNBRIG at www.ALUNBRIG.com

On April 28, 2017 Novartis reported the US Food and Drug Administration (FDA) has approved Rydapt (midostaurin, formerly PKC412) for two indications (Press release, Novartis, APR 28, 2017, View Source [SID1234518731]). The first indication is for the treatment of acute myeloid leukemia (AML) in newly diagnosed patients who are FMS-like tyrosine kinase 3 mutation-positive (FLT3+), as detected by an FDA-approved test, in combination with chemotherapy[3]. Rydapt is also approved to treat adults with advanced systemic mastocytosis (SM), which includes aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) and mast cell leukemia[3]. This approval follows a prior Breakthrough Therapy designation in FLT3-mutated AML, as well as Orphan Drug designation and Priority Review in both indications by the FDA. Worldwide filings for Rydapt are currently underway.

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"Rydapt represents a remarkable advance as the first and only targeted therapy approved for patients who had limited options for many years," said Bruno Strigini, CEO, Novartis Oncology. "We are proud to continue our leadership in hematology as we work diligently to bring innovative medicines to patients worldwide."

Rydapt is the only approved targeted therapy for newly diagnosed FLT3-mutated AML
AML is a rare and aggressive cancer of the blood and bone marrow[4]. In the US, about 21,000 people are estimated to be diagnosed with AML in 2017[5]. Approximately one-third of these AML patients, or 7,000, will have a FLT3 gene mutation[6]. FLT3 is a type of cell-surface receptor which plays a role in increasing the number of certain blood cells[7]. The FLT3 gene mutation can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML[6],[7],[8]. Prior to the approval of Rydapt, the AML therapeutic strategy had remained relatively unchanged for more than 25 years[1],[2].

"The overall survival advantage for midostaurin plus chemotherapy seen in the RATIFY trial was a significant advancement for newly diagnosed AML patients with the FLT3 mutation," said Dr. Richard Stone, Chief of Staff and Director of the Adult Leukemia program at Dana-Farber Cancer Institute, and Alliance for Clinical Trials in Oncology study chair for the RATIFY trial. "The availability of midostaurin now helps to establish a new standard of care in this high-risk patient population."

Rydapt is indicated for use in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test[3]. Rydapt is not indicated as a single-agent induction therapy for the treatment of patients with AML[3].

The FDA approval is based on the Phase III RATIFY (CALGB 10603 [Alliance]) clinical trial, which was conducted in collaboration with the Alliance for Clinical Trials in Oncology and its 13 contributing international cooperative groups. In the trial, newly diagnosed FLT3+ patients who received Rydapt plus chemotherapy experienced significant improvement in overall survival with a 23% reduction in the risk of death compared with chemotherapy alone (hazard ratio [HR] = 0.77, 95% confidence interval [CI], 0.63, 0.95; 2 sided p=0.016)[3].

Event-free survival (EFS; event defined as no complete remission within 60 days of the start of induction therapy, relapse or death) was significantly higher for Rydapt plus chemotherapy versus chemotherapy alone (median of 8.2 months compared to 3.0 months, HR = 0.78, 95% CI 0.66, 0.93 and 2 sided p=0.004)[3]. RATIFY is the largest worldwide clinical trial in newly diagnosed FLT3-mutated AML to date, as 3,279 AML patients were screened for the FLT3 mutation and 717 patients were enrolled[9]. All FLT3+ patients enrolled in the trial were treated regardless of whether or not cytogenetic status was normal or abnormal[3].

The most frequent adverse reactions (incidence greater than or equal to 20%) in the Rydapt plus chemotherapy arm were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae (small red skin spots), device-related infection, epistaxis, hyperglycemia and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence greater than or equal to 10%) were febrile neutropenia, device-related infection and mucositis[3].

In order to identify FLT3+ AML patients who may benefit from Rydapt, Novartis collaborated with Invivoscribe Technologies, Inc. on the development of LeukoStrat CDx FLT3 Mutation Assay, a companion molecular diagnostic test, which was also approved by the FDA today. LeukoStrat CDx FLT3 Mutation Assay is the first molecular companion diagnostic in AML and identifies both FLT3 internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations and is performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.

Rydapt provides an innovative treatment option for advanced SM
Advanced SM is a rare blood disorder characterized by uncontrolled growth and accumulation of mast cells – or mediators of allergic responses – in one or more organs[10]. In advanced SM, mast cells accumulate in such high quantities that they begin to cause organ damage[10]. Median overall survival is currently less than six months for mast cell leukemia[11], two years for SM-AHN and 3.5 years for ASM[12].

Rydapt is approved in the US for the treatment of adult patients with ASM, SM-AHN, or mast cell leukemia[3]. The approval of Rydapt was based on two single-arm open-label multicenter trials, including the Phase II study (CPKC412D2201), which was the largest and longest-running prospective trial ever conducted in this ultra-rare disorder. The efficacy of Rydapt was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by six cycles of treatment per the modified Valent criteria (n=89), in which CR and ICR are the two most rigorous subcategories of a major response. This analysis demonstrated an overall response rate of 21% (95% CI, 13, 31)[3]. Efficacy was also assessed in a post-hoc analysis using the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria (n=115)[2]. This assessment estimated complete remission or partial remission rate of 17% (95% CI, 10, 25)[3].

The most frequent adverse reactions (incidence greater than or equal to 20%), excluding laboratory terms, were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache and dyspnea. The most frequent Grade 3 or greater adverse reactions (incidence greater than or equal to 5%), excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain and renal insufficiency[3].

About AML
AML is the most common acute leukemia in adults; it accounts for approximately 25% of all adult leukemias worldwide, with the highest incidence rates occurring in the US, Europe and Australia[13]. It also has the lowest survival rate of all adult leukemias[13].

AML prevents white blood cells from maturing, causing an accumulation of "blasts," which do not allow room for the normal blood cells[5]. Mutations in specific genes are found in many cases of AML[6], and genetic testing for mutations in newly diagnosed AML patients can help to determine prognosis and potential treatment strategies[14].

About advanced SM
In advanced SM, the uncontrolled growth of neoplastic mast cells causes organ damage (e.g., liver dysfunction), low blood counts and weight loss[10]. Patients also suffer from debilitating systemic symptoms such as pruritus (severe itching of the skin) caused by mast cells releasing inflammatory mediators, such as histamine, into the blood[10].

The uncontrolled proliferation of mast cells is caused in many people by a KIT gene mutation – the most common mutation, encoding the D816V substitution, occurs in approximately 90% of patients[15]. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells[16].

About Rydapt (midostaurin)
Rydapt (midostaurin) is an oral, multi-targeted inhibitor of multiple kinases, including FLT3 and KIT, which help regulate many essential cell processes, interrupting cancer cells’ ability to grow and multiply[3].

Rydapt is available in 25 mg capsules. In AML, the recommended dosage for Rydapt is 50 mg orally twice daily on days 8 to 21 each cycle of induction therapy and on days 8 to 21 each cycle of consolidation therapy[3]. For a description of the experience with single-agent treatment beyond induction and consolidation, healthcare professionals should refer to the Clinical Studies section of the Prescribing Information (14.1)[3].

In advanced SM, the recommended dosage for Rydapt is 100 mg orally twice daily[3].

The full prescribing information for Rydapt can be found at: View Source

Rydapt Important Safety Information
Patients who are allergic to midostaurin or any of the ingredients in Rydapt should not take Rydapt. If a patient taking Rydapt develops signs of an allergic reaction, they should seek medical help immediately. Signs of an allergic reaction include trouble breathing, flushing, chest pain, throat tightness, and swelling of lips, mouth or throat.

Rydapt should be not be used during pregnancy since Rydapt may harm an unborn baby. Pregnancy testing should be conducted for women who might become pregnant. Effective birth control should be used during treatment and for at least four months after stopping Rydapt. If a patient becomes pregnant or thinks she may be, the patient should tell their doctor right away. Women should not breastfeed during treatment with Rydapt and for at least four months after the final dose. Men taking Rydapt who have female partners that are able to become pregnant should use effective birth control during his treatment with Rydapt and for at least four months after the last Rydapt dose. Rydapt may cause fertility problems in women and men, which may affect their ability to have children.

Rydapt may cause lung problems that may lead to death. Patients on Rydapt who develop a new or worsening cough, shortness of breath, or chest discomfort should get medical help right away. These may be signs of serious lung problems.

Common sides effects reported during Rydapt treatment for AML included low level of white blood cells with fever (febrile neutropenia); nausea; redness, pain or ulcers inside the mouth (mucositis); vomiting; headache; bruising; muscle or bone pain; nose bleeds; device-related infection; high blood sugar levels (hyperglycemia) and upper respiratory infections.

Common side effects reported during treatment for ASM, SH-AHM or mast cell leukemia included nausea; vomiting; diarrhea; swelling of the hands, feet or ankles; muscle or bone pain; stomach-area pain; tiredness; upper respiratory infection; constipation; fever; headache and trouble breathing.

If side effects including nausea, vomiting, and diarrhea occur, get worse or do not go away during treatment with Rydapt, patients should contact their doctor. Depending on the side effect and/or severity of the side effect that occur, their doctor may decrease their dose, temporarily stop, or completely stop treatment with Rydapt.

Patients should tell their doctor about all the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Rydapt may affect how these medicines work or these other medicines may affect how Rydapt works.

On April 28, 2017 Sanofi reported financial results for the quarter ended March 31, 2017 (Press release, Sanofi, APR 28, 2017, View Source [SID1234518740]).

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Q1 2017 sales growth supported by Specialty Care, Vaccines and Emerging Markets

Net sales were €8,648 million, up 11.1% on a reported basis and 8.6%(4) at CER reflecting the acquisition of Boehringer Ingelheim’s (BI) CHC business and full consolidation of Sanofi’s European vaccine operations. At constant structure and CER, net sales were up 3.5%.
Sanofi Genzyme (Specialty Care) GBU sales increased 15.5% at CER driven by Multiple Sclerosis products.
Diabetes and Cardiovascular GBU sales were down 7.7% at CER; Global Diabetes franchise sales decreased 6.0%.
Sanofi Pasteur GBU grew 13.2% at CER and constant structure due to the strong performance of pediatric combinations.
CHC GBU sales were up 4.7% at CER and constant structure driven by the performance in Europe.
Emerging Markets(5) sales increased 8.5% at CER and constant structure.

Strong financial results and 2017 guidance confirmed

Business operating income of €2,442 million, up 7.6% at CER and constant structure.
Business EPS(2) grew 3.0% at CER to €1.42 and increased 6.0% on a reported basis.
Sanofi continues to expect 2017 Business EPS(2) to be stable to -3%(6) at CER, barring unforeseen major adverse events.
IFRS net income of €5,701 million (up 424%) included a net gain of €4,427 million resulting from the divestment of Merial.

Sanofi progresses on its 2020 roadmap

Integration of Boehringer Ingelheim CHC business on track, enhancing Sanofi’s position in key categories and regions.
Following the termination of the SPMSD JV, European vaccine business now fully driven by Sanofi.
Dupixent, a breakthrough therapy for moderate-to-severe atopic dermatitis, now available to adult patients in the U.S.
Soliqua100/33, first once-daily fixed combination of Lantus and lixisenatide for type-2 diabetes, launched in the U.S.
Kevzara BLA for the treatment of rheumatoid arthritis granted PDUFA date of May 22, 2017.
FDA approval of Xyzal Allergy 24H for OTC use and launch underway ahead of the U.S. spring allergy season.


Sanofi Chief Executive Officer, Olivier Brandicourt, commented:
"We have started the year with robust growth driven by Specialty Care and Vaccines as well as good performance in Emerging Markets. Our top line in the first quarter also benefited from the integration of the Boehringer Ingelheim CHC and European vaccine businesses. At the same time, the simplified organization continues to contribute to Sanofi’s financial performance. The U.S. launch of Dupixent for moderate-to-severe atopic dermatitis marks a key innovation milestone on our strategic roadmap and lays the foundation for our new immunology franchise. We are excited to bring this highly innovative medicine to patients suffering from this devastating disease".

(1) CS: constant structure: adjusted for BI CHC business, termination of SPMSD and others; (2) In order to facilitate an understanding of operational performance, Sanofi comments on the business net income statement. Business net income is a non-GAAP financial measure (see Appendix 8 for definitions). The consolidated income statement for Q1 2017 is provided in Appendix 3 and a reconciliation of IFRS net income reported to business net income is set forth in Appendix 4; (3) The closing of the disposal of Merial in Mexico is expected in 2017; (4) changes in net sales are expressed at constant exchange rates (CER) unless otherwise indicated (see Appendix 8); (5) See page 7; (6) 2016 Business EPS was €5.68

Investor Relations: (+) 33 1 53 77 45 45 – E-mail: [email protected] – Media Relations: (+) 33 1 53 77 46 46 – E-mail: [email protected]
Website: www.sanofi.com Mobile app: SANOFI IR available on the App Store and Google Play

2017 first-quarter Sanofi sales
Unless otherwise indicated, all percentage changes in sales in this press release are stated at CER(7).
In the first quarter of 2017, Company sales were €8,648 million, up 11.1% on a reported basis. Exchange rate movements had a favorable effect of 2.5 percentage points reflecting mainly the positive evolution of the U.S. dollar, Brazilian Real and Japanese Yen which more than offset the negative impact from the Egyptian Pound, Turkish Lira and British Pound. Company sales benefited from the acquisition of BI’s CHC business and full consolidation of Sanofi’s European vaccines operations leading to an increase of 8.6% at CER. At CER and constant structure, Company sales were up 3.5%.

Global Business Units
The table below presents sales by Global Business Unit (GBU) and reflects the organization of Sanofi which became effective as of January 1, 2016. This structure drives deeper specialization, simplifies reporting and provides clear focus on growth drivers. Please note that in Emerging Markets, Specialty Care and Diabetes and Cardiovascular sales are included in the General Medicines and Emerging Markets GBU.

Net Sales by GBU
(€ million)
Q1 2017
Change
(CER)
Change
at CER/CS*
Sanofi Genzyme (Specialty Care)(a)
1,379
+15.5%
+15.5%
Diabetes and Cardiovascular(a)
1,419
-7.7%
-7.7%
General Medicines & Emerging Markets(b)
3,725
+2.2%
+2.1%
Consumer Healthcare (CHC)
1,341
+42.7%
+4.7%
Total Pharmaceuticals
7,864
+7.4%
+2.6%
Sanofi Pasteur (Vaccines)
784
+22.2
+13.2%
Total Company sales
8,648
+8.6%
+3.5%
(a) Does not include Emerging Markets sales- see definition page 7; (b) Includes Emerging Markets sales for Diabetes & Cardiovascular and Specialty Care;
*CS : constant structure

Global Franchises
The table below presents first quarter 2017 sales by global franchise, including Emerging Markets sales, to facilitate comparisons. Appendix 1 provides a reconciliation of sales by GBU and franchise.
Net sales by Franchise
(€ million)
Q1 2017
Change
(CER)
Change
at CER/CS*
Developed
Markets
Change
at CER/CS*
Emerging
Markets
Change
at CER/CS*
Specialty Care
1,620
+15.6%
+15.6%
1,379
+15.5%
241
+16.3%
Diabetes and Cardiovascular
1,795
-4.0%
-4.0%
1,419
-7.7%
376
+12.3%
Established Rx Products
2,640
+0.6%
+0.3%
1,634
-4.1%
1,006
+8.3%
Consumer Healthcare (CHC)
1,341
+42.7%
+4.7%
937
+6.1%
404
+1.3%
Generics
468
-2.0%
-1.7%
268
-5.0%
200
+3.4%
Vaccines
784
+22.2%
+13.2%
468
+14.6%
316
+11.1%
Total net sales
8,648
+8.6%
+3.5%
6,105
+1.6%
2,543
+8.5%
*CS : constant structure
Pharmaceuticals
First-quarter Pharmaceuticals sales increased 7.4% to €7,864 million. At constant structure, Pharmaceuticals sales were up 2.6% driven by Multiple Sclerosis, CHC, Rare Disease, Oncology and Cardiovascular franchises.
(7) See Appendix 8 for definitions of financial indicators.

Rare Disease franchise
Net sales (€ million)
Q1 2017
Change
(CER)
Myozyme / Lumizyme
190
+12.7%
Cerezyme
176
-4.9%
Fabrazyme
177
+15.4%
Aldurazyme
52
+8.3%
Cerdelga
31
+30.4%
Others
86
+3.8%
Total Rare Diseases
712
+7.6%

In the first quarter, Rare Disease sales increased 7.6% to €712 million driven by the accrual of patients worldwide. Rare Disease sales grew at double digits in the U.S. and Emerging Markets, up 12.2% and 11.1%, respectively.

In the first quarter, Gaucher (Cerezyme and Cerdelga) sales decreased 1.0% to €207 million, due to lower Cerezyme sales in Emerging Markets (down 10.7% to €50 million) mostly driven by ordering patterns in Latin America. Cerdelga sales increased 30.4% to €31 million of which €25 million were generated in the U.S. (up 26.3%).

First-quarter Fabrazyme sales were up 15.4% to €177 million, reflecting a continued accrual of new Fabry patients.
Myozyme/Lumizyme sales increased 12.7% to €190 million in the first quarter, mainly due to new patient accruals and increased worldwide diagnosis of Pompe disease.

Multiple Sclerosis franchise
Net sales (€ million)
Q1 2017
Change
(CER)
Aubagio
371
+29.7%
Lemtrada
125
+40.9%
Total Multiple Sclerosis
496
+32.4%

First-quarter Multiple Sclerosis (MS) sales increased 32.4% to €496 million, reflecting strong Aubagio and Lemtrada performance in the U.S. and Europe.

In the first quarter, Aubagio sales increased 29.7% to €371 million driven by the U.S. (up 33.0% to €259 million) and Europe (up 23.0% to €91 million). In the U.S., Aubagio has achieved market share of 9.0% (source IMS TRX-Q1 2017) and is now the most "switched to" disease modifying therapy in the U.S. (source IMS NPA Market Dynamics).

First-quarter Lemtrada sales increased 40.9% to €125 million, including €67 million in the U.S. (up 39.1%) and €45 million in Europe (up 31.4%).

Oncology franchise
Net sales (€ million)
Q1 2017
Change
(CER)
Jevtana
97
+5.6%
Thymoglobulin
72
+7.7%
Taxotere
47
+2.2%
Eloxatin
45
+7.1%
Mozobil
40
+11.4%
Zaltrap
16
-5.9%
Others
95
+46.0%
Total Oncology
412
+12.8%

First-quarter Oncology sales increased 12.8% to €412 million driven mainly by Jevtana and boosted by a U.S. government order for Leukine. Jevtana sales were up 5.6% to €97 million in the first quarter led by Europe (up 5.7% to €37 million) and Japan. In the first quarter, Thymoglobulin sales increased 7.7% to €72 million supported by the U.S. (up 8.1% to €41 million).

Eloxatin sales increased 7.1% to €45 million in the first quarter supported by China (Emerging Markets sales were up 27.6% to €37 million) which offset generic competition in Canada. First-quarter Taxotere sales increased 2.2% (to €47 million) driven by Emerging Markets (up 23.3% to €37) which offset continued generic competition in Japan.

Diabetes franchise
Net sales (€ million)
Q1 2017
Change
(CER)
Lantus
1,226
-14.1%
Toujeo
192
+78.6%
Total glargine
1,418
-7.7%
Apidra
98
+14.1%
Amaryl
89
+5.7%
Insuman
27
-15.6%
BGM (Blood Glucose Monitoring)
17
–
Lyxumia
7
-22.2%
Soliqua
4
–
Total Diabetes
1,663
-6.0%

In the first quarter, Diabetes sales decreased 6.0% to €1,663 million, including lower Lantus sales in the U.S. First-quarter U.S. Diabetes sales were down 14.7% to €839 million. Sales in Emerging Markets increased 12.1% to €373 million. Sales in Europe were €326 million, a decrease of 3.0%.

In the first quarter, Sanofi glargine (Lantus and Toujeo) sales decreased 7.7% to €1,418 million. In the U.S., Sanofi glargine sales of €805 million were down 15.5% and reflected the impact of the exclusion from various CVS commercial formularies. The U.S. Diabetes sales decline is expected to accelerate over the remainder of the year primarily due to the United Health formulary exclusion which started April 1, 2017 as well as an incremental impact from the CVS formulary exclusion. In Europe, Sanofi glargine sales decreased 3.1% to €245 million due to biosimilar competition in several European markets.

Over the quarter, Lantus sales were €1,226 million down 14.1%. In the U.S., Lantus sales decreased 20.9% to €690 million mainly reflecting lower average net price and patients switching to Toujeo as well as the aforementioned impact of formulary exclusions. In Europe, first-quarter Lantus sales were €199 million (down 14.8%) due to biosimilar competition and patients switching to Toujeo. In Emerging Markets, sales were up 9.6% to €253 million.

First-quarter Toujeo sales were €192 million (up 78.6%) of which €115 million (up 42.3%) were recorded in the U.S. and €46 million in Europe.

Amaryl sales were €89 million, up 5.7% in the first quarter, of which €73 million were generated in Emerging Markets (up 8.5%).

First-quarter Apidra sales increased 14.1% to €98 million, reflecting double digit growth in the U.S. (up 12.0% to €29 million), Europe (up 12.9% to €35 million), and Emerging Markets (up 20.0% to €24 million).

Since January 2017, Soliqua 100/33 (insulin glargine 100 Units/mL & lixisenatide 33 mcg/mL injection; lixisenatide was in-licensed from Zealand Pharma) has been available in the U.S. Soliqua sales were €4 million in the first quarter.

Cardiovascular franchise
First-quarter Praluent sales (collaboration with Regeneron) were €34 million of which €24 million was in the U.S. and €8 million in Europe. This reflected significant payer utilization management restrictions in the U.S. and limited market access in Europe.

In January 2017, the U.S. District Court for the District of Delaware issued an injunction that required Sanofi and Regeneron to stop marketing, selling and manufacturing Praluent in the U.S. starting from February 21, 2017.

However, on February 8, 2017, the Court of Appeals for the Federal Circuit stayed (suspended) the permanent injunction for Praluent pending the companies’ appeal. As a result, Sanofi and Regeneron will continue marketing, selling and manufacturing Praluent in the U.S. during the appeal process. The Court of Appeals is scheduled to hear oral arguments on June 6, 2017.

First-quarter Multaq sales were €98 million, up 10.5% reflecting 9.6% growth (to €83 million) in the U.S.
Established Rx Products
Net sales (€ million)
Q1 2017
Change
(CER)
Lovenox
415
+2.2%
Plavix
380
-1.8%
Renvela/Renagel
246
+2.1%
Aprovel/Avapro
193
+13.0%
Synvisc /Synvisc-One
90
-1.1%
Myslee/Ambien/Stilnox
73
-1.4%
Allegra
68
-13.3%
Other
1,175
-0.2%
Total Established Rx Products
2,640
+0.6%

In the first quarter, Established Rx Products sales increased 0.6% to €2,640 million, reflecting strong performance in Emerging Markets (up 8.2% to €1,006 million) which offset the impact of generic competition to Plavix in Japan. In the U.S., Established Rx Products sales decreased 4.9% (to €365 million). In Europe, Established Rx Products sales decreased 2.1% to €907 million.

Lovenox sales increased 2.2% to €415 million in the first quarter, driven by strong performance in Emerging Markets (up 14.3% to €120 million), which offset lower sales in Europe (down 1.5% to €257 million).
In the first quarter, Plavix sales were down 1.8% to €380 million due to generic competition in Japan that started in June 2015 (sales in Japan were down 33.7% to €64 million). In Emerging Markets, Plavix sales increased 10.8% to €262 million sustained by the performance in China.

First-quarter Renvela/Renagel sales increased 2.1% to €246 million. In the U.S. where Sanofi expects generic competition before the end of 2017, first-quarter sales were up 3.1% to €207 million. In Europe, Renvela/Renagel sales were down 13.6% to €18 million due to generic competition.
Aprovel/Avapro sales were up 13.0% (to €193 million) driven by product sales to our partner in Japan and sales in China.

Consumer Healthcare
CHC sales by geography and category are provided in Appendix 1.
Net sales (€ million)
Q1 2017
Change
(CER)
Change
at CER/CS*
Allergy Cough & Cold
414
+58.7%
+12.6%
of which Allegra
145
-0.7%
–
of which Mucosolvan
35
na
na
Pain
324
+45.1%
+10.2%
of which Doliprane
83
+7.8%
–
of which Buscopan
42
na
na
Digestive
229
+55.6%
-8.3%
of which Dulcolax
47
na
na
of which Enterogermina
47
+9.5%
–
of which Essentiale
35
-17.9%
–
of which Zantac
27
na
na
Nutritionals
164
+36.3%
-1.3%
of which Pharmaton
17
na
na
Other
210
+11.0%
+3.1%
of which Gold Bond
50
+2.1%
–
Total Consumer Healthcare
1,341
+42.7%
+4.7%
*CS : constant structure

In the first quarter, Consumer Healthcare (CHC) sales increased 42.7% to €1,341 million reflecting the closing of the acquisition of Boehringer Ingelheim CHC business on January 1st, 2017 and the transfer of some Sanofi products to the new Chinese joint-venture between Sanofi and China Resources Sanjiu (CR999). At constant structure, Sanofi CHC sales increased 4.7% in the first quarter mainly driven by the strong performance in Europe.

In Europe, CHC sales were up 68.2% to €406 million. At constant structure, sales were up 10.0%, due to an early cough and cold season. Over the period double-digit growth at constant structure was achieved by the Allergy Cough and Cold category (up 21.6%, driven by Mucosolvan, Bisolvon and Allegra) and the pain category (up 15.7% driven by Buscopan and Doliprane).

In the U.S., first quarter CHC sales increased 18.7% to €348 million. At constant structure, CHC sales were up 2.4% driven by the launch of Xyzal Allergy 24HR (sales of €43 million) which was approved in February as an over-the-counter treatment for the relief of symptoms associated with seasonal and year-round allergies. In the first quarter, the performance at constant structure of the Allergy, Cough and Cold (up 12.9%, driven by Xyzal launch) and Pain categories (up 16.7%) were partially offset by lower sales of the Digestive category (down 19.2%, impacted by lower sales of Dulcolax and Zantac).

In Emerging Markets, first-quarter CHC sales increased 20.9% to €404 million. At constant structure, CHC sales were up 1.3% reflecting lower sales in Russia which continued to be impacted by the economic environment. In Emerging Markets, the strong performance at constant structure of the Allergy Cough and Cold category (up 14.1%) was partially offset by lower sales of the Digestive category due to Essentiale.

In the rest of the world, CHC sales were up 151.5% to €183 million. At constant structure, CHC sales were up 4.9% mainly driven by the Nutritionals and Pain categories.

Generics
In the first quarter, Generics sales decreased 2.0% to €468 million reflecting lower sales in Europe (down 3.4% to €198 million), and a 2.8% increase in Emerging Markets (to €200 million).

As announced in our 2020 strategic roadmap, Sanofi has carefully reviewed all options for our Generics business in Europe and made the definitive decision to initiate a carve-out process expected to be completed by the end of 2018. Importantly, Sanofi confirms its commitment to Generics in other parts of the world with a greater focus on the Emerging Markets.
Vaccines
Net sales (€ million)
Q1 2017
Change
(CER)
Change
at CER/CS*
Polio/Pertussis/Hib vaccines
(incl. Pentacel, Pentaxim and Imovax)
432
+46.2%
+38.0%
Influenza vaccines
(incl. Vaxigrip and Fluzone)
38
+85.0%
+85.0%
Adult Booster vaccines (incl. Adacel )
79
-5.0%
-23.2%
Meningitis/Pneumonia vaccines
(incl. Menactra)
95
-24.6%
-24.6%
Travel and other endemic vaccines
106
+25.3%
+8.3%
Dengvaxia
17
-5.3%
-5.3%
Other vaccines
17
+23.1%
+14.3%
Total Vaccines (consolidated sales)
784
+22.2%
+13.2%
*CS : constant structure

First quarter consolidated Vaccines sales were up 22.2% to €784 million and reflected the termination of the Sanofi Pasteur MSD joint-venture in Europe from December 31, 2016. At constant structure, sales were up 13.2% mainly driven by the Polio/Pertussis/Hib (PPH) franchise. In the U.S., sales were up 13.5% to €287 million. In Emerging Markets, sales grew 11.5% to €316 million. In Europe, sales were up 110.4% to €100 million reflecting the termination of SPMSD JV. At constant structure, European sales were up 4.1%.

In the first quarter, Polio/Pertussis/Hib vaccines sales increased 46.2% to €432 million. At constant structure, PPH sales grew 38.0% reflecting supply recovery of Pentacel and CDC order phasing in the U.S. (U.S. Pentacel sales: €89 million versus €21 million in the first quarter of 2016), and increased release of Pentaxim batches in China.
Influenza vaccines sales were up 85.0% to €38 million boosted by supply to Butantan in Brazil in the first quarter.
First-quarter Adult Booster vaccines sales were €79 million, down 5.0%, or down 23.2% at constant structure impacted by Repevax supply disruption in Europe.

First quarter Dengvaxia sales were €17 million mainly reflecting the sales of the third dose for the public immunization program implemented in the Philippines at the beginning of 2016.

First-quarter Menactra sales were down 21.6% to €90 million mainly due to the U.S. CDC ordering pattern in the previous year.

First-quarter Travel and other endemic vaccines sales were €106 million up 25.3% and up 8.3% at constant structure.
Company sales by geographic region
Sanofi sales (€ million)
Q1 2017
Change
(CER)
Change
(CER/CS)
United States
2,764
+3.0%
+1.2%
Emerging Markets(a)
2,543
+11.3%
+8.5%
of which Latin America
676
+18.6%
+12.0%
of which Asia (including South Asia(b))
983
+13.4%
+12.4%
of which Africa, Middle East
546
+1.6%
-0.7%
of which Eurasia(c)
298
+14.3%
+9.9%
Europe(d)
2,411
+10.4%
+1.8%
Rest of the World(e)
930
+14.9%
+2.2%
of which Japan
529
+19.9%
-0.6%
Total Sanofi sales
8,648
+8.6%
+3.5%
*CS : constant structure

World excluding U.S., Canada, Western & Eastern Europe (except Eurasia), Japan, South Korea, Australia, New Zealand and Puerto Rico
India, Bangladesh, Sri Lanka
Russia, Ukraine, Georgia, Belarus, Armenia and Turkey
Western Europe + Eastern Europe except Eurasia
Japan, South Korea, Canada, Australia, New Zealand, Puerto Rico
First-quarter sales in the U.S. were €2,764 million, an increase of 3.0% or 1.2% at constant structure driven mainly by the Multiple Sclerosis franchise (up 34.2%), Vaccines (up 13.5%), Oncology (up 23.1%), Rare Diseases (up 12.2%) and Cardiovascular (up 25.6%) which offset lower sales of Diabetes (down 14.7%).

First-quarter sales in Emerging Markets were €2,543 million, up 11.3% or 8.5% at constant structure driven by Established Rx products (up 8.3% at constant structure), Diabetes (up 12.1%), Vaccines (up 11.5%), Oncology (up 22.6%) and Rare Disease (up 11.1%). In Asia, first quarter sales were up 13.4% (up 12.4% at constant structure) to €983 million reflecting strong performance in China (up 17.0% at constant structure to €597 million), driven by Pharmaceuticals and also by the end of the vaccines market disruption. In Latin America, first quarter sales increased 18.6% (up 12.0% at constant structure) to €676 million sustained by Brazil. First-quarter sales in Brazil increased 24.5% at constant structure to €320 million supported by performance of Established Rx Products, Vaccines, generics and CHC. First-quarter sales in the Eurasia region increased 14.3% (9.9% at constant structure) to €298 million supported by strong growth in Turkey. Over the quarter, sales in Russia were €147 million up 0.9% and down 4.3% at constant structure impacted by local economic conditions. In Africa and the Middle East, sales were €546 million up 1.6% or down 0.7% at constant structure reflecting lower sales in Middle East due to phasing of vaccines supply and a modest growth in Africa.

First-quarter sales in Europe were €2,411 million, up 10.4% or 1.8% at constant structure, mainly driven by the performance of the Multiple Sclerosis franchise (up 25.7%) and CHC (up 10.0% at constant structure) which offset lower sales in Diabetes (down 3.0%) and Established Rx Products (down 3.1% at constant structure).
Sales in Japan increased 19.9% to €529 million in the first quarter. At constant structure, sales in Japan were down 0.6% impacted by generic Plavix competition which was partially offset by strong growth of vaccines sales.

R&D update
Consult Appendix 6 for full overview of Sanofi’s R&D pipeline
Regulatory update
Regulatory updates since the publication of 2016 full-year results on February 8, 2017 include the following:
In April, the FDA approved a new dosing regimen for Praluent of 300 mg administered subcutaneously once monthly (every 4 weeks).

In April the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion for the marketing authorization of Kevzara (sarilumab), recommending its approval for use in adult patients with moderately to severely active rheumatoid arthritis.

In March, the U.S. Food and Drug Administration (FDA) approved Dupixent (dupilumab), the first and only biologic medicine approved for the treatment of adults with moderate-to-severe atopic dermatitis (AD) whose disease is not adequately controlled with topical prescription therapies, or when those therapies are not advisable.

Following successful conclusion of Le Trait manufacturing site inspection by FDA, the Kevzara (sarilumab) U.S. BLA was accepted in April for the treatment of rheumatoid arthritis with a PDUFA date of May 22, 2017.

At the end of April 2017, the R&D pipeline contained 46 pharmaceutical new molecular entities (excluding Life Cycle Management) and vaccine candidates in clinical development of which 13 are in Phase 3 or have been submitted to the regulatory authorities for approval.

Portfolio update
Phase 4:
Top-line results of the ODYSSEY OUTCOMES study on Praluent are now expected to be reported in the first quarter of 2018 based on communications from the independent DSMB (Data and Safety Monitoring Board). Recruitment for this 18,600-patient cardiovascular outcomes trial was completed in November 2015 and the scheduled two-year follow-up of patients is underway.

Phase 3:
The results of the CAFÉ study evaluating dupilumab in cyclosporine-resistant patients in moderate-to-severe atopic dermatitis were positive and demonstrated an acceptable safety profile. These results will be submitted to the EMA and presented at a scientific Congress.

In March, detailed results from the one-year Phase 3 CHRONOS study were presented at the Annual Meeting of the American Academy of Dermatology (AAD). In this study, patients receiving Dupixent with topical corticosteroids (TCS) achieved significantly improved measures of overall disease severity compared to TCS alone in adults with uncontrolled moderate-to-severe AD with a safety profile consistent with previous studies.

Phase 2:
SP0232 / MEDI8897 (partnership with MedImmune), a monoclonal antibody, entered the portfolio in Phase 2 for the prevention of lower respiratory tract illness in infants caused by respiratory syncytial virus.
SAR566658, a maytansin-loaded anti-CA6 monoclonal antibody, entered into Phase 2 for the treatment of triple negative breast cancer.

A Phase 2 study was initiated to evaluate isatuximab in acute lymphoblastic leukemia.
Phase 1:
SAR440181 / MYK491 (collaboration with MyoKardia), for the treatment of dilated cardiomyopathy (DCM1 myosin activation), entered Phase 1.

2017 first-quarter financial results(8)
Business Net Income(8)

In the first quarter of 2017, Sanofi generated sales of €8,648 million, an increase of 11.1% (up 8.6% at CER).
First-quarter other revenues increased 71.7% (up 66.9% at CER) to €249 million including VaxServe sales of non-Sanofi products of €173 million (versus €83 million in the first quarter of 2016).

First-quarter Gross Profit increased 13.1% to €6,200 million (up 10.6% at CER). At CER and constant structure*, Gross Profit increased 5.4%. The gross margin ratio improved by 1.3 percentage points to 71.7% versus the first quarter of 2016, mainly reflecting the positive impact of the growing Multiple Sclerosis business, a favorable product and geographical mix in our Established Rx Product franchise, as well as industrial productivity improvements. These impacts more than offset the negative U.S. Diabetes net price evolution. In the first quarter, the gross margin ratio of Pharmaceuticals was 73.1%, an improvement of 1.6 percentage points and the gross margin ratio of Vaccines decreased 0.6 percentage points to 58.0%. Sanofi expects its gross margin ratio to be approximately 70% at CER in 2017.

Research and Development expenses increased 6.0% to €1,309 million (up 4.0% at CER) in the first quarter. At CER and constant structure*, R&D expenses were up 2.1% reflecting the increased spending on our development programs in oncology (isatixumab, PD-1) and sotagliflozin.

First-quarter selling general and administrative expenses (SG&A) were up 12.0% to €2,478 million (up 9.5% at CER).
At CER and constant structure*, SG&A was up 1.5% mainly reflecting launch costs for Dupixent, Kevzara and Xyzal, commercial and marketing investments behind key Emerging countries and our Europe Vaccines business, as well as one-time costs associated with the integration of Boehringer Ingelheim CHC business. On the other hand, our Diabetes sales and marketing spending in the U.S. was adapted to the new competitive environment.

First-quarter other current operating income net of expenses was €34 million versus €93 million for the same period of 2016. In the first quarter of 2016, this line included an arbitration award of €192 million to Sanofi and also a foreign exchange loss related to Venezuela (€92 million).

The share of profits from associates was €30 million in the first quarter versus €23 million for the same period of 2016. The share of profits from associates included Sanofi’s share in Regeneron profit.

In the first quarter, non-controlling interests were -€35 million versus -€27 million in the first quarter of 2016.
First-quarter business operating income increased 15.0% to €2,442 million. At CER, business operating income increased 11.7%. At CER and constant structure*, business operating income increased 7.6%. The ratio of business operating income to net sales increased 0.9 percentage point to 28.2% versus the same period of 2016. In the first quarter, the business operating income ratio of Pharmaceuticals was 30.1%, 1.4 percentage points higher and the business operating income ratio of Vaccines increased 0.7 percentage points to 13.5%.

Net financial expenses were €63 million in the first quarter versus €117 million in the first quarter of 2016, reflecting mainly a lower cost of net debt.

First-quarter effective tax rate was 24.5% compared with 22.6% in the first quarter of 2016.
First-quarter business net income(8) increased 4.2% to €1,795 million (up 1.0% at CER). The ratio of business net income to net sales increased 0.9 percentage points to 20.8% versus the same period of 2016 (excluding Animal Health business).

In the first quarter of 2017, business earnings per share(8) (EPS) increased 6.0% to €1.42 on a reported basis and 3.0% at CER. The average number of shares outstanding was 1,262.4 million in the first quarter of 2017 versus 1,288.4 million in the first quarter of 2016.

(8) See Appendix 3 for 2017 first-quarter Consolidated income statement; see Appendix 8 for definitions of financial indicators, and Appendix 4 for reconciliation of IFRS net income reported to business net income.

* Adjusted for BI CHC business and termination of SPMSD

2017 guidance
Sanofi expects 2017 Business EPS to be stable to -3% at CER, barring unforeseen major adverse events, consistent with its previously announced Strategic Roadmap guidance for the 2016-17 period. Applying the average March 2017 exchange rates to the rest of the year, the currency impact on 2017 Business EPS is estimated to be +3% to +4%.
Reconciliation of IFRS net income reported to business net income (see Appendix 4)

In the first quarter of 2017, the IFRS net income was €5,701 million reflecting the acquisition of BI’s CHC business and full consolidation of Sanofi’s European vaccine operations. The main items excluded from the business net income were:
A net gain of €4,427 million resulting from the divestment of the Animal Health business (subject to post-closing adjustment).

\A €503 million amortization charge related to fair value remeasurement on intangible assets of acquired companies (primarily Aventis: €104 million, Genzyme: €231 million and BI CHC business €66 million) and to acquired intangible assets (licenses/products: €37 million). These items have no cash impact on the Company.

A charge of €36 million mainly reflecting an increase of Bayer contingent considerations linked to Lemtrada (charge of €21 million) and CVR fair value adjustment (charge of €16 million).

Expenses of €88 million arising from the impact of the acquisition of BI CHC business and the termination of SPMSD joint venture on inventories.

Restructuring costs and similar items of €119 million mainly related to the organizational transformation program at the industrial level in Europe and North America.

A €248 million tax effect arising from the items listed above, comprising €182 million of deferred taxes generated by amortization charged against intangible assets, €43 million associated with restructuring costs and similar items, €28 million associated with the impact of acquisition on inventories and €6 million associated with fair value remeasurement of contingent consideration liabilities.

An expense of €24 million net of tax related to restructuring costs of associates and joint-ventures, and expenses arising from the impact of acquisitions on associates and joint-ventures.

Capital Allocation
In the first quarter of 2017, net cash generated by operating activities was €954 million after capital expenditures of €382 million and an increase in working capital of €766 million. This net cash flow largely funded acquisitions and partnerships net of disposals (€222 million) and restructuring costs and similar items (€211 million). The swap between BI CHC business and Sanofi Animal Health business generated a net cash flow of €5,288 million (pre-tax amount as tax payments on the gain are expected in the next quarters), partially used to finance share repurchases (€1,289 million) over the quarter. As a consequence, net debt decreased from €8,206 million at December 31, 2016 to €3,685 million at March 31, 2017 (amount net of €14,924 million cash and cash equivalents).