Sanofi: Weathering Patent Erosion
Sanofi executives continue to have faith in strategic plans to get the company to new heights despite continued impact from patent expirations.
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|Product||2016 Sales||2015 Sales|
All sales are in millions of dollars and were translated using the Federal Reserve Board’s average rate of exchange in 2016: €1.1072.
|1H 2017||1H 2016|
All sales are in millions of dollars, except EPS, and were translated using the Federal Reserve Board’s average rate of exchange in 2016: €1.1072.
According to Olivier Brandicourt, CEO of Sanofi, “2016 was a busy year for Sanofi as we progressed on our 2020 strategic roadmap.”
The successful closing of an asset swap wth Boehringer Ingelheim lifted Sanofi into a leadership position in Consumer Healthcare, and Brandicourt asserts that a streamlined organization started to deliver and supported a stronger financial performance than initially anticipated.
At the same time, Sanofi completed the filing of Dupixent for its first indication, atopic dermatitis, in the United States and Europe. Separately, the company advanced five new molecules into registrational studies.
“In 2016, we made strong progress on our 2020 strategic roadmap, as we transform into an agile and innovative global pharmaceutical leader serving the needs of patients worldwide,” Brandicourt says. “Our work in dynamic franchises – such as rare diseases, multiple sclerosis, and vaccines – and our performance in emerging markets enabled us to achieve solid financial results.
Financial & Product Performance
According to executives, full-year 2016 sales excluding the Animal Health Business increased 1.2 percent, reaching €33.82 billion ($37.45 billion). However, as reported, sales were slightly less than during the previous year.
In 2016, executives say sales growth was driven by the Specialty Care and Vaccines businesses. Sanofi Pasteur sales were up 7.4 percent to €4.58 billion ($5.08 billion) and benefited from the strong performance of the AcXim family of pediatric combination products, which grew nearly 40 percent to €700 million ($775 million), setting a new record year for the flu vaccine franchise.
“So overall, our financial performance in 2016 was stronger than we had initially expected,” Brandicourt says.
Net income as reported was €4.71 billion ($5.21 billion), 9.8 percent more than in 2015. Diluted earnings per share were €3.63 ($4.02), an increase of 11.7 percent.
For the first half of 2017, revenue was €17.31 billion ($19.17 billion) 8.7 percent more than in first-half 2016. Reported net income was €6.74 billion ($7.46 billion) compared with €2.25 billion ($2.49 billion), but this figure includes the exchanged/held for exchange Animal Health business. Diluted earnings per share in first-half 2017 were €5.20 ($5.87) compared with €1.73 ($1.92) in the previous period.
Brandicourt says in the second quarter of 2017, once again the major contributors to the company’s performance were Sanofi Genzyme, Sanofi Pasteur, and Emerging Markets. “The continued growth of these businesses, together with disciplined expense management, enabled us to more than offset the headwinds in our Diabetes franchise,” he says. “Consequently, we feel confident in our full-year outlook and raise our 2017 business EPS guidance.”
In 2016, Sanof had 10 products with sales of more than $500 million: Lantus, Lovenox, Plavix, Aubagio, Renagel/Renvela, Cerezyme, Myozyme and Lumizyme, Avapro/Aprovel, Fabrazyme, and Toujeo.
The diabetes drug Lantus remained Sanofi’s top-selling product in 2016 at €5.71 billion ($6.33 billion) but sales declined 10.6 percent due to continued generic competition. In the first half of 2017, Lantus sales were €2.42 billion ($2.68 billion), 15.3 percent less than in the same period last year.
In August 2017, Sanofi announced that it filed a patent infringement suit against Merck Sharp & Dohme Corp., the U.S. company of Merck KGaA, in the United States District Court for the District of New Jersey. In its suit Sanofi alleges infringement of two patents for Lantus.
The suit was triggered by a notification received from Merck in late June, in which Merck stated that it had filed an NDA (505(b)(2) New Drug Application) with FDA for an insulin glargine vial drug product. Merck also stated that its NDA included a paragraph IV certification challenging all of the Sanofi patents then listed in the FDA Orange Book for Sanofi’s Lantus and Lantus SoloStar products.
The antithrombotic Lovenox was No. 2 in sales in 2016, earning €1.64 billion ($1.81 billion), 4.8 percent less than in 2015. First-half 2017 sales were €817 million ($905 million), about the same as in the first half of 2016.
The company’s third best-seller in 2016 was the atherothrombotis drug Plavix, which had sales of €1.54 billion ($1.71 billion), a drop of 20 percent from 2015. Sales of the medicine in the first half of 2017 were €765 million ($847 million), 1.9 percent less than in the same period of 2016.
No. 4 in 2016 sales was the multiple sclerosis drug Aubagio, which generated €1.3 billion ($1.43 billion), 48.7 percent more than in 2015. Sales continued to climb in the first half of 2017, when the drug posted €796 million ($881 million), 34 percent more than in first-half 2016.
In fifth place was the hyperphosphatemia drugs Renagel/Renvela, which posted sales of €922 million ($1.02 bilion), 1.4 percent less than in 2015. Sales in the first half of this year were €494 million ($547 million), 11.8 percent more than in the same period last year.
No. 6 in 2016 sales was the Gaucher disease drug Cerezyme. Sales declined 1.2 percent from 2015, to €748 million ($828 million). In the first half of 2017, sales were €369 million ($409 million), 3.1 percent less than in the same period of 2016.
The seventh best seller in 2016 were the Pompe disease drugs Myozyme and Lumizyme. Sales grew 11.5 percent from 2015, to €725 million ($803 million. First-half 2017 sales expanded 12.9 percent compared with the same period last year, to €393 million ($435 million).
Sales of the hypertension product Avapro/Aprovel, Sanofi’s No. 8 best seller in 2016, were €681 million ($754 million), 10.6 percent less than in 2015. In the first half of 2017, sales totaled €383 million ($424 million), 11.3 percent more than in the first half of 2016.
Coming in at No. 9 in sales for Sanofi in 2016 was the Fabry disease drug Fabrazyme, at €674 million ($746 million), 13.9 percent more than in 2015. In the first half of 2017, sales reached €367 million ($406 million), 16.1 percent more than in the first six months of 2016.
No. 10 in 2016 sales was the diabetes drug Toujeo, which generated €649 million ($719 million) compared with €164 million ($182 million) in 2015. First-half 2016 sales were €402 million ($445 million) compared with €244 million ($270 million) in the first half of 2016.
Sales for all the company’s established prescription products amounted to €10.31 billion ($11.42 billion), 8.7 percent less than in 2015. First-half 2017 sales of all established prescription product were €5.2 billion ($5.76 billion), about the same as in the first half of 2016. Executives say this reflects a solid performance in Emerging Markets, but weaker sales in Europe and reduced sales of Plavix in Japan due to generic competition.
Sanofi’s generics business produced sales of €1.85 billion ($2.05 billion) in 2016, 3.3 percent less than in 2015. During the first half of 2017, generics posted sales of €910 million ($1.01 billion), 2.5 percent less than in the same period of 2016. “In line with our ‘Strategic Roadmap 2020,’ we have been examining all options for our Generics business in Europe, and have committed to a phased withdrawal from this business that we expect to be complete by the end of 2018,” executives say. “We have however reiterated our commitment to our Generics business in other parts of the world, and will sharpen our focus on Emerging Markets.”
The Consumer Healthcare business pulled in €3.33 billion ($3.69 billion), a decline of 4.6 percent from 2015. Sales in first-half 2017 were €2.5 billion ($2.77 billion), 46.9 percent more than in the first half of 2016. Executives say the increase reflects the acquisition of Boehringer Ingelheim’s consumer business in January.
Sanofi Pasteur, the company’s vaccines business, generated 2016 sales of €4.58 billion ($5.08 billion), 7.4 percent more than the previous year. In the first half of 2017, sales amounted to €1.8 billion ($1.99 billion), up 26.6 percent compared with the same period in 2016. Executives attributed the increase to the end of the Sanofi Pasteur MSD joint venture in Europe. Sanofi treated the transaction as a divestment of its share in the joint venture, and the acquisition of the vaccines portfolio reverting to Sanofi.
R&D, Pipeline Progress
At the beginning of February 2017, executives say Sanofi’s R&D pipeline contained 44 pharmaceutical new molecular entities (excluding life cycle management) and vaccine candidates in clinical development of which 13 were in Phase III or had been submitted to regulatory authorities for approval.
During the first nine months of 2017, Sanofi reported advances in the company’s pipeline.
In June, Sanofi shared positive results from two Phase IIIb/IV trials (ODYSSEY-DM) evaluating Praluent in patients with diabetes and hypercholesterolemia. In the studies, Praluent, when administered on top of maximally tolerated doses of statins, significantly reduced low-density lipoprotein cholesterol (LDL-C) (ODYSSEY DM-INSULIN study) and non-high-density lipoprotein cholesterol (non-HDL-C) (ODYSSEY DM-DYSLIPIDEMIA study). Both studies also found that a majority of patients reached their lipid goals with Praluent 75 mg every two weeks, with an overall safety profile comparable to the ODYSSEY Phase III program.
In March Sanofi and Regeneron Pharmaceuticals Inc. presented detailed results from the one-year Phase III CHRONOS study, which showed that patients receiving Dupixent (dupilumab) with topical corticosteroids (TCS) achieved significantly improved measures of overall disease severity compared to TCS alone in adults with uncontrolled moderate-to-severe atopic dermatitis.
Dupixent is a human monoclonal antibody that is designed to specifically inhibit overactive signaling of two key proteins, IL-4 and IL-13, which are believed to be major drivers of the persistent underlying inflammation in atopic dermatitis.
Dupixent received FDA approval in March for the treatment of adults with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies, or when those therapies are not advisable.. The drug received a positive opinion in March from the European Medicine Agency’s Committee for Medicinal Products for Human Use to recommend Dupixent’s approval in Europe for use in adults with moderate-to-severe atopic dermatitis who are candidates for systemic therapy.
Results from the CAFÉ study evaluating dupilumab in the treatment of cyclosporine-resistant adults with moderate-to-severe atopic dermatitis were positive, and showed a satisfactory safety profile. Two Phase III studies with dupilumab were initiated during the first half of 2017, one in the treatment of persistent asthma in children aged 6 to 11 years and the other in the treatment of atopic dermatitis in adolescents aged 12 to 17 years.
SAR439684 (PD-1 inhibitor), developed in collaboration with Regeneron, entered Phase III in the treatment of non small cell lung cancer.
Among Phase II trials advancing was SP0232/MEDI8897, a monoclonal antibody for the prevention of respiratory syncytial virus-associated illness in newborns and infants. The drug is a collaboration with MedImmune. The partnership was announced in March.
SAR566658, a maytansine-loaded anti-CA6 monoclonal antibody, entered Phase II clinical trials in the treatment of triple negative breast cancer.
GZ402671/venglustat, a glucosylceramide synthase inhibitor, entered Phase IIb for the treatment of Gaucher disease type 3. The product also entered Phase IIa in the treatment of Fabry disease.
Two Phase II studies have begun to evaluate isatuximab in acute lymphoblastic leukemia and latent multiple myeloma.
A Phase II trial has begun studying SAR439684 (PD-1), developed in collaboration with Regeneron, in the treatment of basocellular carcinoma.
Among the products entering Phase I trials in the first half of 2017 were SAR440181/MYK491 for the treatment of dilated cardiomyopathy (DCM1 myosin activation); and SAR439459 (TGFb inhibitor, monoclonal antibody), which in combination with SAR439684 is being developed for the treatment of metastatic melanoma. SAR440181/MYK491c is being jointly developed with MyoKardia.
Sanofi reports that volunteers are being recruited to a Phase III clinical trial evaluating the efficacy of the vaccine against Clostridium difficile symptomatic infections.
Additionally, a Phase III trial of the high-dose quadrivalent inactivated influenza vaccine Fluzone QIV HD in patients aged over 65 years is currently in preparation.
Phase III clinical trials are ongoing for the second-generation meningococcal ACYW conjugate vaccine Men Quad TT, indicated for a broader population (from children to seniors).
In one of the most exciting R&D developments for Sanofi this year, in September Sanofi Genzyme, the specialty care global business unit of Sanofi, and Alnylam Pharmaceuticals Inc. announced the APOLLO Phase III study of patisiran, an investigational RNAi therapeutic being developed for patients with hereditary ATTR amyloidosis with polyneuropathy, met its primary efficacy endpoint and all secondary endpoints.
The primary endpoint for the study was the change from baseline in the modified neuropathy impairment score (mNIS+7) at 18 months. The key secondary endpoint was improvement in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN).
The APOLLO trial enrolled 225 hATTR amyloidosis patients with polyneuropathy, representing 39 genotypes, at 44 study sites in 19 countries around the world. Patients were randomized 2:1 to patisiran or placebo, with patisiran administered intravenously at 0.3 mg/kg once every three weeks for 18 months. For both the mNIS+7 and Norfolk QOL-DN endpoint measures provided below, a lower score indicates a better clinical result.
At 18 months, the mean change from baseline in mNIS+7 was significantly lower in the patisiran group as compared with placebo (p less than 0.00001).
The mean and median changes in mNIS+7 impairment scores for patisiran both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline.
Patients in the patisiran group experienced improvement in quality of life compared to placebo, as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) (p less than 0.00001).
The mean and median changes in QOL scores for patisiran also both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline.
All five other secondary endpoints also demonstrated statistically significant favorable differences in the patisiran arm compared to placebo (p less than 0.001). These were: NIS-W, the subdomain of mNIS+7 assessing muscle strength; Rasch-built Overall Disability Scale (R-ODS), a patient reported outcome measure of daily living and disability; 10-meter walk test, assessing gait speed; modified body mass index (mBMI), assessing nutritional status; and COMPASS-31, a questionnaire to assess autonomic symptoms.
Based on these positive results, Alnylam expects to file its first New Drug Application in late 2017 and first Marketing Authorization Application shortly thereafter. Sanofi Genzyme is preparing for regulatory filings for patisiran in Japan, Brazil and other countries to begin in the first half of 2018. Pending regulatory approvals, Alnylam will commercialize patisiran in the U.S., Canada and Western Europe, with Sanofi Genzyme commercializing the product in the rest of the world.
“This is a significant milestone that supports our belief that RNAi therapeutics have the potential to become an innovative new class of medicines for patients with rare genetic diseases,” says Elias Zerhouni, M.D., president, Global R&D, Sanofi. “The APOLLO data suggest that patisiran could help improve the lives of people living with hATTR amyloidosis with polyneuropathy, a patient population in urgent need of additional treatment options. We look forward to working with Alnylam to make patisiran available around the globe as quickly as possible.”
Full results, including data from an exploratory analysis of the subgroup of patients with cardiac involvement, were expected to be presented at the 1st European ATTR Amyloidosis Meeting for Patients and Doctors, on November 2, 2017.
Also in September, Sanofi and Regeneron announced positive results from the Phase III CAFÉ study of Dupixent in adults with moderate-to-severe atopic dermatitis (AD) who are inadequately controlled with or intolerant to the broad immunosuppressant drug cyclosporine A (CSA), or when this treatment is medically inadvisable. In the study, Dupixent with topical corticosteroids (TCS) significantly improved measures of overall disease severity, skin clearing, itching, and patient reported quality of life measures. CSA is approved for the treatment of atopic dermatitis in most European countries and Japan. but is not approved in the U.S. for this use.
In another September development, Sanofi and Regeneron announced that the pivotal Phase III LIBERTY ASTHMA QUEST study of dupilumab in a broad population of patients with uncontrolled, persistent asthma met its two primary endpoints.
Dupilumab, when added to standard therapies, reduced severe asthma attacks (exacerbations) and improved lung function. At 52 weeks, in the 300 mg dose group, dupilumab reduced severe asthma attacks by 46 percent in the overall population, 60 percent in patients with 150 eosinophilic cells/microliter or greater, and 67 percent in patients with 300 eosinophilic cells/microliter or greater (p less than 0.001 for all groups).
At 12 weeks, in the 300 mg dupilumab dose group, mean improvement in lung function over placebo as assessed by forced expiratory volume over one second (FEV1) with dupilumab was 130 mL (9 percent) in the overall population, 150 mL (11 percent) in patients with 150 eosinophilic cells/microliter or greater, and 240 mL (18 percent) in patients with 300 eosinophilic cells/microliter or greater (p less than 0.001 for all groups).
The companies plan to submit a Supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) by the end of this year.
“We believe that therapies like dupilumab, which focus on specific molecular pathways such as the Th2 pathway associated with multiple chronic allergic diseases, are important targets for further investigation,” Dr. Zerhouni says. “The positive data from this large second pivotal trial in uncontrolled persistent asthma, following the positive results of dupilumab in atopic dermatitis, further support this view in our opinion. We will work diligently with health authorities to bring this new application of dupilumab to the patients who most need it.”
In another success for Sanofi and Regeneron, the companies reported in September that FDA granted Breakthrough Therapy designation status to cemiplimab (REGN2810) for the treatment of adults with metastatic cutaneous squamous cell carcinoma (CSCC) and adults with locally advanced and unresectable CSCC, the second deadliest skin cancer after melanoma. Cemiplimab is an investigational human, monoclonal antibody targeting PD-1.
Sanofi and Regeneron previously reported positive, preliminary results for cemiplimab from two expansion cohorts involving 26 advanced CSCC patients in a Phase 1 study of nearly 400 patients, at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2017.
EMPOWER-CSCC 1 – which is a Phase II, potentially pivotal, single-arm, open label clinical trial of cemiplimab – is enrolling patients for metastatic CSCC and locally advanced and unresectable CSCC. Cemiplimab is being jointly developed by Sanofi and Regeneron under a global collaboration agreement. Pending data results, the companies anticipate submitting a biologics license application for cemiplimab with the FDA in the first quarter of 2018.
In a setback for one of Sanofi’s and Alnylam’s partnership programs – for the investigational RNAi therapeutic fitusiran, in development for the treatment of hemophilia A and B with or without inhibitors – in September Alnylam reported a fatal thrombotic event had occurred in a patient with hemophilia A without inhibitors enrolled in the Phase II Open Label Extension (OLE) study. As a result, Alnylam, the sponsor of the study, had to suspend dosing in all ongoing fitusiran studies pending further review of the safety event and development of a risk mitigation strategy.
While Sanofi and Alnylam are jointly developing and jointly commercializing fitusiran, Alnylam has primary responsibility for executing the development program.
In July, the two companies had shared new positive results from the ongoing phase II open-label extension (OLE) study with fitusiran in patients with hemophilia A and B, with or without inhibitors. These results were presented in an oral presentation at the International Society on Thrombosis and Hemostasis (ISTH) 2017 Congress in Berlin, Germany. The clinical results in the fitusiran Phase II OLE study showed that the safety and tolerability profile of fitusiran remains encouraging, with no thromboembolic events, including during co-administration of replacement factor or bypassing agents.
In May, Sanofi and Regeneron received the news that FDA approved Kevzara (sarilumab) for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease modifying antirheumatic drugs (DMARDs), such as methotrexate. Kevzara is a human monoclonal antibody that binds to the interleukin-6 receptor (IL-6R), and has been shown to inhibit IL-6R mediated signaling.1 IL-6 is a cytokine in the body that, in excess and over time, can contribute to the inflammation associated with RA.
“Despite the many advances made in the treatment of rheumatoid arthritis, patients continue to need new treatment options,” Brandicourt says. “Today’s approval in the U.S. not only underscores our ongoing commitment to making a difference in the lives of patients, but also demonstrates our drive to accelerate science and medicine in immunology.”
The European Commission granted marketing authorization for Kevzara in June in combination with methotrexate for the treatment of moderately to severely active rheumatoid arthritis (RA) in adult patients who have responded inadequately to – or who are intolerant to – one or more disease modifying anti-rheumatic drugs (DMARDs).
The EC approval is based upon receipt of a positive opinion by European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP), which evaluated results from seven Phase III trials in the global SARIL-RA clinical development program. These studies incorporate data from more than 3,300 adults with moderately to severely active RA who have had an inadequate response or intolerance to one or more biologic or non-biologic DMARDs. The program includes the Phase III MONARCH study, in which treatment with Kevzara 200 mg monotherapy was superior to adalimumab 40 mg (marketed by AbbVie as Humira) monotherapy in reducing disease activity and improving physical function, with more patients achieving clinical remission over 24 weeks.
Sanofi continues to work to expand its generics product line. In May, Sanofi announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for the marketing authorization of Insulin lispro Sanofi (insulin lispro 100 Units/mL). CHMP recommended the use of Insulin lispro Sanofi to treat adults and children who have diabetes and need insulin to keep their blood sugar level controlled, including those patients whose diabetes has just been diagnosed. This positive opinion is the company’s first major regulatory milestone for a biosimilar diabetes treatment.
“We welcome the CHMP positive opinion for Insulin lispro Sanofi and look forward to the final decision of the European Commission,” says Jorge Insuasty M.D., senior VP, global head of development, Sanofi. “Our development of this investigational biosimilar product reflects Sanofi’s expertise and long-term heritage in developing and manufacturing high-quality insulins for people with type 1 or type 2 diabetes and their physicians.”
The recommendation is based on a clinical development program involving more than 1,000 adults with type 1 or type 2 diabetes. This program comprised a pharmacokinetic/pharmacodynamic (PK/PD) Phase I study to evaluate the product’s similarity in exposure and activity compared to insulin lispro 100 Units/mL as currently approved in the United States and the European Union; two multi-center Phase IIIa clinical trials (SORELLA 12 and SORELLA 2) evaluating its safety and efficacy compared to insulin lispro 100 Units/mL as currently approved in the United States and European Union in adults with type 1 or type 2 diabetes; and a safety study in insulin pumps in adults with type 1 diabetes.
“Insulin lispro is an important and widely used treatment for people with diabetes who require rapid control of their blood sugar at mealtime,” says Peter Guenter, executive VP and general manager, Diabetes & Cardiovascular, Sanofi. “By broadening our portfolio of quality insulin options, we acknowledge our commitment to expand the affordability and sustainability of insulin treatments.”
The European Commission was expected to make a final decision on marketing authorization for Insulin lispro Sanofi in the coming months.
Sanofi bolstered its Sanofi Pasteur R&D capabilities in August with the completion of the acquisition of Protein Sciences, a vaccines biotechnology company based in Meriden, Connecticut.
Through the acquisition, Sanofi Pasteur adds a promising product to its influenza vaccine portfolio: Flublok (Influenza Vaccine), the only recombinant protein-based influenza vaccine approved by FDA. In October 2016, Protein Sciences received approval from the FDA for the quadrivalent version of Flublok vaccine (Flublok Quadrivalent vaccine), indicated for adults 18 years and older.
“We are thrilled to welcome the talented employees and assets of Protein Sciences within Sanofi Pasteur,” says David Loew, Sanofi executive VP and head of Sanofi Pasteur. “The addition of Flublok Quadrivalent vaccine represents a very attractive opportunity to complement our influenza vaccines portfolio.”
The acquisition of Protein Sciences fits with Sanofi Pasteur’s strategic initiative to explore non-egg-based influenza vaccine manufacturing technologies.
“This acquisition is consistent with our strategic ambition of expanding our presence in the respiratory vaccine market, and builds on the recently announced collaboration on an investigational respiratory syncytial virus (RSV) monoclonal antibody,” Loew says.