Jet d'eau, emblème de Genève
Le Jet d'eau et ses millions de bulles d’air vous éblouiront.
Le Jet d'eau et ses millions de bulles d’air vous éblouiront.
Genève brille de mille éclats !
Les grandes figures de la Réforme veillent sur le Parc des Bastions.
L'histoire de Genève à ciel ouvert.
Quatre visites inédites.
Une ambiance bohème.
Accélérateur mondial de sciences.
Symbole de Genève, capitale de la paix.
Tout un art de vivre !
Prenez de la hauteur !
Les lieux d'intérêt à Genève : Jet d’eau de Genève, Vieille-Ville, Palais des Nations, horloge fleurie, musées, Mont-Salève, CERN, Carouge… et bien plus encore. Découvrez les lieux incontournables à visiter à Genève pour un séjour inoubliable !
The Pulse of the Pharmaceutical Industry
The pharma industry’s R&D concentration has been shifting towards specialty therapy areas as research and development returns decline for some leaders.
With the average cost of getting a novel medicine to the marketplace at nearly $2.5 billion, it is more crucial than ever for drug companies to succeed in their R&D efforts. However, according to a recent study generated by Deloitte in collaboration with the research and consulting firm GlobalData, leading pharma companies’ R&D returns continue to slide. The study showed that although the R&D divisions of 12 leading pharma companies advanced 306 assets into late-stage pipelines since 2010 – with projected lifetime returns of over $1.41 trillion – the returns are continuing to decrease in percentage terms: from 10.1 percent in 2010 to just 4.2 percent in 2015, while the average cost of asset development increased by one third.
There is plenty of good news though. For example, FDA during 2015 approved 45 new medicines, the highest tally since the record-setting total of 53 in 1996. And there are a lot more promising new products coming to market in 2016 and beyond, including a variety of drugs detailed in this article.
This annual special report has identified 10 company pipelines that are striving to buck the aforementioned trend of sliding R&D returns. The 10 companies were selected based on current projects in the pipeline, which therapeutic fields they are focused on, R&D deal-making activity, recent drug approvals, and other relevant criteria.
Sales for AbbVie continue to be driven by the world’s top-selling prescription medicine, the TNF inhibiting anti-inflammatory medication Humira (adalimumab). AbbVie’s long-term strategic and financial objectives, as announced at the end of October 2015, include 2020 global Humira sales of $18+ billion. The North Chicago-based biopharma company reports that its pipeline has the potential to generate nearly $30 billion in nominal peak-year sales by 2024 (excluding sales from already on-the-market products).
AbbVie is on pace to introduce more than 20 new products or indications through 2020, including seven approvals that will contribute during 2016 and beyond, including:
• Imbruvica indication expansion, including first-line chronic lymphocytic leukemia (CLL)
• Humira indication expansion, including hidradenitis suppurativa (HS) and uveitis
• Viekira approval for genotype 1B patients in Japan
• Venetoclax for relapsed/refractory CLL patients with the 17p genetic mutation
• Zinbryta for relapsing remitting multiple sclerosis
• Elotuzumab for relapsed/refractory multiple myeloma
AbbVie is developing leading medicines in these therapeutic fields: immunology, oncology, neuroscience, kidney disease, liver disease and women’s health.
Through spending in new technologies and approaches, AbbVie is breaking ground in some of the most widespread and difficult-to-treat cancers, including glioblastoma multiforme, multiple myeloma and chronic lymphocytic leukemia. AbbVie’s oncology pipeline contains multiple new molecules in development being investigated in more than 15 different cancers and tumor types.
AbbVie’s next big approval could come in the form of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax. The company has filed a New Drug Application (NDA) and a Marketing Authorization Application (MAA) for venetoclax in patients with relapsed/refractory (R/R) CLL in patients with chromosome 17p deletion. Priority review status was granted by U.S. regulators during January 2016 and validation has been provided by the EMA based on results from a Phase 2, open-label study. In the clinical trial, venetoclax demonstrated a 79.4 percent overall response rate as monotherapy treatment, including patients that achieved complete remission.
Three FDA Breakthrough Therapy Designations have been granted by FDA for venetoclax. The first designation was received in early 2015 for treating patients with R/R CLL with chromosome 17p deletion. The second designation for venetoclax was received during the earlier part of January 2016 for combination therapy with rituximab for patients with R/R CLL, including those with chromosome 17p deletion. A third designation was received in late January 2016 for venetoclax in combination with hypomethylating agents (HMAs) in patients with untreated (treatment-naïve) acute myeloid leukemia (AML) who are ineligible to receive standard induction therapy (high-dose chemotherapy).
Venetoclax is being developed in partnership with Genentech and Roche. Venetoclax in on track to gain FDA approval in 2016 and generate global blockbuster sales by 2020.
AbbVie has been jointly developing with Bristol-Myers Squibb another medicine expected to generate blockbuster sales. FDA during the fourth quarter of 2015 approved Empliciti (elotuzumab) for treating multiple myeloma (MM) as a combination therapy in patients who have received one to three prior therapies. Marketing clearance was based on data from a Phase 3 trial that showed patients treated with Empliciti plus standard of care therapy achieved a 30 percent reduction in the risk of disease progression or death compared to standard of care alone. This represents the first FDA clearance for an immune-stimulatory antibody for MM in this indication. FDA granted breakthrough designation for Empliciti, which will be marketed by Bristol-Myers Squibb.
Imbruvica (ibrutinib) attained blockbuster sales during 2015, recording sales of $754 million for AbbVie and $689 million for partner Janssen. The drug is approved for treating patients with CLL who have received at least one prior therapy, CLL patients who have del 17p and patients with Waldenstrom’s macroglobulinemia. The medicine is additionally marketed for treating patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
A first-in-class, oral, once-daily therapy, Imbruvica inhibits a protein called Bruton’s tyrosine kinase (BTK). This was one of the first products to receive FDA marketing clearance after being granted a Breakthrough Therapy Designation, and is one of the few therapies to gain three separate designations.
BTK is a key signaling molecule in the B-cell receptor signaling complex that has a significant role in the survival and spread of malignant B cells. Imbruvica blocks signals that inform malignant B cells to multiply and spread uncontrollably.
Imbruvica is being investigated alone and in combination with other treatments in several blood cancers. More than 6,100 patients have been treated in clinical studies performed in 35 countries by 800-plus investigators. As of December 2015, 16 Phase 3 studies have been initiated with Imbruvica and 67 trials were registered on www.clinicaltrials.gov.
AbbVie submitted a sNDA for ibrutinib for use in treatment-naïve CLL patients, based on results from the Phase 3 RESONATE-2 study. These data, published in The New England Journal of Medicine (NEJM), found that the product significantly decreased the risk of progression or death (progression-free survival, PFS) and significantly decreased the risk of death (overall survival, OS) versus chlorambucil in treatment-naïve patients 65 years and older with CLL.
During the fourth quarter of 2015, it was reported that the U.S. regulatory agency accepted AbbVie’s sNDA and granted priority review for Viekira Pak without ribavirin in patients with genotype 1b (GT1b) chronic hepatitis C virus infection (HCV) and compensated cirrhosis (Child-Pugh A). The application was supported by data from the TURQUOISE-III trial, which demonstrated 100 percent sustained virologic response at 12 weeks post-treatment (SVR12) in this patient population.
In early December 2015, AbbVie announced that FDA accepted the company’s NDA for a once-daily, fixed-dosed version of Viekira Pak to treat GT1 HCV. The proposed dosing for the fixed-dose form is three oral tablets, taken once per day with a meal, with or without ribavirin. AbbVie expects FDA action on the new formulation during 2016. If approved for marketing, this regimen will be the first all-oral, co-formulated three direct-acting antiviral treatment for adult patients with GT1 chronic HCV infection.
Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) is a prescription medicine used with or without ribavirin for the treatment of adults with genotype 1 chronic hepatitis C virus infection, including people who have a certain form of cirrhosis (compensated). FDA marketing approval was initially granted in December 2014.
Among other fourth-quarter 2015 R&D highlights, AbbVie presented data from its next-generation HCV regimen (ABT-493 and ABT-530) being assessed as a pan-genotypic, once-daily treatment option for patients with HCV. Results showed 12 weeks of treatment resulted in 97-100 percent SVR12 in GT1 non-cirrhotic HCV, 96-100 percent in genotype (GT2) and 83-94 percent in genotype 3 (GT3) patients. Also, data from the SURVEYOR-I trial demonstrated that non-cirrhotic GT1 HCV patients who received shorter duration of treatment for eight weeks with ABT-493 and ABT-530 achieved SVR12 rates of 97 percent. AbbVie launched Phase 3 trials during the fourth quarter.
At the American College of Rheumatology Annual Meeting in November 2015, AbbVie presented the full 12-week, Phase 2b safety data for ABT-494 from the BALANCE-I trial (efficacy data was previously top-lined). This study assessed a broad dose range to understand the boundaries of JAK-1 selectivity and the efficacy of the investigational oral JAK-1 inhibitor ABT-494 compared to placebo in previously treated patients with rheumatoid arthritis with persistent and active disease. The clinical trial met its primary endpoint, achieving an ACR20 response after 12 weeks of treatment using an LOCF approach, and ACR20 for all dose levels. The BALANCE I and II results support AbbVie’s decision to advance the new drug candidate into Phase 3 trials with a once-daily dosing. The Phase 3 program began during late 2015 and a Phase 2 study of ABT-494 is under way for treating Crohn’s disease.
AbbVie is exploring the orally administered gonadotropin-releasing hormone (GnRH) antagonist elagolix in diseases that are mediated by sex hormones, including uterine fibroids and endometriosis. The new drug compound has been investigated in more than 40 studies totaling 3,000-plus subjects. Phase 3 development of Elagolix for the management of endometriosis-associated pain is under way in cooperation with Neurocrine Biosciences.
AbbVie and The University of Texas MD Anderson Cancer Center are teaming up to discover new ways to unleash the immune system’s potential to fight cancer. Announced during January 2016, the three-year collaboration deal provides a framework for MD Anderson and AbbVie to efficiently choose and carry out preclinical and clinical studies evaluating new ideas in the cutting-edge area of immuno-oncology.
Amgen cracked the top 10 pharma R&D spenders during 2014, ranking ahead of some traditional pharma powerhouses such as Bristol-Myers Squibb and AbbVie. The biotech company’s continuing annual increase in R&D expenditure is paying off, and during 2015 Amgen was rewarded with approval of a new-generation cholesterol-lowering medication and anticipated blockbuster brand: Repatha.
The human monoclonal antibody Repatha inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver’s ability to remove low-density lipoprotein cholesterol (LDL-C), or “bad” cholesterol, from the blood. The drug binds to PCSK9 and inhibits circulating the protein from binding to the low-density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and allowing LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, Repatha increases the amount of LDLRs available to clear LDL from the blood, thereby reducing LDL-C levels.
The European Commission was the first regulatory health body to grant marketing clearance to Repatha on July 21, 2015, when it became the first PCSK9 inhibitor to be approved anywhere worldwide. The Food and Drug Administration followed suit on Aug. 27, 2015, with U.S. launch occurring the following week. On Jan. 21, 2016, Repatha became the first PCSK9 inhibitor to be approved for marketing in Japan.
A single-dosing option for the monthly administration of Repatha Injection was filed for U.S. approval in September 2015. Marketing clearance of this application would allow for the 420-mg monthly dose to be administered as a single injection. Repatha is already available as a single-use 140 mg/mL prefilled SureClick autoinjector or prefilled syringe that individuals can self-administer at the recommended dose for adults of 140 mg every two weeks or 420 mg once monthly. For patients with homozygous familial hypercholesterolemia, the recommended dose is 420 mg once monthly.
Additional Phase 3 trials are under way to study Repatha for cardiovascular outcomes, on cognitive function, in statin-intolerant subjects, in subjects with genetic low-density lipoprotein disorders, and with intravascular ultrasound.
GLAGOV, the intravascular ultrasound study, is being conducted to determine the effect of Repatha on coronary atherosclerosis in 950 patients undergoing cardiac catheterization to test the hypothesis of robust LDL-C reduction resulting in a reduction or change in the build-up of artery plaque. Data from the GLAGOV trial are anticipated during second-half 2016.
The FOURIER outcomes study is designed to explore whether treatment with Repatha in combination with statin therapy, versus placebo plus statin therapy, reduces the risk of recurrent cardiovascular events in patients with high cholesterol and clinically evident cardiovascular disease. Top-line results from the 27,500-patient event-driven FOURIER trial are expected in second-half 2016.
Amgen continues to expand the available usage of the blood cancer medicine Kyprolis (carfilzomib) for Injection, which was initially granted accelerated approval during June 2012 by FDA as a single agent. In January 2016, U.S. regulators approved the supplemental NDA of Kyprolis in combination with dexamethasone or with lenalidomide plus dexamethasone for treating patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. FDA additionally approved Kyprolis as a single agent for treating patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
The marketing clearance is based on results from the Phase 3 head-to-head ENDEAVOR trial. This was a superiority study in which the primary endpoint was progression-free survival (PFS). The data demonstrated patients with relapsed multiple myeloma treated with Kyprolis and dexamethasone achieved 50 percent greater PFS of 18.7 months versus 9.4 months in those receiving Velcade (bortezomib) and dexamethasone (HR=0.53; 95 percent CI: 044, 0.65 p<0.0001), a current standard of care in relapsed multiple myeloma.
The newest indication for Kyprolis was the second in six months to be granted by FDA for the drug. During July 2015, the U.S. regulatory agency approved another expanded indication for Kyprolis in combination with lenalidomide and dexamethasone (KRd) for treating patients with multiple myeloma who have received one to three prior lines of therapy.
The European Commission during December 2015 approved the use of Imlygic (talimogene laherparepvec) for treating adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC and IVM1a), with no bone, brain, lung or other visceral disease. In late October 2015, FDA approved the genetically modified oncolytic viral therapy for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery.
This is the first oncolytic immunotherapy to show therapeutic benefit for patients with metastatic melanoma in a Phase 3 study. The pivotal study demonstrated that Imlygic significantly increased durable response rates in patients with unresectable melanoma that is regionally or distantly metastatic.
Imlygic is derived from HSV-1, which is commonly known as the cold sore virus. The therapy has been modified to replicate within tumors and produce the immune stimulatory protein human GM-CSF. Imlygic causes the death of tumor cells and release of tumor-derived antigens. It is believed that, in combination with GM-CSF, a systemic anti-tumor immune response and an effector T cell response will be promoted.
Amgen and Merck agreed during December 2015 on a cancer immunotherapy collaboration to support a Phase 1b/3 study investigating Blincyto (blinatumomab) in combination with Keytruda (pembrolizumab) in patients with diffuse large B-cell lymphoma. DLBCL is the most common type of non-Hodgkin lymphoma (NHL). Blincyto is Amgen’s CD19 bispecific T cell engager, trade marked as BiTE. Keytruda is an anti-PD-1 therapy marketed by Merck. The open-label, multicenter, randomized study is investigating safety and efficacy.
Blincyto (blinatumomab) was granted breakthrough therapy and priority review designations by U.S. regulators. The drug is FDA-cleared for treating Ph- relapsed or refractory B-cell precursor ALL via accelerated approval. BiTE antibody constructs are a form of immunotherapy being studied for fighting cancer by helping the body’s immune system to detect and target malignant cells. BiTE antibody constructs are being explored for their potential to treat various cancers.
Amgen and Merck additionally announced a second immunotherapy cancer collaboration to support a Phase 1/2 study of AMG 820, Amgen’s anti-colony-stimulating factor 1 receptor (CSF1R) antibody, in combination with Keytruda in patients with select advanced solid tumors. The open-label trial is designed to assess safety and efficacy in patients with select advanced solid tumors, including non-small cell lung, colorectal and pancreatic cancers.
Amgen is seeking FDA approval of etelcalcetide for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) on hemodialysis. If cleared for marketing, etelcalcetide (formerly AMG 416) will be the first calcimimetic agent that can be administered intravenously. The Prescription Drug User Fee Act (PDUFA) target action date for the etelcalcetide application is Aug. 24, 2016.
The novel calcimimetic agent suppresses the secretion of parathyroid hormone. Etelcalcetide acts by binding to and activating the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in PTH. Sustained PTH elevations are known to be associated with significant clinical consequences for CKD patients.
The novel cardiac myosin activator omecamtiv mecarbil is being developed by Amgen in collaboration with Cytokinetics. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell directly responsible for converting chemical energy into the mechanical force leading to cardiac contraction. Omecamtiv mecarbil, which enhances cardiac function by increasing cardiac contractility, is being developed for the potential treatment of heart failure.
In November 2015, the two companies reported top-line results from COSMIC-HF, a Phase 2 study of omecamtiv mecarbil in patients with chronic heart failure. The new drug candidate demonstrated statistically significant improvements in several measures of cardiac function, including systolic ejection time, stroke volume and N-terminal-pro-brain natriuretic peptide, at 20 weeks following randomization.
The investigational bone-forming monoclonal antibody romosozumab is being jointly developed by Amgen and UCB for treating osteoporosis. Romosozumab is designed to work by inhibiting the protein sclerostin, thereby increasing bone formation while decreasing bone breakdown. The drug compound is being explored for its potential to reduce the risk of fractures in an extensive worldwide Phase 3 program, including two large fracture studies. The trials are exploring the safety and efficacy of romosozumab versus either placebo or active comparator in more than 10,000 postmenopausal patients with osteoporosis. Data from the Phase 3 registrational trials in women with postmenopausal osteoporosis is anticipated during first-quarter 2016.
Amgen is studying the human monoclonal antibody AMG 334 for the prevention of migraine. AMG 334 inhibits the receptor for calcitonin gene-related peptide. Phase 3 trials in episodic migraine are under way, as well as an ongoing Phase 2 study in chronic migraine. Data from the Phase 2b trials in patients with chronic migraine is expected in second-half 2016.
While a variety of its medicines are being targeted in development as copycat versions by other companies, Amgen also is active in the biosimilars arena. FDA during January 2016 accepted for review Amgen’s Biologics License Application for ABP 501, a biosimilar candidate to AbbVie’s Humira (adalimumab). The Biosimilar User Fee Act target action date is Sept. 25, 2016. In December 2015, a MAA was filed to the European Medicines Agency for ABP 501. Adalimumab is an anti-TNF-alpha monoclonal antibody approved in many regions for treating several inflammatory diseases. Amgen conducted Phase 3 comparative efficacy and safety trials in moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid arthritis.
The AstraZeneca pipeline contains more than 130 projects, including 15 new molecular entities undergoing late-stage development. Those NMEs include three potentially transformative medicines and mega-brands: Tagrisso (AZD9291), durvalumab (MEDI4736) and acalabrutinib.
Tagrisso 80-mg once-daily tablet gained U.S. marketing clearance during November 2015. The product was approved for treating patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. Tagrisso was one of fastest development programs – from the start of clinical studies to approval in just more than two and a half years to meet unmet patient need.
Tagrisso (osimertinib) is the first approved product indicated for patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer. This indication was granted under FDA’s accelerated approval process based on tumor response rate as well as duration of response.
A targeted cancer therapy, Tagrisso is designed to inhibit the activating, sensitizing mutations (EGFRm), and T790M, a genetic mutation responsible for EGFR-TKI treatment resistance. Nearly two-thirds of NSCLC patients who are EGFR mutation-positive and experience disease progression after being treated with an EGFR-TKI develop the T790M resistance mutation, for which there have not been many treatment opportunities.
AstraZeneca has collaborated with Roche to develop the cobas EGFR Mutation Test v2 as the companion diagnostic for Tagrisso. The cobas EGFR Mutation Test v2 is intended to identify a range of EGFR mutations in individuals with non-small cell lung cancer, such as T790M.
Tagrisso was granted Fast Track, Breakthrough Therapy, Priority Review and Accelerated Approval status by U.S. regulators. In Europe and Japan, AZD9291 has been granted Accelerated Assessment and Priority Review status respectively. Interactions with regulatory authorities in the other parts of the world are under way.
AZD9291 is being studied in AURA3, an open-label, randomized Phase III trial designed to assess efficacy and safety compared to platinum-based doublet chemotherapy in patients with EGFR T790M positive, locally advanced, or metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI. The drug is additionally being explored in the adjuvant setting and in the metastatic first-line setting, including in patients with brain metastases, as well as in combination with other compounds.
An investigational human monoclonal antibody, durvalumab is directed versus PD-L1. Signals from PD-L1 help tumors evade immune system detection. According to AstraZeneca, durvalumab blocks these signals, countering the tumor’s immune-evading tactics. The new drug candidate is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being studied in an extensive clinical-trial program: as monotherapy or in combination with tremelimumab, in NSCLC, head & neck, gastric, pancreatic, bladder and blood cancers.
A comprehensive durvalumab registration program ranges across multiple tumor types, disease stages, and lines of therapy as monotherapy and in combination. This forms part of AstraZeneca’s late-stage immuno-oncology platform and includes more than 9,000 patients in 16 clinical studies in lung, bladder, head & neck, and other cancers.
“Durvalumab is a cornerstone of our immuno-oncology portfolio with a fast-advancing development program focused primarily on novel combinations,” stated Sean Bohen, executive VP, global medicines development and chief medical officer at AstraZeneca.
During December 2015, AstraZeneca agreed to invest in a majority equity stake in Acerta Pharma, a privately owned biopharma company based in the Netherlands and United States. The deal provides AstraZeneca with a potential best-in-class irreversible oral Bruton’s tyrosine kinase (BTK) inhibitor, acalabrutinib (ACP-196). The drug compound is undergoing Phase III trials for B-cell blood cancers and Phase I/II studies in multiple solid tumors.
An extensive development program is advancing for acalabrutinib with the opportunity for initial regulatory filings during second-half 2016 for treating patients with specific types of hematological malignancies. Expanding further into B-cell cancers, acalabrutinib has potential peak-year sales potential in excess of $5 billion worldwide.
“The investment is consistent with our focus on long-term growth and reflects the role targeted business development plays in our business model,” commented Pascal Soriot, AstraZeneca CEO. “We are boosting a key area in our comprehensive oncology portfolio with a late-stage, potential best-in-class medicine that could transform treatment for patients across a range of blood cancers.”
According to AstraZeneca, oncology is a therapy field in which the company has deep-rooted heritage. Oncology will be potentially transformational for AstraZeneca’s future, becoming its sixth growth platform. By 2020, the company intends to bring six new cancer medicines to patients.
AstraZeneca’s broad pipeline of next-generation oncology medicines is concentrated on four main disease fields – lung, ovarian, breast and hematological cancers. These areas are being targeted through four key platforms – immuno-oncology, the genetic drivers of cancer and resistance, DNA damage repair as well as antibody drug conjugates.
A new collaboration was announced during January 2016 to study the efficacy and safety of Incyte’s Janus-associated kinase (JAK) 1 inhibitor INCB39110 in combination with Tagrisso. The combination will be evaluated as a second-line treatment for patients with EGFR mutation-positive non-small cell lung cancer, who have been treated with a first-generation EGFR tyrosine kinase inhibitor and subsequently developed the T790M resistance mutation.
Increasing evidence shows that signaling via the JAK-STAT (signal transducer and activator of transcription) pathway could be a contributing factor in resistance to EGFR TKI treatment in patients with EGFR mutation NSCLC. Blocking JAK and EGFR activity may therefore offer an improved targeted treatment benefit in some individuals.
This transaction builds on an existing collaboration between AstraZeneca and Incyte. Announced during May 2014, the collaboration was set up to explore durvalumab in combination with Incyte’s oral indoleamine dioxygenase-1 (IDO1) inhibitor, epacadostat (INCB24360).
AstraZeneca’s oral poly ADP-ribose polymerase (PARP) inhibitor Lynparza (olaparib) was granted Breakthrough Therapy designation by FDA during January 2016. The designation was granted for the monotherapy treatment of BRCA1/2 or ATM gene mutated metastatic Castration Resistant Prostate Cancer (mCRPC) in patients who have received a prior taxane-based chemotherapy and at least one newer hormonal agent (abiraterone or enzalutamide).
Lynparza is approved by regulatory bodies in 40 countries for the maintenance treatment of women with BRCA-mutated ovarian cancer. An innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor, Lynparza exploits tumor DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives olaparib the potential for activity in various tumor types with DNA repair deficiencies.
AstraZeneca and its worldwide biologics R&D arm MedImmune struck a deal with Moderna Therapeutics during January 2016. The collaboration will discover, jointly develop and jointly commercialize messenger RNA (mRNA) therapeutic candidates for treating a range of cancers. The two companies agreed during 2013 to develop mRNA Therapeutics for treating cardiovascular, metabolic and renal diseases as well as selected targets in oncology.
The new collaboration combines MedImmune’s protein engineering and cancer biology expertise with Moderna’s mRNA platform. mRNA-based therapies are an innovative treatment approach that allows the body to produce therapeutic protein in vivo, opening up new treatment options for a wide array of diseases that cannot be addressed using existing technologies.
In other collaboration news, AstraZeneca and Eli Lilly announced in October 2015 an extension to their existing immuno-oncology alliance exploring novel combination therapies for treating patients with solid tumors. Durvalumab will be combined with Lilly molecules that target the immune system, including: the TGF-beta kinase inhibitor galunisertib; a CXCR4 peptide antagonist; and an anti-CSF-1R monoclonal antibody that will be assessed also with AstraZeneca’s anti-CTLA-4 monoclonal antibody tremelimumab.
AstraZeneca and Lilly will investigate other combinations targeting tumor drivers and resistance mechanisms. These include Lilly’s abemaciclib (CDK4 and 6 small molecule inhibitor) with Faslodex, AstraZeneca’s marketed selective estrogen receptor down regulator (SERD); and Cyramza (ramucirumab) and necitumumab, Lilly’s anti-VEGFR and anti-EGFR monoclonal antibodies respectively, with AZD9291, AstraZeneca’s investigational third-generation EGFR inhibitor.
In other therapeutic areas, AstraZeneca in December 2015 brought its new gout medicine to the U.S. marketplace. FDA approved Zurampic (lesinurad) 200-mg tablets in combination with a xanthine oxidase inhibitor (XOI) for treating hyperuricemia associated with gout in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone.
Zurampic inhibits the urate transporter, URAT1, which is responsible for most of the renal reabsorption of uric acid. By inhibiting URAT1, the drug increases uric acid excretion and thereby lowers sUA. In combination with the current standard of care, XOIs allopurinol or febuxostat, Zurampic provides a dual mechanism of action to increase excretion and decrease production of uric acid, allowing more patients with inadequately controlled gout to attain target treatment goals.
In December 2015, AstraZeneca completed the acquisition of the biopharma company ZS Pharma. The deal bolsters AstraZeneca’s cardiovascular and metabolic disease (CVMD) portfolio with the addition of the potassium-binding compound ZS-9 (sodium zirconium cyclosilicate). ZS-9 is a potential best-in-class treatment for hyperkalemia, a condition associated with increased mortality in patients with chronic kidney disease, diabetes mellitus, and chronic heart failure.
ZS-9 is undergoing FDA approval review with a Prescription Drug User Fee Act goal date of May 26, 2016. A filing for European Marketing Application Authorization is also advancing as planned. ZS-9 complements AstraZeneca’s increasing concentration on CKD and CHF, including the investigational medicine roxadustat, which is undergoing Phase III trials for patients with anemia associated with CKD, as well as its leading diabetes portfolio, a comorbidity often associated with CKD and CHF patients.
AstraZeneca, GlaxoSmithKline and J&J announced in January 2016 a partnership with three world-class universities – Imperial College London, the University of Cambridge and University College London – to create the Apollo Therapeutics Fund. This pioneering new consortium is seeking to convert outstanding academic science from the three universities into innovative medicines for a wide array of diseases. All therapy fields and modalities (including small molecules, peptides, proteins, antibodies, cell and gene therapies) are in scope.
Biogen makes this year’s Top 10 Pipelines listing partly based on a recently restructured corporate-wide R&D program as well as ongoing clinical development of two high-risk, high-reward pipeline assets.
Upon announcing the company’s third-quarter 2015 financial results, Biogen revealed a corporate restructuring that includes the termination of various pipeline programs and an 11% workforce reduction. These changes are projected to reduce the current annual run rate of Biogen’s operating expenses by $250 million. Management intends to reinvest these savings to support key commercial initiatives – including increased sales and marketing activities behind Tecfidera – as well as the advancement of high potential pipeline candidates in fields such as Alzheimer’s disease, multiple sclerosis, and spinal muscular atrophy.
The Cambridge, Mass.-based biotech company was reported in January 2016 to be hiring roughly 150 individuals during the course of this year for Biogen’s neuroscience R&D program. This news arrived only several months after Biogen announced its plan to cut about 880 jobs. That restructuring was reported to occur due to concerns over Tecfidera revenue growth despite the medicine’s multibillion-dollar peak sales projections. On July 24, 2015, Biogen reportedly more than halved its Tecfidera sales growth forecast for 2015, expecting U.S. demand for the company’s flagship multiple sclerosis brand to continue slowing for the rest of the year. After generating $721 million in U.S. sales during second-quarter 2015, Tecfidera produced $754 million in third-quarter 2015 sales, so Biogen management was accurate in its projection at least in the near term.
“The decision to reduce the company’s workforce was extremely difficult, but we believe these actions are necessary to fulfill our mission of bringing important new medicines to patients,” stated Biogen CEO George A. Scangos, Ph.D. “We have several high-quality programs that are now or soon will be in Phase 3, and the cost savings from the restructuring will be reinvested to carry out those programs aggressively and hopefully to bring them to patients as quickly as possible.”
Biogen discontinued several R&D programs, including the Phase 3 program for Tecfidera in secondary progressive MS, the development of anti-TWEAK in lupus nephritis, as well as certain activities in immunology and fibrosis research. The restructuring is expected to yield savings for 2016 and beyond and provides extra financial flexibility to support marketed therapies and concentrate on meaningful pipeline opportunities. These opportunities include:
• Commercial initiatives targeted at raising sales of Tecfidera, including new DTC marketing programs
• Aducanumab in Phase 3 for Alzheimer’s disease
• BAN2401 in Phase 2 for Alzheimer’s disease
• E2609 in Phase 2 for Alzheimer’s disease
• SMN-Rx in Phase 3 for spinal muscular atrophy
• Anti-LINGO in Phase 2 for multiple sclerosis
• Subject to deal closure, MT-1303: a Phase 3 ready asset for inflammatory bowel disease with potential additional development in MS
• Raxatrigine (product code CNV1014802), a Phase 3 ready asset for trigeminal neuralgia and Phase IIb ready for lumbar radiculopathy
Biogen is focused on two key, potentially transformative products: The Alzheimer’s medicine aducanumab and the multiple sclerosis drug anti-Lingo-1.
During September 2015, the company announced that the first patient has been enrolled in the Phase 3 trials – ENGAGE and EMERGE – for the investigational treatment aducanumab for early Alzheimer’s disease. ENGAGE and EMERGE are worldwide clinical research studies assessing the efficacy and safety of aducanumab to determine whether it can slow progression of symptoms in early Alzheimer’s disease. The studies are each intended to enroll 1,350 patients with early AD.
Aducanumab, also known by the product code BIIB037, has been developed in collaboration with Neurimmune. The memory loss and functional decline of Alzheimer’s disease have been associated with amyloid plaques, which are abnormal protein deposits that build up in the brain. The antibody BIIB037 binds to and may reduce amyloid plaques from the brain, potentially slowing the progress of Alzheimer’s disease.
During July 2015, Biogen presented new data from the Phase Ib PRIME trial of aducanumab. Consistent with previously reported results, the one-year data from the 6 mg/kg arm showed a statistically significant reduction of beta amyloid in the brain. In exploratory analyses, the 6 mg/kg dose demonstrated an improvement in the slowing of clinical decline. In a pre-specified analysis across placebo and all doses of aducanumab, the slowing of clinical decline was demonstrated to be dose-dependent, and this dose-dependence achieved statistical significance for each scale. In this analysis, aducanumab showed acceptable safety and tolerability.
“The company (also) continues to invest in the science that is core to our future, and we are continuing to advance our pipeline in areas where patients have limited or no treatment options,” Dr. Scangos noted. “We are excited to report we are now actively recruiting for two global Phase 3 studies of aducanumab in patients with early Alzheimer’s disease. We see aducanumab as a potentially transformational opportunity for Biogen, and for patients with this devastating disease.”
The investigational compound Anti-LINGO-1 (product code BIIB033) is undergoing clinical development for treating multiple sclerosis. The fully human monoclonal antibody targets LINGO-1, which is a protein expressed selectively in the central nervous system. LINGO-1 is known to have a focal role in regulating axonal myelination and regeneration.
As a neurologic protein, LINGO is involved in developing myelin, which is a protective sheath that covers nerve fibers. Multiple sclerosis causes the body’s immune system to attack myelin. Damage to myelin “short circuits” communication between the brain, spinal cord and other parts of the body, severely impairing neurological functions such as mobility, vision and thinking. In time, the nerves themselves can become permanently damaged.
In MS patients, LINGO may inhibit myelin growth when the antibody binds with its normal receptor. Data demonstrated that anti-LINGO-1 could block this process, potentially enabling the re-myelination and restoration of nerve communication in patients with multiple sclerosis.
Two worldwide Phase 2 studies, RENEW and SYNERGY, were designed to assess the biological activity and clinical potential of anti-LINGO-1 in acute optic neuritis (AON) and relapsing forms of MS. In RENEW, anti-LINGO-1 was assessed in patients following a first episode of AON. Anti-LINGO-1 showed an improvement in recovery of optic nerve latency (time for a signal to travel from the retina to the visual cortex) relative to placebo. RENEW was the first trial to provide evidence of biological repair in the central nervous system by facilitating remyelination after an acute inflammatory injury.
SYNERGY is a separate Phase 2 trial that aims to measure the impact of anti-LINGO-1 in combination with an anti-inflammatory therapy on improving and slowing disease progression among participants with relapsing forms of MS Results from the ongoing clinical trial are anticipated in 2016.
Through a transaction with Mitsubishi Tanabe Pharma, announced during September 2015, Biogen exclusively licensed MT-1303. The Phase 3-ready experimental medicine has potential in multiple autoimmune indications, such as inflammatory bowel disease and multiple sclerosis. A potentially best-in-class oral compound, MT-1303 targets the sphingosine 1-phosphate (S1P) receptor.
Biogen and AbbVie are jointly developing Zinbryta (daclizumab high-yield process), an investigational compound intended for treating relapsing forms of multiple sclerosis. A new form of a humanized monoclonal antibody, Zinbryta selectively binds to the high-affinity interleukin-2 receptor subunit that is expressed at high levels on T-cells that become abnormally activated in MS. The potential new drug candidate modulates IL-2 signaling without causing general immune cell depletion.
Zinbryta is believed to work by decreasing abnormally activated T-cells and pro-inflammatory lymphoid tissue inducer cells, and increasing CD56bright natural killer (NK) cells, important cells that assist in the regulation of the immune system. Zinbryta is undergoing regulatory review in the United States, Australia and the European Union.
In August 2015, Biogen, the ALS Association and Columbia University Medical Center announced a new collaboration to better understand the differences and commonalities in the process of Amyotrophic Lateral Sclerosis disease and how genes influence the clinical features of ALS.
During July 2015, Biogen and the Parkinson’s Institute and Clinical Center announced the formation of a strategic alliance concentrated on enhancing the understanding of the underlying biology of Parkinson’s disease.
Gilead Sciences, Med Ad News’ 2015 Company of the Year, has taken the industry by storm in recent years with its ultra-successful hepatitis C drugs Harvoni and Sovaldi. The company’s total hepatitis franchise is anticipated to continue rolling along with the eventual market arrival of projected blockbuster reinforcements such as the combination treatment GS-9857/SOF/GS-5816 and tenofovir alafenamide. According to EvaluatePharma’s Net Present Value (NPV) Analyzer as of May 22, 2015, those two drug prospects ranked No. 1 and No. 4 in total value amongst all of the industry’s R&D projects. GS-9857/SOF/GS-5816 was given an NPV of $24.8 billion (with a 2020 sales forecast of $4.58 billion), and tenofovir alafenamide’s net present value was reported at $10.64 billion (with a 2020 sales projection of $3.13 billion).
Harvoni (ledipasvir/sofosbuvir) and Sovaldi (sofosbuvir) are the most successful new drug launches of all-time. Introduced in the United States in December 2013, Sovaldi’s 2014 sales performance reached $10.28 billion before dropping to $3.73 billion in the January-September 2015 period due to the arrival of Harvoni. Uniting Sovaldi (sofosbuvir) with ledipasvir, Harvoni was FDA-approved in October 2014 and generated $10.52 billion in sales during the first nine months of 2015.
“We continue to advance our understanding of the safety and efficacy of Sovaldi and Harvoni in diverse groups of HCV patients, including several special patient populations that historically have not been studied,” commented Norbert Bischofberger, PhD, executive VP of R&D and chief scientific officer at Gilead, in mid-November 2015 at The Liver Meeting in San Francisco. “We are also pleased to share data evaluating our next-generation investigational sofosbuvir-based therapies SOF/VEL and SOF/VEL plus GS-9857. In total, the data highlighted (this week) demonstrate the strength of sofosbuvir as the backbone of multiple hepatitis C treatment regimens in numerous hepatitis C-infected patient populations.”
GS-9857/SOF/GS-5816 consists of an investigational pangenotypic NS3/4A protease inhibitor (GS-9857), a hepatitis C nucleoside NS5A inhibitor (sofosbuvir/SOF), and an investigational pan-genotypic NS5A inhibitor (velpatasvir/VEL/GS-5816). Being explored in patients with HCV genotype 1 and 3 infection, SOF, VEL and GS-9857 co-formulated into a fixed-dose combination will be advanced into Phase 3 trials.
Gilead reported during early January 2016 that FDA has granted priority review to the company’s New Drug Application for the SOF/VEL combination for the treatment of chronic genotype 1-6 hepatitis C virus infection. The NDA for SOF/VEL was submitted by Gilead to U.S. regulators on Oct. 28, 2015, and FDA has set a target action date under the PDUFA of June 28, 2016.
The U.S. regulatory agency assigned SOF/VEL a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options. The NDA for SOF/VEL is supported by data from four Phase 3 ASTRAL studies, which assessed the fixed-dose combination in hepatitis C genotypes 1-6. A marketing application for SOF/VEL is undergoing EU regulatory review, and was validated by the European Medicines Agency (EMA) during December 2015. If approved for marketing, SOF/VEL would be Gilead’s third HCV medication and the first all-oral, pan-genotypic, single tablet HCV regimen.
In January 2016, Gilead announced the submission of a New Drug Application with U.S. regulators for tenofovir alafenamide (TAF) 25 mg as an investigational, once-daily treatment for adults with chronic hepatitis B virus infection. TAF is a novel, targeted prodrug of tenofovir that has shown high antiviral efficacy similar to and at a dose less than one-tenth that of Gilead’s Viread (tenofovir disoproxil fumarate, TDF), as well as improvements in surrogate lab markers of renal and bone safety versus Viread. The NDA for TAF is supported by 48-week data from two Phase 3 trials, which met their primary objective of non-inferiority in efficacy compared to Viread among treatment-naïve and treatment-experienced adults with HBeAg-negative and HBeAg-positive chronic HBV.
“Given its lower dose, efficacy and safety profile, TAF has the potential to offer patients an improved treatment option that may advance their long-term care of chronic HBV,” Dr. Bischofberger remarked.
The company anticipates filing a regulatory application for TAF in the European Union during first-quarter 2016.
Galapagos and Gilead entered into a collaboration for the worldwide development and commercialization of filgotinib in inflammatory diseases during December 2015. The companies are jointly collaborating on the global development of filgotinib beginning with the initiation of Phase 3 studies in rheumatoid arthritis. Galapagos is jointly funding 20 percent of worldwide development activities and Gilead is responsible for manufacturing as well as global marketing and sales activities. Galapagos has the option to jointly promote filgotinib in the UK, Germany, France, Italy, Spain, Belgium, the Netherlands and Luxembourg, in which case the companies will share profits equally.
Genvoya during November 2015 became the first TAF-based regimen to receive U.S. and EU marketing clearance. FDA and the European Commission granted marketing authorization for the once-daily single tablet regimenGenvoya (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg or E/C/F/TAF) for treating HIV-1 infection. The approvals are based on a Phase 3 HIV clinical program in 3,500-plus patients across 21 countries, including treatment-naïve, virologically suppressed, renally impaired and adolescent patients. Marketing clearance was approved in all 28 EU countries.
Harvoni’s label was expanded by FDA during November 2015 to include patients with genotypes 4, 5 and 6 as well as patients co-infected with HIV. Also, Harvoni in combination with ribavirin for 12 weeks was approved as an alternate therapy to 24 weeks of Harvoni for treatment-experienced, genotype 1 patients with cirrhosis.
Gilead additionally reported during November that Zydelig combined with bendamustine and rituximab demonstrated superior efficacy to bendamustine/rituximab in a Phase 3 trial of patients with relapsed chronic lymphocytic leukemia. Study 115 is a randomized, double-blind, placebo-controlled, Phase 3 trial assessing the efficacy and safety of Zydelig in combination with bendamustine and rituximab among 416 adult patients with previously treated CLL. Zydelig is FDA-approved in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to comorbidities.
Third-quarter 2015 highlights for Gilead included Harvoni’s approval in Japan as the first once-daily single tablet regimen (STR) for treating chronic hepatitis C genotype 1 infection in adults. Additionally, Gilead filed an NDA with FDA for an investigational, once-daily STR combining Gilead’s emtricitabine 200 mg and tenofovir alafenamide (TAF) 25 mg with rilpivirine 25 mg (R/F/TAF) from Janssen Sciences Ireland UC for treating HIV-1 infection in adult and pediatric patients 12 years of age and older. Meanwhile, the Marketing Authorization Application for R/F/TAF was fully validated and under evaluation by the EMA. Also, Gilead announced a Phase 3 trial of F/TAF for treating HIV-1 infection met its primary objective. The clinical trial was designed to explore the efficacy and safety of F/TAF-based regimens among virologically suppressed adult patients switching from HIV-treatment regimens composed of emtricitabine/tenofovir disoproxil fumarate.
Shortly before this magazine went to press, Merck received FDA approval for an anticipated blockbuster medication for treating hepatitis C. Zepatier gained U.S. regulatory clearance for treating adult patients with chronic hepatitis C virus (HCV) genotype (GT) 1 or GT4 infection, with or without ribavirin (RBV). The once-daily, fixed-dose combination tablet is composed of the NS5A inhibitor elbasvir (50 mg) and the NS3/4A protease inhibitor grazoprevir (100 mg). Zepatier was granted priority review by FDA as well as two Breakthrough Therapy designations: for the treatment of chronic HCV GT1 infection in patients with end-stage renal disease on hemodialysis, and for treating patients with chronic HCV GT4 infection.
Across multiple clinical trials, the new medicine achieved high rates of sustained virologic response (SVR) ranging from 94 to 97 percent in GT1-infected patients, and 97 to 100 percent in GT4-infected patients. SVR is defined as HCV RNA levels measuring less than the lower limit of quantification at 12 weeks after the cessation of treatment, indicating that a patient’s HCV infection has been cured. Zepatier was approved with a treatment duration of 12 or 16 weeks, depending on HCV genotype, previous treatment history and – for patients with GT1a infection – the presence of certain baseline NS5A polymorphisms.
“This approval provides patients and physicians with an additional treatment option that has the potential to cure many patients with chronic hepatitis C in the United States,” noted Dr. Ira Jacobson, site chair, department of medicine, Mount Sinai Beth Israel, New York. “Zepatier is a once-daily, single-tablet direct-acting antiviral that has demonstrated high cure rates in genotype 1 and in genotype 4, including treatment-naïve and treatment-experienced patients with or without compensated cirrhosis and those with chronic kidney disease.”
Merck anticipates a European Commission decision on the MAA for elbasvir/grazoprevir (50mg/100mg) for treating adult patients with chronic hepatitis C infection in mid-2016.
Despite its strong profile, Zepatier faces stiff market competition, mainly from Gilead’s behemoths Harvoni and Sovaldi as well as AbbVie’s blockbuster Viekira Pak (each product was discussed earlier in this article). Worldwide sales for Zepatier have been estimated at near the $2 billion mark by 2020.
Merck continues to make significant progress with its pipeline and key therapeutic fields of diabetes, hospital acute care, oncology and vaccines. “Our late-stage pipeline and ongoing launches create both near- and longer-term opportunities to generate value through innovation aimed at addressing some of the world’s biggest medical needs – cancer, antibiotic resistance, cardiometabolic disease, hepatitis C and Alzheimer’s disease,” commented Kenneth C. Frazier, chairman and CEO of Merck.
In making Med Ad News’ Top 10 Pipelines listing, Merck received extra credit for the company’s continued efforts to tackle R&D in the area of neuroscience, and Alzheimer’s disease in particular. For more than a decade, Merck has been researching ways to treat AD across the continuum of the disease –- exploring ways to modify disease progression and improve symptoms management in later stages.
In late January 2016, Merck confirmed the completion of enrollment for EPOCH, a Phase 2/3 randomized, placebo-controlled, parallel-group, double-blind trial of verubecestat. Formerly known as MK-8931, the investigational oral small molecule selective beta secretase (BACE1) inhibitor verubecestat is being studied in EPOCH in patients with mild-to-moderate Alzheimer’s disease. The clinical trial started during November 2012, completed enrollment in fourth-quarter 2015, and is projected to reach primary trial completion as of July 2017.
EPOCH is designed to assess the safety and efficacy of two oral doses of verubecestat (12 mg and 40 mg) administered once per day versus placebo in patients with mild-to-moderate AD currently using standard of care treatment. Merck is exploring the safety and efficacy of verubecestat in the earlier, prodromal phase of AD in another Phase 3 study, APECS.
The amyloid cascade hypothesis proposes that build-up of toxic amyloid beta peptides result in amyloid plaque deposits in the brain. This process triggers neurodegeneration in the brain, leading to the progressive decline in cognition and function in patients with Alzheimer’s disease. BACE1 performs the first step in the amyloid cascade and is considered to be focal to the pathology of AD. Evidence suggests that inhibiting BACE1 lowers the production of toxic amyloid beta peptide and may therefore decrease amyloid plaque formation and modify AD progression.