2016 Annual Report: Top 10 Pipelines
The pharma industry’s R&D concentration has been shifting towards specialty therapy areas as research and development returns decline for some leaders.
Top 10 Pipelines
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.
On the cancer battle front, Merck and Eli Lilly during December 2015 announced an additional immuno-oncology collaboration that will study abemaciclib (LY2835219), Lilly’s cyclin-dependent kinase (CDK) 4 and 6 inhibitor, and Merck’s Keytruda (pembrolizumab) in a Phase I trial across multiple tumor types. The collaboration has the potential to advance to Phase II trials in patients diagnosed with either metastatic breast cancer or non-small cell lung cancer (NSCLC).
Abemaciclib is a cell cycle inhibitor designed to block the growth of cancer cells by specifically inhibiting CDK4 and CDK6. The humanized monoclonal antibody pembrolizumab works by increasing the ability of the body’s immune system to help detect and combat tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect tumor cells as well as healthy cells.
The two companies during November 2015 also extended their existing collaboration to assess the safety and efficacy of the combination of Lilly’s Alimta (pemetrexed for injection) and Keytruda in a pivotal Phase III trial in first-line NSCLC. The clinical trial is sponsored by Merck and is open to patients with NSCLC in the first-line setting, regardless of PD-L1 status.
The expansion of this oncology collaboration follows the release of encouraging data from a Phase I trial investigating pemetrexed, carboplatin and pembrolizumab in first-line nonsquamous NSCLC. The companies say pemetrexed is a leading therapeutic option used in combination with platinum-based therapies in this setting, making it an ideal candidate for combo studies with immunotherapy treatments.
The Keytruda program is tackling more than 30 tumor types in 160-plus studies, including more than 80 trials that combine the humanized monoclonal antibody with other cancer treatments. Within this program, there is a strong concentration on hematological malignancies, with 20 studies investigating Keytruda in blood cancers. This includes four registration-enabling trials in Hodgkin lymphoma and multiple myeloma, and more than 15 combinations of the anti-PD-1 therapy with other treatments for specific hematologic malignancies.
Registration-enabling studies of Keytruda are additionally enrolling patients suffering from melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, and breast cancer. Additionally studies are being planned for other malignancies.
Merck reported in December 2015 that new study findings exploring the use of Keytruda across a variety of hematological cancers were presented at the 57th American Society of Hematology Annual Meeting. New and updated data showed a potential role for Keytruda in multiple myeloma, Hodgkin lymphoma, B-cell lymphoma, and Richter’s transformation in chronic lymphocytic leukemia. Also, Merck reported that responses were observed in three-quarters of heavily pre-treated multiple myeloma patients receiving Keytruda combined with lenalidomide and low-dose dexamethasone, which are two common treatments for MM.
Findings featured at the Society for Melanoma Research 2015 International Congress in San Francisco during November demonstrated robust anti-tumor activity with Keytruda in combination with three immunotherapies for advanced melanoma: epacadostat, Imlygic (talimogene laherparepvec), and ipilimumab. In addition, updated data presented at SMR from a Phase 3 trial of Keytruda as a single agent demonstrated superior overall response rates and progression free survival versus ipilimumab in ipilimumab-naïve patients. Twice as many patients achieved PFS on Keytruda compared to ipilimumab.
Merck is exploring two investigational all-oral, triple-combination treatment regimens – a regimen of grazoprevir, MK-36822 and elbasvir; and a regimen of grazoprevir, MK-3682 and MK-84084 – in treatment-naïve patients with chronic HCV genotypes (GT) 1, 2 or 3 infection. Based on the strong results of this initial study, Merck announced in November 2015 the initiation of another trial of grazoprevir (100mg), MK-3682 (450mg) and MK-8408 (60mg) in the second phase (Part B) of the C-CREST Phase 2 clinical development program. MK-3682 is an oral prodrug HCV nucleotide analog NS5B polymerase inhibitor and MK-8408 is an HCV NS5A replication complex inhibitor.
GlaxoSmithKline and Merck in November announced the initiation of a phase I study designed to evaluate the investigational immunotherapy GSK3174998 as monotherapy and in combination with Keytruda in patients with locally advanced, recurrent or metastatic solid tumor(s) that have progressed after standard treatment. GlaxoSmithKline’s GSK3174998 is a humanized IgG1 anti-OX40 monoclonal antibody that was identified via a collaboration with MD Anderson Cancer Center. OX40 is a tumor necrosis factor receptor that is expressed on the surface of activated CD4+ and CD8+ T cells. OX40 agonism leads to the stimulation of immune effector and memory functions, while additionally attenuating the immunosuppressive regulatory T cells that are sometimes found in tumors.
Merck agreed during October 2015 on a collaboration to study the combination of the clinical-stage biopharma company MacroGenics’ anti-HER2 product candidate margetuximab with Keytruda in a Phase 1b/2 study in patients with advanced gastric cancer. The Fc-optimized monoclonal antibody margetuximab targets the human epidermal growth factor receptor 2, which is an antigen vital to the growth of many types of tumors, including breast and gastroesophageal cancers.
Incyte and Merck during October expanded the companies’ ongoing clinical collaboration to include a Phase 3 trial evaluating the combination of Incyte’s investigational selective IDO1 inhibitor epacadostat with Keytruda as first-line treatment for patients with advanced or metastatic melanoma. The Phase 3 trial, which is anticipated to start during first-half 2016, is being jointly funded by Incyte and Merck.
In other October news regarding Keytruda, Merck entered into an oncology clinical trial collaboration to explore the efficacy and safety of DNAtrix’s oncolytic immunotherapy DNX-2401 in combination with Keytruda in a Phase 2, multi-centered trial of patients with recurrent glioblastoma, the most aggressive form of brain cancer for which there is no cure. DNX-2401 is a conditionally replicative oncolytic adenovirus designed to specifically target cells defective in the Retinoblastoma pathway, which is located in many cancers. Several DNX-2401 trials have shown a favorable safety profile and strong tumor-killing potential in recurrent glioblastoma patients.
The No. 1 company in terms of global prescription drug sales, Novartis is projected to retain that top ranking for years to come. To maintain its leading performance level, Novartis will need to continue churning out successful new molecular entities. One of those NME approvals is the angiotensin II receptor (AT1) antagonist and neprilysin inhibitor (ARNI) Entresto. EvaluatePharma’s NPV Analyzer assigned the breakthrough treatment for chronic heart failure with reduced ejection fraction a net present value of $16.25 billion during May 2015, along with a 2020 global sales projection of $4.16 billion.
Containing the active ingredients sacubitril and valsartan, Entresto is also known by the product code LCZ696. The product gained U.S. market clearance in July 2015 for treating heart failure with reduced ejection fraction. The first-in-class medicine reduces the strain on the failing heart. A twice-daily tablet, Entresto works to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful system (the RAAS).
The European Commission during November 2015 approved Entresto for treating adult patients with symptomatic chronic heart failure with reduced ejection fraction. According to Novartis, Entresto represents peak sales potential of more than $5 billion for the reduced ejection fraction indication.
Cosentyx (secukinumab) represents another 2015 market launch and projected blockbuster brand for Novartis. The drug was approved during January 2015 as the first IL-17A inhibitor in the United States and Europe for treating moderate-to-severe plaque psoriasis. In fourth-quarter 2015, the European Commission approved Cosentyx for treating two new indications: ankylosing spondylitis (AS) and psoriatic arthritis (PsA). In January 2016,
U.S. regulators gave the green light to the product for AS and PsA. Cosentyx represents the first treatment advance in 16 years since anti-tumor necrosis factor (anti-TNF) therapy, which serves as the current standard of care.
A fully human monoclonal antibody, Cosentyx selectively neutralizes circulating IL-17A. Cosentyx is the first IL-17A inhibitor with positive Phase III results for treating PsA and AS. Research suggests that IL-17A may play a significant role in driving the body’s immune response in psoriasis, PsA and AS.
During December 2015, the results of the MEASURE 1 and MEASURE 2 Phase III trials for Cosentyx in AS were published in the New England Journal of Medicine (NEJM). These pivotal trials showed significant clinical improvements with Cosentyx compared to placebo in the signs and symptoms of active AS – a long-term, painful and debilitating inflammation of the spine. Collectively the clinical trials form the largest R&D program ever conducted in AS, involving 590 patients.
Novartis launched during in 2015 a new immuno-oncology research team led by cancer vaccine pioneer Glenn Dranoff. The team quickly built a broad portfolio of clinical and pre-clinical programs concentrated on stimulating the body’s immune system to combat cancers via targeting critical regulatory steps in the anti-tumor immune response. The immuno-oncology portfolio contains novel checkpoint inhibitors, chimeric antigen receptor T-cell (CART) technology, myeloid cell targeting agents, the T cell stimulating factor IL-15, STING agonists that enhance immune recognition of cancers, and adenosine receptor antagonists and TGF-beta blocking antibodies that overcome immunosuppression in the tumor microenvironment.
Novartis continues to expand its immuno-oncology pipeline. During January 2016, Novartis announced a collaboration and licensing deal with Surface Oncology. Novartis acquired access to four pre-clinical programs that target regulatory T cell populations, inhibitory cytokines, and immunosuppressive metabolites in the tumor microenvironment.
Before the Surface Oncology transaction, the diverse immuno-oncology portfolio for Novartis already included seven programs in clinical studies. Five additional programs are anticipated to enter the clinic either individually or as a combination by year-end 2016. The company’s myeloid cell targeting program (MCS110), anti-TIM-3 program (MGB453), IL-15-agonist (NIZ985) checkpoint inhibitors targeting PD-1 (PDR001) and LAG-3 (LAG525), and a small molecule adenosine receptor antagonist (NIR178) are in phase 1. The CART program (CTL019) is undergoing phase 2 development. A STING agonist (MIW815), a GITR agonist, and an anti-TGF-beta antibody are advancing toward first-in-human trials in 2016.
“This rich immuno-oncology pipeline together with a deep targeted therapy portfolio provides Novartis with the opportunity to attack cancer in powerful and complementary ways: through enhancing immune-mediated tumor destruction and promoting direct tumor cell killing,” according to Novartis. “Together, these synergistic approaches may accomplish more durable clinical benefits for a larger proportion of cancer patients.”
Novartis inked a collaboration in January 2016 with Qualcomm via its subsidiary, Qualcomm Life, in digital innovation with the Breezhaler inhaler device to treat chronic obstructive pulmonary disease. Qualcomm Life is supplying the technology solution for the connectivity of the next generation of the Breezhaler inhaler, a device used for Novartis’ portfolio of COPD treatments of Onbrez Breezhaler Seebri Breezhaler, and Ultibro Breezhaler, the leading LABA/LAMA treatment.
This next generation of the Breezhaler inhaler will allow patients to have access to their own data on the use of their inhaler in near real time. The small, disposable and low power module contained within the inhaler device can detect and report usage, the time that the inhaler is used, as well as other relevant information for patients and physicians. The module then wirelessly sends the data to the patient’s smartphone and a Novartis COPD mobile application, which transmits the data to the cloud, enabling patients and potentially their healthcare providers to monitor COPD.
Pipeline highlights during Q4 2015 included reported Phase III PKC412 data demonstrating survival benefit in certain ALS patients. The RATIFY trial of adult patients with newly diagnosed FLT3-mutated acute myeloid leukemia showed that PKC412 (midostaurin) in combination with standard induction and consolidation chemotherapy improves overall survival by 23% versus standard induction and consolidation chemotherapy alone.
New CTL019 data in relapsed/refractory ALL was presented at the 2015 American Society of Hematology Annual Meeting. An ongoing Phase II trial in children and young adults with relapsed/refractory acute lymphoblastic leukemia (r/r ALL) found that 93 percent (55/59) experienced complete remissions with CTL019. This trial is the largest study of a CART therapy in pediatric patients with relapsed or refractory ALL.
Novartis and the University of Pennsylvania have an exclusive worldwide collaboration to research, develop and commercialize CART therapies for the investigational treatment of cancers. The U.S. regulatory agency has designated CTL019 as a Breakthrough Therapy for treating pediatric and adult patients with r/r ALL under the Penn Investigational New Drug application. Novartis is responsible for the global rights to CARTs developed via the collaboration with Penn for all cancer indications, including the lead program, CTL019.
On the biosimilar front, FDA during fourth-quarter 2015 accepted Novartis company Sandoz’s regulatory filing for the biosimilar Neulasta (pegfilgrastim), a recombinant human granulocyte colony-stimulating factor from Amgen. The filing was based on the Phase III PROTECT 2 trial, which demonstrated the proposed biosimilar to be equivalent and non-inferior to Neulasta for preventing neutropenia in patients with breast cancer. Sandoz is seeking marketing clearance for the same indication as the reference product. Sandoz reported Phase III data demonstrating its proposed biosimilar pegfilgrastim has similar safety and efficacy as Neulasta.
Also in Q4 2015, the EMA accepted Sandoz’s regulatory filing for the company’s biosimilar version of Enbrel (etanercept), a TNF-alpha inhibitor marketed by Amgen. Sandoz is seeking marketing clearance for all indications in the reference product’s label, including rheumatoid arthritis and psoriasis.
Roche continues to be a leader in the research and development of biotechnology products and cancer medicines. The company is studying more than 20 drugs in cancer immunotherapy, eight of which are in clinical studies.
One of the most enticing prospects in Roche’s R&D program is atezolizumab (additionally known as MPDL3280A). The monoclonal antibody is designed to target and bind to a protein called PD-L1 (programmed death-ligand 1), which is expressed on TCs and tumor-infiltrating ICs. PD-L1 interacts with PD-1 and B7.1, each of which are found on the surface of T cells, resulting in inhibition of T cells. By blocking this interaction, atezolizumab may allow for the activation of T cells, restoring their ability to effectively detect and attack tumor cells.
Roche during January 2016 presented updated results for the investigational cancer immunotherapy atezolizumab in a phase II trial – known as IMvigor 210 – for advanced bladder cancer. According to the results, higher expression of PD-L1 was associated with higher response rates, however low levels of PD-L1 expression did not preclude response. Ongoing responses were evident in most people. Complete Responses were observed regardless of levels of PD-L1 expression. Roche planned to submit these data to worldwide health authorities and the U.S. Food and Drug Administration under Breakthrough Therapy designation.
In addition to IMvigor 210, Roche is conducting a randomized phase III trial, IMvigor 211, comparing atezolizumab with standard-of-care chemotherapy in people who have mUC that worsened after initial treatment. All clinical trials include the evaluation of a companion test developed by Roche Tissue Diagnostics to determine PD-L1 status.
Industry analysts have projected $2+ billion in 2020 global sales for atezolizumab Another promising new drug candidate for Roche is lampalizumab, which is also anticipated to attain blockbuster drug status within the next few years.
Lampalizumab is being studied globally in phase III trials for geographic atrophy. GA is an advanced form of age-related macular degeneration, a progressive condition that can lead to blindness. The phase III program is assessing the safety and efficacy of lampalizumab and its potential to slow the progression of GA. The clinical trials are additionally investigating whether people with a specific genetic biomarker, a mutation in complement factor I, may benefit more from lampalizumab treatment.
The humanized monoclonal antibody fragment ampalizumab (anti-Factor D Fab) targets complement factor D. The new drug molecule is designed to inhibit complement activation and chronic inflammation in tissues. Complement Factor D is a member of the trypsin family of peptidases as well as a component of the alternative complement pathway. Managed by Genentech Research and Early Development, ampalizumab is not expected to be filed for regulatory approval before 2017.
The Roche drug pipeline recently produced a new drug approval in the United States. In December 2015, FDA granted accelerated approval for Alecensa (alectinib) for treating individuals with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. In pivotal studies, Alecensa shrank tumors in up to 44 percent of patients with ALK-positive NSCLC who progressed on crizotinib.
Alecensa is being studied for use as an initial (first-line) treatment for people with advanced ALK-positive NSCLC. ALEX is a worldwide, randomized phase III trial comparing Alecensa to crizotinib as an initial treatment for people with advanced NSCLC whose tumors were characterized as ALK-positive by a companion VENTANA ALK (D5F3) CDx Assay immunohistochemistry (IHC) test developed by Roche Diagnostics.
The oral medicine Alecensa (RG7853/AF-802/RO5424802/CH5424802) was discovered by Chugai and is being developed for people with NSCLC whose tumors are identified as ALK+. The worldwide phase III trials of Alecensa include a companion test developed by Roche. Alecensa is marketed in Japan by Chugai Pharmaceutical, which is a member of the Roche Group.
Another product to recently emerge from the company’s R&D portfolio is Cotellic, which represented Roche’s seventh new medicine to gain FDA marketing clearance during the past five years. Cotellic (cobimetinib) was approved for treating people with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma in combination with Zelboraf.
Cotellic and Zelboraf (vemurafenib) are used together for the treatment of melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal “BRAF” gene. Found in half of melanomas, mutated BRAF results in abnormal signaling inside certain cancer cells leading to tumor growth. Zelboraf is designed to inhibit some mutated forms of BRAF and Cotellic is designed to inhibit certain types of MEK. BRAF and MEK are proteins in a cell signaling pathway that assist in controlling cell growth and survival. When used together, Cotellic and Zelboraf are believed to reduce cancer cell growth longer than with Zelboraf alone.
Roche and Upsher-Smith Laboratories – through its wholly owned UK subsidiary Proximagen – at the beginning of December 2015 announced a global deal. The companies agreed to develop a novel, oral small molecule inhibitor of Vascular Adhesion Protein 1 (VAP-1). The cell-adhesion molecule may be effective in treating inflammatory diseases. The VAP-1 inhibitor is undergoing phase II clinical trials.
Roche is granted a global exclusive license to develop and commercialize the new drug compound. In a novel collaboration model, Roche and Proximagen will perform other phase II trials to further define the therapeutic potential of the VAP-1 inhibitor. Based on these data, Roche will assume responsibility for late-stage development and global commercialization.
At the congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in October 2015, Roche presented positive phase III data for ocrelizumab in people with relapsing forms of multiple sclerosis and in primary progressive MS. Ocrelizumab is the first medicine to demonstrate a clinically meaningful impact on the progression of disability in people with primary progressive MS (PPMS) in a pivotal phase III study. Roche will submit these data to worldwide health authorities during 2016 to seek approval of ocrelizumab for relapsing forms of MS and PPMS. Projected global sales for ocrelizumab in 2020 are $2.7 billion.
FDA granted Breakthrough Therapy Designation during September 2015 for ACE910 to prevent bleeding episodes in hemophilia A patients aged 12 and older. ACE910 became the ninth Breakthrough Therapy Designation granted to a Roche drug.
At the end of October 2015, Sanofi’s research and development program consisted of 41 pharma new molecular entities (excluding Life Cycle Management) vaccine candidates in clinical development. Of that amount, 13 were in Phase III or had been filed for marketing clearance with regulatory health bodies. Research area include diabetes, vaccines & infectious diseases, rare diseases, immunology & inflammation, cardiovascular & metabolism, multiple sclerosis, cancer, and neurodegnerative diseases.
Sanofi during November 2015 revealed a strategic roadmap for long-term growth for the period 2015-2020 and its ambition to become the pre-eminent diversified global healthcare company. As part of the strategy, Sanofi announced plans to continue to strengthen its R&D pipeline and evolve the company’s research and development model based on project teams and alignment with its Global Business Units. The organization will additionally foster its existing R&D collaborations and increase Sanofi’s capacity for external innovation.
Sanofi delivered the anticipated blockbuster Praluent (alirocumab) injection to the U.S. market in 2015 after FDA approval. Praluent is the first cholesterol-lowering treatment approved in a new class of drugs known as proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. Praluent is an antibody that targets a specific protein, known as PCSK9, which works by reducing the amount of receptors on the liver that remove LDL cholesterol from the blood. By blocking PCSK9’s ability to work, more receptors are available to remove LDL cholesterol from the blood and, as a result, reduce LDL cholesterol levels.
The European Commission in September 2015 granted marketing authorization for Praluent for treating certain adult patients of hypercholesterolemia characterized by high level of low-density lipoprotein (LDL) cholesterol. This approval followed the U.S. marketing clearance granted on July 24, 2015. During the following month, Praluent was additionally filed for approval with Japanese health authorities.
Sanofi and Regeneron Pharmaceuticals announced in November 2015 completed enrollment in the worldwide Phase 3 ODYSSEY OUTCOMES study. The clinical trial is prospectively evaluating the potential cardiovascular benefits of Praluent after an acute coronary syndrome. The 18,000-patient ODYSSEY OUTCOMES study is anticipated to be completed during 2017. The trial is designed to determine whether the addition of Praluent to intensive statin therapy reduces major adverse cardiac events among patients who had previously experienced an ACS, including a heart attack or unstable angina.
The worldwide ODYSSEY program includes 16 Phase 3 trials performed at more than 2,000 study centers globally, and once complete will evaluate 25,000-plus patients. Data from this program helped form one of the most comprehensive data sets ever used for the initial regulatory submission of a cholesterol-lowering therapy. In completed studies, Praluent reduced LDL cholesterol by up to an additional 62 percent compared to placebo.
Another anticipated future blockbuster in Sanofi’s arsenal is the asthma treatment prospect dupilumab. The investigational therapy inhibits signaling of IL-4 and IL-13, two cytokines necessary for the Th2 (or Type 2) immune response.
During 2015, Sanofi and Regeneron announced the initiation of a Phase 3 study of dupilumab in patients with uncontrolled persistent asthma, known as Liberty Asthma Quest, which is serving as the second required pivotal efficacy trial. The worldwide, placebo-controlled Phase 3 trial involves more than 1,600 patients with uncontrolled persistent asthma and is evaluating two doses of dupilumab, 200 milligrams (mg) and 300 mg, subcutaneously administered every other week.
A pivotal Phase 2b trial of dupilumab in adult patients with moderate-to-severe asthma who are uncontrolled despite treatment with inhaled corticosteroids and long-acting beta agonists (ICS/LABA) met its primary endpoint of improving lung function in asthma patients with high blood eosinophils counts (greater than or equal to 300 eosinophilic cells/microliter). Such high counts are believed to be a marker for patients more likely to have “atopic” or “allergic” asthma.
Sanofi filed a New Drug Application to the U.S. FDA in December 2015 for the company’s investigational fixed-ratio combination of insulin glargine 100 units/mL and lixisenatide. If approved for marketing, the combo medicine would be administered as a single daily injection for treating adults with type 2 diabetes. The NDA filing is based on data from the LixiLan-O and LixiLan-L Phase III trials, which reported positive top-line results earlier in 2015. These clinical trials enrolled more than 1,900 patients globally to evaluate the safety and efficacy of the fixed-ratio combination when used in patient populations uncontrolled after oral antidiabetic agents (OADs) and after basal insulin therapy, respectively.
An NDA for the investigational once-daily prandial GLP-1 receptor agonist lixisenatide for treating adults with type 2 diabetes was accepted for FDA review in September 2015.
Positive Phase III data were revealed by Sanofi and Regeneron in November 2015 for sarilumab, a human antibody against the IL-6 receptor. The clinical trial met its co-primary endpoints of improvements in signs and symptoms of rheumatoid arthritis and improvements in physical function, as well as secondary efficacy endpoints. Sarilumab (REGN88/SAR153191) binds with high affinity to the IL-6 receptor. The drug blocks the binding of IL-6 to its receptor and interrupts the resultant cytokine-mediated inflammatory signaling. Sarilumab was developed incorporating Regeneron’s VelocImmune antibody technology.
Sanofi and Warp Drive Bio struck a deal on Jan, 11, 2016, for the development of novel oncology therapies and antibiotics based on proprietary platforms. Warp Drive Bio is a privately held biotech company using the molecules and mechanisms of nature to discover and develop transformative medicines. The companies agreed to extend and reshape their existing collaboration using Warp Drive’s proprietary SMART (Small Molecule Assisted Receptor Targeting) and Genome Mining platforms to discover novel oncology therapeutics and antibiotics.
Also on Jan. 11, Sanofi entered into a research collaboration and licensing deal to apply Innate Pharma’s new proprietary technology to the development of innovative bispecific antibody formats engaging natural killer (NK) cells to kill tumor cells via the activating receptor NKp46. The companies are partnering on the generation and evaluation of up to two bispecific NK cell engagers, using technology from Innate Pharma and Sanofi’s proprietary bispecific antibody format as well as tumor targets. Sanofi is managing the development, manufacturing and commercialization of products resulting from the collaboration.
Sanofi and AstraZeneca announced in November 2015 a direct exchange of 210,000 compounds from their respective, proprietary compound libraries. The exchange represents a novel, open innovation model of collaboration between them. The exchange enhances the chemical diversity of the compound collections of each company and allow for them to screen a broader, more diverse chemical space as the starting point in the search for new, small-molecule medicines.
“Sanofi is committed to open innovation in our R&D platforms because we recognize that collaboration is the foundation of every medical breakthrough,” stated Elias Zerhouni, president, Global R&D, Sanofi.
Sanofi Pasteur during November revealed the company’s research on a “universal” influenza vaccine. The vaccines division of Sanofi is developing broadly cross-reactive antigens against seasonal and pandemic influenza. Sanofi Pasteur’s experimental, novel synthetic vaccine is generated from key genetic sequences of many flu viruses and is designed to protect against many strains over several years, because of the common sequences many flu viruses share. The key advantage is broader coverage versus several seasonal flu strains, which is significant when there is a mismatch to the vaccine strain. Another advantage of this method is not relying upon annual strain selection, allowing year-round manufacturing.
Additionally during November, Sanofi and Lexicon Pharmaceuticals agreed on a collaboration and license pact for the development and commercialization of sotagliflozin. The investigational new oral dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT-1 and SGLT-2) represents a potential treatment option for individuals with diabetes. Sotagliflozin (product code LX4211) is being explored in two pivotal Phase 3 studies in type 1 diabetes, for which top-line results are anticipated to be reported on during second-half 2016.
November was a busy news month for Sanofi, as the company and Hanmi Pharmaceutical came to terms on a license transaction to develop a portfolio of experimental, long-acting diabetes treatments. Hanmi was provided with an upfront payment of €400 million and is eligible for up to €3.5 billion in development, registration and sales milestones, as well as double-digit royalties on net sales. In exchange, Sanofi gained an exclusive global license to develop and commercialize 1) efpeglenatide, a late-stage long-acting glucagon-like peptide-1 receptor agonist (GLP1-RA); 2) a weekly insulin and 3) a fixed-dosed weekly GLP-1-RA/insulin drug combo. These therapeutic offerings are known as a group as the “Quantum Project” using Hanmi’s proprietary Long Acting Protein/Peptide Discovery Platform LAPSCOVERY technology. Hanmi retains an exclusive option to jointly commercialize the products in Korea and China.
In another November deal, Sanofi and BioNTech agreed on a multiyear exclusive collaboration and license transaction. The research collaboration is leveraging the scientific expertise of the two organizations to discover and develop up to five cancer immunotherapies, each consisting of a mixture of synthetic messenger RNAs (mRNAs).
During October 2015, Sanofi’s VaxiGrip QIV (Quadrivalent inactivated influenza vaccine) for children 3 years old or above was filed for approval with European health regulators.
Vertex Pharmaceuticals’ R&D program attained a significant milestone in 2015 with the U.S. and EU marketing clearance of Orkambi. The prescription medicine is available for treating cystic fibrosis in patients age 12 years and older who have two copies of the F508del mutation (F508del/F508del) in their CFTR gene.
Composed of the active ingredients lumacaftor and ivacaftor, Orkambi is recommended to be taken every 12 hours – once in the morning and during the evening. Lumacaftor is designed to increase the amount of protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein. Ivacaftor is designed to enhance the function of the CFTR protein once it reaches the cell surface.
Orkambi ranked No. 3 on EvaluatePharma’s NPV Analyzer as of May 2015 with a net present value of $16.04 billion. At that time, the analysts were projecting 2020 worldwide sales of $5.08 billion for the cystic fibrosis transmembrane conductance regulator (CFTR) corrector.
Vertex continues to invest in cystic fibrosis R&D, with the goal of developing treatments for all individuals with the disease. Various Phase 2 and Phase 3 clinical trials are under way for different products.
Vertex is carrying out two Phase 3 trials of lumacaftor/ivacaftor in children 6 to 11 years old. The first study is assessing lumacaftor/ivacaftor in 50 children to support potential FDA clearance in children ages 6 to 11 old. The primary endpoint of this six-month clinical trial is safety. Vertex intends to file a supplemental NDA with U.S. regulators during first-half 2016, pending data from this study. To support EU approval, a six-month Phase 3 efficacy trial is exploring lumacaftor/ivacaftor in 200 children. The primary endpoint of the second trial is the absolute change in lung clearance index.
Vertex reported during October 2015 that a supplemental New Drug Application for the use of Kalydeco in people ages 2 and older with one of 23 residual function mutations was accepted for FDA review. U.S. regulators granted Vertex’s request for Priority Review of this supplemental NDA, with a target review date of Feb. 7, 2016 set under the PDUFA.
Vertex is preparing to launch a clinical study of Kalydeco in children younger than 2 years old to assess the drug’s effect on markers of CF disease in young children. The clinical trial will use a weight-based dose of Kalydeco granules that can be mixed in soft foods or liquids. The study is anticipated to start during first-quarter 2016 and will enroll infants with one of the 10 mutations for which Kalydeco is marketed for.
The CFTR potentiator Kalydeco (ivacaftor) is indicated for treating cystic fibrosis in patients age 2 years and older who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or R117H.
Four Phase 3 trials of the combination of VX-661 and ivacaftor are under way in multiple different groups of CF patients who have at least one copy of the F508del mutation. In addition to assessing the efficacy of the combination regimen, the four Phase 3 trials will provide safety data on the combination of VX-661 and ivacaftor. That data is expected to support the planned development of a triple combo regimen, including a next-generation corrector used with VX-661 and ivacaftor.
Vertex and Parion Sciences are developing the investigational epithelial sodium channel (ENaC) inhibitor VX-371 as a potential treatment for all CF patients, regardless of CFTR mutation. Parion is performing an exploratory Phase 2a trial (known as the CLEAN-CF study) of inhaled VX-371 (P-1037) in 120 people with cystic fibrosis. Vertex intends to conduct a placebo-controlled Phase 2a trial to study VX-371 in patients taking lumacaftor/ivacaftor, with and without the addition of hypertonic saline, who have two copies of the F508del mutation. The Phase 2a trial was on track to start during Q1 2016.
Vertex has launched clinical development of a pair of next-generation correctors known as VX-152 and VX-440. Both new drug candidates are being assessed alone and as part of a triple combination with VX-661 and ivacaftor in Phase 1 studies in healthy volunteers. These trials are investigating escalating doses of VX-152 and VX-440 for up to two weeks in duration. Pending results of these studies, Vertex expects to begin Phase 2 trials in CF patients to evaluate VX-440 or VX-152 in combination with VX-661/ivacaftor during second-half 2016. The Phase 2 trials of a triple combination (VX-152/VX-661/ivacaftor and VX-440/VX-661/ivacaftor) are expected to enroll three groups of cystic fibrosis patients.
Vertex entered into a strategic research collaboration in October 2015 with CRISPR Therapeutics. The collaboration is concentrating on the use of CRISPR’s gene editing technology – known as CRISPR-Cas9 – to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. The companies are studying use of CRISPR-Cas9 across multiple diseases where targets have been validated via human genetics. Vertex and CRISPR are assessing CRISPR-Cas9 to potentially correct mutations in the CFTR gene known to result in the defective protein leading to CF and to edit other genes contributing to the disease.
Beyond cystic fibrosis, Vertex is advancing multiple R&D programs concentrated on treating key mechanisms in multiple serious diseases. The Boston-based company has three investigational medicines in early development that are designed to inhibit DNA repair pathways fundamental to the survival and proliferation of certain cancers. These investigational drugs, which were discovered by Vertex scientists, may be applicable to treating multiple tumor types.
Vertex’s most advanced drug candidate in oncology is VX-970. By inhibiting the protein kinase ATR, VX-970 targets a critical regulator of the DNA damage repair system. Cancer cells frequently have defects in the DNA damage repair system that contribute to disease progression and drive reliance on ATR for survival from DNA damage. According to Vertex, inhibition of ATR may therefore selectively kill cancer cells under DNA damaging conditions.
In addition to its two ongoing trials of VX-970, Vertex has entered into two cooperative R&D deals (CRADAs) with the National Cancer Institute to support evaluation of VX-970 across other cancer forms. The CRADA allows NCI to perform multiple clinical studies that will assess treatment with VX-970 in individuals with non-small cell lung, head and neck, bladder, ovarian and other cancers. The first trial performed under the CRADA with the NCI Center for Cancer Research is under way, and the first of up to 7 planned studies under the NCI Division of Cancer Treatment and Diagnosis sponsorship is on track to start during the first half of 2016.
Vertex is developing a second ATR inhibitor known as VX-803, which is administered orally. A Phase 1 trial is evaluating escalating doses of VX-803 alone and with chemotherapy.
The company is developing VX-150 as a potential medicine for treating pain. VX-150 is designed to block pain signaling via inhibition of a sodium channel called NaV 1.8. Vertex recently started a two-week Phase 2 proof-of-concept trial of VX-150 in 100 people with symptomatic osteoarthritis of the knee. Vertex is advancing a second investigational sodium channel inhibitor called VX-241, which is an inhibitor of a sodium channel known as NaV 1.7.
VX-210 is being developed as a potential medicine for acute spinal cord injury. The drug compound is designed to inhibit a protein known as Rho that blocks neural regeneration after injury. A randomized, double-blind, placebo controlled Phase 2b/3 trial is set to begin during first-half 2016 to evaluate its efficacy and safety in patients with certain acute cervical spinal cord injuries.
Vertex and CRISPR Therapeutics are seeking to discover and develop multiple other gene-based treatments for other genetic diseases. The companies will first attempt to discover and develop gene-based treatments for hemoglobinopathies, including sickle cell disease. Other discovery efforts concentrated on a specified amount of other genetic targets will be conducted via the collaboration. Vertex has the option to an exclusive license for up to six gene-based treatments produced from the four-year research collaboration.