Deal activity is rampant as Big Pharma gobbles up next-generation medicines and technologies to help overcome maturing pipelines and biosimilar threats.
TOP 10 PIPELINES
JOHNSON & JOHNSON
M&A and deal-making action constitute a common theme among the 10 companies analyzed in this annual report as the industry’s R&D leaders seek out new game-changing medicines and technologies to complement and bolster their existing product arsenals. This article features a bevy of pipeline drug prospects and recently approved medicines with anticipated blockbuster potential spanning a wide range of therapeutic areas, from immuno-oncology to rare diseases.
Criteria used to determine this year’s selected 10 companies include current pipeline projects and their sales & marketing potential, fields of therapeutic concentration,
M&A and deal production and its R&D impact, and recent approvals for new molecular entities as well as expanded indications for existing brands.
This is an exciting time for AbbVie – we are poised to launch a number of differentiated products over the next 12 to 18 months that will fuel significant growth in the coming years,” stated AbbVie Chairman and CEO Richard A. Gonzalez in late January when the company released its full-year 2017 financial results. Those words should sound like sweet music to the ears of investors considering that AbbVie’s sales dynamo Humira (adalimumab) for treating inflammatory disorders established a new industry record for prescription medicines during 2017, as the company reported growth of 14 percent on a reported basis to $18.45 billion for the biologic, and the juggernaut is not slowing down anytime soon.
AbbVie’s R&D activities are concentrated on the following therapeutic areas: immunology (including rheumatology and dermatology); oncology; neuroscience (including multiple sclerosis, Parkinson’s disease and Alzheimer’s disease); virology (HIV-1 and hepatitis); and general medicine (including cystic fibrosis, endometriosis, uterine fibroids and diabetic neuropathy).
Some of AbbVie’s new molecular entities in development that are anticipated to eventually enter the marketplace and generate blockbuster sales include rovalpituzumab tesirine (Rova-T), upadacitinib, elagolix, and risankizumab.
The investigational antibody-drug conjugate (ADC) Rova-T targets delta-like protein 3 (DLL3), which is expressed in about 80 percent of small cell lung cancer (SCLC) patient tumors. DLL3 is prevalent on SCLC tumor cells, but not present in healthy tissue. Rova-T brings together a targeted antibody with a cytotoxic agent to deliver a substance toxic to cells directly to the DLL3-expressing cancer cells.
Rova-T is being studied for the treatment of SCLC. An open-label, single-arm Phase 2 trial is under way to investigate Rova-T in the third-line setting in relapsed or refractory DLL3-expressing SCLC. Two randomized Phase 3 studies were initiated in the second-line and first-line maintenance setting. Other clinical trials are under way in multiple neuroendocrine tumor types, metastatic melanoma, and glioblastoma.
According to EvaluatePharma’s “World Preview 2017, Outlook to 2022” report, Rova-T ranked No. 4 among the top 20 most valuable R&D projects ranked by Net Present Value with an NPV of $8.49 billion as of May 2017.
AbbVie reported positive top-line results in December from the Phase 3 SELECT-MONOTHERAPY study investigating upadacitinib (ABT-494) as a monotherapy treatment in patients with moderate-to-severe rheumatoid arthritis who did not adequately respond to treatment with methotrexate. Results demonstrated that after 14 weeks of treatment, both once-daily doses of upadacitinib (15 mg and 30 mg) met the clinical trial’s primary endpoints of ACR20 and low disease activity versus continuing prior stable methotrexate therapy. The company expects data from two additional registrational studies during first-half 2018, supporting regulatory filings in second-half 2018.
In other upadacitinib news, AbbVie announced in January that the FDA granted Breakthrough Therapy Designation for the once-daily oral JAK1-selective inhibitor in adults with moderate-to-severe atopic dermatitis who are candidates for systemic therapy. The designation was supported by positive Phase 2b trial results. The Phase 3 clinical program for upadacitinib in atopic dermatitis is expected to start in first-half 2018.
Discovered and developed by AbbVie, the oral agent upadacitinib is engineered to selectively inhibit JAK1, which plays a significant role in the pathophysiology of immune-mediated disorders. In addition to being developed for rheumatoid arthritis and atopic dermatitis, Phase 3 studies are under way for psoriatic arthritis and Crohn’s disease. Upadacitinib is also being evaluated for treating ulcerative colitis and ankylosing spondylitis.
According to EvaluatePharma analysis, upadacitinib represented the most promising anti-rheumatic R&D asset during 2017.
At the American Society for Reproductive Medicine Scientific Congress & Expo (ASRM), AbbVie – in cooperation with Neurocrine Biosciences – presented detailed results from two replicate Phase 3 extension trials. The studies are exploring the long-term efficacy and safety of elagolix, which is an investigational, orally administered gonadotropin-releasing hormone (GnRH) antagonist intended for the management of endometriosis with associated pain. In the extension studies, elagolix showed sustained reduction in average monthly menstrual pelvic pain and non-menstrual pelvic pain in women through the 12-month treatment period.
Elagolix is undergoing priority regulatory review for the management of endometriosis with associated pain.
Elagolix is an orally administered, short-acting molecule that blocks endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Product use results in readily reversible, dose-dependent inhibition of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, resulting in reduced ovarian production of the ovarian sex hormones – estradiol and progesterone – while on therapy. Elagolix is being explored in diseases that are mediated by ovarian sex hormones, including uterine fibroids and endometriosis. The GnRH antagonist has been studied in more than 40 clinical trials totaling 3,000-plus subjects. The U.S. regulatory agency granted priority review for AbbVie’s New Drug Application for endometriosis during fourth-quarter 2017. Phase 3 studies of elagolix for the management of uterine fibroids are under way.
AbbVie presented top-line results in December from the IMMhance study, the fourth pivotal clinical trial assessing risankizumab as a treatment for patients with moderate-to-severe plaque psoriasis. Results demonstrated that risankizumab met all co-primary and ranked secondary endpoints in the clinical trial. AbbVie intends to file its regulatory approval applications during the first half of 2018. The investigational interleukin-23 (IL-23) inhibitor is being developed in collaboration with Boehringer Ingelheim.
The investigational compound risankizumab is designed to selectively block IL-23 by binding to its p19 subunit. The key cytokine IL-23 is involved in inflammatory processes and is believed to be linked to various immune-mediated diseases. In addition to Phase 3 studies in psoriasis, risankizumab is being evaluated to treat Crohn’s disease and psoriatic arthritis. Also, future studies are planned to investigate risankizumab in ulcerative colitis.
In December, clinical results were revealed by AbbVie from the Phase 3 MURANO trial of Venclexta/Venclyxto (venetoclax) in combination with the blockbuster anti-cancer agent Rituxan at the American Society of Hematology (ASH) Annual Meeting. The results showed that patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL ) achieved significantly prolonged median progression-free survival (PFS) with Venclexta in combination with Rituxan versus bendamustine in combination with Rituxan. Regulatory applications were recently filed for Venclexta in combination with Rituxan for treating patients with R/R CLL.
The oral B-cell lymphoma-2 (BCL-2) inhibitor Venclexta/Venclyxto targets a specific protein in the body called BCL-2. For individuals with CLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally. Venclexta/Venclyxto targets BCL-2 to help restore the process of apoptosis, through which the body allows cancer cells and normal cells to self-destruct.
Venclexta/Venclyxto is cleared for marketing in 49 nations, including the United States and in the European Union. Venclexta/Venclyxto is being developed by AbbVie and Roche, and is jointly commercialized by AbbVie and Genentech – which is a member of the Roche Group – in the United States. AbbVie markets the product outside of the United States. The companies are dedicated to BCL-2 research with venetoclax, which is being studied in clinical trials for several hematologic cancers.
Also at the ASH meeting, AbbVie reported new and updated Imbruvica (ibrutinib) data, including pooled analysis results of the longest follow-up data to date in Bruton’s tyrosine kinase (BTK) inhibition for R/R mantle cell lymphoma (MCL) patients treated with Imbruvica. The data demonstrated that, at three years, 45 percent of patients were able to achieve overall survival and 26 percent had PFS. AbbVie additionally presented new three-year follow-up data from the RESONATE-2 clinical trial (PCYC-1115/1116), which found that previously untreated CLL/SLL patients reported sustained improvements in measures of well-being with Imbruvica compared to chemotherapy with chlorambucil. The blockbuster brand Imbruvica is jointly developed and marketed with Janssen Biotech.
The Phase 3 iNNOVATE study evaluating Imbruvica in combination with Rituxan in patients with treatment-naïve and previously treated Waldenström’s macroglobulinemia (WM) successfully met its primary endpoint and showed improvement of PFS compared to Rituxan alone, according to AbbVie. The Independent Data Monitoring Committee recommended that the trial be unblinded based on the positive outcome from the pre-specified interim analysis data. AbbVie expects to submit these data for label augmentation during 2018.
The first-in-class, oral, once-daily therapy Imbruvica mainly works by blocking the BTK protein. 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 as well as other serious, debilitating conditions. The product blocks signals that tell malignant B cells to multiply and spread uncontrollably.
Imbruvica is approved by the FDA in six distinct patient populations: CLL, SLL, WM, along with previously treated MCL, previously treated marginal zone lymphoma (MZL) and previously treated chronic graft-versus-host disease (cGVHD). Imbruvica was AbbVie’s second-largest sales generator during 2017 at $2.57 billion, up 70 percent on a year-over-year reported basis.
The FDA during August 2017 approved AbbVie’s Mavyret (glecaprevir and pibrentasvir) to treat adults with chronic hepatitis C virus genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate-to-severe kidney disease and those who are on dialysis. Mavyret is additionally approved for adults with HCV genotype 1 infection who have been previously treated with a regimen either containing an NS5A inhibitor or an NS3/4A protease inhibitor but not both. Industry analysts have projected blockbuster sales for Mavyret in 2018, the product’s first full year on the marketplace.
As a pioneer in neuroscience, Biogen discovers, develops and delivers worldwide innovative therapies for people living with serious neurological and neurodegenerative diseases. Founded during 1978 as one of the world’s first global biotech companies by Charles Weissman and Nobel Prize winners Walter Gilbert and Phillip Sharp, Biogen now has the leading portfolio of medicines to treat multiple sclerosis; has introduced the first approved treatment for spinal muscular atrophy; and is concentrating on advancing neuroscience research programs in Alzheimer’s disease and dementia, neuroimmunology, movement disorders, neuromuscular disorders, pain, ophthalmology, neuropsychiatry, and acute neurology. Biogen additionally manufactures and commercializes biosimilars of advanced biologics.
During 2017, Biogen added seven clinical programs to the company’s neuroscience pipeline including BIIB098 (MMF prodrug) for MS, BIIB092 (anti-tau antibody) for Alzheimer’s disease and progressive supranuclear palsy, BIIB076 (anti-tau antibody) for Alzheimer’s disease, BIIB080 (tau antisense oligonucleotide) for Alzheimer’s disease, BIIB093 (IV glibenclamide) for large hemispheric infarction, and natalizumab for drug-resistant focal epilepsy.
Biogen’s most highly touted pipeline prospect is aducanumab for Alzheimer’s disease. The new drug candidate is being assessed in two global Phase 3 trials, ENGAGE and EMERGE. The studies are designed to test aducanumab’s safety and efficacy in slowing cognitive impairment and the progression of disability in people with early Alzheimer’s disease.
Also known by the product code BIIB037, aducanumab is a human recombinant monoclonal antibody (mAb) derived from a de-identified library of B cells collected from healthy elderly subjects with no signs of cognitive impairment or cognitively impaired elderly subjects with unusually slow cognitive decline using Neurimmune’s technology platform called Reverse Translational Medicine (RTM). Biogen licensed aducanumab from Neurimmune through a collaborative development and license deal.
Aducanumab is believed to target aggregated forms of beta amyloid, including soluble oligomers and insoluble fibrils that can form into amyloid plaque in the brain of patients with Alzheimer’s disease. Based on pre-clinical and Phase 1b data, treatment with aducanumab has been demonstrated to reduce amyloid plaque levels.
Biogen during early November 2017 reported that two-year data from a Phase 1b trial suggest a continued benefit on amyloid plaque reduction and the rate of clinical decline in the titration regimen group, which received a gradually increased aducanumab dose. In August 2017, the company announced that Phase 1b study results supported the design of ongoing Phase 3 trials of aducanumab for early Alzheimer’s disease.
Aducanumab was accepted into the European Medicines Agency’s PRIME program during August 2016. The U.S. Food and Drug Administration accepted aducanumab into its Fast Track program in September 2016. Aducanumab was accepted into the Japanese Ministry of Health, Labour and Welfare’s (MHLW) Sakigake Designation System as of April 2017.
Biogen licensed the worldwide rights to aducanumab from the biopharmaceutical company Neurimmune Holding during 2007. Biogen and Eisai entered into a worldwide collaboration pact during October 2017 to jointly develop and commercialize the investigational anti-amyloid beta (Aβ) antibody. Biogen continues to lead Phase 3 clinical development and remains solely responsible for all development costs for aducanumab until April 2018.
Through an existing agreement, the companies will continue to jointly develop the beta amyloid cleaving enzyme inhibitor elenbecestat (E2609) and BAN2401. A humanized monoclonal antibody intended for Alzheimer’s disease, BAN2401 is the result of a strategic research alliance between Eisai and BioArctic AB. Since March 2014, Eisai and Biogen have been jointly developing BAN2401.
According to Eisai CEO Haruo Naito, “Genetic epidemiological studies such as the Icelandic genetic research as well as the knowledge recently gained from various clinical studies such as the aducanumab Phase 1b trial have deepened our conviction in the amyloid hypothesis. We hope to establish a new treatment paradigm for fighting dementia by expanding the strategic collaboration between Biogen, a company that leverages its cutting-edge biotechnology to develop innovative therapies for people living with serious neurological and neurodegenerative diseases, and Eisai, a company which possesses a rich pipeline based on holistic approaches. In accordance with this new paradigm, we plan to further co-develop the collaboration products and hope to advance the world’s potentially first new treatment for Alzheimer’s disease based on the amyloid hypothesis.”
Biogen aims to increase therapeutic options available for the devastating neuromuscular disease spinal muscular atrophy (SMA). During December 2017, Biogen and Ionis Pharmaceuticals reported entering into a new collaboration deal to identify new antisense oligonucleotide drug candidates for treating SMA. Biogen holds the option to license therapies stemming from this collaboration and is responsible for their development and commercialization. SMA is characterized by loss of motor neurons in the spinal cord and lower brain stem, leading to severe and progressive muscular atrophy and weakness.
Biogen also aims to provide patients with a new oral therapy for multiple sclerosis that may bring differentiated benefits. In November 2017, the Cambridge-Mass. based company and Alkermes agreed on a global license and collaboration to develop and commercialize ALKS 8700. The novel, oral, monomethyl fumarate (MMF) small drug molecule is undergoing Phase 3 development for the treatment of relapsing forms of multiple sclerosis. ALKS 8700 is designed to rapidly and efficiently convert to MMF in the body and to offer differentiated features versus Biogen’s the currently marketed dimethyl fumarate, Tecfidera.
Biogen received an exclusive, worldwide license to commercialize ALKS 8700 and will pay Alkermes a mid-teens royalty on global net sales of the product. Alkermes intends to seek marketing approval of ALKS 8700 under the 505(b)(2) regulatory pathway referencing Tecfidera. The registration package for ALKS 8700 will include pharmacokinetic bridging studies that establish bioequivalence to Tecfidera and data from a two-year safety study called EVOLVE-MS-1.
During January 2018, Biogen acquired the exclusive global rights to develop and commercialize Karyopharm Therapeutics’ Phase 1-ready investigational oral compound KPT-350 for treating certain neurological and neurodegenerative conditions, primarily amyotrophic lateral sclerosis (ALS). The novel therapeutic candidate KPT-350 works by inhibiting XPO1, with the goal of reducing inflammation and neurotoxicity, along with increasing neuroprotective responses.
Biogen dosed the first patient in the Phase 2 SPARK clinical trial of BIIB054 (anti-alpha-synuclein antibody) in Parkinson’s disease in January 2018.
Additionally during January, Biogen joined Regeneron Pharmaceuticals, Pfizer, AbbVie, AstraZeneca, and Alnylam Pharmaceuticals in a collaboration to collect genetic information on 500,000 people in the UK Biobank database. The project could help accelerate new drug discovery and improve approval success rates. Biogen has dedicated $10 million toward this effort.
Biogen and Ionis were awarded the prestigious 2017 Prix Galien USA Award for Best Biotechnology Product for Spinraza during October 2017. The award recognizes extraordinary achievement in scientific innovation that improves the state of human health.
In October 2017, Biogen revealed the initiation of the Phase 2 study AFFINITY, designed to evaluate opicinumab as an investigational add-on therapy in people with relapsing multiple sclerosis. The clinical trial follows the comprehensive review of SYNERGY, a Phase 2 study that identified a specific population may be more likely to respond to treatment. A first-in-class human monoclonal antibody directed against LINGO-1, opicinumab is being tested to determine its potential for improving pre-existing disability in relapsing MS patients through remyelination.
Celgene’s discovery and development platforms for drug and cell-based therapies allow the company to create and retain significant value within its therapeutic franchise areas of cancer and inflammatory diseases. Celgene scientists and physicians are enabling target-to-therapeutic platforms that integrate small-molecule and cell-based therapies.
Celgene sponsors more than 100 clinical studies examining at least 25 unique compounds. According to the company, 28,000 patients are actively enrolled in Celgene-sponsored clinical trials for more than 50 different indications. The corresponding treatments are aimed at addressing the unmet needs of 25 million people around the globe in more than 30 disease areas. Celgene also supports more than 500 investigator-initiated trials that use approved therapies or investigational compounds from the company.
The Summit, N.J.-based biotech company announced in January 2018 two separate acquisitions that will help solidify Celgene’s R&D portfolio.
Celgene entered into an agreement to acquire collaboration partner Juno Therapeutics, an integrated biopharma company concentrated on developing innovative cellular immunotherapies for treating cancer, for $9 billion. According to management, this acquisition will complement Celgene’s leadership in hematology and oncology as well as advance the company’ global leadership in cellular immunotherapy.
Juno is a pioneer in the development of CAR (chimeric antigen receptor) T and TCR (T cell receptor) therapeutics with an expansive, novel portfolio investigating multiple targets and cancer indications. Adding to Celgene’s lymphoma program, JCAR017 (lisocabtagene maraleucel; liso-cel) represents a potentially best-in-class CD19-directed CAR T undergoing a pivotal program for relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL). U.S. regulatory approval for JCAR017 is expected in 2019 with potential worldwide peak sales of $3 billion.
“The acquisition of Juno builds on our shared vision to discover and develop transformative medicines for patients with incurable blood cancers,” noted Mark J. Alles, CEO of Celgene. “Juno’s advanced cellular immunotherapy portfolio and research capabilities strengthen Celgene’s global leadership in hematology and adds new drivers for growth beyond 2020.”
The acquisition additionally adds a novel scientific platform and scalable manufacturing capabilities that will complement Celgene’s leadership in hematology and oncology. In collaboration with Juno’s team in Seattle, Celgene plans to expand the company’s existing center of excellence for immuno-oncology translational medicine by leveraging Juno’s R&D facility in Seattle as well as Juno’s manufacturing facility in Bothell, Was.
In addition to the pivotal-stage asset JCAR017, Juno’s JCARH125 will enhance Celgene’s campaign against BCMA (B-cell maturation antigen), a key target in multiple myeloma. Celgene also acquired other cellular therapy assets in proof-of-concept trials for hematologic malignancies and solid tumors.
Celgene’s other announced acquisition in January was the purchase of Impact Biomedicines. The privately held biotechnology company is developing fedratinib, a highly selective JAK2 kinase inhibitor, for myelofibrosis and polycythemia vera.
Celgene agreed to pay $1.1 billion upfront and up to $1.25 billion in contingent payments based on regulatory approval milestones for myelofibrosis. Additional future payments for regulatory approvals in other indications and sales-based milestones are additionally possible. This acquisition is expected to bolster Celgene’s commitment to myelofibrosis, a disease with high unmet medical need, and expand strategic development options within Celgene’s myeloid portfolio of assets. The transaction is anticipated to close during first-quarter 2018.
Fedratinib was studied in 877 patients across 18 clinical trials. In a randomized, placebo-controlled, phase III pivotal trial (JAKARTA-1) for patients with treatment-naïve myelofibrosis, fedratinib showed statistically significant improvements in the primary and secondary endpoints of splenic response and total symptom score. A multi-center, single-arm phase II study (JAKARTA-2) assessed fedratinib in myelofibrosis patients who were found to be resistant or intolerant to the JAK1/JAK2 inhibitor ruxolitinib (marketed as Jakafi). Based on the reported benefit risk profile of fedratinib from the JAKARTA-1 and JAKARTA-2 studies, regulatory submissions in myelofibrosis are planned beginning in mid-2018.
Various clinical data were presented on Celgene’s marketed and pipeline hematology assets at the 59th American Society of Hematology (ASH) Annual Meeting in December 2017. For example, Celgene and partner bluebird bio presented updated data from the phase I study assessing bb2121 in patients with relapsed and/or refractory multiple myeloma (RRMM). During November, bb2121 was granted Breakthrough Therapy Designation by the FDA and PRIority MEdicines (PRIME) eligibility by the European Medicines Agency (EMA). The pivotal KarMMa study evaluating bb2121 in RRMM was initiated in December.
Additionally at ASH, Celgene and partner Juno Therapeutics presented updated data from the phase I TRANSCEND trial investigating JCAR017 in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). The pivotal TRANSCEND program in the U.S. with JCAR017 in diffuse large B-cell lymphoma (DLBCL) is under way and the TRANSCEND WORLD cohort is on track to begin during first-half 2018.
In other ASH highlights, Celgene and partner Acceleron Pharma presented updated data from ongoing phase II studies with luspatercept in patients with lower-risk myelodysplastic syndromes (MDS). Data from the phase III MEDALIST and BELIEVE studies are expected during mid-2018. Celgene intends to initiate the phase III COMMANDS trial with luspatercept in front-line MDS in the first half of 2018.
Updated data were presented at ASH from the phase Ib trial studying CC-122 in combination with obinutuzumab in patients with DLBCL, follicular lymphoma (FL) or marginal zone lymphoma (MZL). A pivotal program with CC-122 in NHL is planned to begin during 2018.
Updated data were revealed during ASH from the phase I trial investigating CC-486 in combination with rituximab plus chemotherapy (R-CHOP) in patients with DLBCL, FL or transformed lymphoma. Data from the phase III QUAZAR\ AML-001 study evaluating CC-486 as maintenance therapy in post-induction acute myeloid leukemia (AML) is expected during second-half 2018.
Celgene and partner Agios Pharmaceuticals reported data at ASH from the phase I trial exploring ivosidenib or IDHIFA combined with standard induction chemotherapy (7+3 regimen) in patients with newly diagnosed AML with an isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation.
In the area of Inflammation & Immunology, Celgene during December announced that a New Drug Application was filed with the FDA for ozanimod in relapsing multiple sclerosis (RMS). The NDA was based on data from the phase III RADIANCE Part B and SUNBEAM studies evaluating ozanimod in patients with RMS. Celgene plans to submit a Marketing Authorization Application (MAA) with the EMA during first-quarter 2018.
According to Celgene, a robust life-cycle plan for ozanimod is advancing and a phase III pivotal study investigating ozanimod in Crohn’s disease was initiated in fourth-quarter 2017. Also, the phase III TRUE NORTH study with ozanimod in ulcerative colitis is under way and on track to complete enrollment during the second half of 2018.
In August, the U.S. regulatory agency approved the use of the company’s Idhifa (enasidenib) for treating adults with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test.
Celgene reported during third-quarter 2017 that the phase III RELIEF (n= 207) trial investigating Otezla in patients with active Behçet’s disease achieved the primary endpoint of Area Under the Curve (AUC) for the number of oral ulcers from baseline through week 12. These data form the basis of worldwide regulatory applications that are planned starting in 2018.
The phase IIb study evaluating CELMoD compound CC-220 in patients with systemic lupus erythematosus (SLE) was initiated during third-quarter 2017.
Gilead Sciences discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The biopharma company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries, with headquarters located in Foster City, Cali.
Gilead’s pipeline was significantly bolstered when the company in October 2017 completed the acquisition of Kite Pharma for $11.9 billion. Kite Pharma, now a wholly owned subsidiary of Gilead, was included as one of the “Top 10 Pipelines” in Med Ad News’ February 2017 annual report.
The biopharmaceutical company Kite has been engaged in the development of innovative cancer immunotherapies with a goal of providing rapid, long-term, durable response and eliminating the burden of chronic care. Kite has concentrated on chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered cell therapies designed to empower the immune system’s ability to recognize and kill tumors. Kite’s lead pipeline product and projected blockbuster brand Yescarta, which was developed based on such technology, was granted FDA marketing clearance in October 2017.
Yescarta (axicabtagene ciloleucel, or axi-cel) won FDA approval as the first CAR T therapy for treating adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma, or TFL). CAR T therapy is a breakthrough in hematologic cancer treatment in which a patient’s own T cells are engineered to seek and eliminate cancer cells. CAR T therapy is manufactured specifically for every individual patient.
The CD19-directed genetically modified autologous T cell immunotherapy Yescarta is indicated as a treatment for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Kite announced during July 2017 the filing of a Marketing Authorization Application to the European Medicines Agency for axi-cel as a treatment for patients with relapsed/refractory DLBCL, TFL, and PMBCL who are ineligible for autologous stem cell transplant. Yescarta was granted Priority Medicines (PRIME) regulatory support for DLBCL in the EU, where marketing clearance is projected to occur during first-half 2018.
Yescarta is the first product to reach the U.S. market as a treatment for refractory aggressive non-Hodgkin lymphoma, which includes DLBCL, TFL and PMBCL. The FDA and EMA submissions come after positive results from Kite’s ZUMA-1 pivotal study with axi-cel in patients with chemorefractory aggressive non-Hodgkin lymphoma.
“Engineered cell therapies like Yescarta represent the potential for a changing treatment paradigm for cancer patients,” commented David Chang, M.D., Ph.D., Worldwide Head of Research and Development and Chief Medical Officer at Kite. “Together, Gilead and Kite will accelerate studies of CAR T therapy in multiple blood cancers and advance other cell therapy approaches for solid tumors, with the goal of helping patients with diverse cancers benefit from this new era of personalized cancer therapy.”
Physicians say Kite’s promising new technology for harnessing the body’s immune system to fight cancer could save patients with the most serious types of cancer. Kite additionally has other products in its pipeline based on similar technology, including experimental medicines for multiple myeloma, mantle cell lymphoma and solid tumors.
Additional Kite drug candidates in clinical trials in both hematologic cancers and solid tumors include KITE-585, a CAR T therapy candidate that targets BCMA expressed in multiple myeloma.
“The acquisition of Kite establishes Gilead as a leader in cellular therapy and provides a foundation from which to drive continued innovation for people with advanced cancers,” noted John F. Milligan, Ph.D., Gilead’s president and CEO. “The field of cell therapy has advanced very quickly, to the point where the science and technology have opened a clear path toward a potential cure for patients.”
Kite Chairman, President and CEO Arie Belldegrun, M.D., said at the time of the acquisition announcement, “CAR T has the potential to become one of the most powerful anti-cancer agents for hematologic cancers. With Gilead’s expertise and support, we hope to fulfill that potential by rapidly accelerating our robust pipeline and next-generation research and manufacturing technologies for the benefit of patients around the world.”
The Kite acquisition has provided Gilead with a robust product pipeline and technology platform to drive future growth: multiple development programs are under way to broaden axi-cel utilization in earlier lines of therapy in aggressive NHL and other B-cell malignancies; the company is advancing additional CAR Ts to treat multiple myeloma and acute myeloid leukemia; and Gilead is making progress with TCRs for potential use in solid tumors.
“While Kite won’t transform the big biotech’s financial prospects in the near term, the deal definitely deserves to be called transformative because of the effect it will have on Gilead’s position in the oncology arena,” commented analysts from The Motley Fool. “By making this one acquisition, Gilead will instantly become one of the leaders in the exciting new area of using cell therapy to treat cancer.”
Gilead and Kite announced in December a definitive deal to acquire Cell Design Labs, gaining new technology platforms that will enhance research and development efforts in cellular therapy. Gilead will acquire all outstanding shares of Cell Design Labs for up to $567 million, including an initial upfront payment of $175 million, and other payments of up to $322 million.
The transaction builds on Gilead’s acquisition of its cell therapy subsidiary Kite and has the potential to help the two organizations accelerate the development of next-generation cellular therapy candidates. Cell Design Labs has significant expertise in custom cell engineering. The pre-clinical stage company is developing two propriety technology platforms: the synthetic gene expression system synNotc that responds to external cues which, among other applications, can be deployed to engineer CAR T cells that require dual antigen recognition for activation; and Throttle, an “on switch” that modulates CAR T activity using small molecules. The addition of these technologies to existing Kite R&D programs could lead to the treatment of a wider array of hematological malignancies and solid tumors, and potentially offer improved selectivity and safety of future treatments. Cell Design Labs is also developing several preclinical product candidates, including therapies for prostate cancer and hepatocellular carcinoma that use the synNotch technology. The company’s leading pre-clinical candidate targets multiple myeloma.
Kite entered into a clinical trial collaboration with Pfizer in January 2018. The companies are exploring the safety and efficacy of the combination of Yescarta and Pfizer’s fully humanized 4-1BB agonist monoclonal antibody utomilumab in patients with refractory large B-cell lymphoma. A multi-center Phase 1/2 study sponsored by Kite is scheduled to start in 2018. The results of this trial will be used to assess options for further development of this combination or similar ones between Kite’s engineered T cell products and utomilumab.
Also known as PF-05082566, utomilumab is an investigational 4-1BB agonist that has been demonstrated in preclinical models to enhance T cell mediated immune responses. Pfizer is studying utomilumab in hematologic cancers and solid tumors as a single agent and in combination with other anti-cancer therapies. Evidence suggests that 4-1BB, a costimulatory protein expressed on activated T cells, is upregulated upon exposure to CD19-expressing tumor cells. Utomilumab has the potential to enhance T cell proliferation and activity by augmenting the CD28 costimulatory domain of Yescarta with exogenous 4-1BB signaling.
Gilead’s product pipeline included a potentially huge growth driver before the company acquired Kite and Yescarta, known as BIC/FTC/TAF. The fixed-dose combination is composed of bictegravir (50 mg) (BIC), an integrase strand transfer inhibitor, and emtricitabine/tenofovir alafenamide (200/25 mg) (FTC/TAF), a dual-NRTI backbone, for treating HIV-1 infection.
During third-quarter 2017, Gilead announced that the U.S. FDA granted priority review for a new drug application for BIC/FTC/TAF. The company submitted the NDA with a priority review voucher on June 12, 2017, and U.S. regulators set a target action date under the Prescription Drug User Fee Act of Feb. 12, 2018. On Feb. 7, as this magazine went to press, the product captured FDA approval under the trade name Biktarvy.
Also during the 2017 third quarter, Gilead reported detailed 48-week results from two Phase 3 studies investigating the efficacy and safety of Biktarvy for treating HIV-1 infection in treatment-naïve adults. In the clinical trials, BIC/FTC/TAF was found to be statistically non-inferior to regimens containing dolutegravir (50 mg). Also, Gilead’s marketing authorization application for BIC/FTC/TAF has been fully validated and is under review by the European Medicines Agency.
“Bictegravir/F/TAF is expected to become Gilead ’s biggest growth driver, with forecast sales of $5.1bn in 2022,” according to EvaluatePharma sellside consensus. “The project could be the top launch of this year (2018).”
The European Commission and FDA during July approved Vosevi as a once-daily single-tablet regimen for treating HCV infection in adults with genotypes 1-6. Vosevi is the first single-tablet regimen for patients who have previously failed therapy with direct-acting antiviral (DAA) treatments and is the newest regimen in Gilead’s portfolio of sofosbuvir-based HCV DAA treatments.
Appearing for the first time in this annual report, Incyte’s dedicated researchers are focused on transforming the treatment of cancer and the company’s product portfolio is expanding. Incyte’s drug discovery efforts were founded during 2002 by a team of world-class scientists striving to create innovative medicines. According to management, the rigorous pursuit of scientific excellence remains at the core of the Wilmington, Del.-based biopharmaceutical company today.
Incyte’s debut on this yearly list is due in no small part to the exciting market potential of the anticipated blockbuster melanoma medicine epacadostat (product code INCB024360). The immunosuppressive effects of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity on the tumor microenvironment aid cancer cells in evading immunosurveillance. Epacadostat is an investigational, highly potent and selective oral inhibitor of the enzyme IDO1. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has demonstrated proof-of-concept in patients with unresectable or metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck and bladder cancer. In these studies, epacadostat in combination with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitors Keytruda or nivolumab improved response rates versus studies of the immune checkpoint inhibitors on their own.
“Incyte is leading the IDO inhibition field, and is due to release the first rigorous phase III data in this space in the first half of 2018,” according to EvaluatePharma analysis. “Echo-301 tests a combination of epacadostat with Merck’s Keytruda in first-line melanoma, a tumor type that has already been transformed by the arrival of the anti-PD-1 antibodies.”
The ECHO clinical study program was established to investigate the efficacy and safety of epacadostat as a core component of combo therapy in oncology. Phase 1 and Phase 2 trials are assessing epacadostat in combination with PD-1 and PD-L1 inhibitors in a wide range of solid tumor types as well as hematological malignancies. ECHO-301 (NCT02752074) – a Phase 3 randomized, double-blind, placebo-controlled trial evaluating the blockbuster medication Keytruda in combination with epacadostat or placebo for treating patients with unresectable or metastatic melanoma – is under way and fully recruited.
In collaboration with Merck and Bristol-Myers Squibb, preparations for the next wave of eight pivotal Phase 3 studies of epacadostat in combination with PD-1 antagonists continue as planned. Initiation of these studies was expected before year-end 2017.
Incyte got onto the marketing map via its first commercial product, Jakafi (ruxolitinib). Jakafi is approved in the United States for patients with intermediate or high-risk myelofibrosis and for patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea. The first-in-class JAK1/JAK2 inhibitor is marketed by Incyte in the United States and by Novartis as Jakavi outside the country.
Incyte continues to study and develop Jakafi through a variety of clinical trials. In December 2017, Incyte announced new 208-week (4-year) follow-up data from the ongoing, global, multi-center, open-label Phase 3 RESPONSE trial comparing the efficacy and safety of Jakafi with best available therapy in patients with PV who are resistant to or intolerant of hydroxyurea (HU). The pre-planned data analysis demonstrated a durable primary response to Jakafi in patients with PV who are resistant to or intolerant of HU and the overall safety profile remained consistent with previously reported 80-week RESPONSE data.
Incyte announced during November that the first patient had been treated in the RESET pivotal study investigating ruxolitinib versus anagrelide for the treatment of essential thrombocythemia patients who are resistant to or intolerant of HU.
The REACH1 pivotal study exploring ruxolitinib in patients with steroid-refractory acute graft-versus-host disease (GVHD) is on track to deliver results in first-half 2018. If successful, Incyte anticipates filing an sNDA seeking accelerated approval of ruxolitinib in this indication in 2018. Three additional pivotal studies are investigating the role of JAK inhibition in GVHD (REACH2 and REACH3 with ruxolitinib, and GRAVITAS-301 with itacitinib).
Baricitinib is on track to become in the near term Incyte’s second commercial product in the United States. The once-daily oral JAK inhibitor is undergoing clinical trials for inflammatory and autoimmune diseases.
Eli Lilly and Incyte agreed during December 2009 on an exclusive worldwide license and collaboration agreement for the development and commercialization of baricitinib and certain follow-on compounds for patients with inflammatory and autoimmune diseases. Baricitinib was filed for regulatory review seeking marketing clearance for treating rheumatoid arthritis in the United States, the European Union and Japan in 2016. Baricitinib was approved in the EU during February 2017 and in Japan during July 2017. In April 2017, the FDA issued a Complete Response Letter on the NDA for baricitinib. Lilly intended to refile the New Drug Application with the U.S. regulatory agency before the end of January 2018. The companies anticipate that U.S. regulators will classify the application as a Class II resubmission, which would kick off a new six-month review cycle. The drug candidate remains under review in other markets.
Baricitinib is additionally being investigated for the treatment of atopic dermatitis and systemic lupus erythematosus. In September, Lilly and Incyte announced that baricitinib met the primary endpoint in a Phase 2 trial in patients with moderate-to-severe atopic dermatitis. The Phase 3 program for psoriatic arthritis is expected to start during 2018.
During November, Lilly and Incyte reported that patients with moderate-to-severe rheumatoid arthritis treated with baricitinib reported greater improvements in pain control when compared to Humira (adalimumab) or placebo. AbbVie’s Humira is the world’s best-selling Rx medicine.
Incyte and Syros Pharmaceuticals came to terms in January 2018 on a target discovery, research collaboration and option agreement. Syros will use its proprietary gene control platform to identify novel therapeutic targets with a concentration in myeloproliferative neoplasms (MPNs), and Incyte will receive options to obtain exclusive global rights to intellectual property resulting from the collaboration for up to seven validated targets. Incyte will have exclusive global rights to develop and commercialize any therapies through the collaboration that modulate those validated targets.
“Through this collaboration, we believe that Syros’ gene control platform will allow us to advance our understanding of the underlying biology of MPNs and potentially uncover new molecular targets for drug discovery,” noted Reid Huber, Ph.D., chief scientific officer of Incyte.
Incyte and AstraZeneca during October 2017 announced an expanded clinical study collaboration. The companies plan to initiate a Phase 3 study of epacadostat in combination with AstraZeneca’s PD-L1 antagonist Imfinzi (durvalumab) in patients with Stage III non-small cell lung cancer during first-half 2018.
“ … we seek to position IDO1 enzyme inhibition as a key component of combination immunotherapy,” remarked Steven Stein, M.D., chief medical officer at Incyte.
Additionally during October, Incyte and MacroGenics came to terms on an exclusive worldwide collaboration and license pact for MacroGenics’ MGA012. The investigational monoclonal antibody inhibits programmed cell death protein 1. Incyte obtained exclusive global rights for the development and commercialization of MGA012 for all indications.
“Anti-PD-1 therapy is becoming a mainstay of cancer treatment across multiple tumor types, and we believe the addition of MGA012 to our clinical pipeline is important to fulfilling our long-term development strategy in immuno-oncology,” Dr. Stein noted. “This collaboration with MacroGenics will allow us to rapidly explore the potential clinical benefit of developing MGA012 as a monotherapy and also combining anti-PD-1 therapy with several of our existing portfolio assets.”
Johnson & Johnson
Johnson & Johnson revealed an impressive four-year plan during May 2017. Company management anticipates more than 10 new blockbuster products to launch or be filed for regulatory approval by 2021; more than 50 line-extension regulatory submissions are projected by 2021; and beyond that year, J&J’s early-stage pipeline will continue delivering breakthrough medicines while additionally strengthening focus on eliminating disease through prevention, interception and cures.
As an industry leader in research productivity, J&J’s Janssen garnered FDA approval for 11 new molecular entities since 2011 through May 2017. The portfolio has concentrated on five core therapeutic areas – Immunology, Infectious Diseases & Vaccines, Neuroscience, Cardiovascular & Metabolism, and Oncology – and a sixth therapeutic field in Pulmonary Arterial Hypertension was added with the completed acquisition of Actelion during June 2017 for $30 billion in cash. According to management, the addition of Actelion’s specialty in-market medicines and late-stage products is consistent with Johnson & Johnson’s efforts to grow in attractive and complementary therapeutic areas and serve patients with serious illnesses and significant unmet medical need. In addition, the transaction structure provides J&J flexibility to accelerate investment in its industry-leading, innovative pipeline to drive additional growth.
During 2016, Janssen filed two NMEs that were expected to be approved and launched during 2017: guselkumab for psoriasis and sirukumab for rheumatoid arthritis. Guselkumab won FDA clearance in July under the trade name Tremfya. Janssen Biotech during September reported that it received a complete response letter from the U.S. FDA indicating additional clinical data are needed to further evaluate the safety of sirukumab in the treatment of moderately to severely active RA.
Other late-stage blockbuster products projected to be filed for regulatory approvals between 2017 and 2021 include: apalutamide (ARN-509) for pre-metastatic prostate cancer; esketamine for treatment-resistant depression; talacotuzumab (CSL362) for acute myeloid leukemia; erdafitinib (FGFR Inhibitor) for solid tumors; niraparib for prostate cancer; imetelstat for myelofibrosis; pimodivir (JNJ-3872) for influenza A; lumicitabine (JNJ-1575) for respiratory syncytial virus (RSV) infection; and JNJ-7922 (orexin-2 antagonist) for adjunctive treatment for major depressive disorder.
The once-monthly schizophrenia treatment Invega Sustenna (paliperidone palmitate) in January became the first antipsychotic to have the FDA approve real-world data for its labeling. These data derive from the Paliperidone Palmitate Research In Demonstrating Effectiveness (PRIDE) study. Invega Sustenna is the only antipsychotic to show superior effectiveness in delaying time to relapse versus a group of seven commonly prescribed oral antipsychotics in adults with schizophrenia who face common real-world circumstances.
The J&J product portfolio produced some prominent approvals during fourth-quarter 2017, for both new brands and existing indications for already-marketed medicines. During the quarter, the U.S. FDA cleared Juluca (rilpivirine and dolutegravir) as the first, complete, single-pill, two-drug regimen for treating human immunodeficiency virus type 1 (HIV-1) infection; a 10-mg once-daily dose of Xarelto (rivaroxaban) for reducing the continued risk for recurrent venous thromboembolism after completing at least six months of initial anticoagulation therapy; and Simponi Aria (golimumab) for the treatment of adults with active psoriatic arthritis or active ankylosing spondylitis. The European Commission approved Tremfya as a treatment for adults with moderate-to-severe plaque psoriasis and granted marketing clearance to broaden the existing marketing authorization for Zytiga (abiraterone acetate) plus prednisone/prednisolone to include the treatment of newly diagnosed high-risk metastatic hormone-sensitive prostate cancer.
“The approval of Juluca marks a significant milestone in the treatment of HIV,” commented Brian Woodfall, Global Head of Late Development, Janssen Research & Development. “As the first single-pill, complete two-drug regimen, Juluca maintains the safety and efficacy of a traditional three-drug regimen without an N(t)RTI. This is exciting because it offers those living with HIV who are compliant and stably suppressed a new, simplified treatment option to consider.”
Additionally during fourth-quarter 2017, regulatory applications for approval were filed to the FDA and European Medicines Agency to expand the current indication of Darzalex (daratumumab) for use in combination with bortezomib, melphalan and prednisone as a treatment for newly diagnosed patients with multiple myeloma ineligible for autologous stem cell transplantation. A supplemental New Drug Application was submitted to U.S. regulatory officials for two new Xarelto vascular indications: reducing the risk of major cardiovascular (CV) events including CV death, heart attack or stroke in patients with chronic coronary and/or peripheral artery disease (CAD/PAD), and for reducing the risk of acute limb ischemia in patients with PAD.
Johnson & Johnson Innovation kicked off 2018 by announcing more than a dozen new collaborations to drive the development of novel solutions to impact healthcare. These collaborations bring the total amount of strategic transactions executed by Johnson & Johnson Innovation to more than 350 since its establishment in 2012.
This most recent series of deals concentrates on leveraging advances in science and technology to address areas of high unmet medical need, including the use of artificial intelligence to detect signs of Alzheimer’s disease years before it becomes apparent; the identification of throat cancers with a simple saliva test; and harnessing the microbiome to treat sleep disorders.
“Our approach to external innovation has been incredibly fruitful, as we established more than 60 significant new strategic relationships in 2017,” stated Robert G. Urban, Ph.D., Global Head of Johnson & Johnson Innovation.
In December 2017, J&J executed a global collaboration and license deal with Chinese company Legend Biotech, a subsidiary of GenScript Biotech, to develop, manufacture and commercialize a chimeric antigen receptor (CAR) T-cell therapy. LCAR-B38M is intended to target B-cell maturation antigen for treating multiple myeloma. The new product candidate has been accepted for review by the China Food and Drug Administration and is undergoing the planning phase of clinical trials in the United States for multiple myeloma.
“Dark horse Nanjing Legend Biotech was one of the surprising stars of ASCO last summer with its CAR-T data, and now Johnson & Johnson is paying $350 million upfront to join forces with the company and look for a working ‘cure’ for certain blood cancers,” say analysts at FierceBiotech.
J&J’s Janssen Biotech during December announced that the U.S. FDA granted Priority Review designation for the New Drug Application for apalutamide. The investigational, next-generation oral androgen receptor inhibitor is being developed for the treatment of men with non-metastatic castration-resistant prostate cancer (CRPC). There are not yet FDA-approved treatments for patients with non-metastatic CRPC. Apalutamide represents the first agent filed for approval to treat earlier-stage CRPC at high risk for metastasis. U.S. regulators assigned a Prescription Drug User Fee Act target date of April 2018 to render a decision on the apalutamide NDA.
Janssen Research & Development announced in December that the Phase 3 iNNOVATE (PCYC-1127) trial assessing Imbruvica (ibrutinib) in combination with rituximab (branded as Rituxan) in relapsed/refractory and treatment-naïve patients with Waldenström’s macroglobulinemia (WM) successfully met its primary endpoint of progression-free survival. An Independent Data Monitoring Committee advised unblinding iNNOVATE based on efficacy results observed in the pre-specified interim analysis. Imbruvica represents a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Janssen Biotech and AbbVie company Pharmacyclics.
On the eve of World AIDS Day (December 1), Johnson & Johnson revealed that its Janssen Pharmaceutical Companies along with a consortium of global partners initiated the first efficacy study for an investigational mosaic HIV-1 preventive vaccine. The Bill & Melinda Gates Foundation and National Institutes of Health joined forces with Johnson & Johnson to advance the potential prevention option, which is designed to be a “global vaccine” that could prevent a wide array of viral strains responsible for the HIV pandemic.
“Having a preventive vaccine would be a vital tool in a comprehensive global strategy to end the HIV pandemic,” noted Dr. Johan Van Hoof, Janssen Vaccines & Prevention and Therapeutic Area Head, R&D, Infectious Diseases & Vaccines. “Our investigational vaccine is based on mosaic antigens that have been engineered using genes from a wide range of different HIV subtypes. The ultimate goal is to deliver a ‘global vaccine’ that could be deployed in any geographic region to help protect vulnerable populations at risk of infection.”
Janssen Research & Development in November reported longer-term results from a Phase 2 trial testing Tremfya, the first selective anti-interleukin-23 monoclonal antibody to demonstrate positive results in treating active psoriatic arthritis. Based on the Phase 2 results, Janssen initiated two Phase 3 trials to investigate the efficacy and safety of Tremfya for patients with active psoriatic arthritis who may have been previously treated with anti-tumor necrosis factor alpha therapies (DISCOVER-1), and in patients who have not received prior treatment with a biologic therapy (DISCOVER-2).
Janssen Pharmaceutica announced in October 2017 that the pivotal Phase 3 AMBER study achieved its primary endpoint, which focused on virologic response rate, and showed that the investigational single-tablet regimen (STR) containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir alafenamide 10 mg (D/C/F/TAF) was non-inferior to darunavir/cobicistat (D/C) plus emtricitabine and tenofovir disoproxil fumarate (F/TDF) in previously untreated human immunodeficiency virus type 1 positive adults.
An NDA for D/C/F/TAF was submitted on Sept. 22, 2017, with the U.S. FDA for treating HIV-1 infection in adults and pediatric patients 12 years of age and older, based on the results from the pivotal Phase 3 trials EMERALD and AMBER. Three days later, the European Commission approved the use of Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) for treating HIV-1 infection in adults and adolescents aged 12 years and older with body weight of at least 40 kg. This approval allows Janssen to market D/C/F/TAF in all EU member states and the European Economic Area.
A supplemental New Drug Application was filed with U.S. regulatory officials in October for a new indication for Invokana (canagliflozin): to reduce the risk of major adverse cardiovascular events (MACE) – composed of cardiovascular (CV) death, myocardial infarction and stroke – in adults with type 2 diabetes who have established CV disease or are at risk for CV disease. The sNDA additionally applies to Invokana’s fixed-dose combinations, Invokamet and Invokamet XR, and is based on findings from the landmark CANVAS clinical study program.
Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the globe – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases such as HIV and Ebola.
Despite having been approved for U.S. marketing back in September 2014, Keytruda remains Merck’s most significant pipeline asset. The anti-cancer agent’s sales vaulted from $1.4 billion in 2016 to $3.81 billion for 2017, reflecting the company’s continued launches with new indications globally. EvaluatePharma analysis has the blockbuster medicine reaching $6.1 billion in global sales during 2018, with its potential $2.28+ billion year-over-year growth representing the largest increase of any prescription drug this year.
Merck has the industry’s largest immuno-oncology clinical research program, consisting of more than 650 studies exploring Keytruda (pembrolizumab) across a wide range of cancers and treatment settings. The Keytruda clinical program seeks to understand the role of the medicine across cancers and the factors that may predict a patient’s likelihood of benefiting from its treatment, including exploring several different biomarkers.
The anti-PD-1 therapy works by increasing the ability of the body’s immune system to help detect and fight tumor cells. The humanized monoclonal antibody Keytruda blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes that may affect tumor cells and healthy cells.
Merck continues to expand the company’s focus in oncology by further advancing the development program for Keytruda as well as the poly (ADP-ribose) polymerase inhibitor Lynparza (olaparib), which is co-developed and co-commercialized with AstraZeneca.
In January 2018, Merck announced the pivotal Phase 3 KEYNOTE-189 study exploring Keytruda in combination with pemetrexed (branded as Alimta) and cisplatin or carboplatin, for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS). Based on an interim analysis performed by the independent Data Monitoring Committee, treatment with Keytruda in combination with pemetrexed plus platinum chemotherapy led to significantly longer OS and PFS than pemetrexed plus platinum chemotherapy alone. Keytruda, in combination with pemetrexed and platinum chemotherapy, is the first immuno-oncology combination to demonstrate improved OS for the first-line treatment of patients with metastatic non-squamous NSCLC.
The FDA accepted for priority review the sBLA for Keytruda for treating adult and pediatric patients with refractory primary mediastinal B-cell lymphoma, or who have relapsed after two or more prior lines of therapy. FDA set a PDUFA date of April 3, 2018, and granted Breakthrough Therapy Designation for this indication in January 2017.
During January 2018, U.S. regulators issued Breakthrough Therapy Designation for Keytruda in combination with Eisai’s multiple receptor tyrosine kinase inhibitor Lenvima (lenvatinib) for the potential treatment of advanced and/or metastatic renal cell carcinoma. The combo product is jointly developed as part of a Merck and Eisai collaboration. This marked the 12th Breakthrough Therapy Designation awarded to Keytruda.
The Japanese Ministry of Health, Labour and Welfare granted approval in early January for Keytruda for treating patients with radically unresectable urothelial carcinoma who progressed after cancer chemotherapy. This approval marked the first anti-PD-1 therapy cleared in Japan for previously treated urothelial carcinoma, a form of bladder cancer.
The European Organization for Research and Treatment of Cancer (EORTC) announced on Jan. 8 the Phase 3 EORTC1325/KEYNOTE-054 study exploring Keytruda as monotherapy for surgically resected high-risk melanoma met the primary endpoint of recurrence-free survival. Based on an interim analysis and following review by the Independent Data Monitoring Committee, Keytruda’s performance resulted in significantly longer recurrence-free survival than placebo.
The FDA gave the green light to Lynparza in January 2018 for a new indication: for use in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer who have been previously treated with chemotherapy either in the neoadjuvant, adjuvant or metastatic settings. Lynparza represents the first PARP inhibitor approved for breast cancer. A supplemental New Drug Application was filed to Japan’s Pharmaceuticals and Medical Devices Agency for the same usage.
Lynparza is the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, including BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have demonstrated that Lynparza-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, leading to DNA damage and cancer cell death.
The Japanese Ministry of Health, Labour and Welfare during January granted approval to Lynparza for use as a maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, regardless of their BRCA mutation status, who responded to their last platinum-based chemotherapy. Lynparza is the first PARP inhibitor to win marketing approval in Japan.
AstraZeneca and Merck announced during July 2017 a worldwide strategic oncology collaboration to jointly develop and commercialize Lynparza and the potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. The collaboration is based on increasing evidence that PARP and MEK inhibitors can be combined with PD-L1/PD-1 inhibitors for various tumor types. The companies will jointly develop Lynparza and selumetinib in combination with other potential new medicines and as a monotherapy. Independently, Merck and AstraZeneca will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.
FDA approval was granted in December to Merck and Pfizer for the oral sodium-glucose cotransporter 2 inhibitor Steglatro (ertugliflozin) tablet, the fixed-dose combination Steglujan (ertugliflozin and sitagliptin) and the fixed-dose combination Segluromet (ertugliflozin and metformin hydrochloride) to help improve glycemic control in adults with type 2 diabetes. In addition, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion for these products.
The FDA approvals are supported by seven Phase 3 trials of 4,800 patients. Steglatro was studied as monotherapy and in combination with metformin and/or sitagliptin, as well as with insulin and a sulfonylurea, in adult patients with type 2 diabetes and moderate renal impairment.
The FDA and European Commission granted approval in November to Prevymis (letermovir), once-daily tablets for oral use and injection for intravenous infusion, for the prevention of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant. Prevymis represents the first new medicine FDA-approved for CMV infection in 15 years.
Prevymis belongs to a new class of non-nucleoside CMV inhibitors (3,4 dihydro-quinazolines) and inhibits viral replication by specifically targeting the viral terminase complex. Letermovir has been granted orphan designation for the prevention of CMV disease in at-risk populations in the United States, EU and Japan. The product is undergoing accelerated review in the EU and Japan.
Two NDAs were accepted for U.S. regulatory review during January for Merck’s investigational non-nucleoside reverse transcriptase inhibitor doravirine as a treatment for HIV-1 infection in adults. The NDAs include data for doravirine as a once-daily tablet for use in combination with other antiretroviral agents, and for use of doravirine with lamivudine and tenofovir disoproxil fumarate in a once-daily fixed-dose combo single tablet as a complete regimen. The PDUFA action date for each application is scheduled for Oct. 23, 2018.
Doravirine (MK-1439, DOR) is being studied in several Phase III clinical trials as a once-daily single-entity tablet in combination with other antiretroviral agents in a tailored regimen, and as a once-daily fixed-dose combination (DOR/3TC/TDF) in a complete single tablet regimen.
The U.S. regulatory agency during November issued marketing approval to Isentress (raltegravir) for use in combination with other antiretroviral agents for treating HIV-1 in newborn patients from birth to 4 weeks of age weighing at least 2 kg. Isentress is the only integrase inhibitor approved in the United States for this indication. The medicine was initially cleared for U.S. marketing during 2007 as the first integrase inhibitor for the treatment of HIV-1 infection.
Denmark’s Novo Nordisk in December received U.S. regulatory approval for semaglutide, a once-weekly diabetes drug that industry analysts have been excited about for quite some time. Approved under the trade name Ozempic, the product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The glucagon-like peptide 1 (GLP-1) receptor agonist was approved for use in two therapeutic dosages – 0.5 mg and 1 mg – and was launched in the Ozempic Pen, the latest generation of Novo Nordisk prefilled devices.
The FDA review of Ozempic was based on SUSTAIN, a global clinical development program consisting of eight phase 3a trials encompassing more than 8,000 adults with type 2 diabetes. The phase 3a program involves a wide array of people with type 2 diabetes, including some with high cardiovascular risk profiles and individuals with and without renal disease.
In August 2017, Novo Nordisk demonstrated that the GLP-1 semaglutide was superior to once-weekly dulaglutide on glucose control and weight loss in people with type 2 diabetes in the SUSTAIN 7 study. Dulaglutide is marketed by Eli Lilly as Trulicity, a blockbuster medicine that captured FDA approval in September 2014.
A positive 16-0 recommendation was issued by an FDA advisory committee meeting on Oct. 18, 2017. In people with type 2 diabetes, Ozempic produced clinically meaningful and statistically significant reductions in HbA1c versus placebo, sitagliptin, exenatide extended-release and insulin glargine U100. In the clinical trials, treatment with Ozempic led to statistically significant reductions in body weight. Ozempic showed a safe and well-tolerated profile across the SUSTAIN program.
As part of the post-approval requirements, Novo Nordisk is conducting a pediatric study in adolescents younger than 18 years old and will add Ozempic to the 15-year MTC (medullary thyroid carcinoma) registry that is being conducted for all other long-acting GLP-1 products.
Ozempic is undergoing review by several other regulatory agencies, including the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency. During December 2017, Ozempic was issued a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency as a treatment for adults with type 2 diabetes. Novo Nordisk anticipates winning marketing approval from the European Commission during first-quarter 2018.
A promising sales future is anticipated for Ozempic, which is a longer-acting version of Novo Nordisk’s once-daily blockbuster medicine Victoza. The once-weekly convenience of Ozempic along with strong efficacy in reducing blood sugar levels and helping patients lose weight bolster the product’s market potential.
The consensus of industry analysts is that Ozempic will represent the second-largest pharmaceutical product launch of 2018 after Gilead’s Bictegravir/F/TAF combo treatment for HIV. According to an EvaluatePharma report in November 2017, semaglutide is projected to generate 2022 worldwide sales of $2.72 billion.
Down the road, semaglutide’s sales potential could explode if the drug is approved in a once-daily pill formulation. Novo Nordisk could become the first company to bring to market such a product, potentially in 2020, if its late-stage studies are successful.
Novo Nordisk reported on Dec. 7, 2017, that people with either type 1 or type 2 diabetes treated with Tresiba had fewer episodes of low blood sugar (hypoglycemia) compared with people on insulin glargine U100 regardless of whether they had achieved blood sugar targets. The new post-hoc analyses derived from the SWITCH 1 and 2 clinical trials.
Switching to Tresiba from another basal insulin benefits people with diabetes regardless of whether or not their blood sugar levels are controlled, Novo Nordisk reported on Dec. 5. This was the conclusion of a post-hoc analysis of data from the EU-TREAT study collected in a real-world clinical setting for people with type 1 and type 2 diabetes.
Once-daily Xultophy (insulin degludec/liraglutide) was a better option to manage diabetes versus multiple daily injections of insulin (basal-bolus regimen), according to a Novo Nordisk announcement on Dec. 5. This was reported by people with type 2 diabetes whose blood sugar was not controlled on insulin glargine U100 with metformin, and who completed quality-of-life questionnaires as part of the DUAL VII clinical study. Also, more individuals preferred to stay on Xultophy compared with basal-bolus therapy (84.5% versus 68.1%).
The FDA during September 2017 approved Fiasp, a new fast-acting mealtime insulin, for treating adults with diabetes. In clinical studies, Fiasp showed benefits for people in need of improved overall glucose control. Fiasp is an innovative formulation of insulin aspart (NovoLog) developed with the aim of obtaining pharmacokinetic and pharmacodynamic properties that more closely match the natural physiological insulin mealtime response of people without diabetes.
Fiasp is insulin aspart in an innovative formulation, in which two excipients have been added: Vitamin B3 (niacinamide) to increase absorption speed and a naturally occurring amino acid (L-Arginine) for stability. The review of Fiasp was based on the ‘onset’ program, a set of four phase 3 studies encompassing more than 2,100 people with type 1 and type 2 diabetes.
Novo Nordisk was seeking to strengthen its product pipeline through what resulted in a failed acquisition attempt of Ablynx as the biopharmaceutical company wound up being gobbled up by Sanofi for about EUR 3.9 billion in late January 2018. Novo Nordisk confirmed on Jan. 8 that it made a proposal on Dec. 22, 2017, to acquire Ablynx for EUR 2.6 billion. On Jan. 29, Novo Nordisk stated that the Danish company “looks forward to continuing its productive research collaboration with Ablynx.”
Since 2015, Novo Nordisk has had a research collaboration with Ablynx and its Nanobody platform.
Sanofi is investing in seven research fields to find innovative solutions for unmet needs: cardiovascular, diabetes, vaccines and infectious diseases, immunology, multiple sclerosis/neurology, oncology, and rare diseases (focused mainly on Gaucher disease, Pompe disease, Fabry disease and non-neurological forms of acid sphinogomyelinase deficiency, also known as Niemann-Pick disease type B).
As of Dec. 13, 2017, Sanofi’s pipeline encompassed 71 R&D projects, including 37 new molecular entities and novel vaccines. The company generated seven NME and vaccine approvals since 2015 through mid-December 2017. As of Dec. 13, the company planned to submit nine drug submissions during the next 18 months and start at least 10 pivotal studies within a one-year period.
Potential new medicines being evaluated in late-stage testing during 2018 include dupilumab for chronic obstructive pulmonary disease and eosinophilic esophagitis; venglustat for autosomal dominant polycystic kidney disease; the once-weekly GLP-1 agonist efpeglenatide for type 2 diabetes; a GLP-1/GCG dual agonist for obesity; alemtuzumab for primary-progressive multiple sclerosis; and cemiplimab for first line NSCLC.
The regulatory submissions anticipated in 2018 include the investigational cancer drugs cemiplimab and isatuximab, the novel therapy sotagliflozin for type 1 diabetes, and dupilumab for uncontrolled, persistent asthma.
As a key pillar of the company’s 2020 Roadmap, the new Sanofi R&D model is based on three key strategic shifts: from small molecules to biologics; from mono-targeting to multi-targeting compounds; and from licensing to proprietary assets.
“We aim to advance multi-targeting therapeutic approaches for core disease pathways that have the potential to attack more than one disease at a time or bring improved risk benefit in the treatment of a single disease,” commented Elias Zerhouni, M.D., Global Head of R&D at Sanofi. “2018 will be an important year as we expect multiple milestones for Sanofi’s late-stage pipeline, made possible through the prioritization principles we have consistently applied to our early-stage research programs.”
In a seven-day span, Sanofi made two multi-billion biopharma company acquisitions that will help bolster its R&D prospects moving forward. On Jan. 22, 2018, Sanofi acquired Bioverativ for $11.6 billion and one week later announced the purchase of Ablynx for $3.9 billion. The Bioverativ acquisition expands Sanofi’s presence in specialty care and strengthens its leadership in rare diseases. Bioverativ provides Sanofi with a leader in the growing hemophilia market and a platform for expansion in other rare blood disorders.
“With Bioverativ, a leader in the growing hemophilia market, Sanofi enhances its presence in specialty care and leadership in rare diseases, in line with its 2020 Roadmap, and creates a platform for growth in other rare blood disorders,” noted Olivier Brandicourt, CEO of Sanofi.
Bioverativ markets two extended half-life therapies, Eloctate [Antihemophilic Factor VIII (Recombinant), Fc Fusion Protein] and Alprolix [Coagulation Factor IX (Recombinant), Fc Fusion Protein] for the treatment of hemophilia A and B, respectively.
Sanofi officials believe that factor replacement therapy will remain the standard of care in hemophilia for many years due to excellent safety and its increasingly superior long-acting profile. Company management anticipates leveraging Bioverativ’s clinical expertise and existing commercial platform to advance fitusiran, an investigational RNA interference (RNAi) therapeutic for hemophilia A and B, with or without inhibitors. Sanofi recently announced a restructuring of its rare disease alliance with Alnylam Pharmaceuticals, acquiring worldwide development and commercialization rights to fitusiran.
One of the priorities of Sanofi’s 2020 Roadmap is to “Reshape the Portfolio” and focus on areas where the company currently has, or can effectively build, a leadership position. The addition of Bioverativ supports this priority by adding to Sanofi’s portfolio a differentiated offering of innovative therapies and providing a platform for growth in rare blood disorders.
Beyond its two marketed products for hemophilia – the extended half-life therapies Eloctate and Alprolix – Bioverativ’s pipeline includes a program in Phase 3 studies for cold agglutinin disease as well as early-stage research programs and collaborations in hemophilia and other rare blood disorders, such as sickle cell disease and beta thalassemia. Sanofi’s R&D organization will support Bioverativ in bringing these significant therapies to patients faster.
The Ablynx purchase strengthens Sanofi’s R&D strategy with an innovative Nanobody technology platform. The acquisition also expands the Paris-based company’s growing rare blood disorders franchise with Ablynx’s late-stage investigational treatment caplacizumab for acquired thrombotic thrombocytopenic purpura (aTTP).
The acquisition of Ablynx continues Sanofi’s dedication to breakthrough innovation, concentrated on technologies addressing multiple disease targets with single multi-specific molecules.
Nanobodies represent a novel class of proprietary next-generation biologicals. Ablynx is at the leading edge of such technology, supporting a pipeline of more than 45 proprietary and partnered candidates for a wide array of therapeutic fields including hematology, inflammation, immuno-oncology and respiratory diseases. Eight Nanobodies have started clinical development.
Ablynx’s most-advanced product in development, caplacizumab (anti-vWF Nanobody), has been submitted for approval in the European Union and is anticipated to be filed in the United States during first-half 2018. If cleared for marketing, caplacizumab would represent a first-in-class treatment for the acute, life-threatening disease aTTP. The addition of caplacizumab to Sanofi’s platform bolsters its position in rare blood disorders, complementing the recently announced deals to acquire Bioverativ and obtain worldwide rights for fitusiran from Alnylam.
Ablynx’s ALX-0171 is an inhaled anti-RSV Nanobody undergoing Phase 2b studies. ALX-0171 represents a potential breakthrough for the symptomatic treatment of RSV infections – for which there is no widely used therapy available – and is very complementary to Sanofi Pasteur RSV associated programs.
Sanofi and Regeneron Pharmaceuticals during January agreed to accelerate and expand investment for the clinical development of the PD-1 (programmed cell death protein 1) antibody cemiplimab in oncology and dupilumab in Type 2 allergic diseases. Both breakthrough therapies have the potential to benefit various patient populations and this strategic investment will allow the companies to study cemiplimab and dupilumab in broad clinical development programs.
Cemiplimab is being evaluated as monotherapy and in combination with other therapies in a broad range of cancers including advanced skin cancers, non-small cell lung cancer, cervical cancer and lymphomas, with more clinical trials in other indications planned to start during 2018. Sanofi and Regeneron intend to file U.S. and EU regulatory applications for cemiplimab in advanced cutaneous squamous cell carcinoma (CSCC) during first-quarter 2018. The companies reported positive top-line pivotal results for the PD-1 antibody in advanced CSCC during December.
The additional investment in the dupilumab development program will help accelerate planned new clinical trials in COPD, peanut allergy and grass allergy as well as in patients with multiple allergic conditions. These areas are in addition to ongoing dupilumab studies in pediatric atopic dermatitis, pediatric asthma, eosinophilic esophagitis and nasal polyposis. Dupixent (dupilumab) is approved for treating adults with moderate-to-severe atopic dermatitis in the U.S. and EU. A supplemental biologics license application was filed with FDA for uncontrolled, persistent asthma for patients aged 12 and older in fourth-quarter 2017.
The additional investment will accelerate and expand development of the IL-33 antibody REGN3500, with studies expected to be performed in atopic dermatitis, asthma and chronic obstructive pulmonary disease.
Sanofi during January asked the European Medicines Agency to review fexinidazole as a treatment for sleeping sickness. Fexinidazole is being developed in collaboration with the Drugs for Neglected Disease initiative (DNDi) and would be the first all-oral treatment under investigation for Trypanosoma brucei gambiense human African trypanosomiasis (g-HAT), commonly known as sleeping sickness.
Sanofi Genzyme, the specialty care global business unit of Sanofi, and Alnylam Pharmaceuticals, a leading RNAi therapeutics company, announced in December the filing of a Marketing Authorization Application to the EMA for patisiran. The investigational RNAi therapeutic targeting transthyretin is intended for the treatment of adults with hereditary transthyretin-mediated amyloidosis. The new drug candidate was previously granted accelerated assessment by the EMA, potentially reducing the EMA’s evaluation time from 210 days to 150 days.
On Dec. 18, Sanofi’s alliance partner Alnylam announced completion of the submission of a New Drug Application with the FDA. Three days earlier, the U.S. regulatory health body lifted the clinical hold on fitusiran, including the Phase 2 open-label extension trial and the ATLAS Phase 3 program.
Sanofi Genzyme is preparing regulatory submissions for patisiran in Japan, Brazil and other countries, with filings expected to start during first-half 2018. Pending regulatory clearances, Alnylam will commercialize patisiran in the United States, Canada and Western Europe and Sanofi Genzyme will market the product in the rest of the world, including certain Central and Eastern European countries of the European Union.
In December, Sanofi’s Admelog won U.S. regulatory clearance, becoming the first FDA-approved follow-on mealtime insulin. Admelog is a rapid-acting insulin similar to Humalog, another insulin lispro 100 Units/mL that is marketed in the United States by Eli Lilly. Admelog is available in vials and the SoloStar pen, which is the most-used disposable insulin pen platform in the United States. The product won marketing authorization as a biosimilar, under the proprietary name Insulin lispro Sanofi from the European Commission in July 2017.
Sanofi reached a deal in November to develop South San Francisco-based Principia Biopharma’s experimental oral treatment PRN2246. The clinical-stage oral drug candidate has demonstrated promise in multiple sclerosis and potentially other central nervous system diseases.
The drive to become a leading biotech company focused on innovative approaches to treat rare and specialty diseases shapes the foundation of Shire’s R&D approach, according to its managers. Shire strives to develop best-in-class therapies across a core of rare disease fields such as hematology, immunology, genetic diseases, neuroscience, and internal medicine with growing therapeutic areas in ophthalmics and oncology.
Company management stated in January at the J.P. Morgan Healthcare Conference that Shire continues to have a promising late-stage pipeline with 15 programs undergoing Phase 3 development. Shire is projected to produce total annual revenue of $17-18 billion by 2020 compared to a U.S. GAAP outlook in the range of $14.3-$14.6 billion for 2017.
After performing a strategic review, the company’s board concluded that Shire’s neuroscience business warrants additional focus and investment and that there is a strong business rationale for creating two distinct business divisions within Shire: a Rare Disease Division and a Neuroscience Division. Company executives say both divisions will benefit from sharper management focus, greater strategic clarity, and an increased ability to deploy resources to key growth priorities.
According to managers, Shire’s rare disease business has a recognized track record of sustained growth and will build on its leading market position, investing organically and inorganically to further enhance the division’s innovative pipeline.
Shire anticipates remaining a leader in the hematology space with key brands including Advate and Adynovate, and the expected U.S. launch of MyPKFit during 2018.
Shire also anticipates that Internal Medicine will benefit from an increased demand for Natpara (hypoparathyroidism) and Gattex (short bowel syndrome), while Ophthalmics should drive forward from U.S. and worldwide growth of Xidra for dry eye disease, Shire says the Rare Disease division will have a robust late-stage pipeline including SHP643 for hereditary angioedema, SHP620 for cytomegalovirus infection in transplant patients, SHP607 for the prevention of respiratory morbidity in premature infants, and SHP621 for eosinophilic esophagitis.
According to Shire, the Neuroscience division will build on an industry-leading platform with a focus on neuropsychiatry more broadly. Shire expects to drive growth by expanding internationally and into adjacencies through disciplined R&D and business development. The company will continue to launch and grow in key international markets with Vyvanse and Intuniv to treat pediatric and adult ADHD. The Neuroscience division’s pipeline will include SHP680 for multiple neurological conditions and Buccolam in the U.S.
As of October, Shire was on track to submit a Biologics License Application for lanadelumab (SHP643) by early 2018. The company has projected FDA approval for the product as a treatment for hereditary angioedema in second-half 2018. Industry analysts expect the anti-plasma kallikrein monoclonal antibody lanadelumab to reach annual blockbuster status by 2022.
Shire was hopeful of submitting a New Drug Application for SHP555 by year-end 2017. The small-molecule drug has been undergoing Phase 3 development for chronic constipation and the company was projecting U.S. marketing clearance by first-quarter 2019.
The European Commission during January granted Marketing Authorization for Adynovi [Antihemophilic Factor (Recombinant), PEGylated], an extended half-life recombinant factor VIII (rFVIII) treatment, for on-demand and prophylactic use in patients 12 years and older living with hemophilia A. The product is modified to last longer in the blood and potentially require less frequent injections than unmodified Antihemophilic Factor when used to reduce the frequency of bleeding. Adynovi is built on Advate [Antihemophilic Factor (Recombinant)], a treatment used by hemophilia A patients globally for nearly 15 years. Adynovi’s proprietary PEGylation technology, which is exclusively licensed from Nektar Therapeutics, extends the time between treatments and offers a twice-weekly dosing regimen.
Adynovi was initially approved as Adynovate by the FDA, followed by marketing clearance in Japan, Canada and Colombia. The medicine is available as Adynovi in Switzerland. In Japan, Adynovate garnered regulatory clearance in Japan for use in hemophilia A pediatric patients under 12 years of age and those undergoing surgery during November 2017.
The FDA during January granted Breakthrough Therapy Designation for maribavir (SHP620), a Phase 3 investigational treatment for CMV infection and disease in transplant patients resistant or refractory to previous therapy. By targeting a key CMV enzyme, maribavir is believed to inhibit cytomegalovirus DNA replication and encapsidation, and prevent the escape of viral capsids from the nucleids of infected cells.
The investigational agent maribavir belongs to a class of medicines known as benzimidazole ribosides. The orally bioavailable antiviral therapy is being studied in patients with CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant. By inhibiting the CMV UL97 protein kinase, maribavir potentially affects several critical processes in cytomegalovirus replication including viral DNA synthesis, viral gene expression, encapsidation and egress of mature capsids from the nucleus. Additional research to confirm these findings will be carried out in Phase 3 trials.
The FDA and the European Commission have granted Orphan Drug Designation to maribavir for treating clinically significant CMV viremia and disease in at-risk patients, and treating cytomegalovirus disease in patients with impaired cell mediated immunity, respectively.
A pact was struck at the end of January 2018 granting Shire an exclusive worldwide license to develop and commercialize AB Biosciences’ pan receptor interacting molecule (PRIM) program. The PRIM program utilizes AB Biosciences’ proprietary oligomeric Fc technology platform. The recombinant immunoglobulin product candidate PRIM has demonstrated encouraging preclinical data, including enhanced biological activity relative to currently approved intravenous immunoglobulin (IVIg) therapies, in preclinical models of autoimmune and inflammatory diseases.
A new formulation of lyophilized Oncaspar (pegaspargase) was approved during December by the European Commission as a component of antineoplastic combination therapy in acute lymphoblastic leukemia in pediatric patients from birth to 18 years, and in adults. The approval – which authorizes Shire to market lyophilized Oncaspar in the 28 EU member states as well as Iceland, Liechtenstein and Norway – follows a positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) of the EMA on Oct. 12.
Lyophilized Oncaspar builds on more than a decade of data and research with liquid Oncaspar, a pegylated asparaginase, and works the same way as the liquid form. The new lyophilized formulation offers the same dosing regimen as the liquid version, but with a three-times longer shelf life than the liquid form. Asparaginase is a critical component of the treatment regimen for acute lymphoblastic leukemia patients as it is a proven approach to inducing leukemic cell death.
Shire and Rani Therapeutics, an InCube Labs company, agreed in December on a collaboration to exclusively conduct research on the use of the Rani Pill technology for the oral delivery of factor VIII (FVIII) therapy for hemophilia A patients. The collaboration grants Shire an exclusive option to negotiate a license to develop and commercialize the technology for FVIII therapy delivery following completion of feasibility studies. As part of the collaboration, Shire additionally made an equity investment into Rani Therapeutics.
The FDA in November issued Orphan Drug Designation to Shire’s investigational anti-MAdCAM-1 antibody SHP647 for treating pediatric patients with moderately to severely active ulcerative colitis. The fully human IgG2 monoclonal antibody targets the mucosal addressin cell adhesion molecule-1. Shire is studying SHP647 in Phase 3 trials as a treatment for moderately to severely active UC in adults. Pediatric study plans with SHP647 are under discussion with health regulators. Shire licensed SHP647 from Pfizer during June 2016.
The European Commission in October granted approval for a new indication for Firazyr (icatibant injection), broadening the drug’s use to adolescents and children aged 2 years and older, with hereditary angioedema (HAE) caused by C1-esterase-inhibitor (C1-INH) deficiency. The product has been approved in the EU since 2008 for the symptomatic treatment of acute attacks of HAE in adults with C1-INH deficiency. Firazyr is the first subcutaneous treatment in Europe for acute HAE attacks approved for children 2 years and older.
Fast Track designation was granted in September for the Phase 2 candidate SHP607 for the prevention of chronic lung disease in extremely premature infants. SHP607 is a recombinant human version of the naturally occurring protein complex of insulin-like growth factor 1 (IGF-1) and its most abundant binding protein, IGF binding protein-3 (IGFBP-3). IGF-1 plays an significant role in the development of the fetus in the uterus.
An MAA in the EU for lifitegrast was filed on Aug. 7, 2017. If cleared for marketing, lifitegrast would be the first treatment in a new class of drugs called LFA-1 antagonists to address the signs and symptoms of dry eye disease in adults in Europe. medadnews