As pharma companies bolster their pipelines via multibillion-dollar acquisitions, drug manufacturers continue to heavily invest in the oncology space.
Top 10 Pipelines To Watch
AstraZeneca
Axsome
Bristol-Myers Squibb/Celgene
GlaxoSmithKline
Lilly
Merck
Novartis
Regeneron
Roche
Takeda/Shire
A key development for the industry in 2020 is the impact of merger and acquisition activity initiated or completed during 2019 among large pharma companies. Many of the big deals from 2019 played a hand in the selection process of this year’s Top 10 Pipelines To Watch, including the $74 billion acquisition of Celgene by Bristol-Myers Squibb; Takeda’s $62 billion purchase of Shire; Novartis bought The Medicines Company for $9.7 billion; Lilly obtained Loxo Oncology for about $8 billion; Roche spent more than $4 billion for Spark Therapeutics; and Merck acquired ArQule for $2.7 billion.
According to analysis from OptumRx, 2020 could be a record year for drug approvals. OptumRx research shows that more than 150 drug approvals – including new molecular entities and other products – will be evaluated by the FDA, with at least 64 total drugs already filed with the U.S. regulatory agency and having anticipated approval dates during 2020. Eleven of the potential drug approvals represent projected blockbuster brands.
Oncology has 44 medicines anticipated for approval in 2020, with 70 percent of those drugs having orphan drug designation. “Cancer treatments focused on narrow populations remain a top priority for pharmaceutical manufacturers,” according to OptumRx.
ASTRAZENECA
AstraZeneca has developed a set of priorities that include delivering growth and therapy area leadership, and accelerating innovative science. The company has a focused strategy on three therapy areas, each with significant growth opportunities: Oncology; Cardiovascular, Renal & Metabolism; and Respiratory (and immunology).
The late-stage pipeline and key lifecycle medicines for Oncology include: Tagrisso for non-small cell lung cancer (NSCLC); Imfinzi for multiple cancers; Lynparza for multiple cancers; trastuzumab deruxtecan for breast and other cancers; capivasertib for breast cancer; Calquence for blood cancers; tremelimumab for multiple cancers; selumetinib for the incurable genetic condition neurofibromatosis type 1 (NF1); and savolitinib for NSCLC.
Roxadustat, for anemia of chronic kidney disease (CKD), represents the lead opportunity in the Cardiovascular, Renal & Metabolism sector. Roxadustat is the first orally administered small molecule hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor accepted for FDA review for treating anemia of CKD. The U.S. regulatory agency has set a Prescription Drug User Fee Act (PDUFA) date of Dec. 20, 2020. AstraZeneca and FibroGen are collaborating on the development and commercialization of roxadustat for treating anemia in the United States, China and other markets in the Americas and in Australia/New Zealand as well as Southeast Asia. Analysts’ worldwide sales forecast for roxadustat for the year 2025 ranges up to $3.5 billion.
For AstraZeneca’s Respiratory (and immunology) category, the late-stage pipeline and key lifecycle products consist of Fasenra for multiple indications; Breztri for COPD; PT027 for asthma; tezepelumab for severe asthma; nirsevimab for lower respiratory tract infection; and anifrolumab for lupus.
The AstraZeneca pipeline is chock full of new molecular entities in the areas of Oncology and Biopharmaceuticals, including novel combinations and additional indications for assets where the lead is not yet launched, and some are being developed through partnerships and/or collaborations. As of October 2019, there were 19 NMEs in Phase III, 46 in Phase II, and 34 in Phase I. The one NME that was awaiting regulatory approval as of October has since been cleared for marketing: Enhertu (fam-trastuzumab deruxtecan-nxki).
Enhertu won FDA marketing clearance in December for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting. The indication was granted under Accelerated Approval based on tumor response rate and duration of response. FDA approval of the HER2-directed antibody-drug conjugate was based on the results of the registrational Phase II trial DESTINY-Breast01 of Enhertu (5.4mg/kg) monotherapy in patients with HER2-positive metastatic breast cancer. All patients received prior trastuzumab, trastuzumab emtansine and 66 percent had prior pertuzumab. Developed with Daiichi Sankyo, Enhertu represents significant blockbuster potential. The companies are further exploring the potential of Enhertu in HER2-breast cancer via three Phase III trials.
Brilinta met the primary endpoint in the Phase III THALES study in stroke, according to high-level results reported by AstraZeneca in late January 2020. The medicine reduced the risk of the composite of stroke and death after an acute ischemic stroke or transient ischemic attack.
In other January news, a pair of Lynparza regulatory submissions were granted priority review by the U.S. FDA: for HRR-mutated metastatic castration-resistant prostate cancer and for 1st-line maintenance treatment with bevacizumab in advanced ovarian cancer. In December, Lynparza was granted U.S. marketing clearance as the only PARP inhibitor approved in germline BRCA-mutated metastatic pancreatic cancer. The drug reduced the risk of disease progression or death by 47 percent in patients whose disease had not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.
Farxiga was additionally given FDA priority review during January, for patients with heart failure with reduced ejection fraction.
An approval decision is expected to be rendered in the second quarter of 2020 for the first-in-class, oral once-daily selective inhibitor of human sodium-glucose co-transporter 2 (SGLT2).
AXSOME THERAPEUTICS
Making a first-time appearance in this annual special report, Axsome Therapeutics is building a portfolio of differentiated product candidates that address unmet medical needs. Some of the company’s product candidates combine multiple mechanisms of action to produce novel medicines that address deficiencies of current approaches. Axsome’s pipeline includes four differentiated clinical-stage CNS assets targeting significant and growing markets. The Axsome Pain and Primary Care business unit (Axsome PPC) houses the company’s pain and primary care assets and intellectual property, including three clinical-stage product candidates, which are being developed for multiple pain and primary care indications.
Axsome’s late-stage pipeline consists of four clinical-stage candidates: AXS-05, AXS-07, AXS-12, and AXS-09. These new drug candidates are being evaluated for different indications including treatment-resistant depression, major depressive disorder, agitation in Alzheimer’s disease, smoking cessation, migraine, narcolepsy, and other CNS (central nervous system) disorders.
Axsome Therapeutics stock increased by almost 3,600 percent during 2019. “Despite this mind-boggling rally, there is still significant upside potential in the stock for 2020,” according to Seeking Alpha analysis. “Axsome Therapeutics is set to grab a large share in the major depressive disorder indication.”
Various industry analysts are high on AXS-05 (dextromethorphan/bupropion modulated delivery tablet), which has the potential to represent the standard-of-care in the major depressive disorder (MDD) arena. The novel, oral, investigational non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with multimodal activity is being developed for treating MDD and other central nervous system disorders. AXS-05 consists of a proprietary formulation and dose of dextromethorphan and bupropion, and uses the clinical-stage biopharmaceutical company’s metabolic inhibition technology.
The dextromethorphan component of AXS-05 is a non-competitive NMDA receptor antagonist, also known as a glutamate receptor modulator, which is a novel mechanism of action. The dextromethorphan component of AXS-05 is additionally a sigma-1 receptor agonist, nicotinic acetylcholine receptor antagonist, and inhibitor of the serotonin and norepinephrine transporters. The bupropion component serves to increase the bioavailability of dextromethorphan, and is a norepinephrine and dopamine reuptake inhibitor, and a nicotinic acetylcholine receptor antagonist.
AXS-05 is covered by 40-plus issued U.S. and international patents that provide protection out to 2034. The drug compound has been granted U.S. FDA Breakthrough Therapy designation for treating MDD as well as Fast Track designation for treatment-resistant depression. Axsome is on track to report topline results from the STRIDE-1 Phase III study for AXS-05 during first-quarter 2020.
Axsome is developing AXS-12 for the treatment of narcolepsy. “AXS-12 is racing ahead to become a treatment option in narcolepsy indication,” Seeking Alpha analysts say. During January 2020, Axsome entered into a deal for an exclusive U.S. license to Pfizer’s clinical and nonclinical data, and intellectual property for reboxetine, the active pharmaceutical ingredient in AXS-12. “This deal can help speed up the development of AXS-012 in narcolepsy indication, thereby getting the product earlier into the market,” notes Seeking Alpha analysis.
In addition, the Pfizer transaction provides Axsome exclusive rights to develop and commercialize esreboxetine, a new late-stage product candidate now referred to as AXS-14, in the United States, for the treatment of fibromyalgia.
Axsome recently completed and announced positive results for a Phase II study of AXS-12 for narcolepsy. The company is preparing to advance AXS-12 into Phase III trials for narcolepsy in 2020. Reboxetine is a highly selective and potent norepinephrine reuptake inhibitor. Reboxetine modulates noradrenergic activity to promote wakefulness, maintain muscle tone and enhance cognition. Orphan Drug Designation has been granted by the U.S. FDA for treating narcolepsy.
At the end of 2019, Axsome announced that the novel, oral, multi-mechanistic investigational medicine AXS-07 met the two regulatory co-primary endpoints and significantly improved migraine pain and most bothersome symptoms as compared to placebo in the MOMENTUM Phase III study. AXS-07 additionally met the key secondary endpoint, showing statistically significant superiority to the active comparator rizatriptan on sustained freedom from migraine pain.
AXS-07 is composed of MoSEIC meloxicam and rizatriptan. Meloxicam is a new molecular entity for migraine enabled by the company’s MoSEIC (Molecular Solubility Enhanced Inclusion Complex) technology, which results in rapid absorption of meloxicam while maintaining a long plasma half-life. Meloxicam is a COX-2 preferential non-steroidal anti-inflammatory drug and rizatriptan stems from the 5-HT1B/1D agonist drug class. AXS-07 is designed to provide rapid, enhanced and consistent relief of migraine, with reduced symptom recurrence, according to Axsome.
“AXS-07 is also a key growth driver for Axsome Therapeutics’ stock price,” according to Seeking Alpha analysis. “Axsome Therapeutic now plans to file an NDA for AXS-07 in acute migraine indication in the second half of 2020.”
BRISTOL-MYERS SQUIBB/CELGENE
“By all measures, 2019 was a transformative year for Bristol-Myers Squibb as we progressed our strategy through the acquisition of Celgene, delivered strong operational and financial performance, and continued to drive important science for patients,” stated Giovanni Caforio, M.D., chairman and CEO of Bristol-Myers Squibb, on Feb. 6th, 2020, upon delivering the company’s year-end results. “With an expanded portfolio of high-performing brands, eight potential commercial launch opportunities, a deep and broad early pipeline, and the financial flexibility to continue to invest in innovation, the company entered 2020 uniquely positioned to transform patients’ lives through science and create long-term sustainable growth.”
The $74 billion Celgene acquisition closed on Nov. 20, 2019. The combined entity is forecasted by industry analysts to become the third-largest pharmaceutical company based on 2024 prescription sales. The Bristol-Myers Squibb/Celgene unification comprises one of the broadest late-stage pipelines in the industry. The strategic foundation: a differentiated company that combines the Best of Biotech and Best of Pharma – focused on innovative medicines for patients with cancer and other serious diseases. As of February 2020, Bristol-Myers Squibb’s portfolio encompassed 8 potential near-term launch opportunities, including U.S. regulatory actions for six opportunities during the next 6-month period.
R&D expenses for Bristol-Myers Squibb grew 52 percent to $2.1 billion in the fourth quarter of last year, primarily due to the Celgene acquisition. With the acquisition came two of the eight most highly touted new drug prospects in the industry pipeline according to EvaluatePharma’s “World Preview 2019, Outlook to 2024” report: the potential best-in-class CD19 CAR T lisocabtagene maraleucel (liso-cel) and the immunomodulator ozanimod that is undergoing clinical development for multiple sclerosis (MS), ulcerative colitis and Crohn’s disease.
Bristol-Myers Squibb during December 2019 announced the submission of a Biologics License Application (BLA) to the U.S. FDA for liso-cel. The BLA for the autologous anti-CD19 CAR T-cell immunotherapy is seeking approval for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two prior therapies. Liso-cell is also being studied for various other indications including relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, relapsed or refractory large B-cell non-Hodgkin’s lymphoma patients who were ineligible for high-dose chemotherapy and hematopoietic stem cell transplant, and relapsed/refractory large B-cell non-Hodgkin lymphoma who received liso-cel in the outpatient setting across three studies.
Like liso-cell, ozanimod represented a key component of Bristol-Myers Squibb’s purchase of Celgene. According to reports, part of the payout to Celgene shareholders depends on FDA approvals for three pipeline products by year-end 2020: liso-cell, ozanimod and ide-cel (bb2121). An FDA approval decision for ozanimod, which is expected to be branded as Zeposia, for relapsing forms of MS is expected by March 25, 2020.
Bristol-Myers Squibb and partner bluebird bio announced during December that KarMMa – a pivotal, open-label, single arm, multicenter, Phase II study evaluating ide-cel in patients with relapsed and refractory multiple myeloma (R/RMM) – met the primary endpoint and key secondary endpoint. Bristol-Myers Squibb says ide-cel represents a potential first-in-class and best-in-class BCMA CAR T in multiple myeloma.
The investigational agent CC-486 is being studied as maintenance therapy in a broad population of patients with front-line, newly diagnosed acute myeloid leukemia (AML) who have achieved remission with intensive induction chemotherapy. Bristol-Myers Squibb regards CC-486 as a pivotal clinical asset, with a survival benefit demonstrated in the 1L AML maintenance setting.
The New York-based drug firm is awaiting U.S. marketing clearance for an oncology product joining together two blockbuster medicines. In January 2020, the company announced that the FDA accepted for priority review the supplemental Biologics License Application (sBLA) for Opdivo plus Yervoy for the first-line treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations. The FDA action date is May 15, 2020. U.S. regulators also accepted Bristol-Myers Squibb’s sBLA and granted Breakthrough Therapy Designation for Opdivo plus Yervoy for patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib, with an FDA action date of March 10, 2020.
Celgene and partner Acceleron Pharma received U.S. approval in November for Reblozyl as a treatment for anemia in adult patients with beta thalassemia who require regular red blood cell transfusions. Reblozyl is awaiting FDA approval for the treatment of anemia in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who have ring sideroblasts and require red blood cell (RBC) transfusions, with an FDA action date of April 4, 2020. Encouraging early clinical data has been reported for Reblozyl representing significant new life cycle opportunities for the medicine in chronic anemias.
In February 2020, Bristol-Myers Squibb and partner BioMotiv announced the launch of Anteros Pharmaceuticals. The new biotechnology company is focused on developing a new class of medicines for fibrotic and other inflammatory diseases.
GLAXOSMITHKLINE
Significant progress was made on GlaxoSmithKline’s long-term priorities during 2019. According to company executives, this progress included driving a new innovation approach. “2019 saw our new approach to R&D come to life and drive significant progress,” says GlaxoSmithKline’s executive team.
GlaxoSmithKline in February 2020 announced plans to split into two new companies via a two-year separation program: a leading biopharma company with R&D focused on science of the immune system, genetics and advanced technologies; and a leading Consumer Healthcare company with category leading power brands and innovation based on science and consumer insights. GSK is focused on investment in R&D and future growth drivers. According to GSK Chief Scientific Officer Dr. Hal Barron, the company is strengthening the R&D pipeline through a concentration on science related to the immune system, the use of human genetics and advanced technologies.
Three major drug approvals emerged during 2019 – Dovato, Dectova, and Nucala pre-filled syringe. In the meantime, the company bolstered the product pipeline, including 8 drug submissions with regulatory health bodies: Zejula in 1L ovarian cancer; belantamab mafodotin in 4L+ multiple myeloma; dostarlimab in dMMR/MSI-H recurrent endometrial cancer; cabotegravir + rilpivirine in HIV; fostemsavir in HIV; Trelegy in asthma; Zejula in 4L+ HRD+ ovarian cancer; and daprodustat in anemia (in Japan). GlaxoSmithKline reported six positive data read-outs from pivotal studies: CAPTAIN (Trelegy), PRIMA (Zejula), DREAMM-2 (belantamab mafodotin), GARNET (dostarlimab), HES (Nucala), BLISS-LN (Benlysta). Additionally, four new assets advanced into pivotal Phase II/III trials: otilimab in rheumatoid arthritis (RA), gepotidacin in uncomplicated urinary tract infection (uUTI) and urogenital gonorrhea (GC), bintrafusp alfa in biliary tract cancer (BTC), and ICOS in head and neck squamous cell carcinoma (HNSCC).
GlaxoSmithKline’s pipeline updates during 2019 included 20 progressions/additions and 3 approvals. In the 12-month period, GSK achieved 23 positive pipeline milestones. As of February 2020, the company’s R&D pipeline contained 39 medicines and 15 vaccines.
GSK has outlined a path to drive the company’s growth outlook to 2022 and beyond. Helping to support this plan in addition to new medicines already approved for use are various pipeline assets expected to reach the marketplace by 2022, including belantamab mafodotin, cabotegravir+ rilpivirine, fostemsavir and dostarlimab. For 2023 and beyond, the pivotal new drug candidates expected to help propel the growth trajectory are ‘165 otilimab (aGM-CSF), ‘609 (ICOS agonist), ‘944 gepotidacin (topoisomerase IV inhibitor) and bintrafusp alfa (TGFβ trap/anti-PDL1), each of which have recently entered pivotal studies; as well as ‘863 daprodustat (HIF-PHI) and CAB PrEP (HIV).
As of January 2020, the company has advanced four new assets in pivotal studies. Otilimab is an aGM-CSF in rheumatoid arthritis, with recruitment for Phase III trials under way including H2H vs current treatments. The antibiotic gepotidacin is undergoing Phase III development for uUTI and GC. The novel MoA is active against most resistant bacteria via an oral formulation, with the potential to transform the treatment landscape for patients with limited therapeutic options. A pivotal study in 2L biliary tract cancer is under way for bintrafusp alfa in biliary tract cancer, as well as a Phase II trial versus pembrolizumab in 1L PD-L1+ NSCLC. The bifunctional fusion protein is targeted at TGF-beta and PD-L1 pathways, and is being jointly developed by Merck KGaA. The fourth new asset in pivotal studies is GSK ‘609, a humanized IgG4 agonist antibody targeted at ICOS and low/no T-cell depleting effects. GSK ‘609 has demonstrated activity in both monotherapy and PD-1 combination, and the INDUCE-3 pivotal study (Phase II/III trial with registrational potential) in HNSCC was initiated in combination with pembrolizumab.
GSK is additionally focused on improving the company’s lifecycle management, strengthening the partnership between Development and Commercial. Medicines in this area that are nearing key development updates for new indications include Benlysta for lupus nephritis; Nucala for HES, COPD and NP; and Trelegy for asthma.
Benlysta has the potential to become the first FDA-approved therapy for lupus nephritis, which is a common and serious complication of systemic lupus erythematosus (SLE). Positive headline results have been reported in the Phase III BLISS-LN study, with primary and all secondary endpoints met. Regulatory submission is on pace for 1H 2020.
Nucala represents the first treatment to show significant reduction in flares for patients with hypereosinophilic syndrome (HES). A pivotal HES study demonstrated 50 percent reduction in flares, and a regulatory filing is on schedule for first-half 2020. The first patient was dosed in a pivotal COPD study for Nucala. Meanwhile, a pivotal nasal polyps (NP) study aims to be the first Phase III trial to demonstrate impact of an anti-IL-5 on NP, with results expected to be reported during first-half 2020.
A supplemental NDA for Trelegy was successfully submitted during October 2019, with a U.S. regulatory agency decision anticipated in 2020. Trelegy has the potential to be the first single inhaled triple therapy approved in the United States for treating asthma and COPD patients.
LILLY
Eli Lilly is undergoing an impressive growth phase, including an 8 percent year-over-year revenue hike for 2019, reflecting increased investments in the late-stage pipeline and recently launched medicines. “Lilly is in the early phase of an exciting period of growth for the company. The combination of strong revenue growth from our newer medicines and prudent expense control across our business enabled Lilly to invest more in our R&D pipeline and still deliver impressive earnings growth in the fourth quarter and full-year 2019,” says David A. Ricks, Lilly’s chairman and CEO. “We look forward to continuing this progress in 2020, as our scientists work to expand our portfolio of innovative medicines to offer new treatment options for patients in the areas of diabetes, oncology, immunology, and neuroscience.”
Industry analysts hail tirzepatide/LY3298176, undergoing Phase III studies for diabetes and obesity, as the company’s potentially most lucrative late-stage pipeline prospect. The novel dual gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist combination is projected to attain global blockbuster sale status by 2024.
Another anticipated new drug compound for Lilly is selpercatinib (LOXO-292), which was acquired through the purchase of Loxo Oncology. The highly selective and potent, oral investigational new medicine is in clinical development for treating patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations take place across multiple tumor types with varying frequency. Selpercatinib was designed to inhibit native RET signaling and anticipated acquired resistance mechanisms.
The Food and Drug Administration granted priority review for the New Drug Application for selpercatinib in January 2020 for the treatment of patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancer. The U.S. regulatory agency filed the NDA and set a Prescription Drug User Fee Act (PDUFA) date for third-quarter 2020.
Lilly announced the opening of the LIBRETTO-531 clinical trial [NCT04211337] for selpercatinib for treatment-naïve RET-mutant (MTC) patients in December 2019. This is the second Phase III study to open for selpercatinib. Earlier in December, Lilly opened the first-ever randomized Phase III trial in treatment-naïve RET fusion-positive NSCLC.
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) during January 2020 issued a positive opinion for Lilly’s new mealtime insulin for treating adults with diabetes as part of a multiple daily injection regimen or delivered by an insulin pump. A novel, fast-acting formulation of insulin lispro, URLi (LY900014) is being tested for use in adults with type 1 and type 2 diabetes to reduce blood glucose. The company filed URLi for approval with regulatory authorities in the United States and Japan.
Lilly and Incyte announced during fourth-quarter 2019 that baricitinib met the primary endpoint in two Phase III studies. BREEZE-AD4 assessed the safety and efficacy of baricitinib in combination with topical corticosteroids for treating adult patients with moderate to severe atopic dermatitis who were inadequate responders, intolerant or had contraindication to treatment with cyclosporine. BREEZE-AD5 tested the safety and efficacy of baricitinib for treating adults with moderate to severe atopic dermatitis.
In another Q4 2019 development, Lilly unveiled a definitive deal to acquire Dermira for $1.1 billion in an all-cash transaction. The biopharmaceutical company is dedicated to developing new therapies for chronic skin conditions. The pending acquisition will expand Lilly’s immunology pipeline with the addition of lebrikizumab. The novel, investigational, monoclonal antibody is designed to bind IL-13 with high affinity and is being tested in a Phase III clinical development program for treating moderate-to-severe atopic dermatitis in adolescent and adult patients, ages 12 years and older.
MERCK
The late-stage pipeline for Merck is one of the deepest in the industry. In a move toward Merck reaching management’s aspiration of being the premier research-intensive biopharmaceutical company, in early February 2020 a spin-off was unveiled. Merck plans to concentrate on key growth pillars through the spinoff of Women’s Health, Trusted Legacy Brands and Biosimilars Products into a new, yet-to-be-named, independent, publicly traded company (NewCo.). Merck will continue to benefit from strong growth across the drug firm’s current key pillars of Oncology, Vaccines, Hospital and Animal Health, while remaining fully dedicated to investing in R&D in pursuit of breakthrough innovations across all areas of science and to driving value from the extensive late-stage pipeline. As a premier research-intensive biopharma company, Merck will continue management’s pursuit to advance the prevention and treatment of diseases that threaten people and communities around the globe.
Merck continues to advance the development programs for the mega-brand Keytruda (pembrolizumab), the company’s anti-PD-1 therapy; Lynparza (olaparib), a PARP inhibitor being jointly developed and jointly commercialized with AstraZeneca; and Lenvima (lenvatinib mesylate), an orally available tyrosine kinase inhibitor being jointly developed and co-commercialized with Eisai.
Merck presented results from an exploratory analysis of the pivotal Phase III KEYNOTE-042 study demonstrating that Keytruda improved overall survival as monotherapy for the first-line treatment of metastatic NSCLC regardless of KRAS mutational status.
Merck reported that the Phase III KEYNOTE-604 trial evaluating Keytruda in combination with chemotherapy significantly improved progression-free survival (PFS) versus chemotherapy alone in the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).
The U.S. FDA during January 2020 accepted a supplemental New Drug Application via priority review seeking marketing clearance of Lynparza in combination with bevacizumab for the maintenance treatment of women with advanced ovarian cancer whose disease showed a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab. The sNDA filing was based on results from the Phase III PAOLA-1 study. A Prescription Drug User Fee Act (PDUFA) date is scheduled for the second quarter of 2020.
Additionally for Lynparza in January, Merck announced filing acceptance for priority review by the FDA for a supplemental NDA for treating patients with metastatic castration-resistant prostate cancer (mCRPC) and deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations, who have progressed following prior treatment with a new hormonal agent based on results from the Phase III PROfound trial. A PDUFA date is slated for the second quarter of 2020.
Merck and AstraZeneca received filing acceptance for priority review by the FDA of a New Drug Application (NDA) for selumetinib, an oral MEK 1/2 inhibitor, for the treatment of certain pediatric patients with neurofibromatosis Type 1 (NF1). The NDA submission was based on the results from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP)-sponsored SPRINT Phase II Stratum 1 study. A PDUFA date is on tap for second-quarter 2020. If approved for marketing, selumetinib would become the first medicine indicated for the treatment of certain pediatric patients with NF1 plexiform neurofibromas.
Recarbrio was accepted by the FDA for priority review as a treatment of adult patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by certain susceptible Gram-negative microorganisms. The PDUFA date is scheduled for June 4, 2020.
Merck reported that the Phase III VICTORIA trial assessing vericiguat, a soluble guanylate cyclase (sGC) stimulator being jointly developed with Bayer, met the primary composite endpoint in reducing the risk of heart failure hospitalization or cardiovascular death in patients with worsening chronic heart failure with reduced ejection fraction (HFrEF) versus placebo when given in combination with available heart failure therapies.
A pair of recent transactions have bolstered Merck’s product pipeline. Merck acquired ArQule, diversifying the company’s oncology portfolio with the expansion into targeted therapies that treat hematological malignancies with the addition of ARQ 531. The novel, oral Bruton’s tyrosine kinase (BTK) inhibitor is undergoing Phase II development, among other candidates. The $2.7 billion acquisition closed during January 2020 after being initially reported on Dec. 9.
“ArQule’s focus on precision medicine has yielded multiple clinical-stage oral kinase inhibitors that have novel and important properties,” noted Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “This acquisition strengthens Merck’s pipeline with the addition of these strategic assets including, most notably, ARQ 531, a compelling candidate for the treatment of B-cell malignancies.”
Merck entered into a strategic oncology collaboration with Taiho Pharmaceutical and Astex Pharmaceuticals concentrated on the development of small molecule inhibitors against several drug targets, including the KRAS oncogene, which are currently being studied for the treatment of cancer.
NOVARTIS
Novartis has one of the industry’s most competitive pipelines with more than 200 projects undergoing clinical development. Many of these projects, which include new molecular entities as well as additional indications and different formulations for marketed products, are for medicines that could significantly advance treatment standards for patients around the globe.
The Swiss company has about 114 projects in Phase I/II development, 37 projects in Phase III trials, and 13 products in the registrational stage. According to industry analyst reports, the drug company is projected to rank No. 1 in estimated 2024 sales from products launched between 2019-24.
Novartis has long been highly regarded as an industry innovator. Novartis has 16 advanced platform therapies undergoing clinical development. An impressive 90 percent of the product pipeline represents first-in-class/first-in-indication status. Eighty percent of the company’s pipeline targets areas of high unmet need.
The Novartis pipeline is poised to generate more success during 2020 after 2019 produced an unprecedented 5 NME approvals of potential blockbusters, 30-plus major submissions, and more than 30 clinical data readouts. Beginning with 2020, Novartis anticipates 15 ongoing/upcoming major launches, 80-plus major submissions planned to 2022, and more than 50 late-stage programs. “Looking ahead, we expect to sustain our long-term growth and margin expansion driven by our in-market growth drivers and the 15 ongoing or upcoming major launches, while advancing our rich pipeline,” says CEO Vas Narasimhan.
Management expects the company to sustain long-term growth with a robust pipeline of 25+ potential blockbusters as highlighted at the Novartis R&D Day on Dec. 5, 2019. Of the 60 projects in Phase II, 10+ are expected to advance into Phase III or pivotal studies in each of 2020 and 2021. Novartis says emerging assets addressing areas of high unmet need include iscalimab in transplant and Sjögren’s syndrome, LNP023 in renal diseases and PNH, MBG453 in MDS, and TQJ230 in cardiovascular risk reduction. Expected near-term launches include ofatumumab in relapsing MS, fevipiprant in asthma, the radioligand therapy Lu-PSMA-617 in prostate cancer, Adakveo in sickle cell disease and canakinumab in lung cancer. Novartis bolstered the company’s product pipeline in January 2020 with the completed purchase of The Medicines Company. Through the deal, Novartis added inclisiran, a potentially transformational cholesterol-lowering therapy to address cardiovascular disease. One of the most highly touted pipeline prospects in the industry, inclisiran was submitted for FDA approval in December 2019 for use in secondary prevention patients with atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia (FH). If cleared for marketing, inclisiran would be the first LDL-lowering siRNA medicine that can be administered twice yearly by subcutaneous injection and integrate seamlessly into routine healthcare visits. Fierce Pharma ranked the new drug candidate as the third most anticipated launch of 2020, with estimated 2024 sales of nearly $1.53 billion.
A comprehensive Phase III inclisiran program demonstrated potent and durable reduction of >50 percent in LDL-C on top of standard of care, with excellent safety profile for the new drug compound. The acquisition of The Medicines Co. adds a potentially soon-to-launch, first-in-class investigational product, allowing Novartis to leverage significant synergies with existing global cardiovascular commercial capabilities.
According to Narasimhan, “Acquiring The Medicines Company and inclisiran gives Novartis a unique opportunity to open up a new chapter on the treatment of the world’s leading cause of mortality and disability with a vaccine-like approach. It’s a significant step forward on our journey to focus the company, to reimagine medicine, and to bend the curve of life.”
Ofatumumab (OMB157) was filed with FDA and EMA (January) regulators for treating relapsing multiple sclerosis. If approved, ofatumumab will potentially become a treatment for a broad RMS population and the first B-cell therapy that is easy to start and manage in a monthly self-administered injection at home. Clinical data from the Phase III ASCLEPIOS I and II studies show ofatumumab was superior to the blockbuster brand Aubagio (teriflunomide) in patients with relapsing forms of MS (RMS).
Novartis acquired rights for ofatumumab from Genmab in all indications, including MS, during December 2015. The fully human anti-CD20 monoclonal antibody (mAb) works by binding to the CD20 molecule on the B-cell surface and inducing potent B-cell lysis and depletion.
The U.S. FDA accepted and granted priority review in February 2020 for Novartis’ New Drug Application for capmatinib (INC280). The MET inhibitor is being studied as a treatment for first-line and previously treated patients with locally advanced or metastatic MET exon 14 skipping (METex14) mutated non-small cell lung cancer (NSCLC). If cleared for approval, capmatinib would represent the first therapy to specifically target METex14 mutated advanced lung cancer, a type of lung cancer with a particularly poor prognosis.
Novartis, a leader in immuno-dermatology, reported during January 2020 mechanistic study results demonstrating ligelizumab is more effective at inhibiting the major pathogenic IgE/FcεRI pathway in chronic spontaneous urticaria (CSU), than current therapy Xolair (omalizumab). According to the company, ligelizumab can bind to IgE with an 88-fold higher affinity than the blockbuster medicine Xolair. The data demonstrate that ligelizumab and Xolair recognize and bind differently to IgE, with ligelizumab resulting in a significantly enhanced blockade of IgE/FcεRI signaling.
REGENERON PHARMACEUTICALS
Pipeline progress is perhaps the most important catalyst for biotech stocks, according to analysts for The Motley Fool. Regeneron CEO Leonard Schleifer stated during February, “In 2020, we are focused on driving continued growth with Eylea, Dupixent, and Libtayo and anticipate new regulatory approvals and submissions across our portfolio.”
Motley Fool analysts say Regeneron has plenty of developments taking place during 2020. “The company expects to win FDA approval by May 26, 2020 for Dupixent in treating atopic dermatitis. It should report results from a late-stage study of the drug in treating asthma. Regeneron also plans to announce results later this year from clinical studies evaluating Libtayo in non-small-cell lung cancer and basal cell carcinoma, as well as results from clinical studies of new drugs REGN1979, REGN5458, and fasinumab.”
Regeneron has 22 product candidates undergoing clinical development, including five of the company’s FDA-approved products being studied for additional indications, such as the eye-disease drug Eylea.
Regeneron announced on Feb. 8, 2020, positive two-year results from the Phase III PANORAMA study investigating Eylea (aflibercept) Injection 2 mg (0.05 mL) in patients with moderately severe to severe non-proliferative diabetic retinopathy (NPDR). The new data highlight the significance of proactive Eylea therapy as more than half of untreated patients in PANORAMA developed vision-threatening events over two years. The high-dose aflibercept development program is under way with Phase III trials scheduled for 2020.
For the blockbuster brand Dupixent (dupilumab), FDA accepted for priority review the supplemental Biologics License Application for children aged 6 to 11 years with moderate-to-severe atopic dermatitis, with a target action date of May 26, 2020. Meanwhile, a Marketing Authorization Application (MAA) for children aged 6 to 11 years with moderate-to-severe atopic dermatitis was recently filed in the European Union. Additionally, a Phase II/III trial in bullous pemphigoid and Phase III studies in prurigo nodularis and chronic spontaneous urticaria were initiated during fourth-quarter 2019.
A Phase II/III study in bullous pemphigoid and Phase III studies in prurigo nodularis and chronic spontaneous urticaria were initiated for Dupixent during fourth-quarter 2019. Dupilumab is being jointly developed by Regeneron and Sanofi under a global collaboration deal.
For the cancer drug Libtayo, a Phase II neoadjuvant study in cutaneous squamous cell carcinoma (CSCC) was initiated.
In December 2019, Regeneron revealed updated results from the initial clinical study for REGN1979 – a bispecific antibody targeting CD20 and CD3 – in patients with non-Hodgkin lymphoma. The potentially pivotal Phase II trial has been expanded to include patients with diffuse large B-cell lymphoma (DLBCL) and other non-Hodgkin lymphomas.
For REGN5458, a bispecific antibody targeting BCMA and CD3, the company in December 2019 unveiled positive preliminary results from an initial clinical trial in patients with relapsed or refractory multiple myeloma.
Regeneron also announced during December positive top-line results from a Phase II trial in paroxysmal nocturnal hemoglobinuria (PNH) for pozelimab, an antibody to C5.
Garetosmab, an antibody to Activin A, provided encouraging results as reported during January 2020 in a Phase II trial in fibrodysplasia ossificans progressiva (FOP).
The New England Journal of Medicine published results from the randomized, controlled PALM study demonstrating that Regeneron’s multi-antibody therapy REGN-EB3 and another agent provided the highest overall survival rates among four investigational treatments for Ebola.
On the business-development side, Regeneron and partner Sanofi announced their intent to restructure the companies’ antibody collaboration for Kevzara and Praluent and enter into a royalty-based deal. Sanofi is expected to gain sole worldwide rights to Kevzara and sole rights to Praluent outside of the United States. Regeneron is expected to acquire sole U.S. rights to Praluent. Each company will be solely responsible for funding development and commercialization expenses in their respective territories. The proposed pact, which is expected to be finalized during first-quarter 2020, will not impact the parties’ existing collaboration relating to Dupixent and REGN3500.
Regeneron entered into a research collaboration and option licensing agreement with Vyriad to discover and develop new oncolytic (cancer-killing) virus-based treatments for various forms of cancer.
During early February 2020, Regeneron announced an expanded deal with the U.S. Department of Health and Human Services (HHS) to develop new treatments combating the novel coronavirus, 2019-nCoV, which was recently declared a global public health emergency by the World Health Organization. The HHS and Regeneron Other Transaction Agreement (OTA), initially established during 2017, is focused on discovery, R&D and manufacturing of a portfolio of antibodies targeting up to 10 pathogens that pose significant risk to public health, now including the Influenza virus and 2019-nCoV. This effort uses Regeneron’s proprietary VelociSuite technologies – including the VelocImmune platform that uses a unique genetically engineered mouse with a humanized immune system that can be challenged with all or parts of a virus of interest – to facilitate swift identification, preclinical validation and development of promising antibody candidates. The company’s rapid response VelociSuite technologies are particularly well-suited for use in quickly-developing outbreak situations, as was done for Ebola.
ROCHE
The industry’s leading R&D spender, Roche is expected to maintain the No. 1 or 2 ranking in research and development expenditure in the years to come.
During December 2019, Roche completed the acquisition of Spark Therapeutics. Philadelphia-based Spark Therapeutics is a fully integrated, commercial company dedicated to discovering, developing and delivering gene therapies for genetic diseases, including blindness, hemophilia, lysosomal storage disorders and neurodegenerative diseases. Spark Therapeutics continues to operate as an independent company within the Roche Group.
Spark Therapeutics’ lead clinical asset is SPK-8011, a novel gene therapy for the treatment of hemophilia A, which was expected to start Phase III in 2019. Spark Therapeutics additionally has SPK-8016 in a Phase I/II study aimed at addressing the hemophilia A inhibitor population. Spark Therapeutics was the first company to receive FDA approval for a gene therapy for a genetic disease during 2017 with Luxtruna (voretigene neparvovec-rzyl), a one-time gene therapy product indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Other clinical assets from Spark include SPK-9001, an investigational gene therapy for the potential treatment of hemophilia B in Phase III, and SPK-7001 for choroideremia in Phase I/II. The company has additionally been developing SPK-3006 for Pompe disease and SPK-1001 for CLN2 disease (a form of Batten disease) that were anticipated to be ready for clinical development in 2019, and preclinical programs for Huntington’s disease and Stargardt disease.
A New Drug Application is undergoing FDA priority review for risdiplam, which could be a game changer in the marketplace for spinal muscular atrophy (SMA). If cleared for marketing, the orally administered liquid risdiplam would be the first at-home administered medicine for people living with SMA. An FDA approval decision is set to occur by May 24, 2020. Roche leads the clinical development of risdiplam as part of a collaboration with the SMA Foundation and PTC Therapeutics, and would commercialize the medicine in the U.S. marketplace. Industry analysts estimate that risdiplam could generate $2.5 billion to $3 billion in annual peak sales.
Roche during February 2020 presented one-year data from the pivotal Part 2 of SUNFISH, a global placebo-controlled trial testing risdiplam in people aged 2-25 years with Type 2 or 3 SMA. The study demonstrated that change from baseline in the primary endpoint of the Motor Function Measure scale (MFM-32)1 was significantly greater in people treated with risdiplam, versus placebo (1.55 point mean difference; p=0.0156). In the first placebo-controlled trial to include adults with SMA, the study demonstrated risdiplam improved or stabilized motor function, and medically meaningful and statistically significant results in primary and key secondary endpoints were achieved.
Roche executives say the pipeline during fourth-quarter 2019 delivered a strong, constant flow of positive study results – the basis for the company’s future growth. For example, positive results from the Phase III IMbrave150 study assessing Tecentriq in combination with Avastin demonstrated statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS), compared with sorafenib, in people with unresectable hepatocellular carcinoma (HCC) who have not received prior systemic therapy. Roche proceeded to file a supplemental Biologics License Application to the FDA during January for Tecentriq in combination with Avastin for the most common form of liver cancer.
In other favorable Q4 2019 results, the Phase II Nobility study of Gazyva/Gazyvaro for adults with proliferative lupus nephritis met the primary endpoint with the medicine in combination with standard of care (mycophenolate mofetil or mycophenolic acid and corticosteroids), showing superiority compared to placebo plus standard of care.
Balovaptan (RG7314) is projected to eventually reach the marketplace, and exceed $1 billion in annual sales by 2025. A small molecule antagonist of the V1A vasopressin receptor (V1AR) in the brain, balovaptan is being tested for the potential treatment of Autism Spectrum Disorders (ASD).
TAKEDA PHARMACEUTICAL/SHIRE
Aided by the completed acquisition of Shire at the beginning of last year, 2019 marked a watershed year for Takeda Pharmaceutical. Eighteen assets (including approved products with ongoing R&D investment) were added to Takeda’s clinical pipeline.
Additionally, the acquisition led to the creation of a Rare Diseases Therapeutic Area for Takeda, along with access to world-class gene therapy capabilities.
As of November 2019, the Takeda pipeline included 17 new molecular entities in Phase II and Phase III development. The NMEs represent potentially curative novel mechanisms (e.g. TAK-101, Orexin2R-ag, CAR-NK). Takeda has generated momentum in the area of cell therapies, including a new partnership with MD Anderson for an off-the-shelf CAR NK-cell therapy platform.
According to Takeda, as of November the company had 8 potential best-in-class/first-in-class new drug compounds, including relugolix (Takeda granted Myovant Sciences an exclusive, worldwide license to develop and commercialize relugolix, excluding Japan and certain other Asian countries). The portfolio consisted of 40 NME clinical-stage assets, with about 50 percent of the pipeline granted Orphan Drug designation. The company’s diversified modalities in research include 70 percent representing biologics, cell & gene therapies, peptides & oligonucleotides, and micribiome and other modalities versus 30 percent for small molecules.
Takeda management anticipates the following potential NME pivotal study starts (assuming successful data readouts and projected replenishment): two in fiscal year 2020; 11 in fiscal year 2021; eight in FY 2022; six in FY 2023; and four in 2024. The company is leveraging partnerships to access the best clinical or preclinical innovation.
Takeda executives say, “We have a rich pipeline of innovative NMEs in Wave 1 with target launch by end of fiscal year 2024. Our early-stage NMEs and next-generation platforms in Wave 2 provide sustained growth beyond FY 2025. Fourteen global brands and 12 Wave 1 pipeline assets position Takeda for sustainable revenue growth. The Wave 1 new molecular entities have the potential to deliver more than $10 billion in aggregate peak sales.”
The primary target areas for each of the two waves are oncology, rare diseases (immunology/hematology/metaBOLIC) neuroscience, gastroenterology, and vaccines. Takeda’s business portfolio in those five areas accounts for 79 percent of the company’s total revenue.
For Takeda’s Wave 1 NMEs during the company’s FY 2019 Q3, Phase III studies started for TAK-788 in treating naïve NSCLC and pevonedistat (TAK-924) in unfit AML. Phase III data readouts included part 2 of the TIDES trial for the dengue vaccine candidate TAK-003. Takeda’s investigational live-attenuated tetravalent dengue vaccine candidate is being evaluated in healthy children and adults, in dengue endemic and non-endemic countries. TAK-003’s clinical development program consists of five Phase III studies.
Takeda cultivates the best science through differentiated partnerships, according to the management team. Takeda is involved in 110 research collaborations, 50 in-licensing deals, 20 joint development partnerships and 25 new formations representing a total value in public and private equity exceeding $1 billion.
According to published reports, Takeda is looking at bringing nearly a dozen new treatments to market by 2024. Those products are targeting conditions such as cytomegalovirus infections, the rare disease Hunter Syndrome, and complications of premature birth. Company management believes that these therapies can generate combined peak sales of $10 billion.