Pipelines Report 2023: innovation and diversification
Med Ad News has identified 10 product pipelines that are making significant headway in terms of the discovery and development of innovative products and first-in-class medicines. Ranging from biopharma goliaths to mid-tier and up-and- coming players in the industry, these companies are bringing to market blockbuster brands and targeted therapies that are fundamentally transforming the healthcare arena.
By Andrew Humphreys • [email protected]
Innovation remains strong in the drug development sector as the industry continues to produce a strong crop of novel new therapeutics, despite 2022 being a down year in terms of the amount of new product approvals given the green light by the U.S. Food and Drug Administration – marking a third consecutive year of decline.
“While R&D productivity remained a challenge for pharma in 2022 – the FDA only approved 22 NMEs and 15 BLAs during the year – we might expect the approval rate to recover in 2023 to pre-pandemic levels. While oncology remains a key focus for the industry, as the latest edition of Drugs to Watch shows, we can also expect to see approvals and launches for medicines in other disease areas,” says Mike Ward, Clarivate’s global head of Life Sciences and Healthcare Thought Leadership.
Innovation has not slowed as new modalities including antibody-drug conjugates, bispecific proteins, and cell and gene therapies reportedly accounted for about one third of last year’s approvals. Also, during 2022 the amount of approved biologics kept pace with the total of approved small molecules for the first time ever. In addition, the amount of gene therapies approved for the U.S. market more than doubled during 2022 from the previous tally of two, with the marketing clearance of three new agents for inherited diseases during the second half of last year in what is one of the most exciting areas of drug development. Meanwhile, 2022 marked the arrival of the 40th biosimilar approval in the United States as CDER cleared for marketing seven new biosimilars, including two that are interchangeable.
CDER identified 20 of the 37 novel drugs approved during the course of 2022 (54 percent) as first-in-class. CDER met or exceeded its PDUFA goal dates for 36 of the 37 novel drugs approved (97 percent) during 2022. Additionally, CDER approved 28 of the 37 novel approvals (76 percent) on the first cycle. Also, 24 of the 37 CDER novel drug approvals (65 percent) used one or more of these expedited programs: fast track, breakthrough therapy, priority review, and accelerated approval.
According to Clarivate analysis, despite the many urgent challenges life science companies will face in 2023, from patent cliffs to capital investment, the industry is on the cusp of unlocking revolutionary technologies that could greatly advance human health.
“We are driven by science, united by science, and every day, we push the boundaries of science to deliver life-changing medicines,” according to AstraZeneca. “Guided by our ‘Growth Through Innovation’ strategy, we are committed to investing in four areas, which will help us in our aspiration to create the greatest and swiftest impact on disease.”
The AstraZeneca pipeline forms a robust portfolio of investigational therapies in varied stages of clinical development. “Our unique scientific capabilities enable us to deliver what we believe to be one of the most productive pipelines in the industry,” company officials say.
AstraZeneca had 179 projects in the company pipeline, including 13 new molecular entities in late-stage development, as of November 10, 2022. AstraZeneca’s R&D focus areas are oncology; cardiovascular, renal & metabolism; respiratory & immunology; vaccines & immune therapies; neuroscience; and rare diseases.
“Our ambition is to push the boundaries of science to change the practice of medicine and transform the lives of patients living with cancer,” company management says. During January 2023, AstraZeneca completed the acquisition of Neogene Therapeutics, a global clinical-stage biotech company pioneering the discovery, development, and manufacturing of next-generation T-cell receptor therapies (TCR-Ts). Now a wholly owned subsidiary of AstraZeneca, Neogene is advancing a pipeline of fully individualized TCR therapies as well as TCR therapies targeting shared neoantigens, including mutated KRAS (mKRAS) and mutated TP53 (mTP53).
Identified as a 2023 Drug to Watch by Clarivate analysts, the investigational oral treatment capivasertib is undergoing Phase III studies for treating multiple subtypes of breast cancer, prostate cancer, and a Phase II study for hematologic malignancies. A potent, selective adenosine triphosphate (ATP)-
competitive inhibitor of all three AKT isoforms (AKT1/2/3), capivasertib is being explored as a monotherapy and in combination with existing therapies in tumors harboring alterations in the AKT pathway (PI3K/AKT/PTEN), and in tumors reliant on signaling via this pathway for survival. The drug candidate was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).
Detailed results from the CAPItello-291 Phase III study demonstrated capivasertib in combination with AstraZeneca’s Faslodex (fulvestrant) showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to placebo plus Faslodex in patients with hormone receptor (HR)-positive, HER2-low or negative, locally advanced or metastatic breast cancer, following recurrence or progression on, or after, endocrine therapy (with or without a CDK4/6 inhibitor).
“AstraZeneca is building a cell therapy portfolio that aims to empower and equip the immune system’s T cells to more effectively fight cancer.” Management also says the company is building on the work already performed in blood cancers where chimeric antigen receptor T-cell (CAR-T) therapies, a form of living medicine created by isolating and modifying a patient’s T cells to target their specific tumor, are being used to treat certain hematological malignancies. AstraZeneca’s research teams are exploring new approaches to target and arm CAR-Ts to increase their effectiveness in solid tumors by overcoming the immune-suppressive tumor microenvironment. Looking to the future, the company is working to engineer next-generation cell therapies, where physicians could potentially choose from a library of off-the-shelf
patient-ready therapies already developed from the cells of healthy donors.
“CVRM (Cardiovascular, Renal, and Metabolism) is one of our main therapy areas because science continues to uncover commonalities between metabolism, heart failure, arterial vascular disease, and renal disease – four distinct but interrelated areas,” AstraZeneca says. “Our bold ambition is to stop, reverse, and cure CVRM diseases by maximizing our medicines, delivering innovative solutions and advancing our pipeline. We are fundamentally transforming CVRM care. To do this, we are unraveling the underlying causes of these diseases by identifying novel targets linked to disease biology to create the next generation of therapeutics.”
With more than 25 therapies and therapy combinations throughout the company’s product pipeline, AstraZeneca seeks to bring real science and development to combating life-threatening conditions. “Our first-class scientific research today is setting the stage for our pioneering approach in the fields of disease regression and organ regeneration, putting us a step closer to making science fiction a reality.”
AstraZeneca’s Phase III projects for CVRM as of November 2022 were Andexxa (ALXN2070) for acute major bleed; eplontersen for patients with hereditary or wild-type transthyretin-mediated amyloid cardiomyopathy (ATTR CM) and patients with hereditary transthyretin-mediated amyloid polyneuropathy (hATTR-PN); and roxadustat for anemia in chronic kidney disease/end-stage renal disease.
AstraZeneca entered into a definitive deal in January 2023 to acquire CinCor Pharma. The U.S.-based clinical-stage biopharmaceutical company is concentrated on developing novel treatments for resistant and uncontrolled hypertension as well as chronic kidney disease. Management says the acquisition will bolster AstraZeneca’s cardiorenal pipeline with the addition of CinCor’s candidate drug baxdrostat (CIN-107), an aldosterone synthase inhibitor (ASI) for blood pressure lowering in treatment-resistant hypertension. According to the company, baxdrostat represents a potentially leading next-generation ASI as it is highly selective for aldosterone synthase and spares the cortisol pathway in humans. The opportunity additionally brings the potential for combination with AstraZeneca’s Farxiga and complements the company’s strategy to provide added benefit across cardiorenal diseases, where there is a high unmet medical need.
AstraZeneca says the company is entering an era of unprecedented potential to deliver scientific breakthroughs within asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and chronic cough. “Our portfolio of inhaled and biologic medicines, and our pipeline for the future, seek to address the challenges and vast unmet medical needs patients face today.”
Late-stage candidates for AZ’s respiratory & immunology therapy area as of November 2022 consisted of brazikumab for Crohn’s disease, Fasenra for severe uncontrolled asthma, PT027 for asthma, Saphnelo for systemic lupus erythematosus, and Tezspire for severe uncontrolled asthma.
In November 2022, PT027 (albuterol/budesonide) became the first rescue medication recommended for U.S. approval for people aged 18 years and older that has been demonstrated to reduce severe exacerbations.
Another ambition of AstraZeneca is to develop and deliver transformative vaccines and antibodies, providing long-lasting immunity to millions of people, where the burden of disease is greatest. “During the COVID-19 pandemic, we played an important role as part of a truly global effort to respond to a new and unprecedented challenge. We will continue to advance science in vaccines and immune therapies and work with partners to drive improvements in public health and ensure our science reaches millions more people,” the company says.
Late-stage product development in this area as of November 2022 included Beyfortus (nirsevimab) for passive RSV immunization, Evusheld for the prevention and treatment of COVID-19, and the COVID vaccine Vaxzevria.
According to AstraZeneca, Alexion’s pioneering legacy in rare diseases is rooted in being the first to translate the complex biology of the complement system into transformative medicines. By driving innovative R&D across new disease targets and modalities, the company has diversified its pipeline into additional rare diseases during the last several years. “Today, as part of AstraZeneca, we are building bridges across our scientific platforms with a focus on bringing more innovative medicines to people worldwide.”
Late-stage pipeline projects for AstraZeneca in the rare diseases space include acoramidis (ALXN2060) for transthyretin amyloid cardiomyopathy, ALXN1840 for Wilson’s disease, CAEL-101 for AL amyloidosis, danicopan (ALXN2040) for paroxysmal nocturnal hemoglobinuria with extravascular hemolysis, and Koselugo/selumetinib for pediatric neurofibromatosis type-1.
“Biogen R&D is driven by the potential to transform the lives of patients. We work in disease areas with some of the greatest unmet need. We work relentlessly, knowing that bold new possibilities await discovery. As pioneers in neuroscience, we work toward those once-in-a-lifetime moments that could become a historic point in our pursuit of innovative treatments.” In pursuit of that, Biogen leverages the company’s knowledge of pathophysiological processes and disease characteristics to pioneer new potential treatments and advance other areas of research and development. Biogen is concentrated on advancing one of the industry’s most diversified pipelines in neuroscience that will transform the standard of care for patients in several fields of high unmet need.
The Biogen pipeline as of October 25, 2022, totaled 29 projects: one in Phase IV; 11 in Phase III; eight in Phase II; and nine in Phase I. Since that time, the humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody lecanemab has been approved for Alzheimer’s disease. On January 6, the FDA approved Leqembi (lecanemab-irmb) under the accelerated approval pathway as a 100 mg/mL injection for intravenous use directed against aggregated soluble (“protofibril”) and insoluble forms of amyloid beta (Aβ) for the treatment of Alzheimer’s disease (AD).
The U.S. approval is based on Phase II data that showed Leqembi reduced the accumulation of Aβ plaque in the brain, a defining feature of AD. Using the recently published data from the large global confirmatory Phase III study, Clarity AD, Biogen’s partner Eisai worked quickly to file a supplemental Biologics License Application (sBLA) to the FDA for approval under the traditional pathway.
According to Biogen and Eisai, treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical studies. The product was launched in the United States during January 2023, with Eisai and Biogen jointly commercializing and co-
promoting the product.
“This approval is also a recognition of the many scientists and doctors who have, over many years, patiently and persistently worked to find a treatment for this highly complex disease. Eisai and Biogen have collaborated for nearly a decade to advance research to improve the lives of those suffering from Alzheimer’s, and we know that this commitment must and will continue in the fight against Alzheimer’s disease,” states Biogen President and Chief Executive Officer Christopher A. Viehbacher.
The Marketing Authorization Application for lecanemab as a treatment for early Alzheimer’s disease was accepted by the European Medicines Agency (EMA) near the end of January 2023. Eisai filed for manufacturing and marketing approval of lecanemab to the Pharmaceuticals and Medical Devices Agency (PMDA) on January 16, 2023, with priority review granted by the Japanese Ministry of Health, Labour and Welfare (MHLW) by the end of that month. Eisai initiated the BLA filing of clinical data for lecanemab in China in December 2022.
Leqembi represents the most anticipated new drug launch of 2023, with Evaluate Pharma and Evaluate Vantage analysts predicting sales of $3 billion for the anti-amyloid-beta MAb for the year 2028.
Biogen and Sage Therapeutics announced in February 2023 the FDA’s accepted filing of an NDA for zuranolone as a treatment for major depressive disorder (MDD) and postpartum depression (PPD). Granted priority review, the investigational drug is being assessed as a rapid-acting, once-daily, 14-day oral short course treatment in adults with MDD and PPD. The PDUFA action date was set for August 5, 2023.
In the clinical development program, zuranolone has demonstrated rapid and sustained improvement of depressive symptoms with a generally well-tolerated and consistent safety profile. A neuroactive steroid, zuranolone has a novel mechanism of action as a positive allosteric modulator of GABA-A receptors. In people with depression, zuranolone may help to rapidly rebalance dysregulated neuronal networks to help improve brain function. The once-daily, 14-day, investigational drug targets brain networks responsible for functions including mood, arousal, behavior, and cognition.
The NDA filing includes clinical data from the LANDSCAPE and NEST development programs for zuranolone. The LANDSCAPE program includes five clinical trials of zuranolone in adults with MDD (MDD-201B, MOUNTAIN, SHORELINE, WATERFALL, and CORAL studies). The NEST program includes two trials of zuranolone in adult women with PPD (ROBIN and SKYLARK studies).
Zuranolone was the recipient of fast track designation by the FDA in 2017 and breakthrough therapy designation during 2018 for MDD. The U.S. regulatory agency additionally granted fast track designation for PPD in 2022.
Evaluate Pharma and Evaluate Vantage analysis projected global sales of $1.5 billion during 2028 for the GABA-A modulator for MDD and postpartum depression, assuming a mid-late 2023 U.S. approval.
The FDA was scheduled to convene a virtual meeting of the Peripheral and Central Nervous System Drugs Advisory Committee on March 22, 2023, for the NDA for tofersen. The investigational product is being developed for treating superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS).
SOD1-ALS is an ultra-rare genetic form of ALS that affects 330 people in the United States. SOD1-ALS is progressive, leads to the loss of everyday functions and is uniformly fatal. The company’s NDA for tofersen was accepted for priority review by the FDA under the accelerated approval pathway and was assigned a Prescription Drug User Fee Act action date of April 25, 2023.
The antisense drug is designed to bind to SOD1 mRNA, inducing its degradation by RNase-H to reduce SOD1 protein production. In addition to the continuing open-label extension of VALOR, tofersen is being evaluated in the Phase III ATLAS trial designed to assess whether tofersen can delay clinical onset when initiated in presymptomatic individuals with a SOD1 genetic mutation and biomarker evidence of disease activity. Biogen licensed tofersen from Ionis Pharmaceuticals under a collaborative development and license deal.
The EMA in December accepted the tofersen Marketing Authorization Application to treat the rare, genetic form of ALS. If cleared for marketing, tofersen would be the first treatment to target a genetic cause of ALS.
In other December news for Biogen, the FDA accepted for review the abbreviated Biologics License Application (aBLA) for BIIB800, a biosimilar candidate referencing Actemra (tocilizumab), an anti-
interleukin-6 receptor monoclonal antibody. The Roche medicine is indicated for several indications, including moderate-to-severe rheumatoid arthritis in adults as well as juvenile idiopathic polyarthritis and systemic juvenile idiopathic arthritis. “The FDA filing is supported by Phase III data from a comparative clinical trial demonstrating equivalent efficacy and a comparable safety and immunogenicity profile to the reference product,” noted Biogen Head of Global Biosimilars Ian Henshaw. “We look forward to working with regulators to bring this potential treatment option for people with immune mediated inflammatory diseases.”
At the beginning of 2023, Biogen and Alcyone Therapeutics entered into a license and collaboration deal to develop Alcyone’s ThecaFlex DRx System, an implantable medical device intended for subcutaneous delivery of antisense oligonucleotide (ASO) therapies into the intrathecal space. Through this pact, Biogen aims to leverage the ThecaFlex DRx System with a goal of improving the patient treatment experience and accessibility for a broader population of people suffering from neurological disorders, including spinal muscular atrophy (SMA) and ALS.
Biogen says the ThecaFlex DRx System has the potential to be the first implantable device designed to allow for routine subcutaneous administration of ASO therapies to the cerebrospinal fluid. The ThecaFlex DRx System has garnered a CE mark in Europe. The system has additionally received breakthrough device designation from the FDA and will require further clinical trials before being submitted for FDA review.
“We are inspired by the power of the human immune system to fight diseases. We use our expertise to seek new and transformative antibody technologies and have a proven track record of discovering and developing innovative medicines targeting cancer and other serious diseases,” Genmab management states.
The company’s groundbreaking accomplishments include six approved therapies incorporating Genmab innovation, four proprietary Genmab technologies, and more than 20 products in clinical development incorporating the company’s innovation.
Genmab is applying deep insight into antibody biology and disease targets for solid tumors, B-cell non-Hodgkin lymphoma (NHL), and multiple myeloma. The company’s proprietary technologies – DuoBody, HexaBody, DuoHexaBody, and HexElect – enable Genmab to build a world-class pipeline. Management says the company is seeking to become a leading integrated biotechnology innovation powerhouse.
Genmab proprietary products are being developed through a variety of partnerships including AbbVie, ADC Therapeutics, BioNTech, GBT (now part of Pfizer), Horizon Therapeutics, Janssen Biotech, Lundbeck, Novartis Pharma, Novo Nordisk, Provention Bio, and Seagen. Approved antibody therapeutics incorporating Genmab’s innovation include Darzalex, developed and commercialized by Janssen for multiple myeloma (MM); Kesimpta, developed and commercialized by Novartis for relapsing multiple sclerosis; and Tepezza developed and commercialized by Horizon for thyroid eye disease. Medicines incorporating Genmab’s DuoBody technology include Rybrevant, developed and commercialized by Janssen for non-small cell lung cancer (NSCLC), and Tecvayli, developed and commercialized by Janssen for patients with relapsed/refractory MM.
Tivdak (tisotumab vedotin-tftv), epcoritamab, DuoBody-PD-L1x4-1BB, DuoBody-CD40x4-1BB, DuoHexaBody-CD37, HexaBody-CD38, DuoBody-CD3xB7H4, and HexaBody-CD27 compose a strong pipeline of potential first-in-class/best-in-class products.
Genmab’s first approved therapy was Tivdak in collaboration with Seagen for recurrent or metastatic cervical cancer with disease progression on or after chemo. Additionally, the company is pursuing the potential of Tivdak in early lines of cervical cancer and in other solid tumors.
In collaboration with AbbVie, epcoritamab (DuoBody-CD3xCD20) has shown a manageable safety profile and substantial antitumor activity in patients with heavily pretreated B-cell NHL in a first-in-human trial. The bispecific antibody is delivered as an off-the-shelf, rapid, subcutaneous injection.
Genmab announced during October 2022 the regulatory application filings for epcoritamab as a treatment for relapsed/refractory large B-cell lymphoma (LBCL) to the FDA and diffuse large B-cell lymphoma (DLBCL) to the EMA. The U.S. filing is intended for the treatment of patients with relapsed/refractory LBCL after two or more lines of systemic therapy and the EU submission is for treating patients with relapsed/refractory DLBCL after two or more lines of systemic therapy. The EMA validated for review the Marketing Authorization Application (MAA). Both of the regulatory filings are supported by previously announced results from the LBCL cohort of the pivotal EPCORE NHL-1 open-label, multi-center Phase II study assessing the safety and preliminary efficacy of epcoritamab in patients with relapsed, progressive or refractory CD20+ mature B-cell non-Hodgkin lymphoma (B-NHL), including DLBCL.
Epcoritamab is being jointly developed by Genmab and AbbVie as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the United States and Japan, with AbbVie responsible for additional worldwide commercialization. Genmab and AbbVie are dedicated to studying epcoritamab as a monotherapy, and in combination, across lines of therapy in a variety of hematologic malignancies, including an ongoing Phase III, open-label, randomized trial studying epcoritamab as a monotherapy in patients with relapsed/refractory DLBCL (NCT: 04628494) and a Phase III, open-label study investigating epcoritamab in combination in patients with relapsed/refractory follicular lymphoma (FL) (NCT: 05409066).
Genmab’s Biologics License Application received U.S. priority review during November 2022, with an FDA action date of May 21, 2023. Epcoritamab could become the first subcutaneous bispecific antibody approved as a treatment for LBCL.
As part of a broad collaboration with BioNTech, DuoBody-PD-L1x4-1BB (GEN1046/BNT311) is a first-in-class, bispecific next-generation checkpoint immunotherapy with potential in solid tumors. Genmab says an encouraging clinical activity and manageable safety are in effect. Clinical development includes a Phase II study in combination with pembrolizumab in recurrent NSCLC.
During August 2022, Genmab and BioNTech unveiled an expansion of their global strategic collaboration to develop and commercialize novel immunotherapies for treating cancer patients. Genmab and BioNTech agreed to jointly work to research, develop, and commercialize novel monospecific antibody candidates for various cancer indications. Since 2015, the companies have been working on the joint development of bispecific cancer antibodies intended to improve immunotherapy options for cancer patients. The expanded collaboration leverages the HexaBody technology platform to develop novel monospecific antibodies.
“We’re driven to uncover the next great discovery – the scientific advancement that will lead to a new medicine or the technology that will help us make medicine faster,” Lilly management says. The company’s targeted therapeutic areas are cancer, diabetes, immunology, neurodegeneration, and pain.
In announcing Lilly’s 2023 financial guidance during December 2022, management unveiled plans to launch up to four new medicines (donanemab, mirikizumab, lebrikizumab and Jaypirca (pirtobrutinib)); potential regulatory submissions for tirzepatide in obesity; and numerous other pipeline advancements. Continued pipeline progress in 2023 includes anticipated initiation of Phase III studies for retatrutide (GGG tri-agonist) in obesity and orforglipron (oral GLP-1 NPA) in type 2 diabetes and obesity, and key Phase III readouts, which include donanemab for early Alzheimer’s disease and mirikizumab for Crohn’s disease.
Lilly’s donanemab/LY-3002813 represents one of the biggest potential drug launches of 2023, though the product candidate did come across a road block to start off the year. In January, the FDA issued a complete response letter (CRL) for the accelerated approval submission of donanemab for the treatment of early symptomatic Alzheimer’s disease due to the limited amount of patients with at least 12 months of drug exposure data provided in the submission. No other deficiencies in the new drug application were noted.
The confirmatory Phase III TRAILBLAZER-ALZ 2 study continues on, with topline data read-out expected during Q2 2023, and will form the basis of donanemab’s application for traditional approval shortly thereafter. Lilly continues to work with the regulatory agency to assess the fastest pathway to make this potential treatment option widely available to patients.
In the CRL to the accelerated approval application, the FDA specifically requested that Lilly provide data from at least 100 patients who received a minimum of 12 months of continued treatment on donanemab. While the study included more than 100 patients treated with donanemab, due to the speed of plaque reduction, many patients were able to stop dosing as early as six months of treatment, leading to fewer than 100 patients receiving 12 months of donanemab.
Analysts have forecast nearly $2 billion in annual sales for donanemab by 2028.
Mirikizumab/LY3074828 (formerly known as IL-23 antibody) is a biologic entity that blocks the activity of the cytokine interleukin 23. Mirikizumab is being evaluated in clinical studies for the treatment of ulcerative colitis. The scheduled PDUFA date for mirikizumab was set for May 2023 and industry trackers have projected 2028 sales of $1.2 billion.
The monoclonal antibody lebrikizumab has been designed to bind IL-13 with very high affinity inhibiting the biological effects of IL-13. Lebrikizumab is being investigated as a treatment for moderate-to-severe atopic dermatitis.
According to Lilly, no standalone Phase III clinical study has ever been conducted to concentrate on the critical but unique needs of people with skin of color (SOC) who are suffering from moderate-to-severe atopic dermatitis in the United States. This groundbreaking trial, evaluating the investigational molecule lebrikizumab, recognizes the specific clinical characteristics of AD in people who are Black, Asian, and Latinx and objectively measures them.
Although clinical data on the prevalence of atopic dermatitis in adult skin of color populations is limited, in U.S. patients 17 and younger, the prevalence is higher among African Americans, at almost 20 percent, versus European Americans (16 percent) and Hispanic Americans (8 percent). One clinical study found that African American children are 1.7 times more likely to develop atopic dermatitis than white children.
Near the end of January 2023, the FDA approved Jaypirca for adults with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase (BTK) inhibitor. Jaypirca is the first BTK inhibitor of any kind specifically cleared for marketing for patients with mantle cell lymphoma previously treated with a covalent BTK inhibitor. The new medicine was approved under the FDA’s accelerated approval pathway based on response rate from the open-label, single-arm, international, Phase I/II trial, called the BRUIN trial. BRUIN is an ongoing first-in-human, worldwide, multi-center evaluation of Jaypirca in patients with hematologic malignancies, including mantle cell lymphoma (MCL).
A highly selective kinase inhibitor, Jaypirca uses a novel binding mechanism and is the only FDA-approved non-covalent (reversible) BTK inhibitor. Lilly says Jaypirca can reestablish BTK inhibition in MCL patients previously treated with a covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the BTK pathway.
Lilly continues to advance new indications for marketed products. During January 2023, the FDA accepted the supplemental New Drug Application for the blockbuster medicine Jardiance (empagliflozin) for adults with chronic kidney disease (CKD). The intended indication is to reduce the risk of kidney disease progression and cardiovascular death in adults with CKD.
The sNDA is based on results from the landmark EMPA-KIDNEY Phase III study, which demonstrated Jardiance tablets significantly reduced the risk of kidney disease progression or cardiovascular death in adults with CKD by 28 percent (absolute risk reduction [ARR]: 3.8 percent) versus placebo, both on top of standard of care. Clinical results were presented during the American Society of Nephrology’s Kidney Week 2022 and simultaneously published in The New England Journal of Medicine. EMPA-KIDNEY is the first SGLT2 inhibitor CKD study to demonstrate a significant reduction in risk of hospitalization for any cause, with a 14 percent relative risk reduction with Jardiance versus placebo (24.8 versus 29.2 events/100 patient-years, respectively), both on top of standard of care, in a pre-specified key secondary endpoint. EMPA-KIDNEY is the largest and broadest dedicated SGLT2 inhibitor study in CKD and provides additional data for patients commonly seen in clinical practice.
First approved during 2014, Jardiance is a once-daily tablet used along with diet and exercise to lower blood sugar in adults with type 2 diabetes; and to reduce the risk of cardiovascular death in adults with type 2 diabetes and known cardiovascular disease. The medicine is additionally indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure.
Merck employs about 17,500 people in research and development and invested $13.55 billion in R&D during 2022. The Merck pipeline as of November 3, 2022, included 25-plus programs in Phase III development and 80-plus programs in the Phase II stage, with 10-plus programs under review. The company’s areas of focus are oncology, vaccines, infectious diseases, and cardio-metabolic disorders.
Merck’s immuno-oncology clinical research program is the largest in the industry. There are more than 1,600 studies evaluating Keytruda (pembrolizumab) across a broad range of cancers and treatment settings. According to Merck, 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 treatment with the anti-PD-1 therapy, including exploring several different biomarkers. Keytruda won FDA marketing approval on January 27, 2023, as adjuvant treatment following surgical resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 Centimeters), II, or IIIA NSCLC. This approval marked the 34th indication for the blockbuster brand in the United States.
Moderna and Merck announced during December 2022 that the Phase IIb KEYNOTE-942/mRNA-4157-P201 study of mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda showed a statistically significant and clinically meaningful improvement in the primary endpoint of recurrence-free survival (RFS) versus Keytruda alone for the adjuvant treatment of patients with stage III/IV melanoma following complete resection. Adjuvant treatment with mRNA-4157/V940 in combination with Keytruda reduced the risk of recurrence or death by 44 percent (HR=0.56 [95 percent CI, 0.31-1.08]; one-sided p value=0.0266) versus Keytruda alone.
During October 2022, the companies announced that Merck had exercised its option to jointly develop and commercialize mRNA-4157/V940. Merck and Moderna will share costs and any profits equally under this global collaboration.
Another top-selling drug in the oncology space for Merck is the first-in-class poly (ADP-ribose) polymerase (PARP) inhibitor Lynparza, which is being jointly developed and commercialized with AstraZeneca. Lynparza (olaparib) has a broad clinical trial development program, and the companies are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types. Lynparza represents the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with the medicine results in the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being evaluated in various tumor types with defects and dependencies in the DDR.
AstraZeneca and Merck in December 2022 announced that the FDA would extend by three months the PDUFA date for the supplemental new drug application for Lynparza in combination with abiraterone and prednisone or prednisolone for treating adults with metastatic castration-resistant prostate cancer (mCRPC). The sNDA for the drug in combination with abiraterone and prednisone or prednisolone is based on the Phase III PROpel study, results of which were published in NEJM Evidence during June 2022. The sNDA application was granted priority review by the FDA.
Merck and Kelun-Biotech, a clinical-stage biotech company focused on biologic and small molecule discovery and development, reached a deal in December 2022. The companies agreed on an exclusive license and collaboration to develop seven investigational preclinical antibody-drug conjugates (ADC) for cancer. Kelun-Biotech has granted Merck exclusive worldwide licenses to research, develop, manufacture, and commercialize multiple investigational preclinical ADC therapies and exclusive options to obtain additional licenses to ADC candidates. Kelun-Biotech retains the right to research, develop, manufacture, and commercialize certain licensed and option antibody-drug conjugates for mainland China, Hong Kong, and Macau.
During October 2022, Merck announced positive clinical results from the pivotal Phase III STELLAR study assessing the investigational activin receptor type IIA-Fc fusion protein sotatercept as an add-on to stable background therapy as a treatment for adults with pulmonary arterial hypertension. Based on the results, the clinical trial met its primary efficacy outcome measure, showing a statistically significant and clinically meaningful improvement in six-minute walk distance (6MWD) from baseline at 24 weeks, and eight out of nine secondary efficacy outcome measures, including the outcome measure of proportion of participants achieving multicomponent improvement [defined as improvement in 6MWD, improvement in N-terminal pro-B-type natriuretic peptide level, and either improvement in WHO Functional Class (FC) or maintenance of WHO FC II] and the outcome measure of time to death or the first occurrence of a clinical worsening event.
According to Merck officials, sotatercept was designed to rebalance pro-proliferative (ActRIIA/Smad2/3-mediated) and anti-proliferative (BMPRII/Smad1/5/8-mediated) signaling associated with pulmonary arterial wall and right ventricular remodeling. Sotatercept has been granted breakthrough therapy designation by FDA regulators, as well as priority medicines designation by the EMA for the treatment of PAH.
Merck acquired exclusive rights to sotatercept in the pulmonary hypertension field via the completed acquisition of Acceleron Pharma in September 2021. Sotatercept is the subject of a licensing deal with Bristol Myers Squibb. The product is projected by industry analysts to generate $1 billion in yearly sales by 2028.
Merck reached a deal in November 2022 to acquire, through a subsidiary, Imago BioSciences for $36.00 per share in cash for a total equity value of $1.35 billion. The clinical-stage biopharmaceutical company Imago is developing new medicines for treating myeloproliferative neoplasms (MPNs) and other bone marrow diseases. The company’s lead candidate bomedemstat (IMG-7289), an investigational orally available lysine-specific demethylase 1 (LSD1) inhibitor, is being assessed in multiple Phase II studies as a treatment for essential thrombocythemia (ET), myelofibrosis (MF), and polycythemia vera (PV), in addition to other indications.
“We continue to invest in our pipeline with a focus on applying our unique capabilities to unlock the value of breakthrough science for the patients we serve,” states Merck President and Chief Executive Officer Robert M. Davis. “This acquisition of Imago augments our pipeline and strengthens our presence in the growing field of hematology.”
Infectious disease pipeline highlights include Merck initiating a new Phase III clinical program with islatravir for treating people with HIV-1 infection. These new Phase III trials are studying a once-daily oral combination of doravirine 100 mg and islatravir (DOR/ISL) 0.25 mg. One clinical trial will assess DOR/ISL in previously untreated adults with HIV-1 infection and two studies will investigate DOR/ISL as a switch in antiretroviral therapy (ART) in adults with HIV-1 infection who are virologically suppressed. The Phase II study (NCT05052996) assessing an investigational oral once-weekly combination treatment regimen of islatravir and Gilead’s lenacapavir in adults with HIV-1 infection who are virologically suppressed resumed under an amended protocol with a lower dose of islatravir.
During August 2022, Merck received fast track status from the FDA for MK-2060. The investigational anticoagulant therapy is being developed for the reduction in risk of major thrombotic cardiovascular events in patients with end-stage renal disease.
Merck and the Bill & Melinda Gates Medical Research Institute (Gates MRI) during October 2022 announced a licensing deal for two preclinical antibacterial candidates for investigation as potential components of combination regimens for treating tuberculosis. The two candidates were discovered by Merck scientists as part of the TB Drug Accelerator (TBDA). The TBDA is a collaboration established among biopharma companies, research organizations, and universities to accelerate the discovery and development of novel therapeutic candidates against tuberculosis. The TBDA initiative was established with support and leadership from the Bill & Melinda Gates Foundation. Merck granted the Gates MRI an exclusive worldwide license for MK-7762 and MK-3854.
“Clinical trials are at the heart of our work to bring innovative medicines to people with a particular disease or condition,” Novartis says. “In our pursuit to discover and develop first or best-in-class medicines for diseases with high unmet need, we explore possibilities to cure disease, intervene earlier in chronic illnesses, and find ways to improve and extend people’s lives.”
According to the company’s management, during the course of 2022 “Novartis has transformed to become a pure-play Innovative Medicines company and is now uniquely
positioned to leverage our scale, strengths, and expertise.” The strategy of New Novartis: “Focusing on high-value innovative medicines that alleviate society’s greatest disease burdens through technology leadership in R&D and novel access approaches.”
Management says Novartis is refining the company’s proven development engine with greater focus on asset value and improving R&D productivity. According to Novartis, the company is an industry leader across first-in-class approved NMEs with 42 (30 NDA and 12 BLA) from 1999-2021, with the next two closest competitors coming in at 34 and 28 total NME approvals during that time frame.
The five core therapeutic areas with the largest growth potential and existing Novartis assets/expertise are cardiovascular, immunology, neuroscience, solid tumors, and hematology. Novartis is prioritizing the company’s pipeline in specific DAs to high-value NMEs across the five core therapeutic areas. “Looking ahead, we have a catalyst rich pipeline with 15 pivotal readouts in the mid-term,” the company reported on February 1, 2023.
A leading pipeline asset and opportunity in the company’s cardiovascular pipeline is iptacopan (LNP023). Novartis presented pivotal Phase III APPLY-PNH data at ASH in December 2022 showing the experimental oral monotherapy iptacopan was superior compared to anti-C5 therapy. According to the results, a vast majority of patients with paroxysmal nocturnal hemoglobinuria (PNH) who received iptacopan achieved clinically meaningful increases in hemoglobin levels versus anti-C5 therapy.
The clinical study met both primary endpoints and most secondary endpoints, with iptacopan showing superiority versus anti-C5 therapy in adults with PNH experiencing residual anemia despite previous treatment with anti-C5 therapy.
The investigational first-in-class, orally administered targeted factor B inhibitor of the alternative complement pathway acts upstream of the C5 terminal pathway, preventing not only intravascular but also extravascular hemolysis in PNH3. As a result, iptacopan targets a key part of the biology responsible for PNH while offering an oral monotherapy option.
Discovered at the Novartis Institutes for BioMedical Research, iptacopan is undergoing clinical development for various other complement-mediated diseases (CMDs) where significant unmet needs exist, such as kidney diseases C3 glomerulopathy (C3G), IgA nephropathy (IgAN), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN), lupus nephritis (LN), and the blood disorders immune thrombocytopenic purpura (ITP) and cold agglutinin disease (CAD). Initial results for Phase III studies in C3G (APPEAR-C3G) and IgAN (APPLAUSE-IgAN) are anticipated in 2023.
Based on disease prevalence, unmet needs and data from Phase II trials, iptacopan has garnered FDA breakthrough therapy designation in PNH, orphan drug designations from the FDA and EMA in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN16-19.
Novartis is advancing a broad portfolio of radioligand therapies for treating cancer and is investing in manufacturing capacity to meet the growing worldwide demand for treatment. The company announced during December 2022 that the pivotal Phase III PSMAfore trial with Pluvicto (INN: lutetium (177Lu) vipivotide tetraxetan), a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, met its primary endpoint. Pluvicto showed a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) in patients with PSMA–positive metastatic castration-resistant prostate cancer (mCRPC) after treatment with androgen-receptor pathway inhibitor (ARPI) therapy, compared to a change in ARPI. According to the company, Pluvicto becomes the first PSMA-targeted radioligand therapy to demonstrate clinical benefit in mCRPC patients before receiving taxane-based chemotherapy, addressing a significant unmet need.
This marks the second positive read-out for Pluvicto in a Phase III study following the VISION trial, where patients with PSMA–positive mCRPC who received Pluvicto plus standard of care after being treated with ARPI and taxane-based chemotherapy had a statistically significant reduction in risk of death. The PSMAfore results continue to support the significant role of Pluvicto for the treatment of patients with prostate cancer. The Phase III data will be discussed with the FDA in 2023 for regulatory approval. Pluvicto is already approved for treating adults with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy in the United States and several other countries.
Novartis is dedicated to continuing to investigate Kisqali in breast cancer. NATALEE is a large Phase III clinical study of Kisqali plus endocrine therapy in the adjuvant treatment of HR+/HER2- early breast cancer being performed in collaboration with Translational Research In Oncology. Novartis is also collaborating with SOLTI, who is leading HARMONIA, to evaluate whether Kisqali changes tumor biology to enable a better response to endocrine-based therapy compared to Ibrance for patients with advanced HR+/HER2-, HER2-enriched subtype, and with the Akershus University Hospital in Norway on the NEOLETRIB trial, a neoadjuvant Phase II study exploring the effects of Kisqali in HR+/HER2- early breast cancer to discover the potentially unique underlying mechanism of action.
Kisqali (ribociclib) was developed by the Novartis Institutes for BioMedical Research (NIBR) through a research collaboration with Astex Pharmaceuticals. Kisqali is the only CDK4/6 inhibitor with proven overall survival benefit across all three pivotal Phase III advanced breast cancer studies and is recognized by the National Comprehensive Cancer Network (NCCN) guidelines as the only CDK4/6i with overall survival benefit in first-line HR+/HER2- advanced breast cancer. Kisqali has been approved in more than 95 countries, including by the FDA and the European Commission, for treating women with HR+/HER2- advanced or metastatic breast cancer in combination either with an aromatase inhibitor or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy. Kisqali in combination with fulvestrant is available in the United States as initial endocrine-based therapy or following disease progression on endocrine therapy in men.
Remibrutinib (LOU064) is one of the company’s pipeline assets that is anticipated to drive outer-year growth and improved productivity as part of the company’s global reorganization. According to Novartis, unprobabilized peak sales of indications in late-stage development for remibrutinib represent more than $2 billion. In immunology, Phase III REMIX-1 and -2 studies for chronic spontaneous urticaria are under way with an expected readout during 2024. In neuroscience, Phase III REMODEL-1 and -2 studies for multiple sclerosis are under way with an anticipated readout in 2025.
Scemblix (asciminib) is the first chronic myeloid leukemia (CML) treatment that acts as a STAMP inhibitor, specifically targeting the ABL myristoyl pocket. This novel mechanism of action may help address resistance in CML patients previously treated with two or more tyrosine kinase inhibitors (TKIs) and overcome mutations at the defective BCR::ABL1 gene, which is associated with the over-production of leukemic cells. Scemblix represents a significant development for patients who experience resistance and/or intolerance to currently available TKI therapies, and the medicine is being studied across multiple treatment lines for chronic myeloid leukemia in chronic phase (CML-CP), both as a monotherapy and in combination. Specifically, the ASC4FIRST Phase III study (NCT04971226) assesses Scemblix in newly diagnosed adults with Ph+ CML-CP versus an investigator-selected TKI.
Novartis has initiated regulatory submissions for Scemblix in multiple countries and regions across the world. In October 2021, the FDA granted accelerated approval of Scemblix for adults with Ph+ CML-CP, previously treated with two or more TKIs based on MMR rate at 24 weeks, and full approval for adults with Ph+ CML-CP with the T315I mutation.
Scemblix has received marketing clearance in several countries outside the United States, including Japan, Switzerland, and the United Kingdom, for adult patients with Ph+ CML-CP with resistance or intolerance to at least two or more previous therapies. European Commission approval in August 2022 is based on results from the pivotal Phase III ASCEMBL study, in which Scemblix nearly doubled the major molecular response rate versus Bosulif (bosutinib) (25.5 percent versus 13.2 percent) with a more than three times lower discontinuation rate due to adverse reactions (5.8 percent vs 21.1 percent) at 24 weeks and confirmed at 96 weeks.
“With 25,000 clinical researchers testing every day and cutting-edge innovations, our science holds the cure,” according to Pfizer. As of January 31, 2023, Pfizer’s total number of discovery projects amounted to 110, consisting of 16 in registration, 23 in Phase III, 37 in Phase II and 34 in Phase I. The pipeline portfolio consisted of 72 new molecular entities (NMEs) and 38 additional indications. Pfizer’s leading research area is oncology with 33 total discovery projects, including 10 in Phase III development as of the end of January 2023.
Pfizer’s NME candidate sasanlimab (product code PF-06801591) is being investigated in Phase III trials in combination with Bacillus Calmette-Guerin (BCG) for high-risk non-muscle invasive bladder cancer. The biologic immunotherapy sasanlimab blocks the PD-1 protein on the surface of immune T-cells that can sometimes attack healthy cells..
The inflammation and immunology segment for Pfizer totaled 23 discovery projects as of late January 2023, with two in registration (ritlecitinib/PF-06651600 for alopecia areata and etrasimod for ulcerative colitis) and one in Phase III (ritlecitinib for vitiligo). Both of these NMEs are believed by industry analysts to represent blockbuster medicines.
The JAK3/TEC inhibitor ritlecitinib is awaiting U.S. marketing clearance for the treatment of the autoimmune disease alopecia areata. Intended for adults and adolescents 12 years of age and older with alopecia areata, an FDA decision on the product candidate’s approval status is anticipated during second-quarter 2023. An investigational oral once-daily treatment, ritlecitinib is the first in a new class of oral highly selective kinase inhibitors that is a dual inhibitor of the TEC family of tyrosine kinases and of Janus kinase 3 (JAK3).
Clarivate’s Drugs to Watch 2023 list identified ritlecitinib as one of 15 late-stage experimental treatments that are each forecast to deliver annual sales of more than $1 billion within five years. “Ritlecitinib will likely benefit from its first-in-class status, rapid onset of action and expected label for both adults and adolescents, potentially providing an effective option to stimulate hair growth in a stigmatizing disease – alopecia areata,” Clarivate experts explain.
The S1P inhibitor etrasimod is awaiting marketing approval from FDA regulators for treating moderately to severely active ulcerative colitis. During December 2022, Pfizer announced that the FDA had accepted for review an NDA for etrasimod. The U.S. regulatory agency’s decision is expected during the second half of 2023. An oral, once-daily, selective sphingosine-1-phosphate (S1P) receptor modulator, etrasimod is designed for optimized pharmacology and engagement of S1P receptors 1, 4, and 5. In addition to ulcerative colitis, etrasimod is being studied for a range of other immuno-inflammatory diseases.
Etrasimod is anticipated to represent one of the biggest product launches of 2023, with a drug rollout expected by the end of the year. Sales for 2028 have been projected to reach $1.2 billion, according to Evaluate Pharma and Evaluate Vantage.
Pfizer’s vaccines category of 19 projects consists of 11 in registration and four in Phase III studies. As the industry’s top-selling product in the world in 2022, the prophylactic mRNA vaccine Comirnaty (COVID-19 Vx) continues to be developed by Pfizer for new indications in collaboration with BioNTech as a booster for various age groups. Pfizer has additionally been developing and advancing the prophylactic mRNA vaccines BNT162b2 bivalent (BA.4/BA.5) and BNT162b2 bivalent (BA.1) as new molecular entities.
Outside of the COVID-19 vaccines, PF-06928316 for respiratory syncytial virus infection in older adults was accepted for priority review by the FDA in December 2022. The PDUFA goal date for a decision by U.S. regulators on the application for the bivalent RSV prefusion vaccine candidate was scheduled for May 2023. This decision follows the FDA’s breakthrough therapy designation of PF-06928316 for individuals 60 years and older in March 2022. Pfizer is the only company with an investigational vaccine being prepared for regulatory applications for infants through maternal immunization and older adults to help protect against RSV. Another NME in the registration phase of development is PF-06886992 for serogroups ABCWY meningococcal infections (adolescent and young adults).
The company’s Phase III NME vaccines include PF-06425090 for primary Clostridioides difficile infection (fast track status).
Pfizer’s 15 discovery projects in the internal medicine category included one in registration. The calcitonin gene-related peptide (CGRP) receptor antagonist zavegepant is awaiting FDA approval in an intranasal formulation for the acute treatment of migraine in adults. The PDUFA goal date for completion of the U.S. regulatory review of the NDA was scheduled for Q1 2023. If cleared for marketing, zavegepant nasal spray would be the only FDA-approved CGRP receptor antagonist in an intranasal formulation.
For rare diseases, Pfizer had one in registration and six in Phase III among 12 total projects as of the end of January 2023. The biologic somatrogon (PF-06836922) is awaiting FDA clearance for pediatric growth hormone deficiency (U.S. orphan drug status). OPKO Health is responsible for conducting the clinical program for somatrogon and Pfizer is responsible for registering and commercializing the product for GHD.
For anti-infectives, the eight projects include one in registration and two in late-stage trials. The SARS-CoV-2 3CL protease inhibitor and oral COVID-19 treatment Paxlovid is being developed and advanced by Pfizer for various populations (high risk, standard risk, pediatric, etc.).
“Our close strategic partnerships across the Group, and our diverse mix of autonomous innovation engines gives us a rich diversity of expertise and scientific thinking, as we seek to discover and develop solutions to the biggest questions in healthcare today,” Roche management says. “To discover and develop the next breakthroughs, we have built a network of independent innovation engines around the world.” Based in Basel, Switzerland, Roche innovation centers are located in 17 countries.
According to analysis from Seeking Alpha reported in January 2023, Roche had the most Phase III product candidates among the world’s top 10 pharma companies based on market capitalization. “Roche is the winner with the highest number of Phase III trials at 56. Roche also scored well financially with a tie for second best R&D expense at 22 percent of revenues and 6th for LFCF margin (20 percent). … I believe that the diverse Phase III asset base will generate plenty of cash to support Roche for years to come.”
As of February 2, 2023, Roche had a total number of 87 new compounds and 65 additional indications in clinical development or registration.
Roche’s focus areas are cardiometabolic diseases (Diagnostics); hematology (Pharma); infectious diseases (Pharma|Diagnostics); inflammatory bowel diseases (Pharma); neuroscience (Pharma|Diagnostics); oncology (Pharma|Diagnostics); ophthalmology (Pharma); rare disease (Pharma|Diagnostics); respiratory (Pharma); and women’s health (Pharma|Diagnostics).
“Roche has been developing medicines for people with malignant and non-malignant blood diseases for more than 20 years; our experience and knowledge in this therapeutic area runs deep,” according to the company. Making significant headway in this space, Roche presented new data in December 2022 showing the potential benefit of glofitamab and Lunsumio as fixed-duration, off-the-shelf treatment options for lymphoma. Data presented at ASH 2022 and simultaneously published in The New England Journal of Medicine demonstrated that glofitamab, administered as a fixed course, induced early and durable responses in people with heavily pre-treated large B-cell lymphoma. Meanwhile, 27-month follow-up data demonstrated Lunsumio continued to induce high and durable responses in people with relapsed or refractory follicular lymphoma (FL), with 60 percent experiencing a complete response.
Lunsumio (mosunetuzumab) emerged from the Roche pipeline with the product’s first U.S. marketing clearance. In December, Lunsumio became the first CD20xCD3 T-cell engaging bispecific antibody approved by the FDA to treat the most common slow-growing form of non-Hodgkin lymphoma, follicular lymphoma. According to Roche, results from the pivotal Phase II GO29781 trial showed that 80 percent of patients who received at least two prior therapies achieved durable response rates, along with the aforementioned 60 percent experiencing complete remission. This indication is approved by the FDA under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory study.
The FDA in January 2023 accepted Roche’s Biologics License Application and granted priority review status for the investigational CD20xCD3 T-cell engaging bispecific antibody glofitamab for treating adults with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after two or more lines of systemic therapy. LBCL is a fast-growing form of non-Hodgkin lymphoma (NHL) and is one of the most prevalent types of blood cancer among U.S. adults. An FDA approval decision regarding this novel cancer immunotherapy is expected by July 1, 2023. If approved, glofitamab would represent the first fixed-duration, off-the-shelf CD20xCD3 T-cell engaging bispecific antibody available to treat people with an aggressive lymphoma who have previously received multiple courses of treatment.
Developed by scientists from Roche Group member Genentech, Lunsumio and glofitamab are being evaluated as SC formulations (i.e., administered under the skin) and in Phase III trials that will expand the understanding of their impact in earlier lines of treatment for individuals with non-Hodgkin’s lymphoma. Additional late-stage development includes the confirmatory Phase III CELESTIMO trial exploring Lunsumio plus lenalidomide as a chemotherapy-free option for patients with R/R FL; the Phase III SUNMO trial studying Lunsumio with Genentech’s first-in-class anti-CD79b antibody-drug conjugate Polivy (polatuzumab vedotin) compared to the company’s blockbuster product Rituxan/MabThera in combination with gemcitabine plus oxaliplatin (R-GemOx) in patients with R/R aggressive B-cell NHL who are ineligible for autologous stem cell transplant (ASCT); and the Phase III STARGLO trial assessing glofitamab in combination with gemcitabine and oxaliplatin (GemOx) versus Rituxan/MabThera in combination with GemOx in patients with R/R DLBCL who are ineligible for ASCT.
Roche presented during December new and updated data for Polivy in previously untreated diffuse large B-cell lymphoma (DLBCL) at ASH 2022. According to the company, updated data from the Phase III POLARIX trials continue to show a statistically significant reduction in the risk of disease worsening or death for people with previously untreated DLBCL. Patients receiving Polivy in combination with R-CHP (Rituxan/MabThera (rituximab), cyclophosphamide, doxorubicin and prednisone) for DLBCL reported similar health-related quality of life outcomes, during and after fixed-duration treatment, to those receiving the current standard-of-care, with superior progression-free survival.
Roche continues to advance the company’s portfolio of blockbuster medicines in clinical development. For example, Roche during January 2023 reported that the Phase III IMbrave050 trial met the study’s primary endpoint of recurrence-free survival at the prespecified interim analysis. The clinical trial is assessing Tecentriq (atezolizumab) in combination with Avastin (bevacizumab) as adjuvant treatment following surgery for people with early-stage hepatocellular carcinoma (HCC) at high risk of disease recurrence. The Tecentriq combination demonstrated a statistically significant improvement in RFS in the intention-to-treat population of HCC patients who have an increased risk of recurrence following resection or ablation with curative intent, versus active surveillance. Tecentriq plus Avastin was the first treatment in more a decade to significantly improve overall survival over the existing standard of care, based on data from the IMbrave150 trial.
Launched in the United States during 2016, the monoclonal antibody Tecentriq is approved for some of the most aggressive and difficult-to-treat types of cancer. Tecentriq was the first cancer immunotherapy approved for treating certain type of early-stage NSCLC, small cell lung cancer (SCLC) and HCC. Available to treat metastatic colorectal cancer (mCRC) and other cancers, Avastin received initial U.S. approval on February 26, 2004, and at its peak was the world’s No. 7-ranked pharmaceutical product in terms of global sales per Med Ad News data.
Roche’s worldwide reach, commercial presence and regulatory expertise are being used in partnership with Sarepta Therapeutics for the gene therapy candidate delandistrogene moxeparvovec (SRP-9001) for Duchenne muscular dystrophy. SRP-9001 would represent the first gene therapy for Duchenne, a one-time treatment designed to treat the underlying cause of DMD by delivering a functional shortened dystrophin to muscle. SRP-9001 has been granted FDA priority review, with a regulatory action date of May 29, 2023. Through the partnership, Roche would accelerate access to SRP-9001 for patients outside the United States. Evaluate analysts have projected 2028 sales of $2.2 billion.
Roche entered into a U.S. focused collaboration with Pfizer during December 2022 to drive awareness and educate on the significance of timely COVID-19 testing, available treatment options, symptoms and the high-risk factors that can increase the chance of advancing to severe illness. The Pilot COVID-19 At-Home Test, which is distributed in the United States by Roche Diagnostics and is manufactured by SD Biosensor, now includes a QR code that directs individuals to covid19knowmore.com, where they can learn more about COVID-19, including CDC guidance on testing and treatment options.
“Travere Therapeutics is determined to bring life-changing treatments, support, and hope to people with rare disease – an area often overlooked,” according to the company. “Together, we can create a better future for families affected by rare disease.”
The company is focused on the following therapeutic areas: Alagille syndrome (ALGS);
bile acid synthesis disorders (BASD); cerebrotendinous xanthomatosis (CTX); classical homocystinuria (HCU); cystinuria; focal segmental glomerulosclerosis (FSGS); IgA nephropathy (IgAN); and peroxisome biogenesis disorder-Zellweger spectrum disorder (PBD-ZSD).
Management provided a corporate update and 2023 outlook during January. “This is a very exciting year for Travere and the rare disease community, with the first potential approvals from our development pipeline of therapies targeting rare diseases with significant unmet needs. We are focused and ready to execute on a successful U.S. commercial launch of sparsentan for IgAN in the first quarter, pending FDA approval following our upcoming PDUFA target action date of February 17, 2023,” states Eric Dube, Ph.D., president and chief executive officer of Travere Therapeutics. “We also look forward to additional data from our Phase III DUPLEX study of sparsentan which has the potential to support a supplemental NDA for FSGS, a condition that is currently lacking effective treatment options. Beyond sparsentan, we anticipate the initiation of a Phase III program for pegtibatinase, which continues to advance in clinical development with the goal of becoming the first disease-modifying therapy for people living with classical homocystinuria. We anticipate that 2023 will be a pivotal year for us as we pursue our mission of delivering life-changing therapies to people living with rare disease.”
Sparsentan represents the first dual endothelin angiotensin receptor antagonist (DEARA) in development for rare kidney disorders. If cleared for marketing, sparsentan would also represent the only non-immunosuppressive treatment indicated for IgAN.
According to management, the company was well-positioned for potential FDA Subpart H accelerated approval and commercial launch of sparsentan during the first quarter of 2023.
Travere, together with its collaborator CSL Vifor, anticipates a review decision by the EMA during second-half 2023 on the potential approval of the Conditional Marketing Authorization (CMA) application for sparsentan for treating IgAN in Europe. If approved for marketing, sparsentan would receive CMA in all member states of the European Union, as well as in Iceland, Liechtenstein and Norway.
Additionally, Travere expects to report topline results during the fourth quarter of 2023 from the two-year confirmatory endpoints in the ongoing Phase III PROTECT trial, which are designed to support traditional approval of sparsentan in IgAN.
Also during 2023, the company intends to expand data generation through a sub study in the open-label extension of the ongoing PROTECT clinical trial, as well as an open-label clinical study to investigate the safety and efficacy of sparsentan in combination with sodium glucose cotransporter-2 inhibitors (SGLT2i) for treating IgAN.
Sparsentan is also being developed as a treatment for FSGS. During second-quarter 2023, management expects to report topline results from the two-year confirmatory endpoints in the ongoing Phase III DUPLEX trial of sparsentan in FSGS. Pending data supportive of approval, Travere anticipates the filing of a supplemental NDA for traditional approval for FSGS during the second half of 2023.
Pending completion of the DUPLEX study of sparsentan in FSGS and data supportive of marketing clearance, a subsequent variation to the CMA of sparsentan as a treatment for FSGS in Europe is targeted for submission by year-end 2023.
According to Clarivate analysts, “Sparsentan is a first-in-class, orally active, single molecule that functions as a high-affinity, dual-acting antagonist of both endothelin type A (ETA) and angiotensin II subtype 1 (AT1) receptors, which are associated with progression of kidney disease. Its development for IgA nephropathy and focal segmental glomerulosclerosis (FSGS) promises to halt that progression for many patients and fills a gap in the treatment armamentarium.”
In other company pipeline updates, Travere continues to advance pegtibatinase (product code TVT-058), a novel investigational enzyme replacement therapy with the potential to become the first disease-modifying therapy for people living with classical homocystinuria. Following positive results from the first five cohorts of the ongoing Phase I/II COMPOSE trial, Travere is assessing pegtibatinase in a final cohort in the COMPOSE study to further inform its potential pivotal development program.
Enrollment was completed during the fourth quarter of 2022 for the sixth and final cohort of the ongoing Phase I/II COMPOSE trial. Travere expects reporting additional data from COMPOSE during mid-2023.
In parallel with completing the final cohort in the COMPOSE trial, Travere is preparing for the initiation of a pivotal Phase III clinical study of pegtibatinase in patients with HCU during second-half 2023.
Travere’s chenodeoxycholic acid (CDCA) program includes Chenodal (chenodiol), a commercially available product that is undergoing clinical assessment to include an indication for cerebrotendinous xanthomatosis (CTX) – a rare, progressive, and underdiagnosed bile acid synthesis disorder – to the product label.
Travere anticipates completing the ongoing Phase III RESTORE trial in CTX in 2023. Pending supportive data, management anticipates the company being in position to subsequently file an NDA for a CTX indication.
“At UCB we’ve moved away from seeing patients as just patients. By really listening and engaging with them as partners we are striving for greater understanding of their needs or ways to improve our clinical studies. To improve and accelerate development, we will keep patients’ needs front and center, leverage new technologies, and adaptive clinical study design to improve the patient experience,” company officials say.
The Belgium-based company sponsors more than 100 clinical studies in various disease areas such as neurology (epilepsy, Dravet syndrome, restless legs syndrome and Parkinson’s disease); immunology (rheumatoid arthritis, osteoporosis, axial spondyloarthritis, psoriatic arthritis, Crohn’s disease, lupus, psoriasis, juvenile idiopathic arthritis and hidradenitis suppurations); and rare diseases such as myasthenia gravis.
“Diversification of clinical trials is critical, and UCB is working to increase representation and inclusion of underrepresented patient populations through digital and
data-driven approaches as well as connecting directly to patient communities,” management says. “We are committed to working toward a clinical trials infrastructure that addresses health disparities and closes the gap in clinical trial diversity to better reflect the intended treatment population. We continue our work to identify best practices around key drivers such as scientific rigor, informing innovation, and addressing health inequities in clinical trials now and into the future.”
The headliner in the UCB pipeline portfolio is bimekizumab, a humanized monoclonal IgG1 antibody that is designed to selectively inhibit both interleukin 17A (IL-17A) and interleukin 17F (IL-17F), two key cytokines driving inflammatory processes.
The FDA during December 2022 accepted for review the BLA resubmission for bimekizumab as a treatment for adults with moderate-
to-severe plaque psoriasis. The U.S. regulatory agency designated the resubmission as ‘Class 2’ with a six-month review period, with FDA action anticipated during second-quarter 2023. UCB announced in November 2022 the BLA refilling for bimekizumab after receipt of a complete response letter in May 2022.
During August 2021, bimekizumab was approved in the European Union (EU)/European Economic Area (EEA) and in Great Britain, for treating moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy. In January 2022, bimekizumab received marketing authorization in Japan for treating plaque psoriasis, generalized pustular psoriasis and psoriatic erythroderma in patients who are not sufficiently responding to existing treatments.
In February and March 2022, bimekizumab was the recipient of marketing authorization in Canada and Australia respectively, for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. During July and October 2022, bimekizumab received marketing authorization in Saudi Arabia and Switzerland respectively, as a treatment for moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy.
The Annals of the Rheumatic Diseases (ARD) in January 2023 published 24-week results from the Phase III BE MOBILE 1 and BE MOBILE 2 trials, assessing the efficacy and safety of bimekizumab in treating adults with active axial spondyloarthritis (axSpA), including active non-radiographic axial spondyloarthritis (nr-axSpA; BE MOBILE 1) and active ankylosing spondylitis (AS; BE MOBILE 2), also known as radiographic axSpA. The BE MOBILE 1 and BE MOBILE 2 trials, which evaluated the drug candidate across the full spectrum of axial spondyloarthritis, met all primary and ranked secondary endpoints at Week 16. The publication of the results in the ARD closely follows UCB news in December that The Lancet published two articles detailing results from two Phase III trials investigating bimekizumab in adults with active psoriatic arthritis.
Top-line results reported during December 2022 demonstrated that the two Phase III trials, BE HEARD I and BE HEARD II, met their primary and key secondary endpoints with statistical significance and consistent clinical relevance. This marks the first Phase III evidence to suggest that targeting IL-17F in addition to IL-17A may be a promising treatment approach in adults with moderate-to-severe hidradenitis suppurativa. Results from the two studies will form the basis of global regulatory applications for bimekizumab in hidradenitis suppurativa beginning in the third quarter of 2023.
Analysts noted in Clarivate’s 2023 Drugs to Watch report, “Bimekizumab is the first dual IL-17 A/F inhibitor to treat moderate-to-severe plaque psoriasis. Phase III trial results showed superior skin clearance outcomes than existing treatments. Its less-frequent dosing schedule and good safety profile will likely be attractive to clinicians and patients.”
UCB announced in January 2023 that the rozanolixizumab BLA for the treatment of generalized myasthenia gravis was filed with the FDA and had been designated for priority review. The BLA seeks approval for treating adults with generalized myasthenia gravis (gMG) who are anti-acetycholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.
The FDA priority review follows the recent EMA validation of the MAA for rozanolixizumab in adults with gMG. The FDA and EMA filings were based on the Phase III MycarinG study in gMG which showed treatment with rozanolixizumab lead to clinically meaningful and statistically significant improvements in MG specific outcomes. UCB anticipates receiving feedback from the regulatory agencies during Q2 2023.
SC administered rozanolixizumab is a humanized monoclonal antibody that specifically binds, with high affinity, to human neonatal Fc receptor (FcRn). The drug candidate has been designed to block the interaction of FcRn and immunoglobulin G (IgG), accelerating the catabolism of antibodies and reducing the concentration of pathogenic IgG autoantibodies.
Rozanolixizumab is undergoing clinical development with the aim of improving the lives of people with pathogenic IgG-autoantibody-driven autoimmune diseases. The FDA granted orphan drug designation to rozanolixizumab in 2019 for treating myasthenia gravis. Orphan designation was granted during 2020 by the European Commission for rozanolixizumab to treat myasthenia gravis.
The FDA accepted for review the New Drug Application for UCB’s investigational treatment zilucoplan in November 2022. The NDA for zilucoplan seeks approval for the treatment of gMG in adults who are acetylcholine receptor antibody positive (AChR-Ab+). Acceptance by U.S. regulators follows the recent EMA validation of MAA for treating adult patients with AChR-Ab+ gMG and who require treatment in addition to steroids or non-steroidal immunosuppressants.
The NDA and MAA are based on the pivotal Phase III RAISE trial in gMG, which showed treatment with zilucoplan lead to clinically meaningful and statistically significant improvements in key MG-specific outcomes versus placebo. The company expects to receive feedback from the regulatory agencies during fourth-quarter 2023.
Zilucoplan is a once-daily SC, self-administered peptide inhibitor of complement component 5 (C5 inhibitor). Zilucoplan inhibits complement-mediated damage to the neuromuscular junction through the drug’s targeted dual mechanism of action. The FDA during 2019 granted orphan drug designation to zilucoplan for treating myasthenia gravis. Orphan designation was granted in 2022 by the European Commission to zilucoplan for treating myasthenia gravis.
UCB and Praxis Precision Medicines during December 2022 agreed on a collaboration, based upon the clinical-stage biopharma company’s PRAX-020 program, to discover small molecule therapeutics as potential treatments of KCNT1 related epilepsies. UCB retains an exclusive option to in-license worldwide development and commercialization rights to any resulting KCNT1 small molecule development candidates.
Andrew Humphreys is contributing editor of Med Ad News and PharmaLive.com.