Drugs to Watch 2020 and Potential Drugs in Research on COVID-19

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Drugs to Watch 2020 and potential drugs in research on COVID-19

Mandakini Goel, M.Pharm., PhD April 2020

Dr. Mandakini Goel Lead, Life Science Consulting Services & Sr. Solution Consultant, South Asia Clarivate Analytics

2. Methodology

3. Trends

4. Individual Drug Deep Dive

5. Covid-19

6. Q&A

• Inclisiran’s inclusion on this year’s Cortellis Drugs to Watch list is an example of target discovery possibilities hiding in plain sight – if companies and institutions are willing to put effort into increasing sample diversity in genomic research. • Antibody-drug conjugates- often dubbed guided missiles- for many years failed due to the complexity of pairing the right antibody with the right toxic agent. On the blockbuster list are two (sacituzumab govitecan and Enhertu), which implies that the technology is finally maturing. • William Kaelin Jr.’s Nobel Prize-winning scientific discoveries on how cells sense and adapt to oxygen availability have proved to be both top-rate science, and very translatable indeed, ultimately enabling the development of multiple therapies targeting anemia and cancer, including vadadustat.

Cortellis is the premier source of life sciences competitive intelligence information and analytics. It covers and includes data gathered from diverse sources, including annual fillings, drug pipelines, clinical trials, patents, chemistry, deals, conferences, and company announcements.

Using the advanced search functions, drugs in phase 2 and phase 3 trials, at prelaunch or registration stage, or already launched in 2020 were selected.

Drugs launched prior to 2020 were excluded.

Drugs that had total forecast sales of > 1 billion were filtered.

Manual review of drugs to determine likelihood of market entry in 2020 based on factors such as regulatory status, trial results, competition, company’s expected approval or launch date,etc. 11

Each of the 11 drugs selected were subsequently searched and evaluated in individual context.

Significantly enhanced patient First-in class therapies Biologics compliance • Biohaven Pharmaceutical Holding Co. Ltd.’s • Rybelsus (Novo Nordisk A/S,)- the first oral rimegepant (BHV-3000) for migraine- first GLP-1 receptor agonist for people with type small molecule CGRP antagonist to launch 2 diabetes- more convenient once-daily for acute treatment of migraine. tablet. • Valrox (Biomarin Pharmaceutical Inc), for • Valrox as gene and cell therapy for Hemophilia • Enhertu (Daiichi Sankyo/ Astrazeneca) - Hemophillia- if approved, would become A delivered a new method for targeting the first gene therapy. • Liso-cel (Bristol-Myers Squibb Co.) - large B-cell certain breast tumors, building on the many • Inclisiran, from The Medicines Co.- first lymphoma, advances in medicine's understanding of the siRNA-based inhibitor of proprotein diseases since the approval of another convertase subtilisin/kexin type 9 (PCSK9) blockbuster, Herceptin (trastuzumab, Roche • Immunomedics Inc.’s sacituzumab Holding AG) in 1998. govitecan - first ADC to target TROP-2, a pan-epithelial cancer antigen.

The eleven drugs between them areholding: • Eighteen orphan drug designations, • Four FDA breakthrough therapy designations, • Two EU PRIME designations and

Rimegepant for Migraine

Migraine is the 3rd most prevalent illness in the world, affecting 39 million people in the U.S. and 1 billion worldwide.

© 2019 Clarivate Analytics 8 First small molecule CGRP (calcitonin gene-related peptide) receptor antagonist for acute treatment of migraine Expected sales: $1.03 billion in 2024 Salient Features: • Fast acting oral dispersible tablet (ODT) formulation • Minimal side effects • No liver safety signals after up to one year of dosing even in those receiving rimegepant daily. Competition: • Direct competition from Ubrelvy (ubrogepant, Allergan plc) and orals from other classes, such as the 5-HT 1f agonist Reyvow (lasmiditan, Eli Lilly and Co.). • Other potential competitors include Trokendi XR (topiramate, Supernus Pharmaceuticals Inc.) and Botox (botulinum toxin type A, Allergan plc). • Triptans have been the mainstay of treatment and work for 60% of migraine patients however they are contraindicated in patients with CV diseases. Approved in Feb 2020 • The first monoclonal antibody injectable molecules that block CGRP, Emgality, Aimovig and Ajovy, are the key drugs for prophylactic use in chronic migraine patients. 10

Ozanimod & Ofatumumab for Multiple Sclerosis In MS, a patient’s immune system attacks the myelin sheath that surrounds neuronal axons, disturbing motor and sensory functions, with damage that can lead to paralysis and cognitive dysfunction. It affects about 2.5 million people worldwide.

© 2019 Clarivate Analytics 10 Oral agonist of the sphingosine 1-phosphatase (S1P) 1 and 5 receptors Expected sales: $1.621 billion in 2024 Salient Features: • Easier to prescribe (no ECG, no ophthalmic evaluations or blood testing required) • Better safety profile as compared to oral S1P disease-modifying agents such as Siponimod and Fingolimod Competition: • Humanized anti-CD20 monoclonal antibody Ocrevus (Ocrelizumab) is the first therapy to treat relapsing forms and the primary progressive forms of MS. • Competition from Mayzent (Siponimod), Gilenya (Fingolimod), Tecfidera (dimethyl fumarate) and Aubagio (teriflunomide) and possibly the not-yet-approved oral therapy, Johnson & Johnson’s ponesimod. • Other oral competitors with different mechanisms are Vumerity (diroximel fumarate), which has shown improved gastrointestinal Approved on 26th March 2020 tolerability compared to Tecfidera, and Mavenclad, which is superior to Gilenya in terms of progressive multifocal leukoencephalopathy risk. Anti-CD20 monoclonal binds to CD20 to eradicate the B cells that would otherwise attack the myelin Expected sales: $1.261 billion in 2024 Salient Features: • Offers at-home once-in a month, subcutaneous delivery • New potential option for Relapsing MS Competition: • Humanized anti-CD20 monoclonal antibody Ocrevus (Ocrelizumab) is the first therapy to treat relapsing forms and the primary progressive forms of MS, however needs to be administered by infusion every six months. 13

Vadadustat & Valrox for Hematological Disorders Millions of people are affected by blood disorders, and the prevalence is expected to grow as our population ages. Worldwide incidence of hemophilia is estimated at more than 400,000.

© 2019 Clarivate Analytics 13 Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzyme inhibitors, a new class of agents for the treatment of anemia in CKD, work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end- stage kidney disease. Expected sales: $1.589 billion in 2024 Salient Features: • Oral delivery and demonstrated non-inferiority with respect to hemoglobin level versus the active injectable comparator Competition: • Direct competition from Evrenzo (roxadustat), the first-in class HIF-PH inhibitor • Intravenous iron replacement products and blood transfusions that offer rapid increases in Hb levels. • Daprodustat, yet-to-be approved, HIF-PH inhibitor Investigational gene therapy for adults with hemophilia A, designed to deliver functional copies of the FVIII gene into patients’ cells, enabling them to make the previously missing or defective FVIII protein. Expected sales: $1.297 billion in 2024 Salient Features: • First potentially curative treatment; Transformative for patients; First-mover advantage • Breakthrough therapy and orphan drug designations from FDA Competition: • Competition from Roche Holding AG's Hemlibra (emicizumab) and Bayer AG's Jivi (antihemophilic factor [recombinant] pegylated) • Potential competition in the pipeline from FVIII gene therapies in development, e.g., Spark Therapeutics Inc.'s SPK-8011 entered phase III development in February 2019, Ultragenyx Pharmaceutical Inc.’s DTX-201 (phase I/II) , Spark’s SPK-8016, Shire plc’s SHP-654 and University College London (UCL)/St. Jude Children's Research Hospital’s AAV2/8-HLP-FVIII-V3. 16

Filgotinib for Rheumatoid Arthritis Almost 20 million people worldwide are suffering from Rheumatoid Arthritis, with one million new cases diagnosed each year.

© 2019 Clarivate Analytics 16 Filgotinib is an oral inhibitor of Janus kinase (JAK) 1 Expected sales: $0.857 billion in 2024 Salient Features: • Oral Treatment • Potentially getting explored as a treatment for ulcerative colitis, Crohn's disease, psoriatic arthritis and ankylosing spondylitis, which might result in five approvals over the next four years. Competition: • Nonsteroidal anti-inflammatory drugs, steroids and disease- modifying antirheumatic drugs (DMARDs) such as methotrexate • TNF-alpha inhibitos-Humira (adalimumab), Orencia (abatacept), • IL-1 blocker- Kineret (anakinra) • IL-6 antibodies- Kevzara (sarilumab), and Actemra (tocilizumab • Anti-CD20- Rituxan (rituximab) • Direct competition with other JAK inhibitors Xeljanz (tofacitinib), Olumiant (baricitinib) and Rinvoq (upadacitinib) 18

Rybelsus & Inclisiran for Metabolic Disorders

Expected sales: $3.2 billion in 2024 Salient Features: • Combines the convenience of a once-daily pill with the glucose- lowering activity and the Cardiovascular benefits of injectable GLP1 agonists, • Already won US regulatory approval Competition: • Competition from Januvia (sitagliptin), Jardiance (empagliflozin,) and Victoza (liraglutide) Inclisiran is subcutaneously injected compound in secondary prevention patients with atherosclerotic cardiovascular disease (ASCVD) and Familial Hypercholesterolemia (FH). Expected sales: $ 1.16 billion in 2024 Salient Features: • First siRNA-based inhibitor of PCSK9 to win approval • First and only cholesterol-lowering siRNA product • Twice-a-year dosing Competition: • Repatha (evolocumab) and Praluent (alirocumab) • In patients with homozygous FH- Kynamro (mipomersen) and Juxtapid (lomitapide) 21

Sacituzumab govitecan, Enhertu & Liso-cel for Cancer

© 2019 Clarivate Analytics 21 Sacituzumab govitecan, is an ADC targeting the Trop-2 receptor expressed by many solid cancers and delivering the moderately toxic drug, SN-38, directly to the tumor. It received Breakthrough therapy designation to treat patients with metastatic triple-negative breast cancer (TNBC) who have received two prior therapies for metastatic disease. Expected sales: $ 1.27 billion in 2024 Salient Features: • Potential to become Standard of Care due to the lack of existing optimal targeted therapies and the modest efficacy of chemotherapy Competition • Competition from Tencentriq (atezolizumab), Keytruda (pembrolizumab) Enhertu is approved as a monotherapy for treating unresectable or metastatic HER2-positive breast cancer after two or more prior anti- HER2-based regimens in the metastatic setting. Expected sales: $ 2.02 billion in 2024 Salient Features: • A new method for targeting certain breast tumors • Approved months ahead of expectations in the US Competition: • Kadcyla (trastuzumab emtansine, Roche Holding AG), the only other ADC in that market, is a direct competitor • Herceptin and other HER2-targeted therapies such as Perjeta and Tykerb (lapatinib) Liso-cel is intravenous anti-CD19 CAR T-cell therapy targeting large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) in which specifically designed T cells seek and destroy CD19-expressing cancer cells. Expected sales: $0.8 billion in 2024 Salient Features: • A new method for targeting certain breast tumors • Approved months ahead of expectations in the US Competition: • Gilead Science Inc.’s Yescarta (axicabtagene ciloleucel) • Novartis’ Kymriah (tisagenlecleucel) Challenges: • The feasibility of large-scale manufacturing of such personalized therapies, • The unknowns of the CAR design itself (e.g., length of construct, choice of hinge region, location of target epitope, etc., • Lack of harmonization across the regulatory landscape, • Potentially prohibitive cost for many payers Coronavirus Disease 2019 (COVID-19) An overview of origin, epidemiology and supporting treatment

Confidential: Internal Use Only 25 Coronavirus disease 2019 – Introduction & History

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the virus SARS-CoV-2 (previously termed as 2019-novel corona virus).

Li Wenliang – Chinese ophthalmologist at Wuhan Central Hospital on 30 December 2019 warned about a possible outbreak of an illness that resembled severe acute respiratory syndrome (SARS), later acknowledged as COVID-19

Confidential: Internal Use Only 26 Epidemiology Covid-19 ✓ The case-fatality rate in a study of the first 44,000 cases in mainland China was 2.3%. ✓ Mortality among symptomatic patients is believed to be in the range of 0.5% to 4%, while among patients who require hospitalization, the rate increases to 5% to 15%. ✓ In the early Hubei Province case series, mortality among critically ill patients ranged from 22% to 62%. ✓ In Italy, a much higher case- fatality rate of 7.2% was reported

27 Targetscape Covid-19 Name of Target Drugs Orf1ab polyprotein (pp1ab) 129 Spike glycoprotein (MERS-CoV) 98 E2 glycoprotein precursor 84

Surface glycoprotein 18

Nucleocapsid protein 10

Human Coronavirus NL63, complete 5 genome

Confidential: Internal Use Only 28 Drug Pipeline Covid-19

Number of Drugs • In total, 644 drugs are linked to the therapeutic category of Anti-

Biological Testing 407 Coronavirus (CoV) Drugs in CDDI and 85 are under active development Preclinical 152 • 41 drugs are targeting Human Clinical 5 Coronavirus (SARS-CoV-2; COVID-19 14 Phase I Virus) Proteins

Phase I/II 6 • 210 drugs are Targeting Human SARS 14 Phase II Coronavirus (SARS-CoV) Proteins • Phase III 5 Efforts on drug repurposing are underway with 34 launched drugs, IND filed 2 getting explored for treatment of Registered 1 Covid-19.

Launched 34 • 407 drugs are in Biological testing

0 50 100 150 200 250 300 350 400 450 stage and 152 drugs are in preclinical stage.

29 Potential Mechanisms Drug Repurposing • Chloroquine, is currently being evaluated in multiple clinical trials in hospitalized patients with severe acute respiratory Identify the related syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19). drugs which are acting • Remdesivir, a nucleoside RNA polymerase inhibitor against on the identified Ebola virus was developed by Gilead Sciences, Inc. The FDA targets for Covid-19 approved the investigational new drug (IND) filing of virus but were Remdesivir for the treatment of COVID-19. This was followed originally tested on by Gilead’s announcement of two Phase 3 clinical studies on some other indications Remdesivir for COVID-19. • Favipiravir, an RNA polymerase inhibitor originally developed for the treatment of influenza by Fujifilm Toyama Chemical has been shown to be effective in treating patients with COVID-19

Confidential: Internal Use Only 30 Potential Mechanisms Novel Drug Development

Identify the • Sichuan Kelun Pharmaceutical is investigating a prophylactic pharmacological polypeptide, as inhalant formulation, from a series targets which are polypeptide targeting SARS-CoV-2 spike protein (S-protein) involved in the and angiotensin-converting enzyme 2 (ACE2) cellular etiology of the disease receptor to block the adsorption and fusion of virus and cell, for the potential prevention of coronavirus COVID-19 caused and develop novel by SARS-CoV-2 (2019-nCoV). In February 2020, the amplified drugs to act on the production of the polypeptide had been completed; at that identified targets time, clinical trials were planned to evaluate the safety of the polypeptide.

Confidential: Internal Use Only 31 Potential Mechanisms Structure Activity Relationship

Identify the potentially active drugs in the related targets and search for the drugs which have structural similarity to the active drugs

• 35 drugs were found to have >80% similarity to Remdesivir, some of which may prove to be effective in treating COVID- 19.

Confidential: Internal Use Only 32 Vaccines Covid-19

As per, WHO1, 70 vaccines are under active development for COVID-19. Few of the vaccines, which are ahead in the developmental stage are summarized: • Ad5-nCoV vaccine from CanSino Biologics and Beijing Institute of Biotechnology, is the only vaccine which is in Phase II development. • CHAdOx1-nCoV19 vaccine from Jenner vaccine foundation and University of Oxford is in Phase I/II development. • LV-SMENP-DC vaccine against Spike glycoproteins on SARS-CoV-2 was developed by Shenzhen Geno-Immune Medical Institute and is in early phase 1/2 clinical trials. • mRNA-1273 vaccine against COVID-19 was developed by NIH researchers in collaboration with Moderna, Inc. A phase 1 study of mRNA-1273 vaccine has begun at Kaiser Permanente Washington Health Research Institute (KPWHRI), Seattle. • INO-4800 vaccine against COVID-19 was designed by INOVIO Pharmaceuticals, Inc. Preclinical studies were started in early 2020 and clinical trials are expected to commence by April 2020. INOVIO has received $9 million grant from Coalition for Epidemic Preparedness Innovations (CEPI) and $5 million from Bill & Melinda Gates Foundation.

1https://www.who.int/blueprint/priority-diseases/key-action/Novel_Coronavirus_Landscape_nCoV_11April2020.PDF?ua=1 Confidential: Internal Use Only 33 Q&A

Confidential: Internal Use Only 34 Mandakini Goel, M. Pharm., PhD [email protected] +91 9148151072