drugs to watch 2020 and potential drugs in …manual review of drugs to determine likelihood of...

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

Mandakini Goel, M.Pharm., PhD

April 2020

1© 2019 Clarivate Analytics


Featured Speaker

Dr. Mandakini Goel

Lead, Life Science Consulting Services &

Sr. Solution Consultant, South Asia

Clarivate Analytics

Agenda Blockbuster Drugs Prediction 2020

Trends

Individual Drug Deep Dive

Covid-19

Q&A

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Methodology2.

• 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.


Key Highlights

Blockbuster Drugs Prediction: 2020


Data is compiled from Cortellis from Clarivate Analytics

Methodology

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.


Eleven potential blockbuster drugs offer hope, threaten budgets

Trends

• Rybelsus (Novo Nordisk A/S,)- the first oral GLP-1 receptor agonist for people with type 2 diabetes- more convenient once-daily tablet.

• Enhertu (Daiichi Sankyo/ Astrazeneca) -delivered a new method for targeting certain breast tumors, building on the many advances in medicine's understanding of the diseases since the approval of another blockbuster, Herceptin (trastuzumab, Roche Holding AG) in 1998.

• Biohaven Pharmaceutical Holding Co. Ltd.’s rimegepant (BHV-3000) for migraine- first small molecule CGRP antagonist to launch for acute treatment of migraine.

• Valrox (Biomarin Pharmaceutical Inc), for Hemophillia- if approved, would become the first gene therapy.

• Inclisiran, from The Medicines Co.- first siRNA-based inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9)

• Immunomedics Inc.’s sacituzumabgovitecan - first ADC to target TROP-2, a pan-epithelial cancer antigen.

• Valrox as gene and cell therapy for HemophiliaA

• Liso-cel (Bristol-Myers Squibb Co.) - large B-cell lymphoma,

Significantly enhanced patient compliance

First-in class therapies Biologics

The eleven drugs between them are holding: • Eighteen orphan drug designations, • Four FDA breakthrough therapy designations, • Two EU PRIME designations and • One Japanese SAKIGAKE designation

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Rimegepantfor Migraine

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

First small molecule CGRP (calcitonin gene-related peptide) receptor antagonist for acute treatment of migraineExpected sales: $1.03 billion in 2024Salient 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.

• The first monoclonal antibody injectable molecules that block CGRP, Emgality, Aimovig and Ajovy, are the key drugs for prophylactic use in chronic migraine patients.

Approved in Feb 2020

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Ozanimod & Ofatumumabfor 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.

Oral agonist of the sphingosine 1-phosphatase (S1P) 1 and 5 receptorsExpected sales: $1.621 billion in 2024Salient 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 FingolimodCompetition:• 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 tolerability compared to Tecfidera, and Mavenclad, which is superior to Gilenya in terms of progressive multifocal leukoencephalopathy risk.

Approved on 26th March 2020

Anti-CD20 monoclonal binds to CD20 to eradicate the B cells that would otherwise attack the myelinExpected sales: $1.261 billion in 2024Salient Features:• Offers at-home once-in a month, subcutaneous delivery• New potential option for Relapsing MSCompetition:• 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.

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Vadadustat & Valroxfor 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.

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 2024Salient Features:• Oral delivery and demonstrated non-inferiority with respect to

hemoglobin level versus the active injectable comparatorCompetition:• 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 2024Salient Features:• First potentially curative treatment; Transformative for patients;

First-mover advantage• Breakthrough therapy and orphan drug designations from FDACompetition:• 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, UltragenyxPharmaceutical 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.

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Filgotinibfor Rheumatoid Arthritis

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

Filgotinib is an oral inhibitor of Janus kinase (JAK) 1Expected sales: $0.857 billion in 2024Salient 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)

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Rybelsus & Inclisiranfor Metabolic Disorders

Rybelsus is oral acting GLP-1 analog and used to treat Type II Diabetes Mellitus.

Expected sales: $3.2 billion in 2024Salient 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 approvalCompetition:• 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 2024Salient 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)

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Sacituzumab govitecan,Enhertu & Liso-cel

for Cancer

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 2024Salient 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 2024Salient Features:• A new method for targeting certain breast tumors• Approved months ahead of expectations in the USCompetition:• 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 2024Salient Features:• A new method for targeting certain breast tumors• Approved months ahead of expectations in the USCompetition:• 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

25Confidential: Internal Use Only

Coronavirus Disease 2019 (COVID-19)An overview of origin, epidemiology and

supporting treatment


Coronavirus disease 2019 – Introduction & History

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

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

27

Covid-19

Epidemiology

✓ 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


Covid-19

Targetscape

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 genome

5

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Covid-19

Drug Pipeline

• In total, 644 drugs are linked to the therapeutic category of Anti-Coronavirus (CoV) Drugs in CDDI and 85 are under active development

• 41 drugs are targeting Human Coronavirus (SARS-CoV-2; COVID-19 Virus) Proteins

• 210 drugs are Targeting Human SARS Coronavirus (SARS-CoV) Proteins

• Efforts on drug repurposing are underway with 34 launched drugs, getting explored for treatment of Covid-19.

• 407 drugs are in Biological testing stage and 152 drugs are in preclinical stage.

0 50 100 150 200 250 300 350 400 450

Launched

Registered

IND filed

Phase III

Phase II

Phase I/II

Phase I

Clinical

Preclinical

Biological Testing

34

1

2

5

14

6

14

5

152

407

Number of Drugs

• Chloroquine, is currently being evaluated in multiple clinical trials in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19).

• Remdesivir, a nucleoside RNA polymerase inhibitor against Ebola virus was developed by Gilead Sciences, Inc. The FDA approved the investigational new drug (IND) filing of Remdesivir for the treatment of COVID-19. This was followed by Gilead’s announcement of two Phase 3 clinical studies on 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


Drug Repurposing

Potential Mechanisms

Identify the related drugs which are acting

on the identified targets for Covid-19

virus but were originally tested on

some other indications

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


Novel Drug Development


Identify the pharmacological targets which are

involved in the etiology of the disease

and develop novel drugs to act on the identified targets

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


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

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.


Covid-19

Vaccines

1https://www.who.int/blueprint/priority-diseases/key-action/Novel_Coronavirus_Landscape_nCoV_11April2020.PDF?ua=1

https://www.who.int/blueprint/priority-diseases/key-action/Novel_Coronavirus_Landscape_nCoV_11April2020.PDF?ua=1


Q&A

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