Development At The Speed Of Light: Pharmas Search For A COVID-19 - - PowerPoint PPT Presentation

Pharma’s Search For A COVID-19 Vaccine

Development At The Speed Of Light:

Agenda

2

Vaccine landscape and frontrunners

Pipeline snapshot Who are the frontrunners? Potential launch timelines and upcoming catalysts Clinical data – what do we know and what questions remain?

Commercialization challenges

How large will vaccine demand be? Can manufacturing capacity meet demand? (active ingredient + fill-finish) How can equitable access to a limited supply of doses be achieved? Pricing dilemma – how to profit without impairing market access?

Regulatory hurdles

Compressed clinical development timelines FDA guidance maintains high standards for pivotal efficacy trials Enrolling clinically-relevant populations Optimal clinical trial site selection

Vaccine landscape

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Explosion in industry-sponsored trials as developers race for approval

Source: Trialtrove, 17 July 2020 4

121 planned or ongoing trials for preventative and therapeutic vaccines

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Unprecedented interest in vaccine development from both established and newcomer companies

Source: Pharmaprojects, 17 July 2020 5

• 168 pipeline vaccines
• 22 vaccines in clinical development
• 6 technologies - inactivated, viral vector, DNA, RNA,

recombinant protein, virus-like particle (VLP) *Showing top 25 companies

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Public funding and partnerships have provided an opportunity for smaller players to evaluate new technologies

Source: Datamonitor Healthcare, July 2020 6

Vaccine Company Phase Technology Public funding

AZD1222 University of Oxford/Vaccitech/AstraZeneca III ChAdOx1 vector vaccine £65.5m from UK government and up to $1.2bn from BARDA Sinopharm inactivated vaccine Sinopharm (China National Pharmaceutical Group Corp) III Inactivated vaccine China state-owned PiCoVacc Sinovac II Inactivated vaccine $8.5m from Chinese government mRNA-1273 Moderna II mRNA vaccine $483m from BARDA BNT162 BioNTech/Pfizer/Fosun Pharma II mRNA vaccine €100m from European Investment Bank (Pfizer has declined US funding) Ad5-nCoV CanSino Biologics/Beijing Institute

• f Biotechnology

II Ad5 vector vaccine R&D support from Chinese Academy of Military Medical Sciences NVX-CoV2373 Novavax I/II Recombinant protein nanoparticle vaccine $1.6bn from US government and $384m from CEPI INO-4800 Inovio I/II DNA vaccine $71m from US Department of Defense and $17.2m from CEPI Trimer-Tag vaccine Clover/GSK/Dynavax I Spike trimer subunit vaccine + adjuvant $69.5m from CEPI CureVac mRNA vaccine CureVac I mRNA vaccine €100m from European Investment Bank and €300m from German government Medicago VLP vaccine Medicago/GSK/Dynavax I VLP Undisclosed funding from Canadian government Imperial College London vaccine Imperial College London I Self-amplifying mRNA vaccine £41m from UK government

Who are the frontrunners?

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Front runners with potential 2020 Emergency Use Authorization

Source: Datamonitor Healthcare, July 2020 8

Phase I/II Phase II/III

Possible EUA in October 2020 (September in UK) Possible EUA in October 2020 Possible EUA in November 2020 Possible EUA by year end Possible EUA by year end Possible EUA by year end Possible EUA by year end

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Later market entrants will play crucial role in boosting supply

Source: Datamonitor Healthcare, July 2020 9

Vaccine Phase Catalyst

NVX-CoV2373 (Novavax) I/II Phase I immunogenicity data expected in July. Phase III to initiate in Autumn, utilizing Warp Speed funds Ad26.COV2-S (Johnson & Johnson) Preclinical Phase I/II trial initiating in July with Phase III targeted for September 2020 and EUA in Q1 2021 Adjuvanted subunit vaccine (Sanofi/GSK) Preclinical Phase I expected in H2 2020, anticipated approval in H2 2021 Measles vector-based vaccine (Merck/Themis) VSV vector-based vaccine (Merck/IAVI) Preclinical Phase I trials in H2 2020

• Novavax, J&J, and Merck & Co are part of the “Operation Warp Speed” program. All three have

received US-government funding to fund clinical development and scale up manufacturing capacity

• Novavax is targeting 100m doses by the end of 2020, and up to 1bn dose by the end of 2021
• J&J is also targeting 1bn doses by the end of 2021 with a single-dose schedule
• Merck & Co is ultimately targeting 1bn doses, and replicative nature of viral vectors may facilitate

single-dose schedules

Phase I insights and remaining questions

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mRNA vaccines have shown great promise in Phase I

Source: BioNTech, July 2020; Moderna, July 2020 11

• BNT162b1 (Pfizer/BioNTech) which encodes S protein receptor-binding domain, and mRNA-1273 (Moderna) which encodes

full S protein, have both demonstrated ability to induce neutralizing antibody titers that were comparable to or exceeded those observed in sera of convalescent patients

• Caveat is that serum panels in both studies were primarily from patients with mild-moderate disease, who have lower

antibody titers. Pfizer/BioNTech panel may also not have been at peak of immune response (“at least 14 days after confirmed diagnosis”) and included individuals older than those who were vaccinated (18-83 years vs. 19-54 years, respectively). Moderna panel were 23-60 days post-symptom onset, age not specified.

• Moderna also released data on cellular immunogenicity showing Th1-biased CD4 T-cell responses without significant

elevation of Th2-biased CD4 T-cell responses

• Cellular immunogenicity data are expected from ongoing BioNTech European study, as well as additional data on the three
• ther constructs being evaluated.

Compelling immunogenicity as measured by neutralizing antibody titers

Vaccine (Phase III dose) Vaccine GMTs Convalescent sera Nab GMTs

BNT162b1 (30ug) 267 (Day 28; PRNT50) 94 mRNA-1273 (100ug) 654 (Day 43, PRNT80) 344 (Day 57, PsVNA ID50) 158 (n=3) 109 (n=38)

BNT162 constructs under evaluation

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Key remaining questions:

Source: Datamonitor Healthcare 12

• Correlates of protection are still unknown meaning there is no guarantee that immunogenicity will translate into protective

efficacy in pivotal studies

Will antibodies/T-cell responses confer protection? Reactogenicity a potential weakness?

• Severe fatigue and severe chills occurred in one patient each in BNT162 30ug arm (post-2nd dose), and severe erythema was observed

in 1 patient in mRNA-1273 100ug arm (post-2nd dose). Highest doses discontinued due to high frequency of severe adverse events.

• Not a barrier to approval, but could emerge as a weakness if other approaches are less reactogenic. We note that all adverse events in

Inovio’s Phase I trial (INO-4800, n=40) were mild.

How durable are neutralizing antibody responses?

• Follow-up has been limited to one month post-vaccination thus far. If responses are not durable, intra-season protection

could be compromised and seasonal vaccination may be required

Will similar immunogenicity be observed in elderly, ethnic minorities, and patients with co-morbidities?

• Both studies were limited to healthy adults aged 18-55 years, but the elderly is a key risk group and immune responses tend

to be lower due to immunosenescence. Future pivotal studies aim to enrol diverse patient groups considered at high-risk

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Mixed data for adenoviral vector vaccines thus far

Source: Doremalen et al., 2020; Zhu et al., 2020 13

• Disappointingly low rates of seroconversion for neutralizing antibodies to live SARS-CoV-2 observed in 108 healthy adults

aged 18-60 years, though T-cell responses were observed

• Single dose administered at three dosing levels (5x1010 vp/ml, 1x1011 vp/ml, 1.5x1011 vp/ml)
• Pre-existing anti-vector antibodies compromised immunogenicity of the vaccine. In addition, recipients aged 45-60 years had

lower neutralizing antibody titers than younger participants.

CanSino Ad5 vaccine immunogenicity impaired by pre-existing anti-vector antibodies Positive Phase I data for AZD1222, but preclinical model suggests it may only provide partial protection

• Phase I data from 500 subjects showed stimulation of both humoral and cellular immunity after a single dose
• However, preclinical challenge study in six rhesus macaques showed that the vaccine did not prevent infection, but did provide

protection from pneumonia compared to unvaccinated controls. No difference in viral loads in nose swabs also suggests vaccine will not prevent individuals transmitting the virus, which has implications for efforts to achieve herd immunity Neutralizing antibodies (live SARS-CoV-2 assay) Low dose (n=36) Middle dose (n=36) High dose (n=36) GMTs (day 28)

14.5 16.2 34.0

≥4-fold increase (day 28)

18 (50%) 18 (50%) 27 (75%)

• Highest dose (1.5x1011 vp/ml) discontinued due to higher frequency of severe adverse events (17%)

Regulatory requirements

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Some helpful definitions for the next slide…

Source: Pharmapremia, July 2020 15

Probability of Success (PoS): The probability of successfully advancing from one clinical stage to another, or from NDA/BLA to approval. PoS is expressed as a percentage. It represents the percentage of products that successfully transitioned through a phase, divided by the number of products in that Phase that have undergone a Phase transition (either successfully or unsuccessfully). For example, if there were 100 drugs in Phase II development and 50 transitioned to Phase III, 20 were suspended and 30 remained in Phase II development, the probability of success would be: 50/70 = 71.4%. Likelihood of Approval (LOA): The probability of a drug gaining FDA regulatory approval from its current phase

• f development.

For example, if a drug is currently in Phase II, and the probability of success for Phase II is 30%, Phase III is 50%, and NDA/BLA is 80%, then the likelihood of approval for the Phase II drug would be: (30%*50%*80%) = 12%

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Urgency has led to unprecedented compression of clinical development timelines

Source: Pharmapremia, July 2020 16

• Average clinical development duration for vaccines is 11 years
• Average likelihood of approval for a a Phase I vaccine is 16.5%
• Pfizer/BioNTech, Moderna, CanSino, and AstraZeneca/University of Oxford have all progressed from Phase I to Phase III

within 2–4 months, with fastest possible approval within a 5-month clinical development timeframe (Pfizer/BioNTech)

• BUT… regulators are rightly insisting on large-scale trials, in at-risk patients, with robust efficacy and safety endpoints

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FDA guidance sets a rigorous standard for clinical trial design

Source: FDA, June 2020 17

• Trial size recommendations: Several thousand participants required to have reasonable probability of demonstrating protective
• efficacy. Moderna/AstraZeneca/Pfizer pivotal trials are targeting 30,000 patients each
• Must enroll ‘at-risk’ patients: This includes the elderly, ethnic minorities, and patients with relevant co-morbidities. This is

essential for both clinical relevance and to maximize the probability of demonstrating efficacy

• Acceptable efficacy endpoints: Either laboratory-confirmed COVID-19 or laboratory-confirmed SARS-CoV-2 infection is an

acceptable primary endpoint. Reduction in severe COVID-19 disease should be evaluated as a secondary endpoint (if not a primary endpoint), and incidence of both symptomatic and asymptomatic infections should be evaluated.

• Required safety endpoints: Solicited local and systemic AEs for at least 7 days after vaccination, unsolicited AEs for at least 21–

28 days after vaccination, and serious and other medically attended AEs for at least 6 months after final dose

• Follow-up: At least 1–2 years to gauge longevity and potential for vaccine-associated enhanced respiratory disease
• Comparator: Placebo control arm is necessary, but active comparators may be possible in future

Key requirements/recommendations:

“There are currently no accepted surrogate endpoints that are reasonably likely to predict clinical benefit

• f a COVID-19 vaccine. Thus, at this time, the goal of development programs should be to pursue

traditional approval via direct evidence of vaccine safety and efficacy in protecting humans from SARS- CoV-2 infection and/or clinical disease.”

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Choice of clinical site locations must reflect changing epicenter of the pandemic

Source: ECDC, July 2020 18

• Trial site selection is crucial to

ensure a high enough COVID-19 attack rate in the placebo arm to be able to demonstrate vaccines have statistically significant protective efficacy

• Brazil, Chile, Russia, South Africa,

Saudi Arabia, UAE, and US are sites in announced pivotal trials

14-day cumulative reported COVID-19 cases per 100,000

Key Commercialization Challenges

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Key challenges:

Source: UN Population Prospects, 2019; WHO, 2020 20

• Which risk groups are likely to be prioritized? WHO suggests 24% of global population (~1.9bn) fall into highest priority groups

(healthcare workers, elderly, and individuals with certain co-morbidities such as diabetes and hypertension)

• What coverage rates are required for herd immunity? What coverage can be realistically achieved? Will public perception be

affected by rushed development process and declining case numbers in some markets?

How large will vaccine demand be? What is an appropriate price to balance need for profitability with ensuring market access?

• Traditional HTA processes are too slow and required data may not be available, thus short-term price agreements will be necessary
• Prices must reflect substantial public investment in the R&D process and lesser ability to pay of lower-income markets
• Initial altruistic approaches of certain companies could act to set short-term price cap for rivals with greater focus on profit
• Possible seasonal recurrence/annual vaccination has implications for longer-term profitability

Can manufacturing capacity meet demand (both active ingredient and finish-fill capacity)?

• Significant CEPI and BARDA investments have allowed manufacturers to partially de-risk scale up process ahead of demonstrating

proof-of-concept

• Competition for finish-fill capacity could be a major hurdle. Manufacturing demand for therapeutics must also be considered

How can equitable access to a limited supply of doses be achieved?

• Nationalistic agreements with manufacturers to secure supplies in advance will inevitably result in lower-income markets losing out
• Supranational national initiatives such as COVAX (ACT-Accelerator vaccines pillar) which aims to secure 2bn doses by 2021, and the EU

Emergency Support Instrument will play crucial roles in ensuring equitable access, though the former is still far off fundraising target ($18.1bn)

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Vaccine supply estimates by end of 2021 = 8.3bn doses*

Source: Company statements 21

*Figure only includes estimates from companies which have explicitly stated a targeted dose capacity in 2021

Questions? Email: pharma@informa.com

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