Development At The Speed Of Light: Pharma’s Search For A COVID-19 Vaccine
Agenda 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? Regulatory hurdles Compressed clinical development timelines FDA guidance maintains high standards for pivotal efficacy trials Enrolling clinically-relevant populations Optimal clinical trial site selection 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? 2
Vaccine landscape
Explosion in industry-sponsored trials as developers race for approval 121 planned or ongoing trials for preventative and therapeutic vaccines informa | Pharma Intelligence Source: Trialtrove, 17 July 2020 4
Unprecedented interest in vaccine development from both established and newcomer companies 168 pipeline vaccines 22 vaccines in clinical development *Showing top 25 companies 6 technologies - inactivated, viral vector, DNA, RNA, recombinant protein, virus-like particle (VLP) informa | Pharma Intelligence Source: Pharmaprojects, 17 July 2020 5
Public funding and partnerships have provided an opportunity for smaller players to evaluate new technologies Vaccine Company Phase Technology Public funding AZD1222 University of III ChAdOx1 vector vaccine £65.5m from UK government and up to $1.2bn Oxford/Vaccitech/AstraZeneca from BARDA Sinopharm inactivated vaccine Sinopharm (China National III Inactivated vaccine China state-owned Pharmaceutical Group Corp) 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 II Ad5 vector vaccine R&D support from Chinese Academy of Military of Biotechnology Medical Sciences NVX-CoV2373 Novavax I/II Recombinant protein $1.6bn from US government and $384m from nanoparticle vaccine 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 $69.5m from CEPI vaccine + adjuvant 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 £41m from UK government vaccine informa | Pharma Intelligence 6 Source: Datamonitor Healthcare, July 2020
Who are the frontrunners?
Front runners with potential 2020 Emergency Use Authorization 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 informa | Pharma Intelligence 8 Source: Datamonitor Healthcare, July 2020
Later market entrants will play crucial role in boosting supply Vaccine Phase Catalyst NVX-CoV2373 I/II Phase I immunogenicity data expected in July. Phase III to (Novavax) initiate in Autumn, utilizing Warp Speed funds Ad26.COV2-S Preclinical Phase I/II trial initiating in July with Phase III targeted for (Johnson & Johnson) 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 Preclinical Phase I trials in H2 2020 (Merck/Themis) VSV vector-based vaccine (Merck/IAVI) 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 informa | Pharma Intelligence 9 Source: Datamonitor Healthcare, July 2020
Phase I insights and remaining questions
mRNA vaccines have shown great promise in Phase I Compelling immunogenicity as measured by neutralizing antibody titers 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 other constructs being evaluated. BNT162 constructs under evaluation Vaccine (Phase III Vaccine GMTs Convalescent dose) sera Nab GMTs BNT162b1 (30ug) 267 94 (Day 28; PRNT50) mRNA-1273 (100ug) 654 (Day 43, PRNT80) 158 (n=3) 344 (Day 57, PsVNA ID50) 109 (n=38) informa | Pharma Intelligence 11 Source: BioNTech, July 2020; Moderna, July 2020
Key remaining questions: Will antibodies/T-cell responses confer protection? Correlates of protection are still unknown meaning there is no guarantee that immunogenicity will translate into protective efficacy in pivotal studies 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 Reactogenicity a potential weakness? Severe fatigue and severe chills occurred in one patient each in BNT162 30ug arm (post-2 nd dose), and severe erythema was observed in 1 patient in mRNA-1273 100ug arm (post-2 nd 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. informa | Pharma Intelligence 12 Source: Datamonitor Healthcare
Mixed data for adenoviral vector vaccines thus far CanSino Ad5 vaccine immunogenicity impaired by pre-existing anti-vector antibodies 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 (5x10 10 vp/ml, 1x10 11 vp/ml, 1.5x10 11 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. Neutralizing antibodies (live Low dose (n=36) Middle dose (n=36) High dose (n=36) SARS-CoV-2 assay) GMTs (day 28) 14.5 16.2 34.0 ≥4 -fold increase (day 28) 18 (50%) 18 (50%) 27 (75%) Highest dose (1.5x10 11 vp/ml) discontinued due to higher frequency of severe adverse events (17%) 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 informa | Pharma Intelligence 13 Source: Doremalen et al., 2020; Zhu et al., 2020
Regulatory requirements
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