Candidate: Vaccine
Type: mRNA-based coronavirus vaccine encoding the full-length spike protein of SARS-CoV-2 and formulated with lipid nanoparticles (LNP). The vaccine uses nucleotides without chemical modifications in the mRNA, and is designed to provide a strong and balanced activation of the immune system.
2021 Status: Q3 Submission Expected in Europe—CureVac said August 31 it expected to complete its rolling submission for CVnCoV in the European Union by the end of the third quarter following publication of primary data from its pivotal Phase IIb/III HERALD trial (NCT04652102; EudraCT Number: 2020-003998-22) in Preprints with The Lancet. The HERALD study enrolled approximately 40,000 participants in ten countries across Latin America and Europe, in the predefined age groups 18 to 60 and above 60. For the final analysis, COVID-19 cases were caused by 15 different virus variants.
48% Efficacy vs. all COVID-19, 15 Variants—CureVac on June 30 announced results from a final analysis of its pivotal Phase IIb/III HERALD trial (NCT04652102; EudraCT Number: 2020-003998-22) showing an overall vaccine efficacy of 48% (COVID-19 cases: 83 vaccine patients vs. 145 placebo patients) against COVID-19 disease of any severity, including single non-respiratory mild symptoms. Efficacy rose to 53% among 18-60 year olds (vaccine 71 vs. 136 placebo) against disease of any severity and across all 15 identified strains, climbed further to 77% protection against moderate to severe disease (9 vaccine vs. 36 placebo) in the same age group, and provided 100% protection (vaccine 0 vs. 6 placebo) against hospitalization or death.
47% Interim Efficacy—CureVac acknowledged June 16 that CVnCoV showed an interim vaccine efficacy of 47% against COVID-19 disease of any severity and did not meet prespecified statistical success criteria in the pivotal Phase IIb/III HERALD trial in approximatively 40,000 participants. HERALD was conducted in 10 countries with a combined 29 COVID-19 variant strains. At least 13 variants were circulating within the study population subset assessed at the interim analysis.
“While we were hoping for a stronger interim outcome, we recognize that demonstrating high efficacy in this unprecedented broad diversity of variants is challenging,” said CureVac CEO Franz-Werner Haas, LLD, LLM.
Investors, however, punished CureVac June 17 by sending shares down 41% to €46.47 ($55.36) in trading on the Frankfurt Stock Exchange, and down 39% to $57.83 on the New York Stock Exchange. CureVac lost $8 billion of market value.
Of the 134 COVID-19 cases assessed in the interim analysis, 124 were sequenced to identify the variant causing the infection. One single case was attributable to the original SARS-CoV-2 virus. More than half (57%) were caused by various variants of concern. Of the remainder, most were caused by less characterised variants such as C.37 (Lambda/Peru; 21% of cases) and B.1.621 (Colombia; 7%). Interim results suggested greater efficacy in younger participants but did not allow for a conclusion on efficacy in participants over age 60, CureVac said.
As of May 28, the HERALD study had enrolled approximately 40,000 participants in 10 countries in Latin America and Europe. Of those participants, approximately 75% were enrolled in Latin America and 25% in Europe. The primary objective of the HERALD study is to demonstrate the efficacy of a two-dose administration of 12µg of CVnCoV in preventing COVID-19 infection of any severity in participants without prior exposure to SARS-CoV-2.
CureVac’s Swiss subsidiary said April 19 that it began a rolling submission to Swissmedic for authorization to market CVnCoV in Switzerland. That country is one of three (the other two are Germany and Austria) where the company holds exclusive commercialization rights for program products developed through the company’s broad GlaxoSmithKline (GSK) partnership in vaccines for infectious diseases as well as second-generation vaccines for COVID-19.
CureVac also disclosed that it successfully completed recruiting in the pivotal Phase IIb/III HERALD study (NCT04652102; EudraCT Number: 2020-003998-22), with a dose of 12 µg to be administered to about 40,000 healthy adult participants in Latin America and Europe.
CureVac CEO Franz-Werner Haas told CNBC’s “Squawk Box Europe” on April 8 that his company was close to finalizing recruitment for the planned Phase III trial of CVnCoV: “We are expecting, according to our calculations, that towards the end of April or beginning of May that we will have the data,” with the hope of being granted European Commission authorization later in the second quarter.
A team of German researchers posted preclinical data March 22 on bioRxiv showing that CVnCoV protected against challenge infections with the South African B.1.351 variant of SARS-CoV-2 and a strain of the original SARS-CoV-2 B1 lineage (BavPat1) in a transgenic mouse model. The neutralization capacity of robust antibody titers was shown to be impacted by the B.1.351 variant compared to the original strain—yet vaccinated animals were fully protected from lethal challenge infections with both strains, CureVac said.
Transgenic mice expressing the human ACE2 receptor were immunized with 8µg of CVnCoV per dose, following a two-dose vaccination schedule at day 0 and day 28. Vaccination resulted in robust antibody responses and complete protection (100% survival) against the original SARS-CoV-2 strain and B.1.351 challenge infections, CureVac reported. CVnCoV vaccination efficiently blocked viral replication of B.1.351 in the lower respiratory tract and brain, and reduced viral replication in the upper respiratory tract in vaccinated and challenged animals, the company added.
Manufacturing agreement with Novartis—CureVac joined Novartis March 4 in announcing the signing of an initial agreement through which Novartis will manufacture the mRNA and bulk drug product for CVnCoV. Preparations for the start of production, technology transfer and test runs are already underway, the companies said.
Following final agreement, Novartis said, it plans to start production in the second quarter of 2021. First deliveries of the bulk drug product to CureVac are expected in the summer. Production will take place in a new high-tech production facility that was already under construction at the Novartis Kundl, Austria site, to be adapted to the needs of messenger RNA vaccine production for CVnCoV.
Novartis plans to produce up to 50 million doses of the mRNA and bulk drug product for the CureVac vaccine in 2021 and up to a further 200 million doses in 2022. The bulk drug product will then be delivered to CureVac for further processing and filling.
On February 12, CureVac initiated a rolling submission with the European Medicines Agency (EMA) for CVnCoV. The process began when the first data package consisting of CVnCoV preclinical data was submitted to EMA and passed the technical validation.
A week earlier, CureVac entered into a collaboration with the U.K. government to develop and manufacture potential vaccine candidates against SARS-CoV-2 variants. The U.K.’s Vaccines Tak Force, informed by the newly-formed Variant Vaccine Expert Advisory Group, and CureVac agreed to assess multiple SARS-CoV-2 variants, and are expected to generate vaccine candidates against those selected.
Clinical studies will be accelerated in the U.K. in order to secure emergency or conditional marketing authorizations for selected vaccine candidates against the most threatening variant viruses. Any resulting vaccine candidates will be manufactured and distributed in the UK and its overseas and dependent territories, subject to regulatory approval, CureVac said.
The agreement includes an initial supply of 50 million doses of variant vaccines to the U.K. with “some” production expected to take place in the U.K., as well as manufacturing capabilities being made available for rapid production of “large” quantities of variant vaccines for the UK if and when needed over the next three years, CureVac said.
GSK agreed to support the manufacture of up to 100 million doses of CVnCoV in 2021, the companies said February 3. The companies also said they will partner exclusively to jointly develop a number of next generation messenger RNA (mRNA) vaccines to protect from COVID-19, including multi-valent and monovalent approaches, with the potential of addressing multiple emerging variants in one vaccine. GSK and CureVac said they aim to introduce their vaccine in 2022, subject to regulatory approval.
Also on February 3, Switzerland’s federal government signed an agreement with CureVac and the Swedish government for the delivery of 5 million doses of the company’s two-dose vaccine. Curevac expects to deliver the doses to Switzerland starting in the second quarter, the Swiss government said.
Bayer said February 1 it will use its manufacturing product supply network, including its site in Wuppertal, Germany, to produce 160 million doses of CVnCoV in 2022—and possibly sooner: “The first commercial product may already be available towards the end of this year,” Bayer added.
Stefan Oelrich, President of Bayer’s Pharmaceuticals Division and member of Bayer’s Board of Management, joined CureVac CEO Franz-Werner Haas, LLD, LLM, North Rhine-Westphalia Minister-President Armin Laschet, and German Health Minister Jens Spahn in announcing Bayer’s commitment at a joint press briefing.
Bayer has agreed to join CureVac to support its development of CVnCoV, the companies said January 7. Under the agreement, whose value was not disclosed, Bayer agreed to support the development, supply, and operations of CureVac within “key territory” markets that include the European Union (EU) and unspecified additional countries. While CureVac will remain the EU Marketing Authorization Holder for CVnCoV, Bayer agreed to provide services for the vaccine that include clinical operations, regulatory affairs, pharmacovigilance, medical information, and supply chain performance.
Not covered by the agreement is manufacturing of CVnCoV, though Bayer is testing whether it can offer production capacity toward the vaccine, a CureVac spokesman told The Wall Street Journal. “We are prepared to pull out all the stops for this,” Bayer CEO Werner Baumann confirmed January 17 to the German newspaper Welt am Sonntag.
2020 Status: CureVac said December 14 it advanced CVnCoV into a pivotal global Phase IIb/III trial. CVnCoV is under study in the Phase IIb/III HERALD trial (NCT04652102), a randomized, observer blind, placebo-controlled study designed to assess the safety and efficacy of the vaccine in adults at a dose of 12 µg. The study was expected to include more than 35,000 participants in Europe and Latin America.
The trial’s Phase IIb component will assess safety, reactogenicity and immunogenicity in study participants stratified according to age (>18 and >60 years old), initially at clinical testing sites in Europe and South America, while the Phase III portion of the trial will further assess safety and efficacy. An interim analysis is set to be carried out within the first quarter of 2021.
On November 17, CureVac announced plans to accelerate the expansion of its manufacturing network to deliver pandemic-scale volumes of its COVID-19 vaccine candidate, CVnCoV, through agreements with CDMO partners for each key manufacturing step for CVnCoV. The company said it expects to significantly increase its existing manufacturing capacities for CVnCoV to up to 300 million doses in 2021 and up to 600 million doses in 2022.
To that end, CureVac said, it is currently developing an additional large-scale production facility at its headquarters in Tübingen, Germany, supported by the European Investment Bank (EIB). CureVac’s CVnCoV manufacturing network will tap into expertise and capacity across Germany, France, the Netherlands, Belgium, Spain, and Austria, as well as potentially Sweden, Poland, Italy, and Ireland.
The European Union has agreed to purchase up to 405 million doses of CureVac’s CVnCoV vaccine, European Commission President Ursula von der Leyen said on November 16. The deal was to be authorized by the Commission the following day. The price was not disclosed.
The purchase agreement calls for the EU to buy an initial 225 million doses, with an option to buy another 180 million. The deal will bring to 1.8 billion the number of COVID-19 vaccine doses procured by the EU.
On November 12, CureVac announced initial stability data showing that CVnCoV remained stable and within defined analytical specifications for at least three months when stored at a standard refrigerator temperature of 5° C (41° F), and for up to 24 hours at room temperature as a ready-to-use vaccine.
CureVac reported positive interim data November 2 from its ongoing Phase I dose-escalation study evaluating the safety, reactogenicity and immunogenicity of CVnCoV. CureVac said the data supported its decision to advance the 12µg dose of CVnCoV in its upcoming pivotal Phase IIb/III study, set to start before the end of 2020.
The Phase I study (NCT04449276) has enrolled 284 healthy individuals aged 18 to 60 years as of. Individuals were vaccinated intramuscularly with CVnCoV at escalating dose levels of 2, 4, 6, 8 and 12µg on days 1 and 29. At all tested dose levels, immunogenicity data showed induction of binding antibody titers, translating into relevant titers of virus neutralizing antibodies. However, at 12µg, Geometric Mean Titers (GMTs) of binding antibodies increased to the level measured in 67 symptomatic convalescent COVID-19 patients.
Per dose level, the trial included up to 10 participants who had previously tested positive for a COVID-19 infection (seropositives) to further evaluate the safety and immunogenicity of CVnCoV in this sub-population. CureVac said it intends to provide detailed Phase I data in a scientific journal “in the coming weeks.”
On September 29, CureVac said the first participant has been dosed in its Phase IIa trial (CV-NCOV-002; NCT04515147), a dose-confirmation study of CVnCoV being conducted in Peru and Panama. The trial is expected to enroll 691 healthy participants in two distinct groups: older adults ages 61 and above, and younger participants 18 to 60 years old.
Participants will receive two vaccinations at intervals of 28 days. Different dose levels will be investigated, starting at 6 µg, with the aim of confirming safety and evaluating reactogenicity of the vaccine in older adults. The trial’s first comprehensive data in older adults is expected later in the fourth quarter of 2020. The humoral immune response after administration of CVnCoV will be assessed, and the safety database expanded, to prepare for the launch of a Phase IIb/III trial that is set to enroll approximately 30,000 participants starting in the fourth quarter of 2020.
CureVac said September 4 that it was notified by the German Federal Ministry of Education and Research (BMBF) that it is expected to receive up to €252 million ($298 million) to support development of CVnCoV. The grant is also expected to fund rapid expansion of vaccine production, with payments tied to achieving milestones. CureVac said it expected to receive up to €103 million ($122 million) in 2020 and up to €149 million ($176 million) in 2021.
CureVac and the European Commission said August 20 they concluded exploratory talks toward an agreement allowing all EU member states to purchase up to 225 million doses of CVnCoV, with an option for an additional purchase of 180 million doses, once the vaccine is proven safe and effective. The vaccine is in a Phase I clinical trial in Germany and Belgium, with first results expected early in the fourth quarter. Depending on the results of the Phase 1 trial, CureVac said, it may also launch a Phase IIb/III clinical trial also in Q4 2020.
On August 14, CureVac launched a very successful initial public offering (IPO), with shares opening at $44 a share and closing at $55.90—more than triple the $16 IPO price. The company had projected total gross proceeds of approximately $213.3 million, based on the sale of 13,333,333 shares at $16 a share. CureVac also granted the underwriters a 30-day option to purchase up to an additional 1,999,999 common shares at the IPO price, less underwriting discounts and commissions.
CureVac estimated in its prospectus it would generate $182.7 million, most of which (approximately $150 million) is intended for use toward funding clinical development of its CVnCoV vaccine against SARS-CoV-2 through the completion of the Phase III clinical trial. Another aproximately $50 million is intended to fund the expansion of short-term manufacturing capabilities.
CureVac on August 4 appointed Igor Splawski, PhD as Chief Scientific Officer overseeing the company’s mRNA biology research, including its COVID-19 vaccine effort. Splawski was previously Executive Director of the Novartis Institutes for BioMedical Research (NIBR), where he also served as Site Head of the NIBR Biologics Center in Cambridge, MA
CureVac also named Franz-Werner Haas, PhD, LLD, LLM, as CEO; he was promoted in March from Deputy CEO to Acting CEO and Chief Operating Officer after Ingmar Hoerr, a former CEO and founder who returned to the helm in March, then took a medical leave of absence.
On July 20, CureVac said its mRNA vaccine program and rabies vaccine research program were not included in its potentially more than £866 million (over $1.1 billion) agreement with GlaxoSmithKline (GSK) to research, develop, manufacture, and commercialize up to five mRNA-based vaccines and monoclonal antibodies (mAbs) targeting infectious disease pathogens. The deal includes an equity investment of £170 million through which GSK agreed to take a 10% stake in CureVac.
CureVac said July 6 it entered into a €75 million (about $89 million) loan agreement with the European Investment Bank, the lending arm of the European Union. The loan is designed to support company expansion of its GMP certified production capabilities, and accelerate the completion of its fourth production site in Tübingen, Germany. The EIB financing will be provided in three €25 million ($29.6 million) tranches upon completion of pre-defined milestones.
The loan is being financed through the €400 million ($474 million) Infectious Diseases Finance Facility of Horizon 2020, the EU research and innovation program for 2014-2020.
Tesla co-founder and CEO Elon Musk tweeted July 2 that his company “as a side project, is building RNA microfactories for CureVac & possibly others,” in a follow-up to an earlier tweet that day in which he praised CureVac’s mRNA technology: “In principle, I think synthetic RNA (and DNA) has amazing potential. This basically makes the solution to many diseases a software problem.”
Musk is expected to apply CureVac’s The RNA Printer™, a transportable, down-scaled, automated mRNA printing platform for which CureVac was awarded a $34 million contract by the Coalition for Epidemic Preparedness Innovations (CEPI). The RNA Printed is designed to provide a rapid supply of lipid-nanoparticle (LNP)-formulated mRNA vaccine candidates targeting known pathogens that include Lassa Fever, Yellow Fever, and Rabies—and enable rapid response to new and previously unknown pathogens.
In June, CureVac launched its Phase I clinical trial for CVnCoV following approval by the German Health Authority Paul-Ehrlich-Institute (PEI) and the Belgian Federal Agency for Medicines and Health Products (FAMHP).
The Phase I dose escalation clinical trial is recruiting 168 healthy subjects between ages 18-60 and will target a dose range of 2 µg to 8 µg. The trial’s aim is to determine the optimal dose as well as to evaluate the safety and immune profile of the vaccine in humans.The trial will be conducted in Germany and Belgium. First subjects will be vaccinated at the Institute for Tropical Medicine in Tübingen and the Ghent University Hospital (Belgium), the Tropical Institute of the University Hospital Munich, LMU (Germany), and the Hannover Medical School (Germany).
In parallel with the trial, CureVac is producing “large quantities” of vaccine at its GMP-certified large-scale mRNA production facility in Tübingen, Haas said in a statement.
Two days earlier, CureVac said the Federal Republic of Germany will invest €300 million ($337 million) in CureVac through the German state-owned developmemt bank Kreditanstalt für Wiederaufbau (KfW). Funds from the capital raise will be used toward the development of the company’s pipeline and mRNA platform technology, as well as the expansion of business activities, CureVac said. According to a draft agreement, the KfW will hold an approximately 23% stake in CureVac.
CureVac’s head of communications, Thorsten Schüller, told GEN in April that the company was on track to launch its vaccine into clinical trials by this summer, in line with its projection in a March 17 telephone briefing. He noted that CureVac’s SARS-CoV-2 vaccine isn’t its first using mRNA technology; the company has been testing its lipid nanoparticle mRNA rabies vaccine in human clinical trials, with results that he said have exceeded expectations: “We have indeed seen a long-lasting immune response in our preclinical studies with our mRNA-based vaccines.”
Also in March, the European Commission offered up to €80 million ($88 million) toward scaling up development and productions of the vaccine. The Coalition for Epidemic Preparedness Innovations (CEPI) awarded the company up to $8.3 million in January for accelerated vaccine development, manufacturing and clinical tests.
CureVac has denied a report in the German newspaper Welt am Sonntag that the administration of President Donald Trump sought to lure German-based CureVac to the U.S. with funding to produce its vaccine exclusively for the American market after then-CEO Dan Menichella visited the White House March 2 with other biopharma executives, while Germany’s government pressed for the company to stay in Tübingen and produce its vaccine for Germany and Europe.
U.S. ambassador to Germany, Richard Grenell denied the German news report via Twitter, but an unnamed German Health Ministry spokeswoman confirmed Germany’s interest in CureVac developing vaccines domestically in a statement to Reuters. Menichella resigned on March 11, and was succeeded by Hoerr, who just five days later took a temporary leave of absence for medical reasons “not caused by coronavirus,” the company said.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types:
● ANTIVIRAL
● VAX
● ANTIBODY
● RNA
