A $60M program jointly funded with CEPI

R

3

RNA

Readiness +

Response

A $60M program jointly funded with CEPI

R

3

RNA

Readiness +

Response

A $60M program jointly

funded with CEPI

R

3

RNA

Readiness +

Response

We need a global network of ‘living’ biofoundries.
Distributed, multi-product, RNA-based manufacturing capabilities will provide increased access to diverse biologics and sustainable pandemic response.

In one of the greatest scientific accomplishments of our generation, mRNA technology has demonstrated the ability to change the timeline for developing and delivering a new vaccine from years to months. And the entire world was witness to that demonstration. The development of an mRNA-based vaccine for COVID-19 took just 63 days from release of the virus sequence to first dosing in humans, leading to accelerated clinical trials and ultimately billions of doses manufactured. The new mRNA vaccines have demonstrated efficacies in the high 90s, with minimal side effects, and have been manufactured by two different RNA technology firms to date, with others adding further production capacity.

The scale of this on-going achievement was made possible because, unlike the established existing vaccine manufacturing techniques, RNA technology shifts the most difficult and complex parts of manufacturing — the key proteins needed for a vaccine — to the natural bioreactor that is the human body. This shift meant the mRNA vaccine could deliver the instructions for how to make the antigen, or spike protein, needed to train our immune systems rather than the antigen itself. The development of lipid nanoparticles (LNPs) ensured that instructions would arrive intact to our cells – a critical element of the mRNA vaccine delivery and effectiveness. Importantly, this RNA-based approach holds promise for treatments beyond vaccines and infectious diseases to diverse biologics as treatments for cancer, metabolic disorders, cardiovascular conditions, and autoimmune diseases.

Given this vaccine breakthrough, it would be reasonable to expect a wave of activity to discover, develop, and deliver new RNA-based biologics – a diversity of organizations; academic, small biotech, private and public research centers around the world flooding clinical facilities with novel, investigational products. All these products could then be tested against diseases that cause millions of deaths per year; thus providing access to these new products, while also securing protection against the next pandemic.

While we see continued and increasing global investments to scale existing mRNA manufacturing capabilities, such investments alone will not be enough to increase the number, diversity, affordability, and pace of discovery for these new biologic treatments, or to provide continuing access to agile, state-of-the-art manufacturing processes likely needed for rapid response to another pandemic. 

What’s holding us back?  The discovery and development of RNA-based products is still subject to the same, existing limitations chronically afflicting biologics: difficult access to current good manufacturing practices (cGMP) material for clinical trials as well as long and large investments (4-8 years and $300-$500 million dollars) in bespoke, manufacturing processes at dedicated facilities. This limits innovation and creates prohibitive production costs.

Today, RNA scientists trying to develop an innovative product are limited to using laboratory-grade materials in pre-clinical studies. Outside of one of the few biopharma corporations investing in cGMP for RNA-based biologics, most researchers have limited or no access to the know-how and resources required to develop a small-scale manufacturing process required for clinical trials. And even within those corporate environments, lacking a product with an expected net present value nearing a billion dollars, it would be challenging to get priority in the large-scale manufacturing strategy of the company.

R3 seeks to change the dynamics and costs of biologics development and production, addressing the limitations of current manufacturing by establishing RNA as a versatile, deployable, standardized, multi-product platform technology, that: 1) in non-emergency times provides developers and researchers with access to cGMP-formulated RNA for the development and production of a diversity of viable RNA-based products, and 2) in emergency times shifts to needed products at speeds & quantities sufficient to mount a globally coordinated, regionally focused response to a pandemic.

The opportunity for R3. The limitations in today’s RNA-based production bears similarities with the limitations faced by the semiconductor industry at the end of the 1970s. In the twenty years following the invention of the first integrated circuit in the late 1950s, the design of semiconductor-based products was almost exclusively confined to a handful of large, vertically integrated companies that could afford the investments required by customized ISO-certified manufacturing processes. Designing a new semiconductor-based product was limited to employees within those companies and often came with adjustment and refinements to manufacturing processes. As one measure of how access to manufacturing constrained innovation, on average there were only 3 to 4 new semiconductor start-ups created globally each year during the decades between 1958 and 1978.

Then, in the decade after 1978, the number of new start-ups more than tripled – tens to dozens of new semiconductor start-ups. What happened to accelerate the number, diversity, and pace of semiconductor innovation?

Two related developments changed the rules of the game for the semiconductor industry. The first was the publication in 1978 of “Introduction to VLSI Systems” by Mead & Conway, outlining the elements of Very Large Scale Integration (VLSI) for the design of semiconductor circuits. Mead & Conway decoupled the design of a circuit from the fabrication of a circuit using digital design, simulation, and verification tools. These tools also captured and characterized different, specific fabrication processes using high-level, parametric descriptions for those processes. The decoupling of design from fabrication and the parametric abstraction of fabrication processes made it possible for a greater number and diversity of people to design integrated circuits (in the decade following publication, 1,000 to 10,000 times more people, ranging from students to experienced chip designers). Just as importantly, the decoupling and parametric abstraction enabled any of these designs to be fabricated at any of a multiplicity of fabrication sites at scale and seamlessly.

The resulting demand for fabrication services from chip designers created the market space for a second breakthrough. In 1987, the first “pure-play” foundry was stood up – a semiconductor company exclusively manufacturing third-party designs, without developing or marketing their own products. With the availability of pure-play foundries, it became possible for a new type of company to emerge – fabless semiconductors companies. These companies designed and delivered chips as their products – notable examples include Broadcom and Nvidia – but had no fabrication facilities of their own.

Vertically integrated companies with captive fabrication facilities thrived alongside the new fabless companies as both types of companies delivered a greater number and diversity of semiconductor products, growing the semiconductor industry at a compound annual growth rate of more than 10% over the last 40 years.

Since then, continued process improvements, the emergence of different lines for different classes of products, and optimization of production load balancing, has led to new speed and vibrancy in the ecosystem, further fueling additional breakthroughs.  Indeed, whenever an industry has succeeded in raising the level of abstraction to allow more innovators to participate and reduce the barriers to product delivery, seemingly explosive growth of innovation has been the result. We need this type of technological advance for RNA-based products.

Program goals.

The R3 program has two goals: one, to increase exponentially the number of biologic products that can be designed, developed, and produced every year, reducing their costs and increasing equitable access; and two, to create a self-sustaining network of manufacturing facilities providing globally distributed, state-of-the-art surge capacity to meet future pandemic needs.

Call for abstracts and proposals.

We are soliciting abstracts and proposals for work over three (3) years (with a potential additional one-year option) in one or more of the following thrust areas (see thrusts in full program announcement), to either develop the platform, develop products, or demonstrate the platform implementation.

Proposers should clearly relate work in these thrust areas to one or more of the program goals, but are not required to provide both platform technologies and end-to-end demonstrations. Synergies among performers will be facilitated by Wellcome Leap.

Program Director.

Duccio Medini, PhD has expertise in extracting knowledge from biomedical data with advanced data analytics, and co-founded the pangenomics discipline. He led global teams contributing to the successful development of vaccines from early discovery to post-implementation surveillance, including the development of the first universal vaccine against serogroup B meningitis. He earned his PhD in Physics from the University of Perugia, with a residency at Northeastern University.

Process and timeline

Program announcement.

30 DAYS FOR PREPARATION AND SUBMISSION OF ABSTRACT

15-Day Abstract review round.

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Day 1

Submission deadline: 13 August 2021

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Day 1

Submission deadline: 13 August 2021

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Day 1

Submission deadline:

13 August 2021

7-page abstracts submitted (from individual organizations or teams) that address one or more thrust areas of the program.

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Day 15

Abstract feedback sent: 27 August 2021

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Day 15

Abstract feedback sent: 27 August 2021

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Day 15

Abstract feedback sent:

27 August 2021

All submissions will receive technical and/or programmatic feedback as well as a recommendation to submit or not submit a full proposal.

30 DAYS FOR PREPARATION OF FULL PROPOSALS AFTER ABSTRACT FEEDBACK

30-Day Full proposal review round.

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Day 45

Submission deadline: 27 September 2021

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Day 45

Submission deadline: 27 September 2021

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Day 45

Submission deadline:

27 September 2021

25-page full proposals including technical approach, milestones, costs, and key personnel submitted. Proposals should specifically address abstract feedback.

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Day 75

Proposal decision sent: 27 October 2021

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Day 75

Proposal decision sent: 27 October 2021

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Day 75

Proposal decision sent:

27 October 2021

All submissions will receive a ‘selected for funding’ or ‘not selected for funding’ decision. Those selected will proceed to contract signature as the final gate with work expected to commence within approximately 30 days.

Mechanics of applying

Who is eligible?

Performers from universities and research institutions: small, medium and large companies (including venture-backed); and government or non-profit research organizations are invited to propose. 

To submit an abstract, applicants will be asked to agree to the following:

I understand that the information being disclosed will be reviewed and evaluated independently on behalf of Leap. I am submitting information with the intention that it imposes no confidentiality obligations on Leap. Furthermore, my submission does not breach any confidentiality obligations that I owe to others; there is no legal reason why I cannot submit information; and I am not underage or otherwise legally incompetent. By submitting, I am not granting, other than for the purpose of evaluation, any rights in relation to any patent, copyright or design. I am not relying upon Leap in any way for legal advice, including (but not limited to) whether the contents of my submission can be protected under IP law. I recognize that Leap may already be aware of or funding the same or related efforts as described by my submission. I agree that no contractual obligation or working relationship is being created between myself and Leap by submitting this information. If the submission is deemed of interest, I may be required to sign a further Agreement with Leap so that any confidential information, that is subsequently shared, is protected.

Abstract application steps.

  1. Download guidelines
  2. Download abstract template (and cost and schedule template ). We’ll remind you when the application portal opens on August 6.  
  3. Upload your abstract and submit your application before August 13 at 11:59pm ET.

More details will be provided for the proposal round of submissions. 

Frequently asked questions.

If you have questions, please review our FAQ section.

Send inquiries to R3@wellcomeleap.org

[i] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat Rev Drug Discov 13, 759–780 (2014); Stanton M.G., Murphy-Benenato K.E. (2017) Messenger RNA as a Novel Therapeutic Approach. In: Garner A. (eds) RNA Therapeutics. Topics in Medicinal Chemistry, vol 27. Springer, Cham.

[ii] Why tech transfer may be critical to beating COVID-19, by Cormac O’Sullivan, Paul Rutten, and Caspar Schatz, McKinsey & Company, July 2020.

[iii] Makurvet, F.D., Biologics vs. small molecules: Drug costs and patient access, Medicine in Drug Discovery, Volume 9 (2021).

[iv] Semiconductor Industry Association (SIA) and SEMATECH annual reports.

[v] Introduction to VLSI Systems, Carver Mead and Lynn Conway, Addison-Wesley (1980).

[vi]Estimates of designers based on the resulting size and number of companies and university VLSI courses.

[vii] Semiconductor Industry Association (SIA) and SEMATECH annual reports.

[viii] van de Berg, D., Kis, Z., Behmer, C.F. et al. Quality by design modelling to support rapid RNA vaccine production against emerging infectious diseases. npj Vaccines 6, 65 (2021).

[ix] Guidance for Industry. Process Validation: General Principles and Practices. Available at: https://www.fda.gov/media/71021/download.

[x] Quality Considerations for Continuous Manufacturing Guidance for Industry (US FDA – Draft Guidance). Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-considerations-continuous- manufacturing; Nino Mihokovic,”Continuous manufacturing – EMA perspective and experience” in “Integrated Continuous Biomanufacturing III”, Suzanne Farid, University College London, United Kingdom Chetan Goudar, Amgen, USA Paula Alves, IBET, Portugal Veena Warikoo, Axcella Health, Inc., USA Eds, ECI Symposium Series, (2017). http://dc.engconfintl.org/biomanufact_iii/69.

[xi] Schuster, J. et al. Machine learning approach to literature mining for the genetics of complex diseases. Database (2019); L. Marchetti, et al. Simulation algorithms for computational systems biology. In Texts in Theoretical Computer Science. An EATCS Series, Springer, ISBN: 978-3-319-63111-0, 2017.

[xii] Increasing by 50% current early probabilities of success (Ph I -> Ph II (Safety): 52.5% -> 78.7%; Ph II -> Ph III (Efficacy): 32.4% -> 48,6%) would lead to more than doubling the overall likelihood of ultimate approval for products entering clinical phase before clinical Proof of Concept: 9.1% (today) -> 20.1% (to be), bringing the average number of novel biologics approved per year from the current 13 to ~30. See: Clinical Development Success Rates and Contributing Factors 2011–2020 © BIO | QLS Advisors | Informa UK Ltd 2021; Wouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA. 2020;323(9):844–853.

[xiii] Leenaars, C.H.C., Kouwenaar, C., Stafleu, F.R. et al. Animal to human translation: a systematic scoping review of reported concordance rates. J Transl Med 17, 223 (2019).

[xiv] Kis, Z.; Kontoravdi, C.; Shattock, R.; Shah, N. Resources, Production Scales and Time Required for Producing RNA Vaccines for the Global Pandemic Demand. Vaccines 9 (3) 2021.

[xv] von Niessen, A.G.O.; Poleganov, M.A.; Rechner, C.; Plaschke, A.; Kranz, L.M.; Fesser, S.; Diken, M.; L wer, M.; Vallazza, B.; Beissert, T.; et al. Improving mRNA-based therapeutic gene delivery by expression augmenting 3’- untranslated regions identified by cellular library screening. Mol. Ther. 2018, 27, 824–836.

[xvi] Mauger, D.M.; Cabral, B.J.; Presnyak, V.; Su, S.V.; Reid, D.W.; Goodman, B.; Link, K.; Khatwani, N.; Reynders, J.; Moore, M.J.; et al. mRNA structure regulates protein expression through changes in functional half-life. Proc. Natl. Acad. Sci. USA 2019, 116, 24075–24083.

[xvii] Patel, A.K. et al. Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium, Advanced Materials 31 (8) 2019.

[xviii] Yin Y., et al. In Situ Transforming RNA Nanovaccines from Polyethylenimine Functionalized Graphene Oxide Hydrogel for Durable Cancer Immunotherapy. Nano Lett. 21 (5) 2021.

[xix] Maruggi G., Ulmer J.B., Rappuoli R., Yu D. (2021) Self-amplifying mRNA-Based Vaccine Technology and Its Mode of Action. In: Current Topics in Microbiology and Immunology. Springer, Berlin, Heidelberg.

[xx] Beissert, T. et al. A Trans-amplifying RNA Vaccine Strategy for Induction of Potent Protective Immunity. Molecular Therapy 28 (1) 2020.

[xxi] See https://www.laronde.bio/erna-science.

[xxii] Lindsay, K. E. et al. Aerosol Delivery of Synthetic mRNA to Vaginal Mucosa Leads to Durable Expression of Broadly Neutralizing Antibodies against HIV. Molecular Therapy 28 (3) 2020. 

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