The COVID-19 pandemic has stretched the limits of pharmaceutical development and manufacturing due to the pressing need for billions of doses to reach patients as soon as possible. It is clear that broad social change, science-driven development, and strong partnerships will be required to combat this public health crisis in the near term, but there will also be long-term benefits from this period of accelerated innovation. Here, we discuss the partnership between Arcturus Therapeutics and Catalent Biologics on a novel mRNA-based COVID-19 vaccine program and how we are collaborating to enable and expedite scale-up to large-scale manufacturing, including how that applies to the pandemic and future vaccine development.

An Unprecedented Challenge

The challenge of developing a vaccine against the SARS-CoV-2 coronavirus for widespread distribution in a fraction of the time typically required is completely unprecedented and logistically daunting. To compete in this high-pressure environment, pharmaceutical companies are stepping up their game — weeding out inefficiencies, doubling laboratory shifts, and reshuffling development stages or even running some processes in parallel. Around the world, upward of 200 companies are attempting to create a vaccine, antiviral, or other therapeutic agent for potential use in the fight against COVID-19. At Arcturus and Catalent, through our current collaboration, we are excited to be among them — for the challenge of bringing a novel mRNA-based vaccine into existence, the contribution we make in helping turn the corner on this pandemic, and the chance to play a role in the industry-wide innovation that is helping to bring a vaccine to market. 

Time to Think Differently

The scale of the challenge and absence of a roadmap have sponsor companies questioning conventional timelines and looking for ways to transform their operations and practices on multiple levels. Some are seeking to access new expertise, production capacities, and geographies. Many are taking on business risks that they would not consider under other circumstances, such as scaling-up production and assuming some significant financial risk before a product is approved. Others are adopting new, more scalable technologies. Regulatory agencies are removing barriers to the timely arrival of an effective vaccine through a variety of approaches, including providing funding for development and scale-up, helping sponsors find manufacturing capacity, and ensuring timely review of materials. Arcturus Therapeutics and Catalent Biologics are leveraging these strategies and more in our effort to meet the challenge to scale production as quickly as possible. 

Strong Partnership

The Arcturus/Catalent partnership is a case study in how cutting-edge technology and collaboration can help address the situation at hand.¹ Arcturus, a leading clinical-stage messenger RNA (mRNA) medicines and vaccine developer, was founded around a biodegradable lipid nanoparticle (LNP) platform with the goal of delivering medicines more safely to the liver. That technology evolved to become LUNAR^®, a proprietary four-lipid component system that binds with cell membranes and endosomes to deliver its contents to cells. 

The inclusion of proprietary ionizable lipids in the LUNAR^® vehicle distinguishes Arcturus’ technology from other mRNA platforms. LUNAR^® works by binding to cell surfaces and entering cells via fusion with the cell’s endosome. As the endosome ages and degrades, pH-sensitive ionizable lipids in LUNAR^® change their shape, disrupt the endosome, and liberate its mRNA contents into the cytoplasm. Antigen expression can then occur, and an immune response is elicited. 

Arcturus has since expanded from a platform company into a therapeutics company, with a focus on mRNA-based therapeutics. The company’s most advanced program is LUNAR-OTC, an intravenous mRNA therapy in phase 1 for the treatment of the life-threatening genetic disease ornithine transcarbamylase (OTC) deficiency.² Other programs in Arcturus’ pipeline include an inhaled agent that addresses the root cause of cystic fibrosis (developed in partnership with The Cystic Fibrosis Foundation), and, in the vaccine space, Arcturus has partnered with pharmaceutical companies in animal health. 

The decision to partner with Catalent to manufacture a novel COVID-19 vaccine was straightforward — Catalent has hands-on experience in mRNA vaccine production, something quite rare in the industry, and suitable manufacturing facilities were available. Their Madison, Wisconsin facility — originally designed for traditional mammalian cell culture using single-use bioreactors — houses three manufacturing clean rooms or “flex suites” where mRNA therapeutics can be made in large volume. An Arcturus/Catalent partnership was already in place for a separate non-COVID program, which was yielding exciting preclinical results, when COVID hit in early 2020. With the technology, the expertise, and the partnership all there, Arcturus felt uniquely poised to develop a vaccine against COVID-19 and felt an obligation to try. 

When approached by Arcturus about manufacturing their mRNA vaccine against COVID-19, Catalent had to consider whether they were willing to procure materials and begin manufacturing before a formal contract was in place for the program. Ordinarily, the answer would be no; it just doesn’t make business sense to take on that risk to order long lead time materials and initiate preparatory activities at the site before an agreement is signed. But these are not ordinary times, the team thoroughly analyzed this case, taking into consideration that every day of delay is a day without a potentially life-saving vaccine available to patients. Catalent concluded that the best course of action was to accept the risk and do what would be best for patients. 

LUNAR-COV19

mRNA vaccine technology avoids some of the potential concerns surrounding conventional vaccines, as live viral particles and adjuvants are not needed. Arcturus’ coronavirus vaccine candidate LUNAR-COV19 leverages the proprietary DNA self-transcribing and replicating mRNA (STARR^TM) technology. Delivered via Arcturus’ non-viral LUNAR^® platform, STARR^TM mRNA encodes not just the vaccine target protein (in this case, the SARS-CoV-2 spike protein), but also the self-replicating bioproteins that sustain production of the antigen. As a result, STARR^TM mRNA does not disappear within hours like native mRNA; it self-perpetuates for about 40 days, allowing for sustained antigenicity and an amplified signal to the immune system. The hope is that a clinically meaningful immune response may be mounted from a minuscule mRNA vaccine dose.

A very low-dose mRNA vaccine — micrograms rather than milligrams needed with a traditional vaccine — has advantages. First, mRNA sequences are fast to make via this process, enabling us to produce a vaccine quickly and respond to wild-type viral mutations should they occur.³ Second, we could make many more doses — perhaps thousands more per batch — from a single manufacturing run. This is critical during a pandemic when the goal is to vaccinate billions of individuals quickly. Third, the vaccine can be formulated for a single injection (most others are looking at a two-shot series), which would likely translate into a more fully immunized population, while lowering the burden on the healthcare system and patients. 

Full Tilt

Within seven weeks of agreeing to collaborate, the first GMP batch was manufactured. That usually takes 10–12 months. Three months after that, phase I clinical trials began. Arcturus plans to enter phase III quickly, in months rather than years and hopes to have a vaccine in 2021. In terms of production, we are currently working on an intermediate-scale process and planning a large-scale process that will ultimately produce hundreds of millions of doses.

At Arcturus, we are taking a multipronged approach to accelerating our timeline. We are using a highly efficient method for making mRNA; so, in our initial stages, we were able to define a construct, manufacture it, and get it into the clinic in rapid succession. The rate-limiting step is making the DNA template. But each microgram of DNA can make 50 micrograms of RNA, enabling RNA production to be scaled up quite easily. We are designing clinical trials with accelerated timelines and working more closely with agencies to get rapid feedback. We have taken a number of steps at risk, such as scaling up to commercial level manufacturing even before we have the readouts from the combined phase I/II clinical trial. 

Improving efficiency from a manufacturing perspective is key. Many vendors for raw materials and consumable supplies have increased the lead time from order to receipt during the pandemic. We are learning to be more proactive about procuring supplies — preordering materials and building inventory — and resolving delays expeditiously when they happen. We are learning to think 9, 12, and even 18 months ahead instead of 3 or 6 months ahead and moving towards a dedicated staffing model for programs run in the flex suites. 

In terms of the process itself, some steps cannot be accelerated, and certain sequences need to be followed. What we have not done is compromise product quality or deviate from GMP. But we have been able to shorten downtime between shifts, for example, by performing them back-to-back rather than waiting overnight. That requires adding second shifts and expanding shift coverage. We are also looking at producing consecutive batches or “campaigning” (rather than producing an individual batch) and accelerating real-time testing for both in-process samples and product release. 

The U.S. Food and Drug Administration (FDA), the National Institutes of Health (NIH), the Biomedical Advance Research Development Authority (BARDA), and other regulatory agencies are prioritizing COVID-related programs via funding, accelerated submissions, and other measures. It may be that sponsor companies will be allowed to submit a “rolling” Biologics License Application (BLA), submitting sections for review as they are completed rather than waiting until the end. In the meantime, once efficacy is demonstrated, it is possible that vaccines can be made available through emergency access or compassionate use protocols. These modified pathways are fluid at the moment, and the guidance can change quickly. Agency guidance around mRNA vaccine development is even less clear but also evolving, which is perhaps appropriate given the novelty of the modality.

Current Status and Ongoing Challenges

In preclinical studies, the sponsor is seeing impressive neutralizing antibody titers and cell-mediated immune response (a balanced T_H1–T_H2 ratio and a strong antigen-specific CD8⁺) to the vaccine. The phase I/II randomized, double-blinded, placebo-controlled, ascending-dose study in collaboration with Duke University and the National University of Singapore is actively enrolling adult subjects.⁴ In phase I, four single-injection dosages will be evaluated sequentially in younger adults (21–55 years). Two dosages will be selected for evaluation in phase II in both younger and older (56–80 years) adult cohorts. The primary outcome is safety and tolerability; secondary outcomes are seroconversion rates and neutralizing antibody titers. 

An mRNA-specific challenge is the need for ultracold storage. In general, most mRNA products require long-term storage at –80 °C, with allowance for brief periods at –20 or –4 °C during shipping. We are addressing this by optimizing our means for gathering temperature-excursion data and looking into product lyophilization. We are confident that the LUNAR^® vehicle and mRNA components can scale up quickly; however, another challenge is the potential for a bottleneck at the fill-finish step. Of course, this will be a challenge for all COVID-19 vaccine manufacturers, regardless of modality, due to the sheer volume of the demand.

An Eye Toward the Future

The availability of effective vaccines will be cause for great celebration. There will be market space for multiple vaccines, given the number of people that will need to be vaccinated. Companies that understand their strengths and excel at collaboration stand the best chance to provide solutions. 

What follows breakthrough vaccine development is anybody’s guess. We don’t know, for example, how long natural immunity and/or vaccine-induced immunity will last. We don’t know if the virus will mutate, and, if so, how often a new vaccine will be needed. It is doubtful that this will be a one-and-done endeavor. COVID-19 may resurface in waves around the world for many years. The industry has to be prepared for ongoing challenges that will require us to think on our feet.

Our new normal in pharmaceutical research and development is going to be very different than our previous experience. From remote work to speed-to-contract, and new ways of communicating between developers and manufacturers, many practices that have evolved rapidly because of COVID-19 will likely survive long after. In the past, for example, clients looking at different contract development manufacturing organizations (CDMOs) would conduct on-site visits and quality audits; but the virtual tours and audits we have been doing during the pandemic have been quite successful. The pandemic is also already causing the industry to rethink how it plans. There will likely be a continued emphasis on secondary sourcing and domestic sourcing for critical materials.

While this is a formidable challenge, it has also been very positive and very heartening. People are working around the clock, all over the world to help. Hopefully, this will get us to an effective vaccine — or a handful of effective vaccines — as soon as it is practically possible. We’re cautiously optimistic that LUNAR-COV19 will be one of them. 

The most impressive aspect of this experience has been the pace. From initiating, contracting, and going through the regulatory approval process — the speed is completely unprecedented. Once COVID-19 becomes less pressing, pharmaceutical production timelines will probably land somewhere in between where we were before and where we are now. We won’t be going back to business as usual anytime soon. 

References

1. Arcturus Therapeutics and Catalent Announce Partnership to Manufacture mRNA-Based COVID-19 Vaccine. Catalent Biologics and Arcturus Therapeutics. 4 May 2020. Web.

2. “Safety, Tolerability and Pharmacokinetics of ARCT-810 in Healthy Adult Subjects.” Arcturus Therapeutics. ClinicalTrials.gov. 4 Jun. 2020. Web. 

3. Mercatelli, Daniele and Federico M. Giorgi. “Geographic and Genomic Distribution of SARS-CoV-2 Mutations.” Front Microbiol. 11:1800 (2020). 

4. “Ascending Dose Study of Investigational SARS-CoV-2 Vaccine ARCT-021 in Healthy Adult Subjects.” Arcturus Therapeutics. ClinicalTrials.gov. 22 Jul. 2020. Web.