The development and delivery of two mRNA COVID-19 vaccines (one by Pfizer and BioNTech and the other by Moderna) in less than a year is an extraordinary pharmaceutical success story. Little wonder that the technology behind these miracle drugs is getting lots of attention. In fact, RNA was making significant headway in several therapeutic areas before COVID-19 took center stage, and we expect the additional interest and investment now flowing into the field to accelerate progress even faster.
Several attributes make RNA one of the most promising new treatment technologies. (See Exhibit 1.) These include a fit-for-purpose molecular design and functional versatility against a wide range of “druggable” targets. While RNA still faces long-term safety and efficacy (as well as likely cost) challenges, recent advances suggest material technology improvements are coming soon. We believe that the success of mRNA COVID vaccines will propel a sooner-than-expected wave of RNA innovation in the industry. Major pharma companies need to take stock and determine how they want to participate (or watch) as the coming wave builds. Those that want a role in shaping the wave should move now if they haven’t already started.
RNA treatments have multiple benefits over other modalities, such as DNA-, protein- and small- molecule-based strategies. RNA’s combination of characteristics means that these treatments are ideal candidates for addressing highly acute medical conditions and deadly diseases that require rapid action. RNA treatments dramatically expand the range of druggable targets for illnesses and conditions, including previously out-of-reach intracellular proteins. As we have seen with the mRNA COVID vaccines, the timeline from target identification to preclinical proof of concept can be as short as several months. Since mRNA drugs can be designed to directly target the underlying cause of a disease and stop (or even reverse) its progression, they have the potential to be highly efficacious—and to achieve greater potency than protein-based drugs. They can also be personalized and designed to act on patient-specific genetic lesions. And their transience and specificity make relevant applications possible with fewer side effects.
There are still major long-term safety and efficacy challenges, arising from instability, poor cellular uptake and fast clearance, off-target effects, and immunogenicity. Such challenges include making RNA more recognizable by the human immune system and developing molecular delivery vehicles for specific tissues. Moreover, in many cases the underlying cause of the disease is unknown, so it is impossible to apply the mRNA modality. Most strategies that have been used to address these challenges leverage the ability to modulate RNA stability and translation as well as the delivery approach (such as chemical modification and lipid nanoparticle encapsulation). Recent advances suggest that technology improvements—including novel delivery and control strategies—are working.
Prior to the pandemic, RNA treatments were focused on rare genetic diseases with small target markets. Examples include Usher syndrome Type 2 (with 15,000 patients in the US and the European Union Five) and Hurler’s syndrome (with 3,000 patients in these countries). RNA therapeutics are now in clinical development to treat more common ailments, such as cancer and cardiovascular disease.
Indeed, as some countries emerge from the pandemic and others continue to fight it, infectious diseases may seem like the ideal application for RNA. But other therapeutic areas are also the subject of significant research and investment activity, including oncology (vaccines and therapies), genetic disease, cardiology, and neurology. (See Exhibit 2.)
There is even some—mostly preclinical—potential for use in combating autoimmune diseases. (See the sidebar.)
The success of the COVID vaccines has ignited substantial interest in RNA-based therapies. Multiple recent transactions suggest this to be the case, including successful fundraising rounds by RNA companies. The collaboration, option, and licensing deal between Gilead Sciences and the mRNA company Gritstone bio is another example. The strong prepandemic momentum has accelerated; an increasing number of assets in late development, capacity expansions, and process improvements could all help pave the way for proving cost-effectiveness to payers at an individual-asset level.
Before 2020, RNA therapeutics were already poised for rapid growth, with five products (Spinraza, Onpattro, Tegsedi, Exondys 51, and Evrysdi) already available and growth in annual revenues for launched assets projected at 38% from 2019 through 2024. Now, makers of these therapeutics are moving from an initial focus on rare genetic diseases toward more common indications in major treatment areas. Prior to 2020, 25% of treatments were concentrated at later clinical stages.
The key challenges for RNA treatments include targeted cell delivery and expression control, both of which affect efficacy. Treatments need to be designed with sophisticated and tailored delivery strategies and high-precision control of RNA activity (which is particularly relevant for mRNA therapeutics). Dose optimization and immunogenicity from naked RNAs and delivery vehicles have had a high failure rate between the second and third phase trials (as much as 75% of prepandemic trials failed). Because this is new technology, the long-term safety of chronic use remains unknown.
High costs are also an issue. RNA's instability creates manufacturing and distribution challenges related to storage and transportation (when ultralow cold storage is required, for example), which add to the technology’s high costs. Limited experience with commercialization and real-world outcomes means that dosing frequency can be unclear and lead to challenges in the pricing approach. In addition, the infrastructure for outcome-based payments is still immature. Before the pandemic, regulatory guidelines were still under development, but these have advanced over the past year.
Whether a company decides to use RNA-based technology depends on its portfolio and strategy. To compete in RNA therapeutics, companies need specialized capabilities—related to R&D and manufacturing infrastructure, for example—and fundamental IP. We see three types of players:
Specialists lead the current RNA ecosystem. They have the key sources of advantage, including intellectual property, talent, development know-how, and manufacturing capability at scale. But many still need partners. The alliance between BioNTech (specialist) and Pfizer (a partner that is fast becoming a specialist) on the COVID vaccine is one model that demonstrates how big pharma can provide key operations and commercial capabilities to bring new treatments to market—and build their own specialized capabilities in the process. Pfizer’s CEO told The Wall Street Journal in March that his company gained a decade’s worth of experience working with BioNTech and now plans to develop additional vaccines that target other viruses and pathogens using mRNA technology. Pfizer is adding at least 50 people to work on mRNA R&D, and the company will leverage the manufacturing network it assembled during the pandemic to compete. More recently, Sanofi has launched a dedicated mRNA-focused center of excellence, with the goal of accelerating its mRNA vaccine portfolio that it developed in collaboration with Translate Bio (the company has recently has entered into a definitive acquisition agreement with Sanofi). Novartis’s chairman has expressed interest in exploring mRNA technology.
From a strategic point of view, nonspecialists need to evaluate the level of maturity of RNA treatments in their therapeutic areas of interest. Some treatments are gaining maturity quickly (mRNA vaccines for infectious diseases and ASOs/RNAi for rare diseases, for example) while others are still emerging, including mRNA vaccines for oncology and RNAi therapeutics for CNS and cardiovascular diseases.
Nonspecialists have three possible paths, and their choices depend, in large part, on starting points. (See Exhibit 3.)
Companies that want to “go big” or “go together” could dramatically improve their positions in the medium to long term with one particular move. These players could invest some resources into fundamental R&D on a next generation of treatments that would provide a source of advantage, such as delivery strategies, RNA expression control, or manufacturing.