Top 10 RNA-Based Biopharmas

Since 2018, COVID-19 vaccines propel revenues of public companies into the stratosphere, while funding for private companies grew much slower

0
3d illustration of a part of RNA chain from which the deoxyribonucleic acid or DNA is composed
In GEN’s initial A-List published in 2018, the top five public companies generated a combined $1.536 billion in revenues for 2017 and the first three quarters of 2018. By contrast, the top five public companies appearing on this list generated a combined $31.218 billion in revenues in 2020 and the first three quarters of this year. [Christoph Burgstedt / iStock / Getty Images Plus]

In institutions and companies, investigators spent some two decades working on RNA-based drugs and vaccines before COVID-19 afforded many of them an opportunity to apply all that research into patients, with support from governments and regulators eager to fight the pandemic.

For two once obscure companies—Moderna, which went public in 2018, and BioNTech, which followed a year later—that opportunity has translated into multiple billions of dollars in new revenues. Not surprisingly as a result, both companies far outpace the other public companies ranked by GEN this year among top RNA-based biopharma companies.

Those companies and many others stand to make billions more from RNA-based vaccines and drugs. Only part of that is due to COVID-19 continuing to spawn a market for their messenger RNA (mRNA) vaccines and booster doses. The rest reflects expanding RNA-based pipelines by those companies and others, reflected recently in Moderna’s dosing its first patient in a Phase III trial of its cytomegalovirus (CMV) vaccine.

A report issued last month by BCC Research projected the market for vaccines and therapeutics based on mRNA alone jumping from $46.7 billion this year—a figure that has already been surpassed by the two leading COVID-19 vaccines alone—to $101.3 billion by 2026, reflecting a compound annual growth rate (CAGR) of 16.8%.

Also standing to make potential billions are companies that have launched RNA-related collaborations during 2021. Just six days into the new year, Genentech, a member of the Roche Group, agreed to apply Ribometrix’s discovery platform to discover, develop, and commercialize small molecule drug candidates against RNA targets, through a collaboration that could generate more than $1 billion for the Durham, NC-based developer of RNA-based small molecule therapeutics.

Through November 12, Eli Lilly had launched two such collaborations with smaller RNA-focused partners. In May, Lilly committed up to $1.25 billion (including $25 million upfront) toward partnering with U.K.-based MiNA Therapeutics to develop small activating RNA (saRNA) drugs for up to five targets across Lilly’s key therapeutic areas of cancer, diabetes, immunology, neurodegenerative diseases, and pain. Four months later, Lilly launched an up-to-$1.3 billion partnership ($50 million of that upfront) with ProQR to also pursue up to five targets by developing editing oligonucleotides using ProQR’s Axiomer® RNA editing platform.

Below is GEN’s updated A-List of top companies in RNA-based biotech, encompassing not only developers of vaccines and drugs based on various forms of RNA, but developers of RNA-based platform technologies.

This list includes the five largest public companies and five largest private companies. The public companies are ranked by their combined revenues for 2020 and 2021 (mostly the first through third quarters) as disclosed in regulatory filings, including sales of products or services, as well as revenue from collaborations and R&D activity.

Private companies are ranked by the total capital they have raised, as disclosed by the companies themselves, either in press statements or in responses to GEN queries verifying figures compiled by other sources. Companies that did not respond to those queries by deadline are listed with the highest figure published by an outside source.

Also included in this list are several “up and comers” that have either raised significant capital in recent months, shown positive data for their technologies, and/or launched significant new collaborations with partners.

Each company is listed with a summary of their recent activity.

To show how much the field has changed in three years: In GEN’s initial A-List published in 2018, the top five public companies generated a combined $1.536 billion in revenues for 2017 and the first three quarters of 2018. By contrast, the top five public companies appearing on this list generated a combined $31.218 billion in revenues in 2020 and the first three quarters of this year.

A much slower jump in total capital has been seen among private companies, with the top five raising a combined $1.715 billion by 2018, and a combined $2.034 billion three years later.

 
Top Public Companies
5. Sarepta Therapeutics

Revenue: $500.426 million in Q1-Q3 2021; $540.099 million in 2020

Sarepta Therapeutics has long focused on Duchenne muscular dystrophy, bringing to FDA approval three antisense oligonucleotides for patients amenable to skipping specific exons. The three—EXONDYS 51 (eteplirsen), VYONDYS 53 (golodirsen), and AMONDYS 45 (Casimersen)—generated strong revenue during the third quarter for Sarpeta, which raised its revenue guidance for 2021 by about $70 million, to between $605 million and $615 million. Also during Q3, Sarepta launched Part B of its MOMENTUM pivotal trial (SRP-5051-201; NCT04004065) for SRP-5051, the company’s next-generation peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) for exon 51 skip-amenable Duchenne patients; and EMBARK (SRP-9001-301; NCT05096221), a pivotal trial for SRP-9001, Sarepta’s micro-dystrophin gene therapy for Duchenne, being co-developed with Roche through an up-to-$2.85 billion collaboration. The three approved drugs are among 14 RNA programs within Sarepta’s pipeline of 42 programs.

4. Alnylam Pharmaceuticals

Revenue: $585.752 million in Q1-Q3 2021; $492.853 million in 2020

Alnylam founding CEO John Maraganore, PhD, in October announced plans to transition into an advisory board role at year’s end, to be succeeded by President Yvonne Greenstreet, MBChB. His accomplishments included laying out several five-year plans (most recently Alnylam P5x25), through which the company has delivered RNA-based medicines for rare and prevalent diseases. These include hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, where Alnylam on October 27 reported positive topline 18-month results from the Phase III HELIOS-A trial (NCT03759379) assessing vutrisiran. The RNA interference (RNAi) therapeutic completed enrollment in August ahead of schedule in the Phase III HELIOS-B trial (NCT04153149) for ATTR amyloidosis with cardiomyopathy. That indication also being pursued in the Phase III APOLLO-B study (NCT03997383) by Alnylam’s patisiran, approved in 2018 as ONPATTRO® for polyneuropathy of hATTR amyloidosis in adults.

3. Ionis Pharmaceuticals

Revenue: $370.450 million in Q1-Q3 2021 ; $729.3 million in 2020.

Ionis Pharmaceuticals during the third quarter expanded its late-stage pipeline to seven Phase III programs, and acknowledged that tofersen (licensed to Biogen) missed its primary endpoint in the Phase III VALOR trial (NCT02623699) in people with superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS), with Biogen evaluating next steps. But Biogen and Ionis added that tofersen showed signs of reduced disease progression across multiple secondary and exploratory measures that included motor function, respiratory function, and quality of life. In November, the company launched a second Phase III trial (CORE; NCT05079919) of its ligand-conjugated antisense (LICA) medicine olezarsen in people with severe hypertriglyceridemia. Ionis expanded its LICA medicine platform in July through technology licensed from Bicycle Therapeutics for $45 million upfront—including an $11 million equity investment in Bicycle.

2. Moderna

Revenue: $11.260 billion in Q1-Q3 2021; $803.395 million in 2020

Moderna’s shares tumbled 33% between November 3 and 12 on investor jitters over distribution delays for its COVID-19 vaccine, earnings that missed analyst forecasts, and ongoing patent disputes with the NIH and Arbutus Biopharma. Yet this past year, Moderna’s COVID-19 vaccine (along with the Pfizer/BioNTech shot) showed how successfully RNA-based biopharmas can disrupt the industry. Moderna’s revenues have multiplied exponentially from $60.209 million in 2019 and $803.395 million in 2020 (about two-thirds consisting of grant funding from the federal Biomedical Advanced Research and Development Authority). Moderna’s mRNA clinical pipeline consists of 37 programs in development across 34 development candidates, including 21 in ongoing clinical studies. In October, Moderna’s six-RNA vaccine mRNA-1647 became only the company’s second candidate (and first besides the COVID-19 vaccine) to advance into a Phase III trial (NCT05085366) dubbed “CMVictory.”

1. BioNTech (made 2018 list as a private company)

Revenue: €13.444 billion ($15.384 billion) in Q1-Q3 2021; €482.325 million ($551.905 million) in 2020

“The last 18 months have demonstrated the power flexibility and the speed of our mRNA vaccine technology,” BioNTech CEO and co-founder Ugur Sahin told analysts November 10. Like Moderna, BioNTech’s revenues have zoomed with development of a COVID-19 vaccine. As of November 2, BioNTech and partner Pfizer delivered 2 billion-plus doses of BNT162b2, one of 22 mRNA candidates among 30 programs disclosed in the company’s pipeline. The COVID-19 vaccine accounted for 99% of BioNTech’s €6,087.3 billion ($6.966 billion) in Q3 revenues, with the company raising its 2021 revenue forecast for the shot from €15.9 billion ($18.2 billion) to between €16 billion and €17 billion ($18.3 billion and about $19.5 billion). BioNTech’s RNA success has extended into oncology with autogene cevumeran (BNT122/RO7198457), under study in colorectal cancer and other solid tumor indications, partnered with Genentech, a member of the Roche Group.

 
Top 5 Private Companies
5. Nutcracker Therapeutics

Total Capital Raised: $219.437 million X

While Nutcracker Therapeutics has been quiet since announcing a $60 million Series B financing last year, the company almost as quietly informed the U.S. Securities and Exchange Commission on September 3 that it raised $144.5 million—$144,499,977, to be precise—toward a planned financing of $200 million ($199,999,994). Nutcracker develops RNA therapeutics through a microfluidic, biochip-based platform it formally and aptly calls ACORN, and informally calls “GMP-in-a-box.” ACORN is a computer-controlled RNA manufacturing system that starts with a nucleic acid sequence of interest and produces optimized nanoparticle-encapsulated RNA therapeutics on dedicated, single-use biochips. According to Nutcracker, all steps are performed in an automated, fully isolated microfluidic path, enabling rapidly scalable, efficient manufacturing of high-quality products within smaller footprint facilities with reduced operating costs compared to conventional bioreactor manufacturing.

4. Deep Genomics

Total Capital Raised: $236.7 million

Deep Genomics says its efforts to develop “programmable” RNA therapeutics based on its artificial intelligence discovery platform were expanded when it completed a $180 million Series C financing led by SoftBank Vision Fund 2* in July. The company focuses on applying AI and machine learning to program and prioritize “transformational” RNA therapeutics for genetic diseases. Deep Genomics’ pipeline consists of preclinical candidates for four CNS conditions—Parkinson’s disease, pediatric epilepsy, Niemann-Pick Disease Type C, and frontotemporal dementia—and two metabolic disorders, Wilson disease and refractory gout. The company also has four undisclosed preclinical programs partnered with BioMarin Pharmaceutical under a collaboration of undisclosed value. That collaboration gave BioMarin an exclusive option to obtain Deep Genomics’ development and commercialization rights to each program.

3. Sirnaomics

Total Capital Raised: $270 million

Sirnaomics has racked up a pair of $105 million financings over the past 13 months—a Series D round completed in October 2020, and a Series E round completed in July. The company said proceeds from the Series E will fund the continued development of its novel RNAi therapeutics for treating human disorders, as diverse as cancers, viral infections, fibrosis, and metabolic diseases. The capital is also going toward developing its delivery technology platforms and expanding its large-scale manufacturing capacity to support its pipeline at different clinical stages. That pipeline is led by STP705 and STP707, which are in clinical phases for 12 indications encompassing cancer and fibrosis. Sirnaomics is headquartered in Gaithersburg, MD, with subsidiaries in Suzhou and Guangzhou, China.

2. Laronde

Total Capital Raised: $490 million

Laronde is French for “the round,” which explains its approach to engineering a new class of RNA that is circular rather than linear. Laronde’s Endless RNATM (eRNA) is a versatile synthetic RNA platform designed to instruct cells to express a desired therapeutic protein inside the body. Because eRNA has no free ends, it is not recognized by the immune system and is stable, enabling a longer duration of protein expression than linear RNA. “We’re talking about weeks to months,” Laronde CEO Diego Miralles, MD, told GEN Edge in September . In August, Laronde completed $440 million in Series B financing led by Flagship Pioneering, which launched the company in 2017 and brought it out of stealth mode in May of this year, committing $50 million to the startup.

1. Abogen Biosciences

Total Capital Raised: $817.5 million X

Abogen flabbergasted analysts and other observers of the RNA therapeutic space in August, when the mRNA-based biotech announced that it completed an eye-popping “more than $700 million” Series C financing with participation mostly from Asian-based investment firms, as well as Eli Lilly’s Lilly Asian Ventures. Suzhou-based Abogen said it intended to use the capital toward developing the mRNA vaccine candidate against COVID-19 it is co-developing with Chinese-based Walvax Biotechnology; advancing more vaccine and oncology programs into the clinic; and reinforcing Abogen’s “leading position” as an mRNA therapy in China. Though less well known globally among Chinese COVID-19 vaccine developers as Sinovac (CoronaVac) and Sinopharm Group (BBIBP-CorV and a second candidate), Abogen in April advanced its shot against the virus into a Phase III trial (NCT04847102).

 
Companies to Watch
Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals develops RNA interference (RNAi) therapies through its Targeted RNAi Molecule (TRiMTM) platform. Revenues were $100.004 million for the nine months ending June 30, and $87.992 million in the fiscal year ending September 30, 2020. On November 15, Arrowhead presented Phase I/II (NCT04720534) data showing ARO-APOC3, which targets apolipoprotein C-III (APOC3), “may represent a promising RNAi therapeutic for the treatment of [severe hypertriglyceridemia] sHTG with infrequent dosing of every 3 months or every 6 months.” Collaboration partner Janssen Pharmaceuticals shared Phase II trial (NCT03982186) data showing the highest 200 mg dose of small interfering RNA (siRNA) therapeutic JNJ-3989 (formerly ARO-HBV) led to 74.7% of patients achieving <100 IU/mL of Hepatitis B surface antibody (HBsAg). In June, Arrowhead licensed ARO-XDH for uncontrolled gout to Horizon Therapeutics through a collaboration that could generate up to $700 million ($40 million upfront) for Arrowhead.

Dicerna Pharmaceuticals

Dicerna Pharmaceuticals–soon to be acquired by Novo Nordisk for $3.3 billion–just missed being ranked among top public companies, finishing with revenues of $151.894 million in Q1-Q3 2021 and $164.307 million in 2020. On November 12, Dicerna declared proof of principle for the first two targets in a potentially $3.7 billion-plus collaboration with Eli Lilly launched in 2018 to develop new treatments based on 10+ targets in cardio-metabolic disease, neurodegeneration, and pain. In September, Dicerna dosed the first subjects in a Phase I trial (NCT05021640) assessing DCR-AUD, Dicerna’s GalXC RNAi therapeutic candidate for the treatment of alcohol use disorder. A month earlier, Dicerna reported positive topline data from its pivotal PHYOX2 trial (NCT03847909) showing that nedosiran, its GalXC RNAi therapeutic candidate for primary hyperoxaluria, showed statistically significant reduction from baseline in urinary oxalate (Uox) excretion compared to placebo.

Locanabio

Locanabio uses gene therapy to deliver RNA binding protein-based systems designed to correct the RNA “message” in severe neurodegenerative, neuromuscular and retinal diseases. In May, Locanabio presented positive preclinical in vivo results at the 24th Annual American Society of Gene and Cell Therapy (ASGCT) Meeting showing a novel PUF RNA-binding protein system delivered via an adeno-associated virus serotype 9 (AAV9) vector was safe and effective in eliminating toxic CUG repeats in a mouse model of myotonic dystrophy type 1 (DM1). In addition to DM1, Locanabio’s pipeline includes candidates for Huntington’s disease, Spinocerebellar ataxia type 1, Amyotrophic Lateral Sclerosis (ALS targeting the C9orf72 gene), frontotemporal dementia, and retinal disease. Locanabio has raised $159 million in total capital, most of that from a $100 million Series B round in December 2020.

ProQR

ProQR landed a big-pharma partner in September when Eli Lilly began collaborating with the Dutch company to discover, develop, and commercialize RNA therapies for genetic disorders in the liver and nervous system, based on ProQR’s Axiomer® RNA editing platform. The collaboration generated $50 million upfront for ProQR and could yield up to $1.25 billion in research, development, and commercialization milestone payments, plus royalties. “There’s significant room beyond that to potentially do additional partnerships,” ProQR Founder and CEO Daniel A. de Boer told GEN. Axiomer is designed to enable the editing of single nucleotides in RNA in a highly targeted and specific manner based on editing oligonucleotides (EONs) designed to recruit endogenous Adenosine Deaminases Acting on RNA (ADAR) enzymes to a selected target adenosine in a disease-associated RNA.

Shape Therapeutics (ShapeTX)

Shape Therapeutics (ShapeTX) launched an up-to-$3 billion collaboration with Roche in August to apply its RNA editing platform RNAfix™ and potentially leverage its AAVid™ technology platform for next-generation tissue-specific AAVs to develop gene therapies against Alzheimer’s disease, Parkinson’s disease, and rare diseases. The company’s pipeline targets 52 genes implicated in these diseases and others, including Rett Syndrome, Stargardt disease, Alpha-1 antitrypsin deficiency (AATD), and Duchenne muscular dystrophy, and cystic fibrosis. ShapeTX’s suite of tech platforms broadly enable RNA targeting, RNA editing, and RNA replacement for patients suffering from genetic disorders with high unmet need. Seattle-based ShapeTX completed a $112 million Series B financing in July, saying the proceeds would enable it to continue building its RNA tech portfolio and accelerate development through partnerships.

Stoke Therapeutics

Stoke Therapeutics gives new meaning to the phrase, “it takes two to tango,”—as in Targeted Augmentation of Nuclear Gene Output (TANGO). The research platform has generated antisense oligonucleotides that bind to pre-mRNA, helping the target genes produce more protein. By selectively restoring protein levels, Stoke reasons it can treat a broad range of diseases where patients have one healthy copy of a gene and one mutated copy that fails to produce an essential protein. On November 8, Stoke nominated a second clinical candidate, STK-002, to treat autosomal dominant optic atrophy (ADOA). Earlier this year Stoke reported positive interim data from its Phase I/IIa MONARCH trial (NCT04442295) assessing its first clinical candidate, STK-001, in children and adolescents with Dravet syndrome. Of 11 patients in single ascending dose cohorts (10mg, 20mg, 30mg), eight showed a reduction in convulsive seizure frequency.

Previous articleSingle Cell Multiomic Atlas of the Human Retina: An Integrative Analysis
Next articleSubtypes of Multiple Myeloma Identified by New Model