It wouldn’t be a stretch to call 2018 the year RNA-based treatments, such as those applying RNA interference (RNAi) or small interfering RNA (siRNA), finally reached the proverbial tipping point predicted ever since Andrew Z. Fire and Craig C. Mello won the 2006 Nobel Prize in Physiology or Medicine for discovering RNAi.
Earlier this month, Moderna Therapeutics carried out the largest-ever initial public offering (IPO) for a biotech. And in August, Alnylam won the first-ever FDA approval for an RNAi drug in the U.S. Both companies appear on GEN’s first-ever list of top biopharmas focused on leveraging RNA-based treatments.
Yet at least one company that didn’t make the list nevertheless left its mark in RNA-based drug development this past year. In June, Translate Bio (which changed its name last year from RaNa Therapeutics) completed its own smaller IPO, raising approximately $113.4 million in net proceeds. Two other companies changed their names this year: RXi Pharmaceuticals became Phio Pharmaceuticals on November 19, while Marina Biotech became Adhera Therapeutics on October 9.
According to Grand View Research, the global antisense and RNAi therapeutics market size is expected to expand at a compound annual growth rate (CAGR) of 8.6% between 2018 and 2025, when it is projected to reach $1.81 billion.
Below is a list of the top 10 biopharmas focused on developing RNA-based drugs—five public companies, and five private companies. The public companies are ranked by their 2017 revenues, whether from sales of products or services, or from collaborations and R&D activity. On that basis, Translate Bio didn’t generate enough revenue to be among the top-five public companies.
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. Each company is listed with a short explanation of their recent activity.
5. Arrowhead Pharmaceuticals
Revenue: $31.408 million (Fiscal Year ending September 30, 2017); $16.142 million (FY 2018)
Arrowhead is half of 2018’s biggest collaboration deal, an eye-popping more-than-$3.7-billion partnership with Johnson & Johnson’s Janssen Pharmaceuticals to develop an RNAi treatment candidate for hepatitis B virus (HBV), plus up to three other RNAi therapies against targets to be selected by Janssen. The deal gives Janssen a global exclusive license to Arrowhead’s ARO-HBV program, designed to develop a third-generation subcutaneously administered RNAi therapeutic candidate as a potentially curative therapy for patients with chronic HBV. On November 9, Arrowhead announced positive Phase I/II results for ARO-HBV, saying it “effectively reduced all measurable viral products, including HBsAg [hepatitis B surface antigen].” Arrowhead also trumpeted positive Phase I results for ARO-AAT, a second-generation RNAi treatment for a rare genetic liver disease associated with alpha-1 antitrypsin (AAT) deficiency.
4. Akcea Therapeutics
Revenue: $55.209 million (2017); $54.670 million (Q1–Q3 2018)
Akcea’s revenues the first three quarters of this year were almost as much as the company generated all of last year, thanks to $12 million in licensing revenue from its collaboration with PTC Therapeutics, plus a more-than-doubling of R&D revenue. All that R&D revenue came from Akcea’s collaboration with Novartis, launched last year, with Akcea amortizing $75 million shelled out by the pharma giant, which also purchased Ionis stock at a premium of $33 million. Akcea is an affiliate of Ionis Pharmaceuticals. In July, the two companies won European Commission approval of their Tegsedi™ (inotersen), an RNA-targeted treatment for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults. The FDA followed suit three months later.
3. Alnylam Pharmaceuticals
Revenue: $89.912 million (2017); $53.875 million (Q1–Q3 2018)
Alnylam won the first-ever FDA approval for an RNA interference (RNAi) drug in the U.S. on August 10, when the agency authorized Onpattro™ (patisiran) for polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults. On August 30, the European Commission followed suit and approved Onpattro, which is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). Onpattro has already begun generating revenue, $0.5 million in Q3 to be precise—a fraction of the company’s nine-month revenue, nearly all of it from collaborations. On December 6, Alnylam announced its R&D plans for 2019; they include continuing the global rollout of Onpattro and launching a Phase III trial for ATTR amyloidosis candidate vutrisiran.
Revenue: $205.825 million (2017); $113.921 million (Q1–Q3 2018)
Moderna made history on December 7 when it traded its first shares on the NASDAQ Global Select Market, in the largest-ever biotech IPO. While Moderna shares finished the day at $18.60, down $4.40 from the IPO price, the company still raised $604.3 million from the sale of 26.3 million shares—capital it says will fund mRNA technology platform development as well as further develop its 21-candidate clinical pipeline and its drug discovery and manufacturing capabilities. Moderna’s mRNA treatments differ by coding region, which according to the company gives its investigational mRNA medicines “a very software-like quality,” and can combine different mRNA sequences encoding for different proteins in a single mRNA medicine.
1. Ionis Pharmaceuticals
Revenue: $507.666 million (2017); $407.559 million (Q1–Q3 2018)
More than half of Ionis’ revenue (55%) came from R&D, the rest from commercial activity—including a near-tripling of royalties (to $168 million) from spinal muscular atrophy (SMA) treatment Spinraza® (nusinersen), co-developed with Biogen. On December 6, Biogen exercised its option to develop BIIB067 for a subtype of ALS based on positive Phase I data. As a result, Ionis received $35 million upfront and could see up to $55 million in milestones plus royalties from Biogen. Ionis suffered a setback in August when it, and its Akcea Therapeutics affiliate, received an FDA complete response letter for their NDA for Waylivra™ (volanesorsen), a candidate for familial chylomicronemia syndrome. Waylivra remains on track for potential approval in Europe, and Akcea has reported continuing talks with the FDA on a regulatory path for the treatment.
5. Gotham Therapeutics
Total capital raised: $54 million
Gotham is perhaps the newest company to make this list, based on the $54 million Series A financing with which it debuted on October 10. While founding investor Versant Ventures, Forbion and S.R. One co-led the round. Gotham attracted two big-name investors of note—the biotech giant Celgene and Alexandria Venture Investments, the strategic venture capital arm of Alexandria Real Estate Equities. Versant created and seed-funded Gotham based upon the research discoveries of co-founder Samie Jaffrey, M.D., Ph.D., a pioneer in epitranscriptomics whose work has shed light on the role of post-transcriptional mRNA modifications in health and disease. The seed funding enabled Gotham to build a platform designed to assess the impact of RNA-modifying proteins on disease biology and developed small molecules against priority targets. Gotham says the Series A financing will allow it to establish clinical proof of concept and invest in a pipeline of preclinical candidates with potential to treat diseases intractable to classical approaches.
4. Quark Pharmaceuticals
Total capital raised: $61.4 million
Quark Pharmaceuticals hasn’t announced a financing round since 2010, when it completed a $10 million private financing by existing investors, namely funds of SBI Holdings Group in Japan. Yet, Quark has kept busy developing novel siRNA therapeutics for unmet medical needs. At the American Society of Nephrology (ASN) 2018 Kidney Week Meeting, held October 23–28 in San Diego, Quark presented positive data from a one-year mortality follow-up of a Phase II trial (NCT02610283) assessing its teprasiran (previously QPI-1002), an siRNA targeting the p53 gene, in subjects at high risk for acute kidney injury following cardiac surgery. Also in Quark’s pipeline is QPI-1007, a siRNA candidate targeting the gene Caspase 2 and being developed to treat non-arteritic ischemic optic neuropathy (NAION). Crunchbase tallies $61.4 million in total capital raised by Quark, which at deadline hadn’t responded to GEN queries seeking to verify that figure.
Total capital raised: $89 million
Gradalis has been on an expansion track this year, closing on a $55 million Series C financing and upgrading its current Good Manufacturing Practice (cGMP) manufacturing facility in Carrollton, TX, to support the launch of a Phase III registration trial of its immunotherapy platform Vigil™ plus chemotherapy drugs Irinotecan and Temozolomide in Ewing’s sarcoma (NCT03495921). Ewing’s sarcoma is one of several advanced cancer indications for which Vigil is being developed; the platform is also in combination studies with checkpoint inhibitors targeting advanced gynecological and other women’s cancers. Gradalis raised $10 million in a Series B round in 2013, and $10 million in a Series A round six years earlier.
Total capital raised: About €450 million (about $511 million)
CureVac delivered promising news in November at the 2018 Society of Immunotherapy of Cancer (SITC) Annual Meeting: One patient treated with its RNA-based solid tumor candidate CV8102 saw complete regression of injected and non-injected lesions while four patients achieved stable disease in a Phase I trial (NCT03291002). A TLR-/RIG-I agonist, CV8102 is one of four clinical-phase candidates for CureVac, which has collaborations with the Bill & Melinda Gates Foundation, Boehringer Ingelheim, CRISPR Therapeutics, Arcturus Therapeutics, Acuitas, and Eli Lilly—with which CureVac is partnering to develop up to five cancer vaccines under a potentially $1.795 billion-plus collaboration. In May, CureVac said it will expand its financial and scientific presence in Boston while retaining its global HQ and manufacturing in Tübingen, Germany.
Total capital raised: More than $1 billion
BioNTech raised a hefty $270 million Series A financing in December 2017 led by the Redmile Group, and intended to advance its clinical immunotherapy pipeline, led by its mRNA-based Individualized Vaccines Against Cancer (IVAC®) Mutanome and FixVAC® cancer vaccines. The Series A came about 10 years after the company attracted $180 million in seed funding in December 2008. BioNTech turned heads again in August by scooping up $120 million upfront, equity and near-term research payments from Pfizer under a collaboration to develop mRNA-based vaccines for prevention of influenza. The collaboration could also generate $305 million for BioNTech in milestone payments from Pfizer, which joined several other biopharma giants in partnering with BioNTech, including Genentech, a member of the Roche Group, Eli Lilly, Sanofi, Genmab, and Bayer Animal Health.