Every year at the Cleveland Clinic Medical Innovation Summit, the Top 10 list of technologies that are predicted to come to the market and change patient care is revealed. Last year's October event saw RNA-based therapies take the No. 10 spot. Certainly, the honor was well earned because, after falling out of favor despite their early promise a few years ago, the technology is now enjoying a major resurgence and the product pipeline is growing once again, driven by increasing investments and business partnerships. Mechanisms of RNA therapy, including antisense nucleotides and RNA interference, can now be directed toward the treatment of a variety of conditions, including cancer, viral and neurologic diseases. This two-part series will take a deep dive into this emerging and growing field. In the first part, the progress of public companies will be featured, and the second part will describe the activities of private companies as well as the partnerships that are being forged by pharma companies looking to gain a competitive position in the area.

Busy period for public companies

The past two years has seen an escalation of activity in the RNA medicines space with several key developments that have brought exciting new treatments, such as those applying RNA interference (RNAi), messenger RNA (mRNA) and small interfering RNA (siRNA), firmly into the spotlight.

For example, Moderna Inc., a clinical-stage company developing therapeutics and vaccines based on messenger RNA for the treatment of infectious diseases, immuno-oncology, rare diseases and cardiovascular diseases, graduated to the public market with an IPO that generated a massive $604 million, representing the largest U.S. biopharma IPO ever. (See BioWorld, Dec. 10, 2018.)

Prior to Moderna's public launch, Translate Bio Inc., a Lexington, Mass.-based company developing mRNA therapeutics to treat diseases caused by protein or gene dysfunction, completed its $122 million IPO offering in June. (See BioWorld, June 29, 2018.)

In addition, Alnylam Pharmaceuticals Inc. was successful in gaining approval for the first RNAi drug to market. Its patisiran, branded Onpattro, is indicated to treat hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis). The drug is designed to interfere with RNA production of an abnormal form of the protein TTR and, by preventing its production, to help reduce accumulation of amyloid deposits in peripheral nerves. (See BioWorld, Aug. 13, 2018.)

Shortly after the approval of Onpattro, Akcea Therapeutics Inc., an affiliate of Ionis Pharmaceuticals Inc., gained the FDA's green light for its antisense oligonucleotide, Tegsedi (inotersen), for polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. (See BioWorld, Oct. 9, 2018.)

New index

Public companies developing RNA therapies have continued to receive strong investor support. That is not surprising considering their market potential, which Infinium Global Research predicts, for global RNAi technology alone, to grow with a CAGR of 19.8% over the next five years.

The new price-weighted BioWorld RNA Medicines index, which will track the performance of public companies developing RNA therapies, has gained more than 23% in value year-to-date (YTD) and outpaced the Dow Jones Industrial Average, which has grown 16% in the same period. (See BioWorld RNA Medicines index, below.)

Among the companies supporting that growth is Pasadena, Calif.-based Arrowhead Pharmaceuticals Inc., with its shares (NASDAQ:ARWR) gaining 138% in price since the start of the year. The company has a robust pipeline created from a portfolio of RNA chemistries designed to trigger the RNA interference mechanism to induce rapid and durable knockdown of target genes. One of the most advanced products is ARO-AAT, its second-generation subcutaneously administered RNAi therapeutic being developed as a treatment for a rare genetic liver disease associated with alpha-1 antitrypsin deficiency. The compound has just been granted FDA fast track designation and the company reports it is in final preparations to initiate SEQUOIA (AROAAT2001), a potentially pivotal phase II/III study in the U.S. and Europe, and AROAAT2002, a phase II open-label study in Europe.

The FDA also granted orphan drug designation to ARO-ANG3 for the treatment of homozygous familial hypercholesterolemia. ARO-ANG3 targets angiopoietin like protein 3, and the company began dosing the compound in a phase I study in January.

The company earned a $25 million milestone payment from Janssen Pharmaceuticals Inc., part of the Janssen Pharmaceutical companies of Johnson & Johnson, after it began dosing in a new triple-combination cohort that includes JNJ-3989 (formerly ARO-HBV) and additional undisclosed agents selected by Janssen in an ongoing phase I/II study in patients with chronic hepatitis B virus (HBV).

Arrowhead entered into a license and collaboration agreement with Janssen in October 2018 to develop and commercialize ARO-HBV. (See Part 2 of this feature.)

Strong year

San Diego-based Arcturus Therapeutics Holdings Inc. has also gained strong investor support, with its shares (NASDAQ:ARCT) doubling this year. The RNA medicines company leverages its LUNAR lipid-mediated delivery and Unlocked Nucleomonomer Analog (UNA) chemistry technologies to build a pipeline of therapeutics that focus on liver and respiratory diseases. It recently reported that the FDA had granted orphan drug designation for its lead candidate, ARCT-810, to treat ornithine transcarbamylase deficiency (OTCD), a common urea cycle disorder that makes it difficult for afflicted patients to remove toxic waste products. ARCT-810 utilizes Arcturus' LUNAR lipid-mediated delivery platform to deliver OTC mRNA to liver cells. The replacement therapy is designed to enable OTC-deficient patients to naturally produce healthy functional OTC enzyme in their own liver cells. The company plans to submit an investigational new drug application to the FDA in the first quarter of next year.

Translate Bio, a clinical-stage mRNA therapeutics company also focusing on OTC deficiency, in June received FDA clearance to start a single ascending-dose phase I/II trial of MRT-5201 in adult patients with ornithine transcarbamylase. The company's shares (NASDAQ:TBIO) grew 21% in value last month and are up 28% YTD.

Cambridge, Mass-based Dicerna Pharmaceutical Inc. has enjoyed a positive year, with its shares (NASDAQ:DRNA) up 44% and up 27% in June. It is developing RNAi therapies based on its GalXC technology platform. The company was just granted FDA breakthrough therapy designation for DCR-PHXC for the treatment of patients with primary hyperoxaluria type 1 (PH1), the only RNAi investigational therapy in development for the treatment of all types of PH, a family of rare inherited disorders of the liver that often result in kidney failure.

Dicerna presented updated data at the Oxalosis and Hyperoxaluria Foundation's International Workshop in June from the PHYOX1 phase I trial of DCR-PHXC, which reported substantial post-dose reductions in 24-hour urinary oxalate levels in adult and adolescent participants with PH1 and PH2.

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