In August 2018, the FDA & European Commission announced the approval of Alnylam Pharmaceutical’s ONPATTRO, a first-of-its-kind RNA interference (RNAi) therapeutic. Evolution Bioscience’s latest timeline visualisation outlines the key events in the development and commercialisation of RNAi therapeutics, from Andrew Fire & Craig Mello’s initial discovery in 1998 through to Arrowhead and Johnson & Johnson’s $3.7B deal in October 2018.
What is RNAi?
RNA interference (RNAi) can be defined as a biological process in which double-stranded RNA molecules prevent the expression of disease-causing genes by enabling the destruction of their messenger RNAs (mRNAs), a consequence of which is the loss of protein expression. The concept offers an elegant mechanism of action to treat rare diseases, chronic liver diseases, cancer, cardiovascular disease and viral infectious diseases.
A Rocky Road to First Approval
The road to the first ever approval, Alnylam‘s ONPATTRO for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults, has been a rocky one. This is due to a combination of foreseen and unforeseen development challenges largely centred around targeting, off-target effects, toxicology, delivery and formulation. Additional commercial challenges have arisen with litigation being a significant complicating factor along with the loss of big pharma interest at key stages.
The following timeline provides an overview of the last 30 years of RNAi research, development and commercialisation, including Alnylam and other key developers:
February 1998
Fire & Mello publish “Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans” (Nature, Volume 391, Issue 6669, pp. 806-811)
December 1998
US Patent application filed for genetic inhibition by double-stranded RNA.
June 2002
Alnylam founded, with headquarters based in Cambridge, MA.
January 2003
US patent issued for “genetic inhibition by double-stranded RNA.”
April 2003
Ribozyme rebrands to Sirna Therapeutics.
June 2004
Alnylam lists on the NASDAQ, raising $26M in what was termed a “less than spectacular” IPO.
September 2005
Novartis takes a 19.9% stake in Alnylam.
Allergan & Sirna Therapeutics announce a development agreement in which Allergan will be responsible for all preclinical, clinical and commercialization activities related to RNAi compounds initially developed by Sirna.
May 2006
Sirna Therapeutics announces that it will provide GlaxoSmithKline with siRNA therapeutics against asthma, respiratory syncytial virus, chronic obstructive pulmonary disease, and allergic rhinitis.
September 2006
Pfizer acquires an exclusive worldwide license to Quark Pharmaceuticals‘ novel human gene RTP-801 and to molecules that modify its expression or function. RTP-801 is involved in the development of pathologic blood vessels which accelerate the progression of age-related macular degeneration (AMD).
October 2006
Merck acquires Sirna Therapeutics for $1.1B.
Nobel Prize in Physiology or Medicine jointly awarded to Andrew Fire & Craig Mello for their discovery.
Dicerna Pharmaceuticals founded.
July 2007
Alnylam grants Roche a non-exclusive license providing access to broad intellectual property (IP) and know-how, including fundamental, chemistry and delivery IP. Alnylam maintains the right to non-exclusively license its IP to additional partners in potential future agreements. The transaction included Roche’s acquisition of Alnylam’s European research site in Kulmbach, Germany. The alliance could be valued at over $1B in consideration of upfront payments, potential product milestone payments for multiple products and field expansion payments, excluding potential royalties on future sales of commercial products.
May 2008
Novartis exercises rights to purchase 213,888 unregistered shares of Alnylam‘s common stock, resulting in a cash payment of $5.4M.
May 2008
Tekmira Pharmaceuticals Announces RNAi Research Collaboration with Bristol-Myers Squibb.
March 2009
Opko halts phase III study of siRNA treatment for AMD on poor preliminary data.
May 2008
Tekmira Pharmaceuticals enters into a potential $50.4M development agreement with Roche to advance Roche’s first two RNA interference (RNAi) product candidates into human clinical testing.
May 2009
Allergan drops development of siRNA for AMD on poor phase II data.
January 2010
Dicerna & Japan’s Kyowa Hakko Kirin announce deal in which Dicerna will receive $4M in upfront cash, plus $120M in milestone payments for success in development and commercialization, as well as royalties on future product sales. The partnership can be broadened over time to include as many as 10 more drug targets for cancer and other diseases, each with the same financial terms.
August 2010
Novartis agrees to pay Quark Pharmaceuticals up to $680M for the licensing rights to a new therapy for kidney-related diseases. Quark will receive upfront for an option on QPI-1002, which is currently in Phase II for kidney-related conditions.
November 2010
Roche discontinues R&D in RNAi therapeutics.
October 2011
Arrowhead acquires Roche’s RNAi Therapeutics group and comprehensive technology IP portfolio, with Roche receiving an equity stake in Arrowhead of just under 10% in restricted common stock. Roche was also given limited rights to negotiate for a defined number of products and will receive late-stage milestone payments, which only trigger after approval, and customary low single digit royalty payments based on sales on certain products.
May 2012
Pfizer & Quark Pharmaceuticals announce that they have amended the existing ophthalmology pharma partnering deal between them, enabling Quark to perform a Phase 2a clinical study to assess the effect of PF-655 in a new indication, looking at visual function in patients with moderate and advanced Open-Angle Glaucoma (OAG).
July 2012
Alnylam and Ascletis Pharmaceuticals, a privately held US-China joint venture pharmaceutical company, announced they have formed a strategic collaboration for the development of ALN-VSP, a first-in-class, systemically delivered RNAi therapeutic for the treatment of liver cancers including hepatocellular carcinoma (HCC), a significant area of unmet need in China.
February 2013
The Medicines Company and Alnylam form strategic alliance to develop and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia.
December 2013
Biocon and Quark Pharmaceuticals announce that they have entered into a licensing & collaboration agreement for the development of a range of siRNA-based novel therapeutics. The collaboration will enable Biocon to co-develop, manufacture & commercialize QPI-1007, a novel siRNA drug candidate for ophthalmic conditions, for India and other key markets.
January 2014
Merck & Co. sells Sirna Therapeutics to Alnylam for $175M in cash and stock, up to $105M in milestones for any new products that emerge from the deal plus a separate $10M milestone on Alnylam products covered by Sirna’s patent estate.
January 2014
Genzyme becomes a major Alnylam shareholder through an upfront purchase of $700M of newly issued stock at approximately $80/share, representing an approximately 12% ownership position.
Dicerna raises $90M in cash from its IPO before underwriting discounts, a significant increase from the $69M it originally forecast.
April 2014
Novartis announces that it will significantly reduce internal drug discovery efforts in RNA therapeutics.
March 2015
Novartis sells RNAi R&D portfolio to Arrowhead in $35M agreement.
September 2016
Amgen and Arrowhead Pharmaceuticals announce two license and collaboration agreements to develop and commercialize RNA interference (RNAi) therapies for cardiovascular disease. Arrowhead will receive $35M in upfront payments; $21.5M in the form of an equity investment; and up to $617M in option payments.
October 2016
Alnylam discontinues development of revusiran, an investigational RNA interference (RNAi) therapeutic that was being developed for the treatment of hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM).
November 2016
Arrowhead announces that it will discontinue development of ARC-520, ARC-521, and ARC-AAT, which are three of its most promising clinical-stage drugs. In addition, management reduces its workforce by approximately 30%.
November 2016
Sanofi commits up to $100M to opt-in on Alnylam’s PhIII RNAi hemophilia trial.
December 2016
Arcturus & Takeda enter into a partnership to develop RNA-based therapeutic candidates for the treatment of NASH and other GI-related disorders.
October 2017
Arcturus enters into a partnership with Janssen, a Johnson & Johnson company, to develop and commercialize nucleic acid-based drug products for the treatment of specified diseases, including HBV.
November 2017
Boehringer Ingelheim and Dicerna Pharmaceuticals agree a research and licensing deal to advance treatments for chronic liver diseases, with an initial focus on non-alcoholic steatohepatitis (NASH). Dicerna receives a $10M upfront payment and could receive up to an additional $191M in potential milestone payments and R&D reimbursements.
January 2018
Alnylam and Sanofi announce a strategic restructuring of their RNAi therapeutics alliance to streamline and optimize development and commercialization of certain products for the treatment of rare genetic diseases. Specifically, Alnylam will obtain global development and commercialization rights to its investigational RNAi therapeutics programs for the treatment of ATTR amyloidosis, including patisiran and ALN-TTRsc02. Sanofi will receive royalties based on net sales of these ATTR amyloidosis products. Sanofi will obtain global development and commercialization rights to investigational RNAi therapeutic fitusiran.
March 2018
Alnylam announces that Sanofi has declined its opt-in for the development and commercialization of lumasiran (ALN-GO1), an investigational RNAi therapeutic for the treatment of Primary Hyperoxaluria Type 1 (PH1).
May 2018
Sylentis (PharmaMar Group) presents results from the clinical studies carried out with tivanisiran for the treatment of dry-eye syndrome, enabling the start-up of the Phase III “Helix” clinical trial.
July 2018
The European Medicines Agency (EMA) issues a positive opinion over Alnylam’s patisiran for hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in adults with stage 1 or stage 2 polyneuropathy.
August 2018
Alnylam receives approval of ONPATTRO™ (patisiran) in the US & Europe, the first-ever RNA interference (RNAi) therapeutic to be approved. Projected sales of $1.21 billion in 2022.
Arrowhead announces that it has earned a $10M milestone payment from Amgen following the administration of the first dose of AMG 890, formerly referred to as ARO-LPA, in a clinical study. Amgen is evaluating AMG 890, an RNAi therapeutic designed to lower Lp(a) for the treatment of cardiovascular disease, in a Phase 1 clinical study designed to assess its safety in volunteers with elevated levels of lipoprotein (a).
September 2018
Arrowhead shares positive data from a study aimed at evaluating the safety and tolerability of a drug candidate (ARO-HBV) it’s developing to treat chronic hepatitis B virus (HBV).
October 2018
The Medicines Company announces recommendation by independent data monitoring committee to continue inclisiran phase III trials following fourth review of unblinded data.
J&J and Arrowhead announce a gene-silencing drug deal worth up to $3.7B. Under the deal, J&J’s Janssen Pharmaceuticals unit will obtain a worldwide license for Arrowhead’s ARO-HBV drug and an option to collaborate on up to three new RNA interference (RNAi) drugs. J&J will make a $75M equity investment and will also receive $175M upfront. Arrowhead is also eligible to receive up to $1.6B in milestone payments for the Hepatitis B license agreement and about $1.9B in option and milestone payments for the collaboration agreement related to up to three additional targets.
Alexion and Dicerna announce a collaboration to discover and develop RNAi Therapies for complement mediated diseases. Dicerna will receive upfront payment of $22M and equity investment of $15M, with potential for additional milestone-dependent and royalty payments.
Dicerna and Eli Lilly announce licensing and research collaboration focussed on RNAi research for cardio-metabolic, neurodegeneration and pain targets. Dicerna will receive an upfront payment of $100M and an equity investment of $100M, and will be eligible to receive up to approximately $350M per target in development and commercialization milestones, plus royalties.
Other Notable RNAi Players
There are other notable players currently at preclinical and early clinical stages which utilise alternative approaches to trigger the RNA Induced Silencing Complex (RISC) response. This differentiates RNAi from other forms of RNA-based therapeutics, such as those of Ionis Pharma and Santaris (Roche), which involve antisense blockade by targeting mRNA but not inducing the RISC response. Companies involved include:
| Company | Focus | Commentary |
|---|---|---|
 | Head and neck squamous cell carcinoma (HNSCC), Oculopharyngeal muscular dystrophy (OPMD), hepatitis B (HBV), wet age-related macular degeneration (AMD). | DNA directed RNAi (ddRNAi) approach relies on the use of introducing DNA templates to utilize the cells’ endogenous transcriptional machinery to produce short hairpin RNAs (shRNAs) that are then processed by the endogenous RNAi machinery into siRNAs. |
 | Melanoma, Ovarian Cancer, Head & Neck Cancer. | Co-founded by Craig Mello, proprietary self-delivering RNAi (sd-rxRNA®) therapeutic platform, process involves ex-vivo treatment of the immune cells with oligonucleotides inhibiting expression of immune checkpoint genes. |
 | Pancreatic cancer, prostate cancer and certain brain cancers. | LODER™ (Local Drug EluteR) is the first cancer drug delivery platform to enable insertion of the RNAi therapeutic pharmaceuticals directly into the core of solid tumors for extended periods of time of a few months or more. |
Conclusions
30 years on from the Andrews & Mello discovery, the first RNAi treatment has finally been approved, and the promise of RNAi is nearing the forefront of the clinical development agenda. The clinical opportunities are significant: of approximately 20,000 genes in the human genome, 600-1,500 are considered “druggable,” as defined as those that can be targeted effectively with existing drug approaches such as small molecules or other inhibitors and proteins such as monoclonal antibodies. The discovery of RNAi has potentially made every gene a druggable target.
Transcriptomics, a key source of understanding gene expression in detail, is entering a new phase with the development and introduction of high-throughput next-generation sequencing (NGS) technologies pioneered by Illumina, Thermo Fisher and others. The consequence of these developments will be the discovery of a host of potential novel targets for RNAi therapeutics.
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