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As the biopharma industry concludes its annual pilgrimage to San Francisco for the JP Morgan investor conference, much of the talk around town inevitably was about gene therapies. Rightfully so, considering the therapeutic promise of such one-time cures, and the spate of M&A activity for gene therapy biotechs and manufacturers, despite justifiable concerns over its scalability and affordability. Spotlighting this technological advance and its impending transition from the clinic to doctors’ offices seems appropriate as we start a new decade. However, rather than add to the increasing column inches surrounding gene therapy, this article looks at drugs that target RNA, either through double-stranded RNA-mediated interference (RNAi) or antisense oligonucleotides (ASOs). Arguably overshadowed by gene therapies and their curative hype, RNA therapeutics are gaining prominence, with a number of approvals in rare disease settings and potential applications in highly prevalent indications. As the technology has been honed over the past decade, the latest generation of RNA-targeting drugs are seamlessly progressing through clinical development with a high probability of success. Being just one step removed from the underlying genetic mutations, targeting RNA offers a closely related treatment modality to gene therapy with greater control over dosing and potential side effects. Although lacking the duration of effect, administration as infrequently as every six to 12 months may be a blessing in disguise and avoid complex payment systems that may hinder market access for gene therapies.

Intensifying competition between two emerging drug platforms
The pipeline for RNA-targeting drugs is certainly busy, now exceeding 100 clinical-stage candidates for the first time, and thus far has yielded nine approved therapies. R&D database Pharmaprojects is tracking a further 200 preclinical-stage projects, pointing towards a healthy appetite for further investment in this emerging drug platform. The comparison between pipelines of RNA-targeting drugs and gene therapies does favor the latter, especially in the last few years (see the figure below), but the work of pioneering companies in this field such as Ionis Pharmaceuticals and Alnylam should not be discounted. As the science is further validated across new therapy areas, and reaches commercial milestones, we can certainly expect these companies to increasingly enter the crosshairs of Big Pharma. Novartis’s takeout of inclisiran developer The Medicines Company in late 2019 for $9.7bn sets an impressive benchmark for potential valuations, and may spur on its competitors to also act quickly. As with gene therapy valuations, much of the value is derived not only from the clinical-stage assets themselves, but also the technological capabilities. RNA-targeting discovery platforms offer the ability to manipulate genetically validated targets with high selectivity and infrequent dosing, in particular targeting “gain of function” mutations that increase aberrant protein production and are not directly addressable via gene therapy.

The growth of RNA and gene therapy assets



Source: Pharmaprojects


Although both technologies have only relatively recently entered clinical practice, the first battleground is already set – spinal muscular atrophy (SMA). Patients with SMA carry mutations in the SMN1 gene, resulting in a lack of SMN protein, which is essential for neuronal growth. In 2016, Biogen gained approval for Spinraza, an RNAi therapy that binds a non-coding region of SMN2 mRNA and encourages splicing, increasing the production of functional SMN protein. SMN2 is a homologous gene for SMN1 and under normal conditions only produces a minority of the total SMN. Spinraza has since established itself as a standard-of-care and is on course to notch over $2bn in 2019 sales, although it did record a slight dip in the quarter that Zolgensma, a rival gene therapy marketed by Novartis, launched. As a gene therapy, Zolgensma is able to directly address the underlying mutation in SMN1 that causes SMA, delivering a corrected version of the gene via an AAV vector. Despite fighting against a high-profile data manipulation scandal, Zolgensma’s launch has exceeded analyst expectations and it may yet become the future SMA market leader, even factoring in competition from subsequent launches. Further development of the two products, including new formulations and expanded age groups, will determine the balance of power, but both products will be able to co-exist and remain lucrative. 

Spinal muscular atrophy market forecast, 2017–27



Source: Datamonitor Healthcare, Drug Sales Analytics


Hemophilia may become the next tussle between the two, with Sanofi’s fitusiran acting to silence antithrombin – the final common pathway in the clotting cascade and amenable across all patient types – while a range of gene therapies are seeking to normalize endogenous factor VIII or IX levels in hemophilia A and B, respectively. Outside of these examples, there is an ongoing tug of war between RNA technologies and gene therapies when it comes to deal-making and fundraising. Gene therapy is being backed with greater resources, as made evident by its comparably larger pipeline and clinical trial activity, not to mention the multiple blockbuster acquisitions by Big Pharma. Novartis is one notable company with fingers firmly in both pies, with its Medicines Co acquisition coming shortly after a similar $8.7bn transaction with AveXis to gain access to Zolgensma.

Updates from the JP Morgan investor conference
Most of the leading RNA-targeting companies were presenting at the 2020 JP Morgan investor conference, providing a timely opportunity to assess corporate strategies and overall health. Of these, Alnylam and Ionis continue to be well placed with a diverse range of revenue streams, and lofty aspirations of emulating and surpassing biotech peers such as Celgene and Regeneron. However, neither Dicerna Pharmaceuticals nor Arrowhead Pharmaceuticals, which are posing notable competition to Alnylam with their own RNAi platforms, took part in a formal webcast session.

Alnylam sets expansive strategy and reveals aspirations in CNS and ocular diseases
Alnylam is on course to exceed the goals set in its 2020 vision, with the company expecting to operate in four strategic therapeutic areas with four different drugs by the end of the year, while building a pipeline of 14 clinical-stage drugs, of which six will be in late-stage. The engine for this success has been its RNAi platform, now delivering between two to four IND-stage candidates each year, with industry-leading probability of success rates. Across the last decade, Alnylam has achieved a 58% cumulative likelihood of approval for Phase I assets, far exceeding the overall average of 5.5% (rising to 10% for all biomarker-driven programs), referencing data from Biomedtracker.

With Onpattro, Alnylam is building a keystone franchise that it hopes to establish into a multi-billion-dollar anchor point, driving the company eventually into profitability and funding continued expansion. 2019 sales came in at $166m, so Alnylam will need significant progress with Onpattro’s target population to include all ATTR amyloidosis patients and scaling of commercial activities. While its second approved drug, Givlaari, has smaller commercial potential, it validates the strength of Alnylam’s discovery platform and has enabled the creation of a unique, prevalence-adjusted payment agreement. Royalty streams from collaborations with Novartis and Sanofi will provide the company with exposure to high-value growth markets in hypercholesterolemia and hemophilia while it commercializes its next late-stage orphan drugs, vutrisiran and lumasiran.

Lastly, Alnylam is attempting to develop its RNAi platform to address new targets outside of the liver, including central nervous system and ocular diseases. Its preliminary work in mice models suggests that an RNAi approach can knock down amyloid precursor protein, implicated across a number of neurological disorders, with a highly durable effect. 

Ionis continues to accrue development partners and progress its internal R&D assets
Ionis is pursuing a slightly different business model to Alnylam, opting to out-license its leading assets to development and commercial partners, while reinvesting into an extensive pipeline of its own. So far this has yielded three approved antisense drugs, the most notable of which being Spinraza. This de-risked approach allows the company to be highly profitable, with Ionis reporting a record year for 2019: $1bn in revenues and $300m net profit, with a cash position of $2.2bn providing notable operational flexibility. As such, it relies heavily on partners to create and expand the markets for its ASO technology.

Although the next commercial launch is not expected until 2021 – the Biogen-partnered tofersen in development for amyotrophic lateral sclerosis (ALS) patients – 2020 will be a busy year in terms of pipeline advancement. This includes the continuation of four current Phase III programs, three new Phase III initiations, >10 new Phase II projects, and six new diseases with clinical proof of concept. Ionis has set the goal of achieving at least 10 NDA submissions by 2025, assigning a high probability of success for each of its pipeline projects owing to its antisense technology and genetically validated targets. In addition to tofersen, the other notable partnered late-stage programs are TQJ230 (Novartis; cardiovascular risk), RG6042 (Roche; Huntington’s disease), and IONIS TTR-LRx (Akcea; hATTR amyloidosis).

The focus of Ionis’s internal pipeline remains on high unmet need neurology indications, where its technology is being applied across a variety of rare indications, in addition to highly prevalent diseases such as Alzheimer’s and Parkinson’s. Outside of CNS, the broader Ionis-owned pipeline is looking at non-neurological rare diseases, in addition to cardiometabolic and renal, and cancer. Improvements in its drug discovery platform are also enabling new dosing routes, with a validated once-daily tablet being trialed for a cardiovascular indication. Ionis also hopes to achieve clinical validation for pulmonary and ocular delivery routes, which would allow for new opportunities in diseases such as IPF, PAH, and retinal disorders.

While still advancing its RNA capabilities, Sarepta is diversifying towards gene therapies
Sarepta originally made a name for itself in the field of RNA therapeutics, designing ASOs that encourage exon skipping and production of functional dystrophin in Duchenne muscular dystrophy (DMD) patients. Its two approved drugs, Exondys 51 and Vyondys 53, allow the company to target approximately 20% of DMD patients based on their genotype. However, it is now pivoting towards gene therapy and gene editing in the longer term. Its most attractive candidate is SRP-9001, which delivers a truncated but functional version of the dystrophin gene, and is amenable for all DMD patients. Data for the four patients dosed so far with nine months of follow-up have been impressive, showing functional improvement where the natural history is progressive decline, so it is logical that in this particular example Sarepta is favoring gene therapy for its longer-term ambitions. There are plans to aggressively pursue pivotal clinical development and achieve commercial-scale manufacturing, boosted by an ex-US partnership with Roche worth $1.15bn upfront and $1.7bn in milestones.

Nevertheless, its pipeline of RNA programs now totals 14, growing from last year. One of these is casimersen, which extends an RNA therapeutic treatment option to DMD patients with mutations amenable to exon 45 skipping, which is a further 10% of the prevalent population. With a rolling NDA now submitted, this would become Sarepta’s third internally discovered drug to attain regulatory approval. Its next-generation ASOs involve peptide conjugation and could lead to higher dosing and direct delivery to new muscle types, such as the heart.

Biogen’s research partnership with Ionis is bearing further fruits
While Biogen has a broad therapeutic focus, with much of JP Morgan spent talking about unrelated programs in Alzheimer’s disease and multiple sclerosis, it owns the most commercially successful RNA therapeutic in Spinraza for SMA, with over 10,000 patients on therapy and annualized sales of approximately $2bn. SMA will remain an important area of investment for Biogen in light of competitive threats, and lifecycle management of its Spinraza franchise is ongoing, with higher doses and novel ASO drug candidates under development.

Beyond its interests in SMA, Biogen reiterated the timeline for its Phase III program of tofersen, an ASO binding SOD1 licensed from Ionis for the treatment of ALS. The VALOR trial, recruiting 183 SOD1+ patients, is due to read out in 2021. Biogen also expects to provide a clinical update for its Phase I trial of its anti-C9orf72 ASO BIIB078, addressing the most common familial cause of ALS, on a similar timeframe. Biogen also lists BIIB094, an ASO targeting genetic subsets of Parkinson’s disease, in its early development pipeline.

Novartis paving the way for widescale adoption of inclisiran as a cardiovascular population health drug
Although Novartis hosted an investor call immediately following its announced acquisition of The Medicines Company and the RNAi asset inclisiran in November 2019, the company again took the opportunity to explain its rationale at the JP Morgan conference. With the deal now closed, Novartis becomes the only Big Pharma with presence across four advanced therapy platforms: cell, gene, radioligand, and RNA therapies. This move to diversify and minimize reliance on single products and technologies is undoubtedly a driver behind the acquisition, but it also allows Novartis to operate within cardiovascular population health.

When critically appraising pipeline assets, Novartis CEO Vas Narasimhan poses three internal questions: “Are we really first in class, can we replace the standard of care, and do we have significant absolute efficacy gains in the medicines we launch?” Due diligence behind the Medicines Co deal will have given a resounding yes to each of these, in order for Novartis to part with $9.7bn. The drug was filed with the FDA for risk reduction in cardiovascular disease in December 2019, meaning Novartis is guiding for a 2020 approval, with submission to the EMA also expected in Q1 2020. Uniquely, Novartis is collaborating with the UK government prior to its approval, with a large-scale trial among NHS patients set to start later this year, ahead of a population-level agreement to ensure market access following approval. The UK government anticipates that the introduction of inclisiran on the NHS has the potential to save up to 30,000 lives over the next 10 years.

Novartis also profiled a second antisense drug in its pipeline, TQJ230, which targets lipoprotein(a), one of the main genetic determinants of cardiovascular risk. Originally discovered by Ionis, the drug has demonstrated very potent reductions in this biomarker, leading Novartis to exercise an option to in-license the drug. The company confirmed its plans to initiate Phase III development during 2020, conducting a major outcomes study, although this was first announced back in February 2019.

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