Impact case study database

Baulcombe’s research and its associated intellectual property have proved fundamental to the development of RNAi-based therapeutics that target previously intractable diseases [S1-S3]. Acting on behalf of Baulcombe and colleagues, Plant Bioscience Limited licensed Baulcombe's patent to Alnylam Pharmaceuticals [R6], and this has ensured Alnylam's freedom to operate, since 2013, to develop, trial and release three RNAi-based drugs that target human genetic disorders, along with a fourth to treat inherited high cholesterol (familial hypercholesterolemia) [S4]. In particular, to target genetic disorders, Alnylam has registered and commercialised the two drugs ONPATTRO^® and GIVLAARI^®, and it has obtained permission for early release of a third drug, OXLUMO^TM, through the UK Medicines and Healthcare Products Regulatory Agency's Early Access to Medicines Scheme [S5] and the United States Food and Drug Administration (FDA) [S6]. It has also received approval of the familial hypercholesterolemia treatment drug LEQVIO^® from the European Commission [S4].

As detailed below, these drugs are providing treatments that patients have described as transformative in their impact on individual lives [S4, S7-S9]. They have also helped underpin the growth of Alnylam Pharmaceuticals as a company and yielded important patent revenues. In this way, the research has had substantial impact on the health and wellbeing of people and on commerce and production in the health sector. As the Managing Director of Plant Bioscience Limited has stated, "the impact of the discovery of siRNAs and understanding of their role in RNAi interference contributed by Sir David Baulcombe and Dr Andrew Hamilton has opened up a new generation of therapeutics. After pioneering development by PBL’s licensing partners these are now having a huge impact across the world, in a wave of new and diverse treatments for previously intractable indications, treating millions of patients with a series of important life-threatening conditions." [S3].

ONPATTRO® (patisiran): The disease hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a life-threatening, autosomal dominant neurodegenerative disease driven by the deposition of misfolded transthyretin protein (TTR protein) in the heart, nerves and gastrointestinal tract. Approximately 50,000 people, aged mainly between 20 and 40, suffer from the disease worldwide [S4]. Without treatment, sufferers typically die between 5 and 15 years after the onset of symptoms. Treatment options are limited, and many cases remain undiagnosed. RNAi therapeutics allow transcripts (messenger RNA) from the faulty gene to be silenced, thereby decreasing the amount of misfolded TTR protein in the body. ONPATTRO^® has been approved by the European Union and United States, along with Brazil, Canada, Israel, Japan, Switzerland and Taiwan, for the treatment of hATTR amyloidosis [S4]. Based on a large-scale randomised clinical trial, ONPATTRO^® significantly reduced patients' symptoms and improved their quality of life, such as walking ability, nutritional status and the ability to perform activities of daily living [S7, S8]. As a result, as at the third quarter of 2020, over 1,150 patients were taking ONPATTRO^® [S4]. In terms of improvement in quality of life, a patient treated with ONPATTRO^® stated, "I'm so much more than this disease, and I can put it in its place and do the things that I love to do with the people who I most love and adore in my life." [S4].

GIVLAARI® (givosiran): Acute hepatic porphyria (AHP) consists of a group of four inherited diseases of the liver with acute neurovisceral symptoms that are often missed or delayed in diagnosis because the clinical symptoms mimic those of other common disorders. Acute intermittent porphyria is the most severe of the set, with 20% of patients with recurrent symptoms developing chronic and ongoing pain. It occurs in about 1 in 1,600 people with a Western European genetic background and, in the EU and US, the patient population is estimated at 3,000 people [S4]. Previously, long-term solutions for treatment involved either infusion with blood products (e.g. IV hemin) or liver transplantation. GIVLAARI^® was developed to treat adults with acute hepatic porphyria and was approved by the US Food and Drug Administration in November 2019 [S4]. It has also been approved for use in the European Union, Brazil and Canada [S4]. This drug significantly reduces the rate of porphyria attacks that require hospitalisations, urgent healthcare visits or infusion with blood products at home. A patient receiving the drug for acute intermittent porphyria stated, “I've had pain for 10 years, I didn't expect that could go away. I'm seeing friends and they're [asking] 'you're not taking any painkillers?' and I was [saying] 'no!'.” [S9]. As at the third quarter of 2020, over 150 patients were being treated with GIVLAARI^® [S4].

OXLUMOTM (lumasiran): This drug is an RNAi therapeutic for the treatment of primary hyperoxaluria type 1 (PH1). In the EU and US, the patient population is estimated at 3,000 symptomatic individuals [S4]. The disease is caused by the build-up of oxalate, which is normally excreted in the urine. In affected people, the accumulated oxalate is deposited in the kidneys and urinary tract, where it combines with calcium to form the main component of kidney and bladder stones (calcium oxalate). Lumasiran is currently under approval and has been granted a "positive scientific opinion" (i.e. approved for use by the National Health Service) through the UK Medicines and Healthcare Products Regulatory Agency's Early Access to Medicines Scheme [S5].

LEQVIO® (inclisiran): LEQVIO^® is the first siRNA drug that reduces low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia. Approximately 3,900,000 people die annually in Europe from cardiovascular disease, of which high cholesterol (hypercholesterolemia) is a leading cause. While reducing low-density lipoprotein cholesterol levels using statins is a common treatment for high-risk patents, the majority of these patients (80%) do not experience reductions to below recommended levels. LEQVIO^® conferred effective and sustained low-density lipoprotein cholesterol reduction of up to 52% in patients. It was approved by the European Commission in December 2020 [S4]. It is estimated that approximately 50,000,000 people with atherosclerotic cardiovascular disease or familial hypercholesterolemia could benefit from treatment with LEQVIO ^® in future [S4]. For example, in the UK, the Managing Director of Plant Bioscience Limited reported that: “NHS projections estimate the drug will save 30,000 lives for every 300,000 patients treated” [S3].

Overall, the scope of using RNAi for drug development is limited only by the identification of sequence targets relevant to a given disease. As such sequences are identified, drugs based on RNAi are being developed to target genes for an increasing range of diseases, including cancer (e.g. vascular endothelial growth factor, VEGF), and to target viruses underpinning viral diseases, including Hepatitis B and the recent pandemic disease COVID-19. Similarly, drugs targeting specific genes are being developed to treat diseases such as haemophilia, Alpha-1 liver disease, hypertension and cerebral amyloid angiopathy [S2, S4]. Hence, RNAi-based drug development has an extremely promising future.

Economic impact of RNAi-based therapeutics. As a young and rapidly growing development, the market in RNAi-based therapeutics has yet to realise its full economic potential. Nonetheless, in 2018, the global size of this market was already estimated to be approximately USD1,090,000,000 (12-2018) [S10]. RNAi drugs have also contributed substantially to the income and financial growth of Alnylam Pharmaceuticals. Specifically, for ONPATTRO^®, the company's quarterly revenues increased from USD46,100,000 (12-2020) in the third quarter of 2019 to USD82,500,000 (12-2020) in the third quarter of 2020 [S4]. In addition, in the third quarter of 2020, GIVLAARI^® earned the company USD16,700,000 (12-2020) [S4]. For Baulcombe and colleagues, the patent [R6] issued for RNAi technology and managed by Plant Bioscience Limited has generated GBP10,000,000 in licensing income since 01-2014 [S3].