< PreviousRNAi THERAPIES 20 Pharma Business International www.pbiforum.net © Shutterstock /nobeastsofierce The growth of gene silencing The growth of gene silencing 20-23.qxp_Layout 1 08/02/2021 13:53 Page 1Pharma Business International 21 www.pbiforum.net RNAi THERAPIES Since its discoverers were awarded a Nobel Prize in 2006, RNAi has been through its ups - with scientists flocking to it to create drugs that can silence genes and block production of proteins that cause disease - and downs, especially where efficacy, side effects, and delivery are concerned. In the last couple of years, however, the gene silencing therapeutic strategy has truly taken off and seen renewed interest from Big Pharma, blossoming in 2018 when Alnylam Pharmaceuticals won the first approval of an RNAi therapy, validating the science underlying such therapies. The drug partisiran (Onpattro) was approved to treat nerve damage caused by hereditary transthyretin amyloidosis, and showed these treatments could be delivered to the liver. Alnylam has since gained two more approvals for RNAi therapies; givosiran (Givlaari) was approved in 2019 for acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules, while at the end of 2020 lumasiran (Oxlumo) was approved to treat primary hyperoxaluria type 1, a rare genetic disorder that leads to an overproduction of oxalate by the liver. A leader in the field, Alnylam is continuing to make strides, announcing at the beginning of 2021 that the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis (a protein misfolding disorder), met its primary and both secondary endpoints at nine months in patients with hATTR amyloidosis with polyneuropathy. It reduced symptoms of polyneuropathy tied to transthyretin- mediated (ATTR) amyloidosis from baseline after nine months of treatment, beating a historical placebo control, and improved quality of life and patient gait speed. Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam, said: “We are excited to report positive topline results from the HELIOS-A study, which show that vutrisiran reduces neurologic impairment and improves quality of life in patients with hATTR amyloidosis with polyneuropathy as soon as 9 months, with an encouraging safety and tolerability profile. We believe that vutrisiran, as a low-dose, once-quarterly, subcutaneously administered therapy, has the potential to be a highly attractive therapeutic option for patients living with this progressive, life-threatening, multi- system disease.” The company plans to submit a New Drug Application for vutrisiran with the US FDA in early 2021, followed by regulatory filings in additional Following a number of obstacles, RNA interference (RNAi) therapies are seeing renewed interest and investment alongside more approvals. 22 Á 20-23.qxp_Layout 1 08/02/2021 13:53 Page 2RNAi THERAPIES 22 Pharma Business International www.pbiforum.net countries. RNAi therapies often focus on the liver (such as Alnylam’s three approvals), due to RNAi molecules congregating in the liver after infusion, but there are many other applications for RNAi in treating diseases of other organs, like the brain and lungs, though attempts to deliver RNAi to these parts of the body have been less successful. Work to expand RNAi therapies outside of the liver is progressing, however. Atalanta Therapeutics launched this year to develop RNAi therapies for (silencing the expression of genes involved in) neurodegenerative diseases. The company – one of whose founders is RNAi discoverer Craig Mello – has $110 million in series A financing, and was founded to address a central limitation for today’s RNAi therapeutics - the difficulty of achieving distribution throughout the brain and spinal cord. Working on therapies for central nervous system (CNS) diseases, like Huntington’s, with Biogen, and Alzheimer’s and Parkinson’s, with Genentech, the company believes its branched RNAi technology, called branched siRNA - where two RNAi molecules are covalently linked - will unlock the potential of RNAi therapies in the brain. Branched siRNA is a novel oligonucleotide architecture that has shown potent ability to silence gene expression in the CNS and can be applied across multiple neurodegenerative diseases. Preclinical research published in Nature Biotechnology has shown that branched siRNA can achieve unparalleled distribution in the CNS, including deep brain structures, and prolonged duration of effect. Meanwhile, Arrowhead Pharmaceuticals is working on a candidate inhaled therapy for cystic fibrosis (CF). A Phase 1/2 clinical trial assessing ARO-ENaC dosed its first participants last year. ENaC is a sodium transport channel overactive in the lungs of those with CF. This contributes to dehydration and reduced mucus clearance in the lungs, leading to persistent lung infections, structural damage, and progressive loss of pulmonary function. Arrowhead’s therapy aims to lower the production of a piece of that sodium channel (the epithelial sodium channel alpha subunit) in the airways of the lung, as a result reducing the amount of total ENaC - it delivers an RNAi molecule to the lungs which binds to the mRNA of ?ENaC and targets it for destruction, stopping ?ENaC proteins being made. There is also promise for RNAi therapeutics in the cancer space. Recently Sirnaomics announced dose administration for the first patient in a Phase 2a clinical study of STP705 for the treatment of cutaneous basal cell carcinoma (a type of skin cancer). The open label, dose escalation study is designed to evaluate the efficacy and safety of intralesional injection of STP705 in adult patients with cutaneous basal cell carcinoma confirmed with biopsy samples. This news followed positive efficacy and safety results from a Phase 2a clinical study of STP705 for treatment of squamous cell skin cancer. Sirnaomics © Shutterstock /Natali _ Mis 20-23.qxp_Layout 1 08/02/2021 13:53 Page 3Pharma Business International 23 www.pbiforum.net RNAi THERAPIES is also proceeding with a Phase I clinical study of STP705 for treatment of multiple types of liver cancer. Further confidence for RNAi therapies can be seen with investment, such as AstraZenica’s 2020 deal with Silence Therapeutics in which it paid Silence $60 million up front and made a $20 million equity investment. The companies are aiming to work on five targets in the next three years, discovering, developing, and commercialising siRNA therapeutics for cardiovascular, renal, metabolic, and respiratory diseases, harnessing Silence’s established siRNA platform. Silence made significant progress in its R&D pipeline in 2020, initiating dosing in its randomised, double-blind, placebo- controlled Phase 1 single- ascending dose study of SLN124, the product candidate for beta- thalassaemia and myelodysplastic syndrome (MDS), in up to twenty-four healthy volunteers. This marks the first dose of a Silence siRNA therapeutic delivered to humans using the company’s GalNAc-siRNA platform. GalNAc is a naturally occurring sugar that binds specifically to a receptor which is highly expressed on liver cells, or hepatocytes. Coupling GalNAc sugars to stabilised siRNA molecules allows them to specifically target liver cells and carry out their function. Moreover Silence’s SLN360 for the treatment of cardiovascular disease associated with high Lipoprotein(a), or Lp(a), levels, received approval from the FDA for an Investigational New Drug application to start dose escalation studies in healthy volunteers and secondary prevention patients with elevated Lp(a). SLN360 is designed to address increased cardiovascular risk, heart disease, heart attack, and stroke, associated with raised levels of Lp(a), which is considered to affect up to ten per cent of the world’s population. Silence presented positive pre-clinical safety data for SLN360 at the American Heart Association’s virtual Scientific Sessions 2020, in November. The results demonstrated that the potent and sustained reduction of lipoprotein(a) levels in in vitro and animal models treated with SLN360 was not associated with any adverse or off-target effects. What is RNAi therapy? RNA interference (RNAi) is a process where small RNA molecules, through neutralising targeted mRNA molecules, inhibit gene expression. The two main types of molecules responsible for RNAi are small interfering RNAs (siRNAs) and microRNAs (miRNAs). 20-23.qxp_Layout 1 08/02/2021 13:53 Page 4LICENSING 24 Pharma Business International www.pbiforum.net I n the context of pharmaceutical research, development and dealmaking, licensing broadly falls into two categories: in-licensing and out-licensing. The former concerns the purchaser or investor and describes the process of creating a contract that allows another firm to provide capital to the development and launch process, thereby taking on financial responsibility. It is a particularly popular option among small biopharma start-ups as it allows them to get their drug of the ground. As with any kind of investment process, it comes with several advantages and disadvantages. So while it may provide the capital a company requires, its profits will need to be shared once said drug comes to market. However, for savvy companies, the benefits of in-licensing are legion. It is, for example, cost effective by virtue of the financial burden of product development being shared. It’s also lower risk for the company buying in as it can make deals based on promising preclinical or clinical results. Now, compare the aforementioned to the traditional drug-discovery process – where a company invests heavily in development, and more often than not with little data to back up expectations. Indeed, the best estimates put the time it takes for new drugs to make it from the lab to market between ten and fifteen years, a journey that comes with an average price tag of £1.5 billion. Although licensing might not necessarily reduce the time it takes – although having multiple companies involved in development will certainly help – the cost will be easier to bear when they are shared. The lure of licensing Licensing has been part and parcel of pharmaceutical dealmaking for decades, but it has become critical in combatting coronavirus as companies share resources and intellectual property. 26 Á 24-27.qxp_Layout 1 08/02/2021 13:54 Page 1Pharma Business International 25 www.pbiforum.net LICENSING © Shutterstock /HQuality 24-27.qxp_Layout 1 08/02/2021 13:54 Page 2LICENSING 26 Pharma Business International www.pbiforum.net In-licensing also holds significant appeal when compared to straight M&A. That’s because licenses allow drug companies to purchase the rights for experimental drugs without taking on another company’s baggage, including unwanted technologies. All of that means in-licensing can hold major appeal for pharmaceutical companies and investors alike. But, as mentioned above, it can also generate confusion — confusion that can lead to ill-informed decisions on the part of investors. Out-licensing, on the other hand, is focused more on opening up the delivery pipeline so companies can effectively get their drug out the door, so to speak. It encompasses finding a partnership – or partnerships – that will help identify a company’s target market and assist in getting its product into the right hands. This process may include working with marketing firms or legal firms. As can be expected, this type of licensing revolves around a different financial relationship than that of in-licensing. Licensing is also playing a key role in the continuing fight against coronavirus. Gilead, for example, has recently signed non-exclusive voluntary licensing agreements with generic pharmaceutical manufacturers based in Egypt, India and Pakistan to further expand supply of remdesivir – broad-spectrum antiviral medication being used to treat COVID- 19. The agreements allow the companies © Shutterstock /Gorodenkof f 24-27.qxp_Layout 1 08/02/2021 13:54 Page 3Pharma Business International 27 www.pbiforum.net LICENSING © Shutterstock /Bernard Chantal – Cipla; Dr. Reddy’s Laboratories; Eva Pharma; Ferozsons Laboratories; Hetero Labs; Jubilant Lifesciences; Mylan; Syngene, a Biocon company; and Zydus Cadila Healthcare – to manufacture remdesivir for distribution in 127 countries. The countries consist of nearly all low-income and lower-middle income countries, as well as several upper- middle- and high-income countries that face significant obstacles to healthcare access. The regulatory approval status of remdesivir varies by country, and the distribution of remdesivir within each country listed below is subject to local laws and regulations. Under the licensing agreements, the companies have a right to receive a technology transfer of the Gilead manufacturing process for remdesivir to enable them to scale up production more quickly. The licensees also set their own prices for the generic product they produce. The licenses are royalty-free until the World Health Organization declares the end of the Public Health Emergency of International Concern regarding COVID-19, or until a pharmaceutical product other than remdesivir or a vaccine is approved to treat or prevent COVID-19, whichever is earlier. Licensing agreements will continue to form keystones in company’s strategies, whether that’s for younger companies to get the ball rolling, or for seasoned firms to share the development costs of new drugs to market. As countries around the globe continue to upscale their vaccine programmes against COVID-19, and more treatments come to the fray, licensing will also maintain an important weapon in our collective arsenal against coronavirus. 24-27.qxp_Layout 1 08/02/2021 13:54 Page 4DELIVERY SYSTEMS 28 Pharma Business International www.pbiforum.net No drug is of use without a robust delivery system to administer it to the body. It goes without saying that the COVID pandemic has brought plenty of attention to this, but how robust is the market expected to be once the vaccination periods are over? According to a report from Data Bridge Market Research, the microneedle market is expected to experience steady growth within the forecast period of 2020 to 2027, with a CAGR of 7.1 per cent as a result of a focus on finding alternative and safer delivery systems than hypodermic needles. Electronic drug delivery systems are also expected to see a significant rise of 8.9 per cent CAGR by 2028, with the high prevalence of chronic disorders and an increase in geriatric patient pool being susceptible to cardiovascular and respiratory diseases being the major driving factors. Forecasts look good but it’s important to note that COVID-19 has impacted many methods of drug delivery, sometimes not in obvious ways such as competing for time or materials, but in how easy it is for medical practitioners to administer drugs during a lockdown. There are some who believe this may lead Delivery on time Logistical delivery of pharmaceuticals is in the news at the moment due to the slow rollout of the COVID-19 vaccine, but systems of delivery treatment to the human body are just as important, and just as impacted by the lockdown. 30 Á 28-31.qxp_Layout 1 08/02/2021 13:55 Page 1Pharma Business International 29 www.pbiforum.net DELIVERY SYSTEMS © Shutterstock /Billion Photos 28-31.qxp_Layout 1 08/02/2021 13:55 Page 2Next >