Alnylam – The Sound Of Silence
04 March 2020
Bottom line:
RNA-based drugs are attractive due to their numerous advantages over protein-based or DNA-based therapies. We believe that Alnylam (recently added to our Biotech certificate) is well-positioned in this market thanks to its proven RNAi platform and various late-stage compounds.
We are currently considering adding other biotechnology companies operating in the RNA-based therapies market and, more broadly, in the gene therapy market, to our certificate.
The Power To Shut Down Genes
RNA-based drugs: the next generation of therapeutics
DNA and RNA-based gene therapies act before the defective protein is made and look to replace current protein-based drugs.
- Compared to DNA-gene therapy, RNA-gene therapy is less invasive and avoids risk of irreversible damaging changes.
- RNA-based therapies are cheaper and more stable than DNA gene therapies.
- At a low and adjustable dosage, RNA-based drugs allow a more extended period between injections than conventional drugs (i.e., biannual vs. daily/weekly administrations).
A big market for RNA-based medicines
Diseases are caused by overproduction or, on the contrary, by the lack of a protein. According to the type of RNA used, the drug can silence the disease-associated protein (e.g., RNAi) or trigger the production of the missing one (e.g., mRNA).
- Given the potential to treat various diseases such as cancers, AIDS and rare diseases, the market could reach $10bn by 2025 (a CAGR of 39%).
- Most RNA-based drugs under development are RNA interference (RNAi).
Alnylam: the pioneer of RNAi technology
With two drugs already approved, Alnylam has demonstrated the effectiveness and safety of its proprietary RNAi platform. By targeting rare diseases, the company benefits from several FDA designations to accelerate and improve its clinical trials.
- Alnylam has significantly increased its probability of success compared to the industry (54.6% from Phase I to end Phase III vs. 5.5%).
- Thanks to its technology platform, Alnylam reduces costs and creates high barriers to entry.
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A Closer Look At The Technology
RNAi put the disease-causing protein under silence
The overproduction of a protein, due to genetic mutations, is the cause of many diseases. Proteins are built according to DNA-based instructions which are carried by an intermediate molecule, called mRNA.
- RNA interference (RNAi) is a process that blocks the translation of mRNA into a protein by cleaving it. RNAi drugs prevent the production of a defective protein.
- So far, RNAi has proven better stability and safety than other silencing drugs such as ASOs (antisense oligonucleotides).
Challenges to overcome before RNAi is widely adopted
RNA can’t be delivered “naked” to the cell because enzymes will degrade it. Alnylam was the first to develop an accurate, efficient and safe delivery capsule, lipid nanoparticles (LNPs). After the Onpattro’s launch, Alnylam is using GalNac as an alternative to LNPs.
- GalNAc is administered subcutaneously vs. LNPs’ intravenously delivery. Patients can self-administer low doses quarterly (or even semi-annually) vs every 3 weeks for LNPs.
A proprietary tech platform targeting rare diseases
After 15 years and $1.5bn of R&D investment, Alnylam was the first company to turn RNA interference technology into a drug. The platform validation demonstrates the company’s capabilities to develop drugs with genetically validated candidates, and restored confidence in the efficacy of RNAi.
- In 2018, Onpattro was approved to treat a rare liver disease and just one year later, Givlaari was approved for the treatment of acute liver porphyria.
- Alnylam can easily replicate this technology on various genetic diseases caused by a defective protein, such as Huntington’s Disease.
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https://www.nobelprize.org/prizes/medicine/2006/7470-the-nobel-prize-in-physiology-or-medicine-2006-2006-2/
A RNAi Pipeline Full Of Promises
Promising strong franchises: Onpattro and Givlaari
To date, Alnylam has obtained two approvals, Onpattro in 2018 and Givlaari in 2019. The latter received FDA approval three months ahead of the PDUFA date.
- Onpattro had solid FY2019 net revenues of $166.4mn as, due to strong physician recommendation, it is preferred to Tegsedi (Ionis), its main rival.
- The company estimates Onpattro FY2020 net revenues at between $285mn to $315mn, a projected annual growth of about 80%.
- Givlaari peak sales could reach $500mn by 2023.
A rich late-stage pipeline
Onpattro is currently being tested for additional applications (wild-type of ATTR and h-ATTR with cardiomyopathy). Also, Lumasiran is one of the most promising latestage candidates, on Primary Hyperoxaluria Type 1 (ultra-rare kidney disease).
- Additional applications would expand Onpattro’s market five-fold (250k patients vs. 50k for the current indication).
- In December 2019, Lumasiran’s Phase III study was succesful, opening the way for an approval by the end of 2020.
Strong collaborations
Alnylam has two partnered late-stage programs: Inclisiran on Hypercholesterolemia with Novartis and Fitusiran on Hemophilia A/B with Sanofi. In 2019, Alnylam partnered with Regeneron on CNS and ocular diseases.
- Inclisaran has reported positive Phase III data, supporting a 2020 approval.
- Fitusiran has Phase III data also expected in 2020.
- In 2019, Regeneron entered the partnership with $400mn upfront payment, $400mn equity, and up-to $200mn in milestone payments.
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Sources:
Coherent Market Insights; Global Data, The Nobel Prize in Physiology or Medicine 2006. NobelPrize.org. Nobel Media AB 2020. Sun. 16 Feb 2020
Companies mentioned in this article:
Akcea Therapeutics (AKCA US), Alnylam (ALYN US), Ionis (IONS US)
Catalysts
- Approvals of Lumasiran and Inclisiran. The company has two expected approvals in 2H20 for Primary Hyperoxaluria Type 1 and for Hypercholesterolemia.
- Full data in March 2020. Full results from the Lumasiran Phase III study will be presented at the OxalEurope International Congress in March, supporting the approval in 2H20.
- Next-generation of GalNAc delivery. Lumasiran and Inclisiran, if approved in 2020, will have better patient adherence, less risk on bad infusion reactions and higher durability than already launched drugs.
Risks
- Safety issues. Safety issues were raised during the development of Givlaari in 2019. Even if it is already approved by the FDA, any incidents emerging from real-world data would dramatically affect Alnylam.
- Onpattro’s competition. Ionis/Akcea’s TEGSEDI should receive the U.S. approval in early 2020 for hATTR patients with polyneuropathy, following its EU market authorization in 2019. They are also initiating the Phase III study on hATTR patients with cardiomyopathy this year.
- Lower than expected commercial adoption. Givlaari was launched at the end of 2019. Expectations are high, due to the success of Onpattro, any disappointment would be a risk to the stock price.
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