Novo Nordisk Partners with LNP Pioneer Genevant to Develop In Vivo Gene Editing Therapy for Hemophilia A

About Genevant

In 2018, Arbutus and Riovant jointly established Genevant and transferred the rights to the LNP delivery technology to Genevant. Genevant owns patents for the LNP delivery system, including patents for nanoparticle preparation and cationic lipid (MC3), with the MC3 patent expected to expire in 2030.

Patent Licensing Status of LNP Delivery Technology

Genevant's LNP platform is one of the few clinically validated LNP delivery technologies, with its safety and efficacy evaluated in multiple clinical programs involving 600+ patients. Genevant's delivery technology can facilitate therapeutic approaches encompassing a wide range of payloads. Currently, the company has initiated projects across various RNA modalities.

According to incomplete statistics,Currently, Genevant has reached licensing cooperation agreements with Takeda, BioNTech, and others.。

About LNP Delivery

The main active components of in vivo gene editing therapy are two types of RNA, which can only function after entering the cells. Currently, one of the primary delivery systems for RNA vaccines and drugs is lipid nanoparticles (LNP). LNP consists of four main components: cationic ionizable lipids, neutral lipids, cholesterol, and PEG.

LNP Structure

Among them, cationizable lipids are the core component, profoundly influencing the release of RNA after delivery into cells. Before entering the cell, cationizable lipids remain neutral under normal physiological conditions. The lipid nanoparticles (LNPs) encapsulating the RNA drug components reach the cell and enter in the form of endosomes. As the internal environment of the endosome gradually acidifies (endosomal acidification), the cationizable lipids become protonated, interact with neutral lipids, disrupt the original LNP and endosome structures, allowing the RNA to escape into the cytoplasm. Therefore, an excellent cationizable lipid and LNP structure can stabilize the LNP before the drug enters the cell, protecting the RNA cargo; after entering the cell, it can fully open up the package, enabling sufficient RNA release into the cytoplasm to achieve better efficacy.

LNP Structure and Release

The specific advantages of LNP are as follows:

• Capable of delivering larger molecular weight drug components into cells. Therefore, it can effectively encapsulate gRNA and Cas9 mRNA.

• Biodegradable. Because its main component is lipids, it can be degraded through normal human metabolic activities, imposing limited burden on the human body.

• Better safety. Compared with other delivery systems, such as viral vectors, it has lower immunogenicity and is therefore less likely to cause an excessive immune response.

• Scalable production is relatively simple, with low difficulty in scaling up, and there is already industrial experience in large-scale production of mRNA vaccines.

• The outer structure can be designed to target specific organs or cell types.

Exploration of Novo Nordisk in Delivery Technology

About Hemophilia A

Hemophilia is a group of X-linked recessive bleeding disorders, clinically divided into two types: Hemophilia A (Factor VIII deficiency) and Hemophilia B (Factor IX deficiency), caused by mutations in the FVIII and FIX genes, respectively.

Hemophilia A is a hereditary disease caused by the deficiency of FVIII leading to coagulation dysfunction. It is also the most common type of hemophilia, with a higher incidence in males. Clinically, it manifests as bleeding in any part of the body. The severity of bleeding in patients mainly depends on the FVIII activity level. Severe Hemophilia A patients (residual FVIII activity <1%) account for 50% of the entire patient population.

According to the "Chinese Expert Consensus on the Diagnosis and Treatment of Hemophilia," the incidence of Hemophilia A in the male population is approximately 1/5000, while the incidence of Hemophilia B is about 1/25000. Among all male hemophilia patients, Hemophilia A accounts for 80%-85%, and Hemophilia B accounts for 15%-20%; female hemophilia patients are extremely rare. By the end of 2021, China's male population was 723 million. Based on this estimate, the number of people with Hemophilia A in China is approximately 144,600, and the number of people with Hemophilia B is about 28,900. The China Hemophilia Treatment Collaboration Group analyzed data from 166 hospitals in China from 2007 to 2019 and found that the proportion of severe Hemophilia A patients in China was as high as 49.7%. Currently, there are still deficiencies in the diagnosis and treatment of hemophilia in China.

As of October 2022, China has approved five plasma-derived and three recombinant coagulation factor products. According to the NMPA, domestically produced coagulation factor products include: Human Coagulation Factor VIII, Human Coagulation Factor IX, Human Prothrombin Complex Concentrate (PCC), Human Fibrinogen, Human Fibrin Sealant, and Recombinant Human Coagulation Factor VIII for injection; imported products include: Recombinant Human Coagulation Factor VIII for injection, Recombinant Human Coagulation Factor VIIa for injection, and Recombinant Human Coagulation Factor IX for injection. Human Coagulation Factor VIII is used for replacement therapy in patients with Hemophilia A, while patients with Hemophilia B are typically treated with Human Prothrombin Complex Concentrate (PCC) containing coagulation factors II, VII, IX, and X.

Coagulation Factor Products Approved in China and Their Indications

However, the on-demand and prophylactic treatment satisfaction rates for hemophilia patients remain relatively low. Taking Hemophilia A as an example, based on China’s estimated 144,600 Hemophilia A patients, with 86.2% being moderate to severe cases, it is projected that there are approximately 124,700 moderate to severe Hemophilia A patients in China. According to the "Chinese Expert Consensus on Diagnosis and Treatment of Hemophilia (2017 Edition)," the theoretical annual usage of Factor VIII (human-derived + recombinant) for on-demand treatment of moderate to severe Hemophilia A patients is 28,800 IU. Assuming factors such as production capacity bottlenecks of human coagulation Factor VIII, intensified competition leading to reduced prices of recombinant human coagulation Factor VIII, and the continued rise of recombinant Factor VIII sales to 75%, the theoretical annual demand for human-derived Factor VIII would be approximately 4.49 million vials (200 IU). Based on data from the National Institutes for Food and Drug Control (NIFDC) and local testing institutes, the batch release volume of human-derived Factor VIII in China in 2021 was about 2.43 million vials (200 IU), indicating a treatment satisfaction rate of only 54%, reflecting unmet market demand.

Calculation of Coagulation Factor VIII Demand for Moderate to Severe Hemophilia A Patients (On-demand Treatment Criteria)

About Novo Nordisk's Layout in Rare Diseases

According to incomplete statistics,Currently, Novo Nordisk has 38 innovative drugs in the rare disease pipeline, of which 15 have been approved.In May this year, Novo Nordisk announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the marketing authorization for the long-acting growth hormone Sogroya (Somapacitan) to treat children aged 3 years and older with Growth Hormone Deficiency (GHD).

Novo Nordisk's Drug Portfolio in the Rare Disease Field

In addition, the company has respectively partnered with 2seventy bio and Life Edit Therapeutics to develop therapies with the potential to cure Hemophilia A and related gene-editing therapies targeting a range of indications.

Novo Nordisk's Deal in the Rare Disease Field