Assembly Biosciences, Inc. (NASDAQ:ASMB) is a biotechnology company developing innovative therapeutics targeting serious viral diseases. The company's pipeline includes two helicase-primase inhibitors (HPI) targeting recurrent genital herpes, an orally bioavailable hepatitis delta virus (HDV) entry inhibitor, a clinical stage capsid assembly modulator (CAM) designed to disrupt the replication cycle of hepatitis B virus (HBV), and research programs focused on a non-nucleoside polymerase inhibitor (NNPI) targeting transplant-related herpesviruses and a small molecule interferon-α (IFN-α) receptor (IFNAR) agonist targeting HBV and HDV.

Financials

In the fiscal year 2023, Assembly Biosciences reported annual revenue of $7,163,000 and a net loss of $61,228,000. The company's annual operating cash flow was $22,743,000, and its annual free cash flow was $22,488,000. These financial results demonstrate the company's continued investment in its research and development efforts to advance its promising pipeline of drug candidates.

For the first quarter of 2024, the company reported collaboration revenue of $5,785,000. Research and development expenses for the first quarter of 2024 were $11,879,000, a decrease of $2,668,000 or 18% compared to the same period in 2023. The decrease in research and development expenses was primarily driven by decreases in external expenses related to the discontinuation of the ABI-H3733 and vebicorvir (VBR) programs, partially offset by increases in expenses related to the ABI-1179 program, which was licensed from Gilead, and the nomination of ABI-6250. General and administrative expenses for the first quarter of 2024 were $4,635,000, a decrease of $377,000 or 8% compared to the same period in 2023. The decrease in general and administrative expenses was primarily due to a decrease in stock-based compensation expense.

The company's cash, cash equivalents, and marketable securities totaled $112,976,000 as of March 31, 2024, providing it with a strong financial position to continue advancing its pipeline. Management believes the company currently has sufficient funds to meet its operating requirements for at least the next twelve months following the date the unaudited condensed consolidated financial statements are issued.

Assembly Biosciences' Clinical Programs and CTA-Enabling Programs

The company expects four of its programs to initiate clinical studies in 2024. By mid-year, the company expects to initiate the Phase 1a portion of a Phase 1a/1b study of ABI-5366 (5366), a long-acting HPI for recurrent genital herpes, and a Phase 1b study of ABI-4334 (4334), a highly potent, next-generation CAM for chronic HBV infection. By the end of the year, the company expects to initiate: the Phase 1b portion of the Phase 1a/1b study of 5366; a Phase 1a study of ABI-6250 (6250), an orally bioavailable HDV entry inhibitor; and a Phase 1a study of ABI-1179 (1179), a long-acting HPI for recurrent genital herpes contributed by Gilead Sciences, Inc. (Gilead) through the Gilead Collaboration.

Recurrent Genital Herpes/HSV-1 and HSV-2

Genital herpes can be caused by either herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2). Approximately 50% of individuals with initial symptomatic genital herpes infection have three or more recurrences per year, including over four million people in the United States and France, Germany, Italy, and Spain (collectively, the EU4) and the United Kingdom (UK). Currently, there are three antiviral drugs (all nucleoside analogs) that have been approved in the United States and the EU4/UK for the treatment of genital herpes. However, no new drugs have been approved in these regions to treat genital herpes for more than 25 years.

To address the limitations of current therapies, Assembly Biosciences identified an opportunity to develop a potent, long-acting HPI for recurrent genital herpes, 5366, which has demonstrated a strong nonclinical profile, with low nanomolar potency in vitro against both HSV-1 and HSV-2 clinical isolates, exceptionally low plasma clearance rates in multiple nonclinical models, and a projected human half-life of more than seven days. The company also acquired rights to 1179, Gilead's HPI program, as part of the Gilead Collaboration in October 2023.

HBV and HDV

The World Health Organization (WHO) estimates that 254 million people worldwide are chronically infected with HBV as of 2022, and 1.2 million new infections occur each year. HDV affects a subset of approximately 12 to 72 million HBV infected people, and these individuals experience a substantially increased disease burden, as they account for 18% of cirrhosis and 20% of hepatocellular carcinoma associated with HBV.

The focus of Assembly Biosciences' HBV program is to improve outcomes and increase the number of patients diagnosed and treated through the development of finite and curative therapies targeting an orthogonal mechanism of action. The company's HDV program is centered on the development of a safe and effective oral small molecule entry inhibitor, which would be a significant innovation for patients living with HDV.

In September 2023, the company nominated ABI-6250 (6250), a novel, orally bioavailable small molecule approach to inhibit entry of HBV and HDV by targeting the sodium taurocholate co-transporting peptide (NTCP). In nonclinical studies, 6250 demonstrated low nanomolar potency against all tested HBV/HDV genotypes, favorable selectivity for NTCP versus other bile acid transporters, good oral bioavailability, and a pharmacokinetic profile in nonclinical species projected to support once-daily oral dosing.

The company's next-generation CAM, ABI-4334 (4334), has shown nonclinical proof of principle, demonstrating the ability to reduce production of HBV DNA levels as well as the surrogate markers for covalently closed circular DNA (cccDNA) establishment: HBV e antigen (HBeAg), HBV core-related antigen (HBcrAg), and HBV pre-genomic RNA (pgRNA). The company believes that 4334 has a best-in-class nonclinical profile, with single-digit nanomolar potency against two key mechanisms of action: disrupting viral replication and preventing the establishment and replenishment of new cccDNA.

Gilead Collaboration

In October 2023, Assembly Biosciences entered into an Option, License and Collaboration agreement (the Gilead Collaboration Agreement) with Gilead, whereby Gilead exclusively licensed to the company its HPI program and NNPI program, while retaining opt-in rights to these programs. Gilead also has an option to take an exclusive license, on a program-by-program basis, to all of the company's other current and future pipeline programs during the 12-year collaboration term (subject to payment of certain extension fees).

Pursuant to the Gilead Collaboration Agreement, Gilead made an $84.8 million upfront cash payment to the company. If Gilead exercises its opt-in right to any current or future program under the collaboration, the company is eligible to receive up to $330.0 million in potential regulatory and commercial milestones on that program, in addition to royalties ranging from the high single-digits to high teens, depending on the clinical stage of the program at the time of the opt-in.

The company and Gilead also entered into a Common Stock Purchase Agreement and an Investor Rights Agreement, pursuant to which Gilead made an upfront equity investment of $15.2 million by purchasing 1,089,472 shares of the company's common stock. Gilead currently holds 19.9% of the company's outstanding voting common stock and may increase its ownership up to a maximum of 29.9%.

The Gilead Collaboration is expected to be a critical part of the development, manufacture, and commercialization of Assembly Biosciences' product candidates. However, the collaboration also poses risks, such as potential conflicts between the companies, Gilead's ability to independently develop competing products, and the company's heavy dependence on Gilead for further development and commercialization of the optioned investigational products.

Research Programs

In addition to its clinical-stage programs, Assembly Biosciences has research programs focused on a NNPI targeting transplant-related herpesviruses and a small molecule IFNAR agonist targeting HBV and HDV.

The NNPI research program aims to develop a potent oral pan-herpes polymerase inhibitor for the treatment of transplant-associated herpesvirus infections, which can increase the risk of severe disease and serious complications, including organ rejection and graft loss, in people receiving transplants.

The IFNAR agonist program is advancing a novel, small molecule designed to selectively activate the IFN-α pathway within the liver, offering the convenience of oral dosing. IFN-α is an injectable immune modulatory therapy approved for HBV that has demonstrated functional cure in some HBV infected people, but its poor tolerability profile significantly limits its use.

Liquidity

As of March 31, 2024, Assembly Biosciences had cash, cash equivalents, and marketable securities totaling $112,976,000, providing it with a strong financial position to continue advancing its pipeline. The company believes its existing cash, cash equivalents, and marketable securities will enable it to fund its operating expenses and capital expenditure requirements into the second half of 2025.

The company has not generated any revenue from product sales to date and currently has no approved products. It has funded its operations to date principally through equity financings, raising an aggregate of $618.8 million in net proceeds, and strategic collaborations, raising an aggregate of $185.7 million through upfront payments.

Risks and Challenges

Assembly Biosciences faces several risks and challenges, including: - Successful development and regulatory approval of its product candidates - Reliance on third-party manufacturers and CROs for the manufacture and testing of its product candidates - Potential competition from other companies developing products with similar mechanisms of action - Ability to maintain and expand its collaborations, such as the Gilead Collaboration - Potential intellectual property disputes - Ability to obtain sufficient financing to fund its operations and pipeline development

Conclusion

Assembly Biosciences is a promising biotechnology company with a diverse pipeline of drug candidates targeting serious viral diseases, including recurrent genital herpes, HBV, and HDV. The company's collaboration with Gilead provides significant financial and strategic support, while also posing certain risks. With a strong cash position and several clinical programs expected to advance in 2024, Assembly Biosciences is well-positioned to continue its progress in developing innovative therapies that could potentially improve the lives of patients worldwide.