In an interview with PharmaShots, Tillman Gerngross, Ph.D., Co-Founder, and CEO of Adagio Therapeutics shed light on the pre-clinical data of ADG2 and how it works on SARS-CoV-2.

Shots:

• ADG2 showed broad and potent neutralizing activity against SARS-CoV and two SARS-related coronaviruses currently known to be circulating in bat populations (WIV-1 and SHC014)
• The company expects ADG20 to enter clinical studies in early 2021. Adagio Therapeutics has raised $130M in four months
• ADG2 binds with high affinity to the 30 most frequently observed SARS-CoV-2 RBD variants reported in the GISAID database, including variants resistant to other monoclonal antibodies in the development

Tuba: Can we have a detail on the preclinical results of ADG2?

Tillman: ADG2 (the precursor to ADG20) provided complete protection against severe SARS-CoV-2 and SARS-CoV disease in mouse models. When compared to other monoclonal antibodies (mAbs) in development, ADG2 showed similar or higher potency against SARS-CoV-2 in two authentic neutralization assays. ADG2 also showed broad and potent neutralizing activity against SARS-CoV and two SARS-related coronaviruses currently known to be circulating in bat populations (WIV-1 and SHC014).

Additionally, ADG2 binds with high affinity to the 30 most frequently observed SARS-CoV-2 receptor-binding domain (RBD) variants reported in the GISAID database, including variants resistant to other monoclonal antibodies in development. Notably, no mutations have been reported at key ADG20 contact residues in full-length viral genomic sequences (>152,000) of SARS-CoV-2 included in the GISAID database as of October 19, 2020, suggesting a low risk of pre-existing resistance to ADG20 in the clinic.

Tuba: What is the mechanism of action for ADG2 and how it works on SARS-CoV-2?

Tillman: What makes ADG2 unique is the epitope it targets is highly conserved across clade 1 sarbecoviruses, it binds with high affinity to a large panel of clade I sarbecovirus receptor binding domains (RBDs). This is what we believe gives it best-in-class breadth against certain SARS-like coronaviruses. In terms of its MOA more generally, it acts as all monoclonal antibodies do  it binds to its target on the spike protein - this disables the virus ability to penetrate the cell.

Tuba: What is the difference between ADG2 and ADG20? Where this is an oral or IV or IM formulation?

Tillman: In vitro engineering of ADG2 avoided many of the common pitfalls associated with monoclonal antibody enhancements. Specifically, ADG2 demonstrated favorable biophysical properties in a series of in vitro assays that have been shown to be predictive of downstream behaviors such as serum half-life, ease of manufacturing, ability to formulate to high concentrations, and long-term stability. Adagio has engineered ADG2 to extend serum half-life and enhance mucosal localization, and this re-engineered molecule is ADG20.

Tuba: Can you please shed some light on with comparators used in the study?

Tillman: We compared ASG2 to multiple other monoclonal antibodies (mAbs) in development and ADG2 showed similar or higher potency against SARS-CoV-2 in two authentic neutralization assays. Additionally, ADG2 showed broad and potent neutralizing activity against SARS-CoV and two SARS-related coronaviruses currently known to be circulating in bat populations (WIV-1 and SHC014).

Tuba: Do you think the ADG2/ADG20 will be eligible for the BTD, FT and PR from regulatory authorities?

Tillman: We are working closely with the regulatory authorities to move ADG20 as quickly as possible through the clinic. We expect ADG20 to enter clinical studies in early 2021. The authorities have also been moving quickly with regard to COVID-19 treatments and vaccines, so it's our hope we will receive the appropriate designations.

Tuba: Is Adagio planning to assess ADG2 in other SARS-like coronaviruses or any other infections?

Tillman: Currently we are laser-focused on advancing ADG20 for the treatment and prevention of COVID-19, however, we have good reason to believe it can also be highly effective against multiple other Clade-1 sarbecoviruses.

Tuba: When is Adagio planning to initiate Ph I study and can you please share details of the design of this Ph I study?

Tillman: We expect to enter clinical studies in early 2021. We have not yet disclosed details on the design of the study.

Tuba: Is Adagio undergoing more funding rounds? Do you have any future plans for an IPO?

Tillman: Adagio has been well, and rapidly funded. We raised $130 million in four months. We have aggressive clinical plans for both treatment and prevention settings, so we do expect additional funding and likely we will access the public markets.

Tuba: Can we have an insight into Adagio's pipeline programs and their targeted indications?

Tillman: Currently we are focused on advancing ADG20 for the treatment and prevention of COVID-19. But our scientists have shown an ability to rapidly develop novel antibodies against emerging viruses including SARS, COVID-19, and Ebola. We believe new viruses will continue to emerge, and SARS-like coronaviruses historically have the highest track record of jumping to humans. If ADG-20 can’t address the next pandemic directly, we have high confidence we can rapidly develop an antibody that can.

Tuba: Are you looking for a collaboration to develop and commercialize your therapies?

Tillman: We remain focused on advancing ADG20 but we have not ruled out any potential business engagements that will enable us to do this more quickly or efficiently, including various financing or partnering strategies.

Image Source: IMF

About Author:

Tillman Gerngross is the Co-founder and CEO of Adagio Therapeutics. He is a Professor of Bioengineering at the Thayer School of Engineering at Dartmouth College, and an Adjunct Professor in the departments of Biology and Chemistry at Dartmouth.

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