PharmaShots Interview: Xencor's Bassil I. Dahiyat Shares Insight on the US FDA's Approval of COVID-19 Antibody Treatment Leveraging its Technology

In an interview with PharmaShots, Dr. Bassil I. Dahiyat, President and CEO of Xencor shared his views on the company's collaborations with BMS and its Xtend XmAb technology. He also shed light on the EUA of Sotrovimab for COVID-19.

Shots:

The FDA has granted EUA to Vir and GSK's sotrovimab, which was engineered with Xencor's XmAb technology, Xtend for the treatment of mild-to-moderate COVID-19 in high-risk adults and pediatric patients
Sotrovimab represents the third drug engineered with Xencor's XmAb to get FDA's approval and it's currently being evaluated in a dozen other clinical-stage programs, including another COVID-19 Ab treatment with BMS
Clinical studies showed Xencor's Xtend technology aided in reducing the dose administered and enhance lung tissue bioavailability. Xencor's Xtend XmAb technology has been shown to increase circulating half-life by increasing binding affinity to the receptor FcRn

BMS Partnership:

Tuba: What are the key points for this license agreement for use of Xtend XmAb technology in Sars-Cov-2 by Xencor and Bristol Myers?

Dr. Dahiyat: We provided Bristol Myers Squibb with non-exclusive access to our Xtend Fc technology, with the hope it will help extend the circulating half-lives of the antibodies used in their novel combination therapy being evaluated to neutralize the SARS-CoV-2 virus for treatment or prevention of COVID-19.

Bristol Myers Squibb is responsible for clinical development, regulatory activities, and potential commercialization, and we are eligible to receive royalties from net sales of products developed with our Xtend Fc technology.

Tuba: How does the Xencor XmAb Fc technology work?

Dr. Dahiyat: Our XmAb Xtend Fc domains increase binding affinity to the receptor FcRn, which is present inside lysosomes in endothelial cells lining the blood vessels and functions to rescue antibodies from the degradation that makes most proteins short-lived in circulation. As a result of interactions with FcRn, all antibodies have half-lives ranging from a few days to a few weeks, allowing less frequent dosing for antibody drugs than most other biologics. We have engineered a series of variants that increase binding of the Fc domain to FcRn to keep antibodies from being degraded, which in turn increases circulating half-life.

Sotrovimab EUA:

Tuba: How will Sotrovimab, an XmAb engineered antibody developed by Vir biotechnology and GSK, be used in emergency cases for covid patients? What will this antibody do? Please lets us know the mechanism and how it will work in emergency cases.

Dr. Dahiyat: It's important to understand that Xencor's XmAb Fc domains are designed to be modular and thus can be used in a plug-and-play manner whenever we or our partners engineer drug candidates to have the enhanced property, like extended circulating half-life. As with Bristol Myers Squibb's duo antibody combination, Vir Biotechnology, and GSK's sotrovimab also incorporates our Xtend Fc technology. And not unlike our collaboration with BMS, Vir and GSK not Xencor are responsible for all development and commercialization.

Preclinical data suggest sotrovimab has the potential to both block viral entry into healthy cells and clear infected cells. The antibody binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1, the virus that causes SARS, indicating that the epitope is highly conserved, which may make it more difficult for resistance to develop.

The FDA's letter of authorization and fact sheet, which outline the use of sotrovimab under its U.S. emergency use authorization, can be found online at sotrovimab.com.

Tuba: When are Vir and GSK evaluating Sotrovimab in further clinical development?

Dr. Dahiyat: Vir and GSK are evaluating sotrovimab in an extensive ongoing clinical development program. Additional studies include COMET-PEAK, a pharmacokinetic study in outpatients with mid-to-moderate COVID-19 investigating intramuscular administration of sotrovimab; COMET-TAIL, a Phase 3 study evaluating intramuscular administered sotrovimab for the early treatment of mild-to-moderate COVID-19 in high-risk non-hospitalized adult and pediatric patients of at least 12 years of age; and a prophylaxis study in uninfected immunocompromised adults.

As the clinical development continues, Vir and GSK have announced that they are working with government agencies around the world to make sotrovimab available to patients in need of treatment.

Tuba: Xtend has demonstrated, in multiple antibodies and through numerous human clinical trials, the ability to extend antibody-drug half-life and reduce dosing frequency in patients, an important feature in anti-viral therapy for pandemic use. Can you please shed some light on this statement, provide additional color?

Dr. Dahiyat: Xtend technology is additionally in multiple clinical-stage programs and one approved therapy, Alexion's Ultomiris (ravulizumab-cwvz). Antibodies with extended half-lives stay circulating in the bloodstream longer, meaning patients may not need to take them as often. In a pandemic this is especially important as it reduces the number of times patients receive the medication as each dose works for a longer period, and given potential manufacturing constraints, more patients can receive the medicine.

Tuba: How does Xencor's Xtend XmAb technology in Sotrovimab reduce the risk of hospitalization or death in high-risk outpatients?

Dr. Dahiyat: As previously mentioned, Vir and GSK's sotrovimab incorporates our XmAb Xtend Fc technology. Recently, they announced final, confirmatory results from the Phase 3 COMET-ICE trial demonstrating that sotrovimab reduced the risk of hospitalization or death among high-risk adult outpatients with mild-to-moderate COVID-19, compared to placebo. Xtend reduces the number of times patients receive the medication as each dose works for a longer period.

It's interesting to note that data from in vitro studies, published online, have demonstrated that sotrovimab maintains activity against circulating variants of concern and interest, including the Delta variant.

Tuba: What phase was the trial when it was submitted for EUA? Is Sotrovimab being evaluated in additional clinical programs?

Dr. Dahiyat: The U.S. FDA granted a EUA for sotrovimab based on interim data from Vir and GSK's Phase 3 trial, COMET-ICE. They are evaluating sotrovimab in an extensive ongoing clinical development program.

Tuba: Tell us about the key features of data on phase 3 COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial).

Dr. Dahiyat: Vir and GSK recently announced final, confirmatory results from the study demonstrating that sotrovimab significantly reduced the risk of hospitalization or death among high-risk adult outpatients with mild-to-moderate COVID-19.

The primary efficacy analysis of all 1,057 patients in the trial demonstrated a 79% reduction (adjusted relative risk reduction) (p<0.001) in hospitalization for more than 24 hours or death due to any cause, by Day 29 compared to placebo, meeting the primary endpoint of the trial. The number of patients in the trial who were hospitalized for more than 24 hours for acute management of any illness or death from any cause at Day 29 was six patients in the sotrovimab arm (1%) versus 30 patients in the placebo arm (6%).

In the safety analysis, 1,037 participants were followed through at least 29 days. The most common adverse events observed in the sotrovimab treatment group in COMET-ICE were rash (1%) and diarrhea (2%), all of which were mild or moderate. No other treatment-emergent adverse events were reported at a higher rate with sotrovimab compared to placebo.

Image Source: WHO

About Dr. Dahiyat:

Dr. Dahiyat has been Xencor's president and chief executive officer since the Company's incorporation in August 1997, and is the co-founder of Xencor, and co-inventor of Xencor's breakthrough XmAb® technology. Dr. Dahiyat holds a Ph.D. in Chemistry from Caltech and B.S. and M.S.E. degrees in Biomedical Engineering from the Johns Hopkins University.