Securing FDA Expanded Access Designation For An Emergent Public Need

A conversation with SIGA Technologies Executive Vice President and Chief Scientific Officer Dennis Hruby

This time last year, many people in the U.S. were hearing for the first time about a rare viral infection called mpox, originally dubbed monkeypox. The number of infections peaked during the summer and early fall of 2022, with the U.S. now totaling more than 30,000 infections to date. The CDC has indicated the outlook for mpox remains uncertain, but among its recommendations for containment include vaccination and targeted therapies.

In the midst of the U.S. outbreak, SIGA Technologies secured an expanded use designation to help treat mpox under a government program called Project BioShield, which aims to “accelerate research, development, purchase, and availability of effective medical countermeasures against biological, chemical, radiological, and nuclear (CBRN) agents.”¹

In this Q&A, SIGA Technologies Executive Vice President and Chief Scientific Officer Dennis Hruby discusses the journey toward expanded access, or compassionate use, of TPOXX and the importance of keeping a pulse on — and reacting to — an emerging public need.

Mpox made headlines and had its first U.S.-based outbreak last year. At the time of this interview, eight new cases of mpox have been reported in Chicago, and you’re reminding the public of their exposure risk. All that understood, there are vaccines for mpox. What do we know about an mpox vaccine and its effectiveness?

The preferred mpox vaccine, JYNNEOS in the U.S., is a live, non-replicating vaccine that is based on the modified vaccinia Ankara (MVA) virus. JYNNEOS was developed to address the threat of poxviruses and has been studied for its safety and effectiveness.

Clinical trials have demonstrated that JYNNEOS induces an immune response against both mpox and smallpox viruses. It has shown efficacy in preventing both diseases and may also help reduce the severity of these illnesses if a vaccinated person becomes infected.

Vaccines are never a failsafe, and so therapies are developed for those who do become ill. SIGA gained compassionate use, or expanded access, designation for its TPOXX smallpox therapy to treat mpox. How, and at what point, did SIGA Technologies discover TPOXX’s ability to treat mpox?

SIGA initially developed TPOXX (tecovirimat) as an antiviral therapy specifically designed to treat smallpox. Smallpox and mpox are closely related diseases caused by similar viruses, and they share many characteristics. During preclinical and early clinical studies, it became evident that TPOXX also exhibited activity against mpox and other orthopoxviruses. In fact, one of the primary animal models used to demonstrate TPOXX efficacy for regulatory approval was nonhuman primates infected with mpox.

The discovery of TPOXX's potential for treating mpox was further confirmed through in vitro and animal studies. These findings paved the way for exploring its use as a therapeutic option for patients infected with mpox when the disease started to widely spread in the summer of 2022. This spread hardly came as a surprise as mpox has been endemic in Africa for years with case numbers rising and the geographic range expanding. In recent years, cases of mpox were imported into the U.S., the U.K., and Israel.

Then, knowing the immediate public need, how did SIGA earn expanded access designation? And what were some of the challenges in securing it?

Recognizing the urgent public health need for effective treatments for mpox, SIGA, in partnership with its U.S. government partners, proactively pursued compassionate use, or expanded access, designation for TPOXX in treating mpox. The company worked closely with regulatory agencies, including the FDA, to demonstrate the safety and potential efficacy of TPOXX in addressing this unmet medical need.

Securing the compassionate use designation for TPOXX was a rigorous process designed to provide the highest achievable levels of safety to patients. One significant goal was to adequately demonstrate the safety and potential efficacy of TPOXX for the treatment of mpox based on available preclinical and clinical data. While TPOXX had already been approved by the FDA for the treatment of smallpox, additional evidence was required to support its use for mpox. It should be noted that TPOXX is approved for use in mpox patients by the EMA and MHRA in Europe.

Another goal involved expediting the regulatory process to ensure timely access to the therapy. Acquiring the compassionate use designation required close collaboration with regulatory agencies and adherence to specific guidelines and criteria. SIGA had to provide comprehensive data, address regulatory inquiries, and work diligently to meet all the necessary requirements as rapidly as possible to obtain the designation. This included sharing all of the data contained within the NDA as well as the unpublished data.

What type of expanded access did you pursue, and what led you to that decision? And, once granted, how did you communicate the availability of TPOXX to healthcare providers and patients?

In the U.S., all TPOXX is held within the Strategic National Stockpile and its distribution is the responsibility of the CDC. As such, the CDC had an IND in place that was expanded to a Compassionate Use IND and modified several times during the pandemic to facilitate patient access. While TPOXX is not available for commercial sale, anyone in the U.S. who tests positive for mpox is encouraged to enroll in a clinical trial that is studying the use of TPOXX for mpox. Adults with severe mpox virus infection or those at high risk for severe disease, including individuals with underlying immune deficiency, a history of or active inflammatory skin conditions, pregnant people, and children will all be enrolled in an open-label arm in which all participants receive tecovirimat. There is also an ongoing trial to test TPOXX in the Democratic Republic of Congo.

What lessons can be learned from this process, in terms of identifying an emerging public need and meeting it with swift action?

The experience with mpox and the development of TPOXX offer several valuable lessons in addressing emerging public health needs. Some key takeaways include:

1. Active Surveillance: Timely detection and surveillance of emerging diseases are crucial in identifying and responding to public health threats as quickly as possible. Robust surveillance systems can play a central role in early recognition of outbreaks and rapid response efforts.
2. Prioritizing Research and Development: Investing in research and development for potential therapeutics and vaccines targeting related diseases can provide a head start in addressing emerging threats. For example, the work done on smallpox treatments laid the foundation for efforts to repurpose TPOXX as a treatment for mpox.
3. Collaboration and Regulatory Engagement: Close collaboration between pharmaceutical companies, healthcare authorities, and regulatory agencies is essential in expediting the development and approval process for new therapies. Proactive engagement with regulatory bodies can help streamline regulatory pathways for necessary designations such as compassionate use.
4. Agile Response: Swift action and flexibility in adapting existing therapies for new indications are also vital. Recognizing where there may be similarities between diseases and repurposing approved treatments can expedite the availability of effective interventions.

By learning from experiences like this, stakeholders in the healthcare ecosystem can enhance preparedness and response capabilities, ensuring faster and better outcomes when addressing emerging public health challenges.

Resources:

1. TPOXX-Fact-Sheet.pdf (siga.com)

About The Expert:

Dennis Hruby, Ph.D., is a distinguished scientist with more than 25 years of experience in poxviruses, virology, and anti-infective research. Dr. Hruby currently serves as executive vice president and chief scientific officer at SIGA Technologies. Dr. Hruby conducted virology research as an NIH postdoctoral fellow at the University of Wisconsin, Madison, and at the State University of New York, Stony Brook. He is currently a courtesy professor of microbiology at Oregon State University, after spending 27 years on the faculty and serving in a number of capacities, including director of the molecular and cellular biology program and chairman of the microbiology department. Dr. Hruby received his Ph.D. in microbiology from the University of Colorado Medical Center and holds an undergraduate degree in microbiology from Oregon State University. He has published more than 210 manuscripts/chapters, 400 abstracts, and currently holds approximately 200 U.S. and international patents.