ACTIV coming into focus, starting COVID-19 therapy trials in June

NIH’s ACTIV consortium plans to start studying COVID-19 therapies in June

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A consortium that is pooling the resources of the U.S. government and global biopharmaceutical companies to discover and develop drugs and vaccines for COVID-19 has selected a first wave of therapies for testing and plans to start two Phase III master protocols this summer, according to documents obtained by BioCentury.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership, will start its first trials in June on repurposed immune-modulators and anticoagulants.

In July, two separate trials of monoclonal antibodies (mAbs) will be launched in hospitalized and outpatient COVID-19 patients.

ACTIV, which is led by NIH and managed by the Foundation for NIH, includes 18 biopharma companies, FDA, CDC and the HHS Office of the Assistant Secretary for Preparedness and Response (ASPR). BARDA, the U.S. biodefense preparedness funding agency, is part of ASPR (see “Collaborating to Clobber COVID-19”).

ACTIV is working in parallel with Operation Warp Speed, the U.S. government program that is accelerating the development, manufacturing, procurement and deployment of drugs, vaccines and diagnostics to combat COVID-19.

The scale and urgency of the COVID-19 pandemic are pushing government and industry to collaborate more intensively than has ever been previously attempted.

ACTIV has operated at extraordinary speed, with government officials and corporate scientists collaborating seamlessly, individuals involved in the initiative told BioCentury.

Biopharma executives who are not involved in the effort, however, have complained that it has not been transparent about the criteria for selecting agents to study or its selections.

ACTIV has not publicly disclosed which agents it has selected to test, the timing of its trials, or when readouts can be expected. The documents BioCentury obtained identify classes, but not the specific agents, the consortium plans to test.

First wave of therapies selected

ACTIV has created a process for prioritizing clinical agents for rapid testing and culled through hundreds of agents, including agents submitted by investigators and in surveys conducted by the consortium, as well as from public databases, including databases collated by BioCentury (see BioCentury Coronavirus Resource Center).

ACTIV members, including R&D leaders from biopharmaceutical companies and government regulators, scored candidates based on pre-selected criteria, assessed supply and logistic considerations, and prioritized a first wave for testing in master protocols.

The consortium plans to launch the first clinical trials in the coming week or two and is starting to prioritize a second set of agents for testing.

ACTIV is developing a portfolio of five separate master protocols for evaluating therapeutics.

The use of master protocols makes it possible to test multiple agents against a single control arm and to rapidly add or withdraw candidates from trials. Because the therapies will be tested using identical endpoints, it will be possible to quickly compare their safety and efficacy.

The ACTIV 1 master protocol is a Phase III trial targeted to enroll about 2,000 patients over age 18 who have been hospitalized with a diagnosis of COVID-19. It will test three host-targeted immune modulators against TNFα, CTLA-4 and CCR2/CCR5.

The three immune targets contribute to disease pathology in different ways. TNFα, along with other inflammatory cytokines such as IL-6, is thought to drive the excessive inflammation that damages the lungs and leads to ARDS (acute respiratory distress syndrome).

While the chemokine receptors CCR2 and CCR5 have also been implicated in runaway inflammation, the immune checkpoint protein CTLA-4 acts as a brake on the T cell responses needed to clear the virus from the body.

At least 95 ongoing trials of immunosuppressants, immunostimulants and immune modulators with more complex mechanisms have primary completion dates by the end of summer.

In contrast to the trials planned by ACTIV, many of these trials are small and poorly controlled, underscoring the need for master protocols (see “Over 200 COVID-19 Trials Nearing Completion”)

The ACTIV 1 master protocol will be launched in late June. It will be conducted by a CRO in the U.S., and may be extended to other countries.

ACTIV 2 and 3 will both test neutralizing mAbs that target the virus itself.

ACTIV 2 is a Phase II/III outpatient trial of COVID-19 positive adults that is slated to launch in early July, while ACTIV 3 will treat hospitalized adult COVID-19 patients.

ACTIV 2 will be conducted in the U.S. and South America by the AIDS Clinical Trial Group, which is managed by NIH’s National Institute for Allergy and Infectious Diseases (NIAID) and by a CRO. It is targeting enrollment of 110 patients per agent in the Phase II portion and 900 patients per agent in the Phase III portion.

ACTIV 3 will be a Phase III trial divided into two stages, with 150 patients in the first stage and 506 patients in the second stage per agent. It will be conducted by two NIH clinical trial networks and a CRO in the U.S. and South America. It is scheduled to start in mid-July.

ACTIV is contemplating combining ACTIV 1 with ACTIV 4, a Phase II/III trial of three anticoagulants currently projected to start in late June and to be conducted by NIH. The number of participants has not been determined.

The rationale behind anticoagulants is based on the observation of elevated D-dimer levels in severe patients, indicating coagulation. Wide-spread coagulation affects a subset patients and can lead to ischemia, even gangrene.

By combining immune modulators with anticoagulants, ACTIV would be able to address two different features of host biology, fine-tuning the immune response while preventing cardiovascular pathology.

A fifth master protocol, ACTIV 5, has been penciled into the consortium’s planning to evaluate promising agents, such as antivirals, that haven’t been investigated elsewhere. The details of this protocol have not been worked out yet.

In contrast to its strategy for therapies, the consortium has developed harmonized protocols rather than master protocols for vaccines. The protocols are intended to make it possible to analyze correlates of protection across trials.

ACTIV is also investigating immune response criteria that could potentially be used to support emergency use or accelerated approvals of vaccines.

Final selections for agents to be studied in ACTIV’s master protocols are being made by its executive committee. ACTIV executive committee members are: Mikael Dolsten, CSO of Pfizer Inc. (NYSE:PFE); Anthony Fauci, director of NIH’s National Institute for Allergy and Infectious Diseases; Gary Gibbons, director of NIH’s National Heart, Lung, and Blood Institute; William Pao, head of pharma research and early development at Roche (SIX:ROG; OTCQX:RHHBY); Andrew Plump, President of R&D at Takeda Pharmaceutical Co. Ltd. (Tokyo:4502; NYSE:TAK); Gary Disbrow, acting director of BARDA, Peter Marks,Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER); and Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.

The co-chair of the executive committee are NIH Director Francis Collins and Paul Stoffels, CSO at Johnson & Johnson (NYSE:JNJ).

Woodcock is also heading up the therapeutics team on Operation Warp Speed (see “Woodcock steps away from CDER”).

While industry is participating in and collaborating with ACTIV, companies have already started trials of COVID-19 candidate therapies that are not operating under the auspices of the consortium. For example the COVID R&D consortium has launched an adaptive trial to study canddiates for treating ARDS (see “COVID R&D Consortium Launches I-SPY Adaptive Trial”).

Identifying trial sites, coordinating preclinical research

One of the concerns that led to the establishment of ACTIV is that clinical trial sites will be clogged with a plethora of underpowered trials of marginal drug candidates. The consortium has put in place procedures to prevent this from happening. While it is not preventing companies or academic centers from runing trials, it is identifying and obtaining access to many of the clinical trial sites and networks.

This will ensure that ACTIV trials will be enrolled and conducted efficiently; it could also crowd out trials from other groups or companies.

To find and recruit potential trial sites, ACTIV’s clinical trial capacity working group surveyed networks from NIH’s institutes and centers, industry, and CROs. It sent capacity surveys to networks sites, CROs and site management organizations and received responses from a total of 640 trial sites in 53 networks. The clinical trial working group is comparing data on site availability with the epidemiology of COVID-19 to maximize the chances that trials are conducted in places with active outbreaks.

On the preclinical side, ACTIV has developed a master inventory of preclinical testing resources and established standard operating procedures for accelerated preclinical agent development.

One of ACTIV’s key contributions has been to develop a strategy to prioritize access to non-human primates that ensures scarce resources are allocated to the most promising agents.

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