ARPA-H coming into focus

How ARPA-H’s first director, Renee Wegrzyn, is creating an agency that aims to do things that seem impossible

The Advanced Research Projects Agency for Health is the child of frustration and optimism, a reflection of disappointment that massive taxpayer investments in biomedical research are yielding a trickle of breakthroughs and confidence that government can tackle immense challenges. It is focused on creating technologies that the private sector and academic researchers cannot or will not develop on their own. 

Renee Wegrzyn has been on the job as ARPA-H’s first director since October 2022, long enough to show how she intends to fulfill its mission to accelerate “better health outcomes for everyone by supporting the development of high-impact solutions to society’s most challenging health problems.”

The optimism that prompted President Joe Biden to propose and Congress to agree to create ARPA-H is fueled by the successes of the Defense Advanced Research Projects Agency (DARPA), an organization that developed some of the technologies that were critical for the vaccines and mAbs that tamed COVID-19.

Wegrzyn is tweaking the DARPA model to make it work in the healthcare ecosystem and to create solutions that could touch the lives of anyone living in the U.S., as well as patients around the world. 

Beyond the specific technologies it develops, ARPA-H is trying to pioneer new, faster and less expensive ways of researching and manufacturing them that Wegrzyn believes can serve as models for the private sector. 

The $2.5 billion Congress has appropriated for ARPA-H’s first three years of operations is far less than the $6 billion the president requested, but more than enough for the agency to show whether the model DARPA pioneered for the U.S. military can be successfully applied to healthcare.

ARPA-H’s mandate, Wegrzyn told The BioCentury Show, is to turn what may seem like fantasies into realities, to focus on technologies and solutions that will provide transformational health benefits, and to infuse its work with a sense of urgency.

These aspects of ARPA-H’s vision are similar to those of leaders of some of the largest biotech venture funds. There are, however, major differences. Unlike a VC firm, ARPA-H doesn’t have to earn a financial return on its investments, so it can fund earlier, more speculative ideas and take bigger risks than private sector investors. Additionally, ARPA-H can and is incorporating explicit social goals beyond those investors typically contemplate.

Under Wegrzyn’s direction, ARPA-H has integrated ideals about equity and access into its DNA, adding layers of challenges on top of steep scientific and medical challenges.

Like DARPA and the U.S. government’s other advanced research projects agencies, ARPA-H organizes its activities around program managers who are given a great deal of autonomy. So far, it has launched six programs that range from attempts to transform the treatment of osteoarthritis (OA) to the creation of tools to better integrate data from across the biomedical ecosystem.

ARPA-H is looking to the biotech industry as a talent pool, to conduct research, and as a source of collaborators to advance and commercialize technologies.

The agency has hired 13 program managers and expects to have 40 or 50 on board by the end of 2024, so it is likely to announce a steady stream of new programs over the coming year.

It is casting a wide net for program managers and hopes to recruit talent from the biotech industry.

Immediately prior to joining ARPA-H, Wegrzyn was VP of business development at Ginkgo Bioworks Holdings Inc. (NYSE:DNA) and head of innovation at Concentric by Ginkgo. Several ARPA-H program managers have experience in the private sector, including Jessica Green, who joined the agency from microbiome analytics start-up Phylagen Inc., where she served as both founding CTO and CEO.

In addition to programs it conceives of and leads, ARPA-H is funding projects proposed by academic research teams and biotechs that are consistent with its mission.

To facilitate the development of medical products it is trying to create, and to make it easier to meet equity and diversity goals, ARPA-H is investing in clinical trials infrastructure. Similarly, to increase the chances that its products will be widely adopted and become available to people who need them, it is creating formal mechanisms for collaborating with the investment community.

Setting expectations

ARPA-H was championed by patient advocates, researchers and politicians who are extremely frustrated by the pace at which NIH’s investments of hundreds of billions of dollars in scientific research is being turned into medicines. Its backers wanted a government entity that would put patients, rather than academic scientists, at the center, and that would focus on solving well-defined problems rather than funding curiosity-driven research projects.

Although some of its supporters, including members of Congress, have described ARPA-H as an antidote to NIH, the Biden administration has promoted it as a complement to the world’s largest biomedical research funding agency.

While ARPA-H’s backers, including President Biden, frequently invoke DARPA’s reputation, moving from defense to health requires more than scrambling an acronym.

DARPA is best known for innovations that are widely used by civilians but it has always been oriented to serving the needs of the military. Civilian applications of its work, such as the Internet and practical GPS devices, were fortuitous spin-offs.

Much of DARPA’s activity has been cloaked in secrecy. As a result, the public is largely unaware of DARPA’s failures. In contrast, ARPA-H’s stumbles will be on display.

Because it is operating in the public spotlight, ARPA-H will not benefit from the perception of overnight success that DARPA achieves when it unveils accomplishments that it has been working on with little or no publicity for a decade or more.

One of Wegrzyn’s challenges is to prevent ARPA-H from being crushed by the disappointment of supporters who expect biological breakthroughs to fly out of the agency at speeds rivaling the pace of innovation in artificial intelligence.

Speaking with BioCentury, Wegrzyn, who has worked as a program manager in DARPA’s Biological Technologies Office and at the Intelligence Advanced Research Projects Activity (IARPA), noted that even in domains with development cycles that are far shorter than biomedicine, the advanced projects approach can take longer to produce results than the public imagines. “ARPAs move very quickly, but sometimes the seeds that we plant” do not mature for 10 or 15 years.

That doesn’t mean that ARPA-H will provide long-term funding Wegrzyn said. Rather, its goal is to find “something that seems to be impossible today,” and then “invest in that, see if it is possible, get to a proof of concept and bring that forward.”

That could mean bringing programs to a state where they can be handed off to investors. “We like to say if a venture capitalist says, ‘come back to me when you’ve demonstrated X, we want to fund X,” Wegrzyn told BioCentury. “We want to take on that high-risk piece” and de-risk it enough so “we can line up downstream funders.”

NITRO for osteoarthritis

She cited the example of the first program ARPA-H announced, Novel Innovations for Tissue Regeneration in Osteoarthritis (NITRO). The program seeks to find and bring to the clinic regenerative technologies that can reverse the disease damage. An ARPA-H program manager, Ross Uhrich, proposed NITRO because he believes breakthroughs are possible, and because the state of the science fits ARPA-H’s sweet spot: the necessary work is not being done by the fundamental research community nor has it advanced to a stage where VCs will fund it.

NITRO is one of six projects disclosed by ARPA-H.

The specifications for NITRO call for “performers,” ARPA-H’s term for the teams it funds, to have each completed a Phase I trial within five years after the start of the program. Examples of technologies ARPA-H believes could achieve NITRO’s goals include implantable scaffolds; genetic engineering; cell therapy; nanoparticles; small molecules; or injectable biomaterials or biologics.

Uhrich has baked in parameters that the medical product developers would be unlikely to adopt on their own, and that could pose substantial challenges. For example, performers must persuade ARPA-H that they can meet ambitious goals for clinical trial diversity, including ensuring that about 20% of the individuals enrolled in trials are Native American/Native Alaskan. ARPA-H hasn’t explained why it plans to require that a fifth of trial participants are Native American or Native Alaskan, a group that makes up about 3% of the total U.S. population and that, according to the CDC, experiences a similar incidence of arthritis to non-Hispanic White and non-Hispanic Black Americans.

“There is a significant representation of Native American, Native Alaskan, in the demographics of that disease, so it’s important to serve those communities,” Wegrzyn told BioCentury. “A lot of those communities are also harder to reach, whether they’re on reservation lands or are in more rural settings, and so really the program manager is making a statement [that] you have to solve for all of these challenges.”

Wegrzyn added that ARPA-H is creating the ARPANET-H nationwide health innovation network to expand access to clinical trials, including by bringing clinical trial capacity to community hospitals that serve diverse populations. “We know that we’re going to need to do clinical trials for ARPA-H broadly for all of our programs, and rather than stand those up on a program-by-program basis, [we decided] to build this infrastructure that supports the entire agency as a longer-term capability.”

Another challenge Uhrich is posing involves reducing the cost of care. To receive funding, applicants will have to present an “insurance action plan” that can meet the goal of “streamlining NITRO therapeutics into the standard of care at ≤25% of the current cost of OA treatments.”

Rather than impose price restrictions, the idea is to force researchers to change the way cell therapies are designed and manufactured in ways that reduce costs, Wegrzyn said. “We are looking for the performers that are willing to rise to that challenge.”

While it may be possible to reduce the cost of manufacturing, there isn’t a straight line between manufacturing costs and prices. 

The clinical trial diversity and cost parameters of NITRO point to an issue that can be a strength or a weakness of the ARPA approach. Program managers have a great deal of power and may not have the kind of accountability or oversight that is typical in industry or the public sector. This allows them to move quickly and set goals that force individuals and institutions out of their comfort zones. It can also create unnecessary problems or blind spots. 

The goal is to spark cost-cutting innovations that can be applied broadly. “We know if we solve that for NITRO, we may also advance the state of the art for multiple cellular therapies, well beyond osteoarthritis. We really want to try to make these strides, not just for the one disease indication that we may be funding in a focused way, but we know that that will bleed into the rest of the ecosystem.”

Details of the final agreements for NITRO will be released in the first quarter of 2024, she said. The agency’s approach to achieving cost reduction targets will lean on technology. “ARPA-H is not a regulator. We’re not a policymaker. We want to innovate through technology.”

Wegrzyn added: “The big levers that we use at ARPA-H are not going to be policy regulation and terms, even though some of those might be peppered in some of the contracts, especially around data sharing. The big levers that we want to innovate on are on the technology side. That’s our role in this ecosystem.”

She also expressed a hope that ARPA-H’s work can increase the efficiency of drug development more broadly. “I’m not the only one who agrees that the price of a lot of therapeutics today has really gotten out of hand. I would love ARPA-H to be in a role to drive down [costs] through innovation.”

Working with FDA

Another area where ARPA-H may increase efficiency and reduce the costs of medicine product development is through working with FDA, Wegrzyn said. “ARPA-H can directly reimburse FDA for working together with us and helping advance some of the innovations that we fund to bring them across the finish line.”

A key part of the NITRO program is the development of standardized animal models for OA. FDA will be an active collaborator in this aspect, Wegrzyn told BioCentury.

ARPA-H is also soliciting ideas on ways it can work with FDA. In April it issued a request for information seeking “unique and creative ideas on how to productively engage with the Food and Drug Administration to encourage and incentivize public-private partnerships in the health ecosystem.“

The RFI stated that ARPA-H “has the authority to partner with the FDA to discuss, confidentially as needed, the development status of medical products and projects that are a high priority to ARPA-H.”

It isn’t clear, however, how closely FDA, as a regulator, can interact with ARPA-H on specific applications. When Operation Warp Speed was launched to speed COVID-19 vaccine development, FDA assured the public that its reviewers had an arms-length relationship with the initiative.

The RFI also stated that “FDA and ARPA-H are working together to address pre-competitive challenges that might help an emerging area, as well as pathways and services for performers to accelerate the impact of their solutions.”

The RFI also sought suggestions of novel incentives, as well as input about “new and innovative models to accelerate pre-competitive development of platform technologies to support downstream development of products resulting from those platform approaches in a disease agnostic manner.”

Broad agency announcements

To supplement the programs it identifies and leads, ARPA-H has authority to disburse funds through a mechanism, “broad agency announcements,” that are less cumbersome than traditional NIH grants. BAAs are milestone-driven contracts that are overseen by ARPA-H program managers.

Although they are intended to support R&D that advances ARPA-H’s mission, not as an economic development program, BAAs could be lifelines for start-up biotechs.

One of ARPA-H’s first BAAs was awarded to Thymmune Therapeutics Inc., a company backed by George Church and John Maraganore, to pioneer thymus cell therapies as the latest application for induced pluripotent stem cell-based manufacturing.

Thymmune announced that it had raised $7 million in seed funding in March, and in September it received $37 million from ARPA-H.

Other ARPA-H BAAs include an award of up to $104 million to a team at Harvard Medical School led by Johan Paulsson to develop an ultra-high throughput imaging and culturing platform for the discovery and development of antibiotics, and for adaptation as a diagnostic tool.