1 In 300 People In The U.S. Is Living With HIV. That's Not Okay With Jeff Galvin.

By Matthew Pillar, Editor, Bioprocess Online

By modifying CD4 T cells using miRNA, Jeff Galvin’s company thinks it can deliver a functional cure for HIV. Here’s the ongoing story of Addimmune and its unique clinical strategy.

The mobilization of the global healthcare community in the face of an AIDS epidemic that claimed more than 2 million lives in 2004 might only be overshadowed by our more recent pandemic response. By 2010, the antiviral and anti-infective therapies developed in response to the AIDS epidemic had made an outsized contribution to the broader effort to halt its spread, nearly halving the death toll. By 2022, 630,000 people succumbed to AIDS, marking a 69% decrease since the 2004 peak.

Jeff Galvin offers high praise for the standard of care. It’s difficult to overstate the impact of antiretroviral therapy, which an estimated 76 percent of HIV patients have accessed globally. But Galvin’s praise doesn’t equate to satisfaction.

Globally, 1.3 million people acquired HIV in 2022. In the U.S., 1 in 300 people is living with the virus, and there are nearly 35,000 new cases per year.

Despite billions of dollars spent on education and awareness over the course of decades, the incorrect assumption that HIV is a “gay man’s disease” persists. In fact, as recently as 2022, women and girls represented 53% of HIV cases. 1.5 million people living with HIV are under the age of 15.  

The disease’s persistence isn’t the only thing that irks Galvin. Despite its statistical progress, he calls the standard of care a healthcare policy nightmare. He points to the multi-million-dollar lifetime cost of care per patient that rolls up to a hundred-billion-dollar burden on patients and payers. A lack of adherence to an aggressive and expensive HIV treatment regimen, he says, puts patients and their partners at risk. Current treatments require daily oral administration, or in some cases, injections of time-release antiretrovirals every other month, for life.

Living With HIV Doesn’t Compute

Galvin’s passion for addressing the HIV problem is palpable, but what fuels it is up for debate. Solving biology problems isn’t what he trained for. He’s a Harvard economics grad who walked that degree into Hewlett Packard in 1981. From HP it was on to Apple, then Blyth Software, then Claris Software, then Argus Software. Galvin was a tech guy in Silicon Valley back when PCs were feeding a software industry that promised to eat the world. He could program, he had that economics degree, and he was investing. He was investing quite well, in fact. Around the time he hit 40, he realized he didn’t need to work anymore. So, Jeff Galvin quit working. Bought a house in Hawaii and jetsetted between there and Silicon Valley. For five years, he lived the rich bachelor life that most men in their mid-40s won’t admit to daydreaming about.

Eventually, his commitment to pioneering software being pervasive as it was, he got married to a woman he met on a then-fledgling startup website called match.com. This newfound relationship status put the kibosh on his playboy ways. Before long, boredom set in. That’s when he decided to dip a toe back into the corporate game. Maybe he’d do some mentoring. Maybe he’d join a board. Maybe he’d make a small investment here and there.

It was those small investments, he says, that “got me into trouble.” When people know you have money, business plans flow over your transom like waves on Deadliest Catch. A particular pitch from the NIH caught his eye. He followed up, and the next thing he knew, he was face-to-face with Roscoe Brady, M.D.

Can We Program Viruses Out Of Human Biology?

If you’re not familiar with the late Dr. Roscoe Brady, Google him up. Galvin might not have known it at the time, but the man he was meeting with was, and posthumously remains, a legendary figure in biochemistry circles.

“Roscoe Brady showed me viral vectors, and my head just exploded,” Galvin recalls. “I said, ‘wait a minute. You just showed me the diskette for the organic computer of the human cell.’”

It’s no surprise that where Brady saw cells and viruses, Galvin saw data and code. Long before he worked as a software engineer at HP, before he led international product marketing efforts for Apple, and before he earned that Harvard economics degree, way back when he was a teenager, Galvin taught computer classes at Harvard. His computationally-gifted-since-childhood mind asked, “if we can reprogram DNA, what can’t we cure?”

“Someone had to be the Microsoft of this new software-for-the-organic-computer revolution,” says Galvin. “I started a company and said it might as well be us.”

The CGT/Software Parallel

With his newfound optimism that viral vectors could be programmed like software to potentially cure anything, Galvin founded American Gene Technologies (AGT) in 2008. The company set out to build a development platform that could address immuno-oncology, monogenic disease, and HIV. When I met with him during JP Morgan week in San Francisco, he elaborated on the computer programmer parallel that drove the company’s vision.

“We’re modifying genes that have very specific outcomes in cells,” Galvin explained “Cells work in a very deterministic manner in terms of what they do internally, and DNA is the operating system of the cell. Each gene serves as the command that results in that very specific outcome, and if you trigger that command, you can direct and predict the outcome.”

The computational analogy doesn’t stop there. The 37 trillion cells, give or take, in the human body are connected by an electrical, chemical, and physical infrastructure that Galvin compares to a computer network. The pathogens that cause disease? Those he equates to “bugs,” those pesky bits of foreign code that infect computer operating systems. In the human operating system, he says Addimmune (the HIV-related portion of AGT’s business) can crack open the viruses that carry these bugs and scoop out the bugged software, that bit of DNA or RNA that hijacks cells and causes disease. “Now that it’s hollowed out, it’s an empty diskette that can deliver anything to any cell,” he says. “When we put something good in there, we’re converting viruses into updates for the organic computer.” In the organic computer, as in the silicon machine, these “updates” fix bugs, add features, and improve existing features. “Viral vectors are the diskettes, and when you go up another level, you have the tools and components that will get you most of the way there when you start developing your drug, the gene construct itself. The tools and components are the middleware of this new genetic software industry.” Another computer industry comparison Galvin is quick to point out is that, like Steve Jobs, he doesn’t have all the answers, and that’s okay. Because, also like Steve Jobs, he has the vision, and because human biology, and the interaction among proteins, enzymes, viruses, and cells that complicate it is hard, really hard, he has a team of Steve Wozniaks in 27,000 square feet of lab space in Rockville, MD to help.

“We’ve got a very broad mission, a very exciting mission, to be a revolutionary force. When I was at Apple, IBM and all the analysts in the industry said Apple’s graphical user interface would never sell. They were wrong. It disrupted an entire industry, and Apple’s vision came to fruition. Cell and gene therapy will impact lives at a similar scale.”

If Viral Vectors Can Cure Anything, Why AIDS?

By 2023, Galvin’s vision of human biology as an organic computer had produced 47 patents that relate to the company’s viral vector development platform. While he doesn’t bite on the platform-versus-product value debate that’s so trendy to tussle over (“what’s more important,” he asks rhetorically, “the iPhone or the app?”), that was the year Galvin recognized that American Gene Technologies was no longer just a platform company. It was ready to spin off a biotech. That’s when Addimmune, a company that lives by the ‘body as an organic computer’ mantra Galvin evangelizes, was born. Where Addimmune would focus its therapeutic endeavors was influenced, as are the launch of so many biotechs, by serendipity.

“Our decision to focus on HIV as the proof point for our approach was blessed,” says Galvin. “We’re headquartered just south of the Institute of Human Virology (IHV). We had access to some top researchers up there to review and replicate our initial experiments.” Through his contacts at IHV, he met Tommy Thompson, former Secretary of Health and Human Services and former chairman of the Global Fund to Fight AIDS, Tuberculosis and Malaria. Thompson now serves as an adviser to the company. “The data supported the launch of a public drug company,” says Galvin. “There are more than 39 million people who are very interested in seeing a cure for HIV, both those living with it, and those who have experienced its scourge.”

AGT is currently working to go public by merging with the SPAC 10X Capital Venture Acquisition Corp. III. In connection with the merger, AGT expects to spin off its non-HIV business. The post-merger combined public company is expected to be named Addimmune and will trade under the ticker “HIV.”

Phase 1B Results Show Promise

The HIV virus infects and kills sentinel T cells (CD4 T cells) that are there to detect it and elicit an immune response. Once CD4 T cells are depleted, HIV patients acquire an immune deficiency to the AIDS-causing pathogen. AGT103-T, Addimmune’s phase 1B lead candidate, delivers modifying miRNAs to patients’ CD4 T cells. Those miRNAs knock out the CCR5 receptor, the point of HIV’s attack. If the cell is already infected with HIV, additional miRNAs in AGT103-T target highly-conserved sites in the HIV genome to help stop further replication of the virus. The company believes the approach will help CD4 T cells become resistant to HIV’s entry and propagation of infection by enabling an effective immune response.

“In our initial Phase 1 safety studies, we introduced a target quantity of a billion of these cells to patients and observed them while the patients stayed on their antiretroviral therapies for a minimum of 180 days, to determine whether we could introduce a billion cells without making patients sick,” explains Galvin. “There were no serious adverse events in the study, so we met our safety endpoint.” Next, the FDA wanted Addimmune to determine whether those cells engrafted, persisted, behaved normally in the immune system, and retained their ability to fight HIV. According to Galvin, the study results, published in Frontiers in Medicine, checked all those boxes. “There's no such thing as success with the FDA, there's just not failure. They haven't told us that we failed, so that is good news” he quips.

Of course, observation of those patients over 6 months revealed a gradual, though expected, depletion of CD4 T cells. That’s the normal immune response as those cells deplete to memory levels capable of supporting their ability to come back to the fight when called on. The next series of studies were intended to address whether these modified CD4 T cell memory levels would support a patient’s ability to fight HIV without antivirals.

Six out of seven patients agreed to an analytic treatment interruption, meaning they’d go off their antiretrovirals, allowing the virus to emerge from their viral reservoirs, to determine whether their immune systems responded to the appearance of the virus. Galvin says all six patients demonstrated an immune response, indicating that the CD4 T cells seemed to be surviving the HIV viral attack and could persist in doing their job.

In that study, there was a “but.” Viremia, the presence of the virus in those patients’ blood, didn’t cap at a level that Addimmune felt safe to remain off antiretroviral treatment. The patients were put back on their antiretrovirals to bring their viremia back to “undetectable” levels.

In the greater effort to land on a functional cure for HIV, this was a problem. But Addimmune believed that given the initial exposure to virus, those T cells might have been “nudged” into activated or effector state (kind of how a vaccine stimulates the immune system). If so, those immune cells should be more potent at suppressing the HIV virus the next time antiretrovirals were removed.

Once patients’ viremia levels dropped to a controlled level, Addimmune asked them if they’d be willing to go back off their antiretrovirals a second time. Four of the six patients agreed. All four saw a reduction in viremia, two of them maintaining approximately 5,000 to 10,000 particles per milliliter for approximately four months. The 5,000 to 10,000 per milliliter concentration is considered a long-term non-progression level without antiretrovirals, and it’s something only .5 percent of HIV patients experience without treatment. As long as this level is maintained by the immune system, those patients won’t get AIDS. Again, there’s a “but.” A viremia level of 5,000 to 10,000 particles per milliliter isn’t considered low enough to prevent the transmission of HIV. Also, although those patients maintained those viral levels to the end of the study, a new study is necessary to see how long the viral suppression lasts (i.e. “durability” of the treatment).

For Addimmune, the study marked progress. The therapy was in the red zone but hadn’t quite reached the goal line. “For us, the goal is to allow the immune system to tamp down the virus so low that it’s non-transmissible.”

What’s Next For Addimmune

While it’s a bit short of the goal line, Addimmune has downs left to play. Its next step is to run the same offensive scheme it did last time, but with a few twists. The company is recruiting 24 new patients for a 3-arm study in which those patients will be given the target dose of its miRNA therapeutic (with slightly different attributes or parameters in each arm of the study), then taken off of their antiretrovirals shortly after the infusion. At a minimum, the company hopes to recreate or improve on the long-term non-progression levels it’s already seen. “We still need to prove that it's durable, but there are a lot of theoretical reasons to be optimistic that it could be,” says Galvin.

Should it fall short of its goal to deliver a functional cure on this series of downs, Addimmune still has a potentially viable product. A dramatic improvement to long-term non-progression status would be a win. To date, all indicators point to a safety profile that removes significant collateral costs of managing the side-effects and long-term care needs associated with the current standard of care. And, while awaiting the outcome of its SPAC deal, Galvin says the company will continue to progress the program.

Addimmune has several other technologies in development in the lab that could give it additional shots on goal with enhancements to the current product that might improve potency and/or reduce costs. Galvin says cancer and monogenic disease targets remain a focus of the platform that shares its foundation with the HIV cure attempt. “Our HIV program could be a proof of concept that we can create powerful gene and cell therapy drugs for other diseases better, faster, and potentially cheaper than other companies,” he says, “And our parallel to the software development industry hasn’t broken down yet. That said, we acknowledge that the human body is way more complex. The organic computer has an amazing command set, but it didn’t come with a manual.”