Headquartered in New Haven, Arvinas achieved two drug development milestones last month. The breast cancer drug that it is jointly developing with Pfizer, called vepdegestrant, received “fast-track” federal review from the U.S. Food and Drug Administration. The company also administered the first human test dose of another drug, labeled ARV-102, which targets neurodegenerative illnesses such as Parkinson’s disease.

Arvinas credits its success to a proprietary technology called PROTAC, an abbreviation for the term ‘proteolysis-targeting chimeras.’ The drugs, taken orally, use cells’ biological machinery to break down disease-causing proteins within the body — an approach that creates a promising avenue for treating a wide range of diseases including cancer and certain neurological disorders.

Arvinas scientists say that the distinct protein-breakdown approach targets proteins that are widely recognized to cause disease, taking the guesswork out of choosing a biological target that might have unintended consequences — or none at all.

“We’ve proven that PROTAC will be a product … a drug that shows up in a bottle on a pharmacy shelf that someone can buy and take,” said Ron Peck, Arvinas’ former medical officer.

The FDA’s fast-track process is designed to accelerate the development and approval of drugs that are considered to potentially meet an unmet medical need. The drugs also must have sufficient data to show that they would be an important and effective potential therapy — criteria that Arvinas’ and Pfizer’s vepdegestrant could meet, said Ian Taylor, the company’s chief scientific officer. 

The breast cancer therapy is currently being evaluated in Phase 3 clinical trials that are evaluating its effectiveness in patients with advanced, or metastatic, breast cancer who have previously been treated with endocrine medications that affect hormones in the body. Vepdegestrant is also being tested in other Phase 3 clinical trials as a combination therapy with other medications, including the breast cancer drug palbociclib.

Meanwhile, Arvinas’ drug for neurodegenerative diseases, ARV-102, dosed its first human subject at the end of February. In a news release, the company detailed how the medication, in preclinical studies, targets a protein called leucine-rich repeat kinase 2, or LRRK2. 

Research suggests that increased expression and activity of LRRK2 are associated with brain diseases like Parkinson’s. In primate studies, the company says, ARV-102 reached deep into the brain to degrade LRRK2 by up to 90 percent.

Arvinas’s recent drug development advancements mirror a broader trend of growth within New Haven’s burgeoning biotech landscape. With its proximity to research institutions like Yale University and a supportive ecosystem for startups, Peck and other biotech entrepreneurs believe that the Connecticut area has emerged as a hub for pharmaceutical companies to innovate.

“Connecticut is a great place to do drug discovery and drug development,” said Martin Mackay, co-founder of the New Haven-based biopharmaceutical company Rallybio. “There is great talent here. We thought we’d be able to really build partnerships with top academics … we thought we could hire great people here.”

Founded in 2013, Arvinas spun off from the lab of Yale biochemist and professor Craig Crews, employing a group of 20 individuals. Since then, the company has ballooned in size to 450, said Taylor. Today, the company has four drugs in development, including vepdegestrant and ARV-102, and has been publicly traded on the stock market since 2018.

For Taylor, the fact that New Haven has a less-saturated biopharmaceutical industry than other cities has helped the company thrive. In a less crowded field, he said, startups have a greater opportunity to establish themselves as key players and expand their operations over time.

Compared with established biotech hubs like Boston or San Francisco, lower rent and overhead costs help startups with limited funding allocate more resources towards research and development, Taylor added.

Mackay described the significance of partnerships between academia, industry and local government in fueling innovation. Rallybio, for instance, launched out of the University of Connecticut’s technology incubator program in Farmington, giving the company access to the university’s offices and laboratories.

He highlighted how university and government partnerships helped Rallybio gain footing during the drug development process.

“I think it starts off with the state government being attractive to come into Connecticut: you feel wanted,” Mackay said. “There was a recognition that there were great people here, that you could actually build companies. Very welcoming local government and local politicians make it a great place to discover new medicines and develop the biotech industry.”

But Arvinas’s researchers still face challenges in drug development, including regulatory hurdles, funding constraints and scientific challenges.

New biopharmaceutical startups face high costs associated with running clinical trials. Though trial costs vary widely, a 2018 analysis found that the median expense for a single Phase 3 trial reached $19 million, with the most expensive multi-thousand patient trials reaching upwards of $340 million.

New Haven’s biopharmaceutical companies are no exception, even if rent costs are lower than in other cities. Rallybio, for instance, laid off nearly half its workforce last month, shrinking from 44 employees to 23. The money that Mackay’s company saved was used to obtain clinical trial data on pregnant mothers.

“You can pay in biotech dearly because you can’t raise the money that you need so easily,” Mackay said. “To extend the runway, we needed to make our money last longer. The people that we parted with were truly great human beings and great individuals, and it was kind of really hard for us to make those decisions. But we needed to make sure that we can get the data to see if this program is going to work”

According to Peck, researchers developing a new drug also face a fundamental obstacle: uncertainty that the molecules or biological mechanisms the drug targets will have positive outcomes for patients. 

But scientists like Taylor remain optimistic, particularly about the promise of Arvinas’ PROTAC technology. The technique, he believes, creates a new way to hit disease-causing proteins, over 80 percent of which are considered to be “non-druggable” by traditional drugs known as inhibitors. 

“The challenge is getting the molecules to have drug-like properties,” Peck said. “Would these things actually work in humans? It’s looked great in laboratory systems, but do they really work?” 

Arvinas is located at 395 Winchester Ave.

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The study, led by Nikolai Jaschke, a postdoctoral researcher in the lab of Andrew Wang, an internal medicine professor at the School of Medicine, found that the introduction of A485 in mice offers a short-term but significant increase in white blood cell counts. A485 is a small molecule — colloquially known as “prohiberin” — that inhibits proteins that modulate gene expression. The researchers hope that the discovery could help human patients with neutropenia, or low white blood cell counts, which is common in those fighting infections and undergoing chemotherapy.

“At this point, from what we know in mice, it seems reasonable that a lot of patients receiving chemotherapy could benefit from this molecule,” Jaschke said. “But it’s not clear if that’s the case and it needs to be tested in clinical trials.”

Jaschke told the News that he first became interested in A485 after researchers from the pharmaceutical company AbbVie and other institutions first published a study in 2017 detailing how it could be used to treat various malignancies.

However, the research team never followed up on the study. A few years later, Jaschke and his team decided to study whether A485 could help restore bone marrow function, hoping to analyze the molecule from a pharmaceutical rather than oncological perspective. From a new scientific viewpoint, they discovered another use for A485.

“We kind of stumbled across [the discovery] in a very different context because we were interested in a pharmaceutical mechanism or pharmacological mechanism to restore bone marrow function,” Jaschke said.

Because many patients with bone marrow failure are more likely to have infections due to diminished white blood cell counts, the researchers explored whether the injection of A485 molecules could help save mice suffering from myelodysplastic syndrome, a group of cancers in which blood cells in the bone marrow don’t properly develop, and chemotherapy-induced bacterial infections, some of which were potentially lethal. 

They found that almost a third of the mice treated with A485 therapy survived, suggesting its potential use as a therapeutic intervention. Jaschke argued that there is currently no available pharmacological remedy with similar capabilities to what A485 expressed in his team’s mouse model.

Jaschke compared the A485 molecule with G-CSF, a glycoprotein hormone that stimulates the bone marrow to increase the number of white blood cells in the bloodstream. He noted that while many doctors prescribe G-CSF to patients undergoing chemotherapy, many still experience low blood counts and subsequent infections. Once they are reinfected, their treatment options are limited to antibiotics, fluids and supportive care.

Lourdes Mendez, assistant professor of hematology at the School of Medicine, is dedicated to both the clinical care of patients and translational research to identify novel therapeutics in high-risk myeloid neoplasms and leukemia to improve clinical outcomes for patients. She told the News, “Neutropenic fever and sepsis remain a critical problem in our field particularly for patients with acute leukemia. This study on A485 raises the exciting possibility that our toolbox, which is currently limited to G-CSF, could expand by targeting p300 HAT activity.”

In contrast, the A485, Jaschke said, could be used in concert with G-CSF to help increase white blood cell counts. Though A485 is a synthetic molecule, it does not need stem cells to proliferate, unlike G-CSF. 

Still, other researchers are cautiously optimistic about the study and A485’s future. In an interview with the News, Andres Hidalgo, a professor of immunobiology at the School of Medicine, noted that the study was conducted with mouse models and was not tested directly next to G-CSF.  

“If [A485] is better than G-CSF, I think that might be a little bit of an overstatement at this point,” Hidalgo said. 

Similarly, Jaschke said that he is unsure whether the promising results will be replicated in future experiments in human subjects. 

“I have no idea if it will even provoke the same effects in humans as it did in mice,” Jaschke said. “This needs to be tested and this needs to be seen, which requires clinical studies, which are very expensive. I don’t know if someone will look into this.”

Jaschke also highlighted several other challenges with their investigation. First, he noted that while the molecule responded effectively to the bacteria Listeria, researchers need to conduct further testing to determine the molecule’s efficacy against other common pathogens, such as pneumococci, staphylococci and E. coli, among others.

He also expressed concerns about the consequences of a potential excessive immune response due to the significant increase in white blood cells induced by the molecule. Jaschke compared the strong immune response to immune checkpoint inhibitors, a set of immunotherapies that are often used in cancer treatment but can sometimes lead to an overly robust immune response. 

He lastly conveyed that they have extensively characterized the compound, addressing many important questions regarding its efficacy and safety. They believe that further confirmation through testing in various models by different laboratories is necessary to validate their findings, particularly regarding the compound’s effectiveness against a wide range of pathogens and in different models of bone marrow injury.

Lohith Gowda, an assistant professor of hematology at the School of Medicine, raised concerns about A485 beyond its safety.

He also discussed the effects of prolonged neutropenia and whether it can lead to altered immunity. 

“Can A485 alter or interact differently with microbiomes?” Gowda questioned. “Can [it] help build a different story if favorable?”

Jaschke also emphasized the need for other laboratories to validate their findings and learn more about the safety and efficacy of the compound in humans. Nevertheless, his lab does not plan on conducting further research with the molecule in the near future.

“That’s not something that we will do necessarily because we have described what we found,” Jaschke said. “From that perspective, we are done.”

About 35.5 million individuals in the United States suffer from neutropenia.

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Scheduled for launch in March 2024 by the medical school’s Section of Biomedical Informatics and Data Science at the School of Medicine, the new 16-week program will be titled “Medical Software and Medical Artificial Intelligence” and will be directed by Xenophon Papademetris, a professor of biomedical informatics & data science at the School of Medicine. The certificate program is intended to help educate medical professionals to better engage with the evolving use of technology in the healthcare industry.

“As technology continues to advance, the need for professionals well-versed in the intricacies of medical software and AI becomes paramount,” Papademetris said. “This course is not just about acquiring knowledge; it’s about fostering leaders who can bridge disciplinary gaps and contribute meaningfully to the intersection of technology and healthcare.” 

According to Papademetris, the program traces its roots back to 2017, when he first taught the undergraduate “Medical Software Design” class. Papademetris also developed a companion Yale Coursera Course titled “Introduction to Medical Software,” which has enrolled over 17,000 students worldwide.

The course aims to address the growing demand for professionals capable of navigating medical software design, AI integration and regulatory compliance in the health and technology fields, he said.

The certificate program will span four consecutive modules using a combination of prerecorded videos, quizzes and live Zoom sessions with industry experts: an introduction to medical software, an introduction to artificial intelligence, a class on the use of AI in medical software and a module about the developing role of AI in medicine. 

According to Dennis Shung, an assistant professor of medicine who helps teach the last module, the certificate program is targeted toward career professionals, including software engineers, data scientists, regulatory professionals and doctors interested in healthcare technology.

“[The course will] level up people who are already in the industry who have already demonstrated interest in medical software and AI,” he said.

Mary-Anne Hartley, an assistant professor of biomedical informatics and data science and an instructor in the program, also hopes that the modules will help students cultivate ethical and effective use of AI tools in healthcare.

In the fourth module of the course, for instance, the program’s students will see examples of these tools’ application at Yale and in a global health setting by Hartley’s ongoing work in Zanzibar.

“This course exposes people to the need, potential and opportunity for them to recognize the importance and responsibility to make or use technology for patients in low resource settings,” Hartley said. “People have to be able to represent patients better and use technology specific for certain target patient groups.”

According to Papademetris, the certificate’s faculty are full-time professors at Yale from various departments, including radiology, biostatistics, emergency medicine and sociology. Applications for the program are set to open in January 2024.

“Since everyone cannot come to Yale, Yale can go there,” Papademetris told the News.

The School of Medicine was founded in 1810.

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