All Things Good for 2023 & Life Sciences

The Top 12 Biopharma Companies Hiring Now

Facing a more challenging economic environment than anticipated, organizations have been forced to pivot from their original recruitment plans. According to BioSpace’s recent Recruitment Market Q2 Update, 38% report that they are recruiting for fewer roles than planned, and 13% have stopped recruiting entirely.

Many companies announced plans to implement restructuring initiatives and cull staff, including sweeping cuts from Biogen and Illumina.

However, the Recruitment Market Q2 Update indicated that far fewer organizations made layoffs between April and June compared to the start of the year.

Additionally, 75% of companies report that they are still actively hiring. BioSpace reveals the top 12 employers with the most job posting activity now. To learn about job opportunities with some of biopharma’s hottest employers, continue reading.

Top 12 Biopharma Companies Hiring Now

1. Moderna

2. Takeda

3. Regeneron

4. AbbVie

5. Eli Lilly and Company

6. Daiichi Sankyo

7. CSL Behring

8. Amgen

9. Gilead Sciences

10. Emergent BioSolutions

11. BioMarin

12. Frederick National Laboratory for Cancer Research

Check out these additional hot companies: Just – Evotec Biologics, Kerecis, Sage Therapeutics, Resilience, Eikon Therapeutics, Bristol Myers Squibb, GRAIL and Ipsen.

Ref: https://www.biospace.com/article/top-12-biotech-companies-hiring-now/?s=76

Introducing Fierce Biotech's 2023 Fierce 15

It’s been a tough year for biotech, so how about a little good news? In between all the layoffs, restructurings and last-ditch strategic option hunting, we wanted to take a moment to shine a spotlight on 15 innovative and truly fierce biotechs.

Everyone we talk to in the Fierce Biotech universe tells us that science doesn't stop for the markets. Financing might be a little tough right now, but innovation, breakthroughs and discoveries are all still being made.

The latest crop of Fierce 15 honorees consists of companies pushing the envelope not only in the lab, in the clinic or on the conference circuit—they are also defining what it means to be a modern biotech company, with modalities ranging from radiopharmaceuticals to cell therapy. Indications as diverse as oncology, neurodegenerative disorders, Pompe disease and even pregnancy complications made the list this year.

We have also turned a greater focus toward celebrating diverse teams. We asked for you to nominate companies pushing boundaries not only in the clinic but in the C-suite and beyond. We wanted to see the best of the best, the biotechs fiercely redefining expectations culturally, ethically and in their pipelines.

And here they are. We examined hundreds of nominations for the Fierce 15 this year. When we say we look at them all, we really truly do. These are the 15 companies that really stood out for us this year and we’re proud to call them the industry’s fiercest biotechs for 2023.

Adaptive Phage Therapeutics

By Gabrielle Masson

Adaptive Phage Therapeutics hopes to overcome bacterial resistance with its unique and expanding library of bacteriophage therapies. Founded: 2016 Based: Gaithersburg, Maryland Clinical focus: Bacterial infections What makes Adaptive Phage Fierce: “Resistance evolves. We adapt.” That’s the motto of the biotech working to tackle antibiotic resistance with bacteriophages—antimicrobial therapeutics designed to be safe, effective and durable.

“The issue is basic biology. Bacteria evolved to survive,” CEO and co-founder Greg Merril told Fierce Biotech. As bacteria evolve to resist antibiotics, the industry has struggled to keep up. Big Pharmas have, of course, developed drugs designed to kill bacteria that exist at that moment in time. But bacteria resistance has evolved so quickly that companies often aren't able to even get a return on their investment for development, Merril explained. This has led to low investment in the area and a broken antibiotics pipeline.

To tackle the problem and treat ever-evolving bacterial infections, Adaptive Phage is ditching antibiotics all together. The biotech instead aims to channel the diversity and specificity of curated bacteriophages from its phage bank to treat infections. The approach matches a phage from its growing library through a proprietary phage susceptibility test that Adaptive is working to commercialize globally via a partnership with Mayo Clinic Laboratories. “If we don't have phage or if a patient develops resistance to the phage that we've got, we can then use the bacteria to find new phage and add that to the collection,” Greg explained. “Phage are the most diverse bacteria killers on earth so you're always going to be able to find phage that's able to kill a bacteria.”

While other phage-focused biotechs exist, no other company was founded by world-renowned bacteriophage scientist Carl Merril, M.D. Carl—Greg’s father—currently serves as Adaptive’s chief scientific officer and has been conducting research in phage since the 1960s.

Things came to a head in 2003 when the National Institutes of Health (NIH) researcher had an article published in Nature about previous limitations in phage therapy—which were mainly related to the narrow range of bacteria that phage would kill—and the promise newer efforts showed in the area. Carl believed using a large library of phage to match to the bacterial strain could tackle how selective phage was.

A few years later, the U.S. Navy’s Biological Defense Research Directorate (BDRD) launched a project to test Carl’s ideas as a potential way to manage biodefense threats tied to multidrug-resistant superbugs.

Things really picked up steam in 2016, after a man got sick from an antibiotic-resistant bacteria, becoming so gravely ill he fell into a coma. The man—Tom Patterson—survived, awaking from his coma shortly after receiving phage therapy, as detailed in "The Perfect Predator: A Scientist's Race to Save Her Husband from a Deadly Superbug: A Memoir," written by his wife and epidemiologist Steffanie Strathdee, Ph.D.

The story shared in the book is the “genesis” of Adaptive, Greg explained, adding that the BDRD experienced further successes with the therapy. On the heels of these events, the father-son duo launched Adaptive and acquired exclusive, global rights to BDRD’s phage tech.

Since then, nearly 60 patients have been treated with Adaptive’s phage therapy on an early-access, compassionate basis, the CEO said.

The biotech also has three candidates in clinical trials, all in midstage development. The first program is testing bacteriophage therapies in patients with diabetic foot osteomyelitis in a phase 2a study. This is the biotech’s first clinical trial in the indication, with Adaptive able to skip a phase 1 because phage therapies are widely known as well tolerated with few—if any—drug-related adverse events, according to Greg.

A second program is evaluating phage for patients with prosthetic joint infections in a phase 1/2 trial. The program was introduced through the compassionate emergency-use program, Greg said, because such infections are very difficult to treat with standard of care. The CEO said standard-of-care treatment is expensive and has high mortality and morbidity rates, so the space offers “a great market opportunity.”

The third trial is run by the NIH’s National Institute of Allergies and Infectious Diseases and the NIH-funded Antibacterial Resistance Leadership Group. The placebo-controlled, phase 1b/2 trial assesses Adaptive’s bacteriophage therapies among patients suffering from cystic-fibrosis-related lung infections.

“We don't suffer from the problems that have driven the antibiotic market to be a failure. We address that directly by having an adaptive approach to how we deal with bacteria,” the CEO concluded. “The traditional drug development process for antibiotics is a failed business model, and we have a totally different business model. So, that's why this is going to succeed.”

Investors: Deerfield Management, the AMR Action Fund, Mayo Clinic, Tedco, Alexandria Venture Investments, Hackensack Meridian Health

Apnimed

By Zoey Becker

Apnimed is working to treat the underlying cause of sleep apnea with the first pharmaceutical treatment for the disease.

CEO: Larry Miller, M.D. Founded: 2017 Based: Cambridge, Massachusetts Clinical focus: Obstructive sleep apnea What makes Apnimed Fierce: With more than 35 million patients in the U.S., most of the population knows someone who sleeps with a tight-fitting mask and a tube forcing air into their mouth or nose.

Since its invention in the 1980s, the continuous positive airway pressure (CPAP) machine has remained the standard of care for the sleep-related breathing disorder obstructive sleep apnea (OSA). The mask attaches to a hose that pushes pressurized air into a patient’s blocked airway.

While the machine has modernized in the last 40 years, the treatment still leaves much to be desired. At least half of OSA patients go untreated due to the general discomfort of the CPAP, Apnimed’s CEO Larry Miller, M.D., said in an interview. Those who do use the machine only average around four hours a night with it on.

A once-daily pill certainly seems like an easier alternative. Apnimed was founded with that goal in mind in 2017. It all started with a phone call Miller received from Andrew Wellman, M.D., Ph.D., who heads the sleep lab at Boston’s Brigham and Women’s Hospital.

Wellman wanted Miller to look over some data in 20 OSA patients that he ended up finding “spectacular.” And so begun the mission of tackling a major clinical problem that’s never had a pharmaceutical solution.

While many researchers have tried, no one has ever been able to produce a drug with therapeutic benefits in the disease. Until Apnimed’s AD109, a combination pill made up of selective norepinephrine reuptake inhibitor atomoxetine—which is marketed as an attention deficient disorder treatment under the brand name Strattera—and novel antimuscarinic aroxybutynin.

In OSA, the muscles at the back of a patient’s throat work as usual during the day but collapse at night, blocking the airway. Those muscles are innervated in the brainstem. The thinking behind AD109 is that “if you can’t get a drug into the brainstem, you can pharmacologically stimulate those muscles,” Miller said.

But a stimulant alone is counterproductive for a sleep disorder. That’s where the antimuscarinic comes in. Combined, the pill allows patients to sleep while also stimulating the muscles blocking off the airway.

In the phase 2 MARIPOSA trial of 294 patients, the med proved successful in lowering the number of instances when breathing stops during sleep, and 44% of patients who took the combination pill saw at least a 50% reduction on that measure.

After starting off the year bagging $79.75 million in extended series C funding that brought its total haul for the round to $142.25 million, Apnimed will soon kick off a historic phase 3 trial. Just getting to that point on the schedule is shocking in itself, Miller said. Phase 3 is a landmark no other researchers targeting OSA have ever achieved.

Apnimed is just at the beginning of its journey, and there’s “plenty of work to be done” in sleep apnea, Miller noted. In the background, the company is working on specialized treatments for many subgroups of the disease such as those with symptoms of sleep disruption and those with insomnia.

Beyond sleep apnea, Apnimed is looking at some other sleep disorders, including a candidate in the orphan sleep disorder obesity hypoventilation.

Eventually, Miller would like to see Apnimed as a broad, “fully differentiated” pharmaceutical company with a major focus on diseases related to sleep. But, for now, the company has all eyes on AD109. Two phase 3 trials are expected to read out by early 2025 with a potential approval and subsequent launch in 2026.

It will be the first time that Miller, who has founded nine other companies in his over 30-year career, has ever launched a drug. Previously, he’s always sold the company before that point, the CEO said. But he doesn’t see that for Apnimed. The team of almost 30, which operates entirely virtually, is zeroed in on bringing the treatment to market.

“This is not a mild disease. We’ve got millions of people suffering, and we’ve got a chance to be the first one to put it all together,” Miller said.

Investors: Alpha Wave Ventures, Sectoral Asset Management, Columbia-Seligman Investors, Tao Capital Partners, Morningside Ventures

Boundless Bio

By Eric Sagonowsky

Boundless Bio aims to improve outcomes in one of the remaining frontiers in oncology by advancing a pipeline of ecDNA-directed therapies.

CEO: Zachary Hornby Founded: 2019 Based: San Diego Clinical focus: ecDNA-directed medicines for cancer What makes Boundless Bio Fierce: Progress in cancer research has been immeasurable in recent decades. But for one group of cancer patients, biopharma’s R&D efforts have not yielded tangible gains. That’s where Boundless Bio aims to change the status quo.

Back in 2018, the company’s scientific co-founder Paul Mischel, M.D., set out with other researchers to learn why a wide swath of patients wasn’t seeing benefits from the scientific advances in oncology achieved by researchers over the last three decades.

Mischel found that oncogene amplifications were driving some patients’ tumor development but that the amplifications weren't affected at all by the industry’s newer targeted therapies. These amplifications came to be known as extrachromosomal DNA (ecDNA) and are a driving force in around a quarter of patients’ cancers, Boundless Bio CEO Zachary Hornby explained in an interview.

“Unfortunately, this large population of patients basically derives no benefit from targeted therapies or immunotherapies and therefore have significantly worse survival and eally no options beyond chemotherapy,” Hornby explained.

In the U.S. alone, the oncogene-amplified cancer population represents around 400,000 new patients per year.

The sheer number of patients, plus their poor prognosis, motivates Boundless to target one of the “last remaining bastions of cancer for which the field has just made no dent,” Hornby said.

“From chemotherapies to targeted therapies to immunotherapies, these patients have been left behind,” Hornby said. “So it’s our quest to really try to deliver something new for these patients.”

In their research, Mischel and his colleagues found that ecDNA can “disappear” and “rapidly adapt and evade targeted pressure,” Hornby explained. The team “realized that if we could understand what’s giving rise to these ecDNA, how do they function, how do cancer cells rely upon them, then maybe we could come up with new strategies for disrupting their functionality so that cancer cells do not use them to their benefit,” Hornby said.

With this goal, Boundless Bio’s founders drafted a business plan and raised funding. Hornby came on board in 2019, when the company revealed itself to the world with $46 million in initial funding. That early financial backing came from Arch Venture Partners, City Hill Ventures and several other investor groups. The first year was basically a “transfer of knowledge from the academic founders … into this nascent company that we were staffing with drug hunters and drug development veterans,” Hornby said. In the time since then, the company has been busy building out its Spyglass platform, which incorporates more than 100 cell lines and 20-plus in vivo xenograft models, plus a “suite of bespoke tools,” to detect ecDNA, the CEO added.

With those tools, Boundless has been working to identify “targetable vulnerabilities” to “selectively kill” ecDNA cells. With those targets in hand, the company has been hard at work developing drugs that might be able to fight ecDNA-driven tumors. In parallel, Boundless Bio has been developing its companion diagnostic platform, dubbed Echo, to identify the appropriate patients for its trials.

The company formed with around 15 to 20 staffers but has grown to a team of around 70, with most of them residing in San Diego. Along the way, it’s added several executives, including most recently Chief Financial Officer Jami Rubin, a veteran of the life sciences industry. After its initial fundraising effort, the company added more investors with subsequent rounds in 2021 and 2023 worth a total of $205 million. A few years into its existence, Boundless Bio has been flexing its drug-development muscles lately. In late July, the company’s lead drug, BBI-355, entered a first-in-human, phase 1/2 clinical trial in patients with locally advanced or metastatic solid tumors with oncogene amplifications. The drug is an orally available, potent, selective inhibitor of checkpoint

kinase 1.

Boundless Bio plans to provide an update on the study later this year at a medical conference, Hornby said. Investigators are enrolling patients at leading cancer centers such as the Memorial Sloan Kettering Cancer Center and MD Anderson.

Elsewhere in its pipeline, Boundless Bio is working on a drug called BBI-825; a target for that program will be revealed later this year. The company hopes to advance that drug into the clinic in the first half of next year. “We’re hoping, over five years, to have a robust pipeline of clinical-stage therapies” that benefit patients with a wide range of oncogene amplified tumors, Hornby said. Investors: Arch Venture Parners, Leaps by Bayer, Nextech Invest, RA Capital Management and many others

Carmot Therapeutics

By Gabrielle Masson

With a clinical pipeline of GLP-1s, Carmot hopes to develop transformative therapies for people with metabolic diseases.

CEO: Heather Turner Founded: 2008 Based: Berkeley, California Clinical focus: Diabetes/obesity What makes Carmot Fierce: The woman-led biotech is trying to tackle one of America’s most pervasive issues—obesity—and comorbidities that can be tied to the condition alongside other metabolic diseases. Carmot is led by Heather Turner, an attorney turned biotech executive with past leadership roles at Lyell Immunopharma, Sangamo Therapeutics, Atara Biotherapeutics and Orexigen Therapeutics. Let's go back a decade or so, when Turner worked at Orexigen, which she fondly remembers as an “obesity 1.0” biotech—one of the few early-stage companies pursuing treatment for the conditions in the mid-2000s.

“It was a really difficult time to be pursuing a drug in obesity because the viewpoint then was very much that it was a lifestyle situation—it wasn't yet agreed upon that it was even a disease,” Turner explained. “And so we spent a lot of time trying to convince people to care.” Now, the CEO is happy to return to a much-changed metabolic space in which companies are hard at work developing disease-modifying treatments that also tackle other comorbidities associated with obesity—just like Carmot. The biotech has three clinical GLP-1 candidates plus two preclinical and discovery programs. All three assets were created in-house using Carmot’s chemotype evolution platform, discovery tech that allows the design of drug molecules so they fit a specific target protein. One peptide—a GLP-1/GIP dual receptor modulator dubbed CT-388—is being studied as a once-weekly treatment for patients who are overweight or obese but otherwise healthy, alongside adults with obesity and Type 2 diabetes. The therapy is being tested in what Carmot considers a phase 1/2 trial because it covers typical phase 1 portions, plus additional cohorts and phase 2a-esque dose exploration and titration, according to Turner. Top-line data from the trial are expected next year.

The Carmot CEO also anticipates launching a related phase 2 trial this year to test out more titration regimes for CT-388, with data expected in 2025. Next on the roster is a daily GLP-1/GIP dual receptor modulator known as CT-868 that will soon be studied in two separate clinical trials: an ongoing phase 1 study assessing impact on blood sugar regulation in participants with Type 1 diabetes and an upcoming phase 2 to assess the therapy's effect on blood sugar levels in patients who are overweight or obese and have Type 2 diabetes.

Patients with diabetes are normally insulin deficient and can end up becoming insulin resistant as the body starts to need higher amounts of insulin to manage blood sugar. More insulin leads to weight gain, Turner said, calling the process a “vicious cycle.” She believes Carmot’s CT-868 is “uniquely situated to break that cycle” because it is designed for both weight loss and glucose control. Early data show that CT-868 may even be able to reduce glucose levels without requiring additional insulin, according to Turner. The third therapy, CT-996, is a GLP-1 receptor agonist designed to be an equivalent to Novo Nordisk’s Ozempic and Wegovy, with one key difference—it’s not an injection. The oral small-molecule weight loss candidate is currently being tested in a phase 1 clinical trial, with data expected next year.

“We're really excited about the prospects of this molecule because we think we have designed a molecule that is once-daily, really potent and highly bioavailable,” Turner explained. “We think it could be a really great alternative for patients.” But Carmot's candidate will have to wow on safety and tolerability, as Pfizer just this June dropped an oral obesity candidate, also a GLP-1 receptor agonist, after seeing elevated liver enzymes in clinical trials.

GLP-1s and obesity drugs are largely a Big Pharma game for now—something Carmot doesn't expect to change. Turner thinks Carmot is well positioned to develop the programs now, but, once approved, they may need help actually getting the product to patients in the primary care space.

"In order to really deliver the benefit to patients, it is probably something that we wouldn't be able to continue to do on our own," Turner explained. "I would expect that at some point we will need help of bigger companies to really bring it to the patients. I mean, we could do it, but it would just be so small scale that we wouldn't really be able to get the benefit out of it." This May, investors funneled $160 million in a series D equity round, a vote of confidence for Carmot’s platform and pipeline.

The biotech’s focus goes beyond just the science, though. Turner has dedicated her attention on both prospective patients and Carmot’s employees. She highlighted the importance of employee mental health and has brought on new benefits for staffers and allows workers to take an extra day off every month for wellness. “I have really, really strived to bring a culture where people feel supported—both with their job and with their lives,” Turner said.

Investors: Deep Track Capital, 5AM Ventures, Franklin Templeton, Frazier Life Sciences, Janus Henderson Investors, RA Capital Management, Millennium Management, TCGX, The Column Group, Venrock Healthcare Capital Partners, Willett Advisors

Cerevance

By Annalee Armstrong

Using a collection of thousands of donated human brain tissue samples, Cerevance is developing a massive database of expression and epigenetic data to identify the best targets for central nervous system disorders.

CEO: Craig Thompson Founded: 2016 Based: Boston Clinical focus: Neurodegenerative diseases such as Alzheimer’s and Parkinson’s What makes Cerevance Fierce: What’s bolder than going after a group of diseases that have long stymied drug developers—and doing so against the flow of other companies? That’s what Cerevance is doing.

“I sound like 'Star Trek,' but we’re going where others haven’t gone before,” CEO Craig Thompson told Fierce Biotech. “We're looking at cells and then breaking those cells down into their 12 to 15,000 genes that we're picking out and then combining AI machine learning into that so we can almost start simulating the way the disease progresses.”

The company emerged from a joint venture between Takeda and Lightstone Ventures seven years ago based on the NETSseq platform, which studies the nuclei from donated postmortem brain tissue to assess targets that can be used to drug diseases. Cerevance has already generated 100 terabytes of data and, using AI and machine learning, hands off possible targets to the chemistry department to build molecules. Through those drug discovery efforts, four clinical candidates in Parkinson’s disease, Alzheimer’s disease, schizophrenia and amyotrophic lateral sclerosis have emerged—with more to follow.

In transitioning from a platform and discovery phase to development, Cerevance brought on Thompson in April 2022. Founding CEO Brad Margus slid into the board chair role. Co-founder of the NETSseq platform, Xiao Xu, Ph.D., serves as director of computational discovery. She developed the technology in her postdoctoral work at The Rockefeller University.

A year ago, Cerevance signed a pact with Merck & Co, which marked the New Jersey pharma’s return to the Alzheimer's space. The biotech received $25 million upfront and could receive $1.1 billion over the course of the discovery deal. Merck has access to three targets and also licensed a single discovery-stage program. Thompson couldn’t say much about the partnership’s current status but said the Big Pharma support was a big boost for Cerevance. “As we get into phase 2 and phase 3, we definitely need support from Big Pharma to run some of those larger trials,” he said. “I think they were impressed with what we were doing and our approach that we were taking, looking at specific cells and then how genes were expressed.”

In Parkinson’s, Cerevance wants to provide something new. The go-to treatment is the 70-year-old medicine levodopa, which turns into dopamine in the brain. CVN424 has already been tested as an additional therapy with levodopa in a phase 2 trial, and Cerevance was able to show a 1.8-hour improvement in off time, which is when patients experience symptoms between medication doses. The goal of Parkinson’s treatment is to improve so-called on time without having dyskinesia, the uncontrolled, involuntary movements associated with the disorder.

Cerevance’s offering avoids the dopamine pathway and instead targets a gene called GPR6, which avoids common side effects of levodopa such as hallucinations and hypertension. The adverse event rate for CVN424 was 4% and included vomiting and nausea; “it's probably as clean as you're gonna get,” Thompson said. Cerevance is working on testing the therapy in a phase 2 trial in patients who have not received levodopa before. With CVN766 nearing phase 2 for schizophrenia, CVN424 in multiple midstage trials, CVN293 nearing the clinic for Alzheimer’s and all those discovery programs still underway, Cerevance has a busy—and expensive—clinical program. Thompson said the biotech has runway until the end of 2024 or even into the beginning of 2025. “It's definitely a nice long runway, but it's always nice to be able to bring in additional capital because it provides us the opportunity to start some of our other trials even sooner,” Thompson said.

“As all biotechs you're always in a fundraising mode,” the CEO added. Having just expanded a series B with another $51 million, Cerevance is working through some business development efforts for rights to its therapies outside the U.S. And, of course, Thompson said it's considering the series C—but not an IPO. Cerevance will try to bring in some new investors during the series C round so that when it is ready to hit the public markets, the support is there.

“We're not in need of raising significant additional capital at this point. So it would just be more of a kind of expansion of the investor group we have right now,” Thompson said. Investors: Bill Gates, Takeda, Lightstone Ventures, Foresite Capital, Casdin Capital, GV, Dementia Discovery Fund, UPMC Enterprises, Dolby Family Ventures

Comanche Biopharma

By Annalee Armstrong

Comanche is aiming RNA therapies at a pregnancy complication that impacts millions.

CEO: Scott Johnson Founded: 2020 Based: Concord, Massachusetts Clinical focus: Preeclampsia What makes Comanche Fierce: What is the current treatment for preeclampsia? It’s “nonexistent,” Comanche Biopharma Chief Medical Officer Allison August, M.D., said in an interview. The only thing a physician can do is deliver the baby to prevent the dangerous consequences of the high blood pressure condition that occurs in pregnancy. But preeclampsia often strikes early—too early to deliver. So steroids are administered to hopefully boost the baby’s lungs to ensure they’re ready for the outside world. It’s a dangerous condition responsible for 10% to 15% of maternal deaths worldwide and between 5% and 8% of deaths during birth in the U.S. But, as with most conditions affecting women, it’s under researched and underfunded.

Comanche wants to change that. It’s that mission that lured August away from none other than Moderna, where she says she worked on “just about every mRNA-based vaccine except the flu vaccine.” Yes, that means the world-famous COVID shot. She specifically focused on vaccines that target maternal health, like cytomegalovirus, RSV and Zika. August is a rare gem in biopharma: an OB-GYN by trade who spent six years at the most famous mRNA company there is.

Messenger RNA is not what Comanche is doing, however. Instead, the company is developing a siRNA therapy to treat preeclampsia that is delivered to the placenta to lower levels of the sFlt1 protein. Comanche was founded by CEO Scott Johnson, also founder of The Medicines Company, which was eventually bought by Novartis for the siRNA therapy inclisiran. That medication is now known as Leqvio and marketed for lowering cholesterol in certain patients. Comanche co-founder and President Mike Young also came from The Medicines Company, where he planned the commercialization strategy for Leqvio.

For their next act, the pair began looking at preeclampsia, going back to the University of Massachusetts’ mRNA Therapeutics Institute. They worked with biochemist and molecular biologist Melissa Moore, Ph.D., as well as Ananth Karumanchi, M.D., who was the first person to make a connection between the elevation of the sFlt1 protein and preeclampsia, to come up with a therapy to bring into the clinic. Both scientists serve on Comanche’s board, and Moore was also previously the chief scientiic officer at Moderna.

The investigational new drug application for CBP-4888 was cleared in March, and a phase 1 trial is underway in non-pregnant women of childbearing age. Completion is expected for the end of the year, at which point the therapy will move into pregnant patients late in the first quarter of 2024 or beginning of the second quarter. The phase 1 trial will check the drug is safe, but Comanche is doing some additional early preclinical testing to ensure CBP-4888 can be safely administered to pregnant people.

The biggest challenge ahead for Comanche is recruiting pregnant people for their upcoming study. The FDA has historically categorized pregnant women as “vulnerable,” along with children, people with mental disabilities and others. This meant that women were not considered to be capable of making informed decisions while pregnant. Now, they have been recategorized as “complex,” which provides for a new set of trial recruitment standards. “The landscape has changed, and if I was trying to lead this program, even 10 years ago, I think I would face challenges that are different,” August said. “Maybe one small silver lining of the pandemic is that we did learn that women actually wanted information about the safety of these vaccines and could they receive it in pregnancy.”

August said the industry has shied away from research in this population out of fear and “the basic tenant of anything in medicine: First do no harm.”

First off, Comanche is engaging physicians who have worked in actual interventional trials in pregnant women, not just studies where the patient was observed for a particular outcome. The company will have to carefully monitor safety in the women as well as the babies. Another important factor is finding women with preeclampsia who are at lower risk of premature delivery.

Another challenge is ensuring that the patient population in the study matches the real-world population. That means recruiting women of color, because Black women have a 60% higher risk of preeclampsia than white women. With such a disproportionate burden, August is certain Comanche can find the right patients. But the company is taking other steps to ensure diversity as well, such as staging the trial in the so-called “hypertension belt” of America: Alabama, Georgia, Florida and Louisiana. Comanche is also adding sites in South Africa to broaden access to the medicine globally.

“So many drugs never make it to low- and middle-income countries, because, by the time they're approved, nobody's going to go back and do those studies in those settings. We're doing it now, designing it now,” August said. “We're already setting up those collaborations so that populations in the world that need it the most get it.” It’s going to be tough, but since emerging from stealth with the acceptance of the IND, August said the company’s mission has resonated. She was asked to join the National Institutes of Health’s Pregnant Women and Lactating Women task force to advise on innovative therapies for these patient groups.

Comanche has established a patient advisory board with preeclampsia advocates and survivors, another step in the drug development timeline that typically happens later. Olympian-turned investor and advocate for women’s health Allyson Felix—herself a preeclampsia survivor—even joined the board of directors in March and calls Comanche her “passion project.”

“Comanche was willing to push the boundaries and say, yes, this is a complex population, but it's not unsolvable,” August said. “So you have to be bold, but you have to be careful.” Investors: Broadview Partners, F-Prime Capital, GV, Population Health Partners

Epic Bio

By James Waldron

The biotech that's downsized a CRISPR-engineered protein to upsize its therapeutic potential has already seen interest from investors and Big Pharma. CEO: Amber Salzman, Ph.D. Founded: 2018 Based: South San Francisco, California Clinical focus: Facioscapulohumeral muscular dystrophy​, heterozygous familial hypercholesterolemia, alpha-1 antitrypsin deficiency, retinitis pigmentosa 4 and retinitis pigmentosa 11

What makes Epic Fierce: For a biotech that just launched in 2022, it’s been an epic first year. “I joined at the end of ’21,” CEO Amber Salzman, Ph.D., explains. “We didn't even have a pipeline then—and we're filing an IND this year.”

The IND in question is for EPI-321, the most advanced of the epigenetics-focused company’s slate of candidates, which Epicrispr (Epic) Biotechnologies hopes to get into the clinic early in 2024. The pipeline has its roots in the Stanford lab of CRISPR co-inventor Stanley Qi, Ph.D. The resulting protein, christened CasMINI, is designed to offer a more compact payload than the better known Cas fusion proteins, meaning it doesn’t exceed the maximum payload of adeno-associated virus (AAV) vectors and so can be delivered into cells in this way. When compared to the more widely researched Cas-9, smaller really is more beautiful, according to Epic’s head of technology development Dan Hart, Ph.D.

“The compact size of CasMINI means that we can package it comfortably into AAV,” he says. “On many different fronts, this is a molecule that has a lot of potential and I think that's why there's excitement around it.”

Initially, Epic has targeted five conditions that it says are insufficiently addressed by today’s genetic medicines, with the facioscapulohumeral muscular dystrophy (FSHD) candidate EPI-321 the closest to entering the clinic. There aren’t currently any treatments available for the rare, progressive muscular disorder, but that may change if Fulcrum Therapeutics’ late-stage mitogen activated protein kinase inhibitor gets to the market. Epic isn’t worried about being a runner-up in the space, however.

“Huge credit to Fulcrum, but where we have a huge advantage … is that we're really going to the root cause of the disease,” Salzman says. “[EPI-321] is a one-and-done … so the expectation would be that this would be game changing.” Along with FSHD, the other genetic disorders that the biotech has set its sights on are the high cholesterol condition heterozygous familial hypercholesterolemia, a lung and liver-related disorder called alpha-1 antitrypsin deficiency and two types of retinitis pigmentosa eye disorders.

But Epic’s ambitions are way bigger than these initial five indications, Salzman reveals. “We now have a platform that basically has addressed, in some ways, a lot of the limitations of the first generations of CRISPR,” the CEO says. One “big, big bonus” is that because CasMINI is not derived from bacteria, it doesn’t trigger an immune response when exposed to a donor’s T cells.

It’s for this reason that other drug developers have come calling, seeing potential for Epic’s tech to improve their cell therapies against cancer. In fact, the biotech is already in talks with a company to improve a CAR-T therapy on the market by making it “more durable and more effective,” according to Salzman. CAR-T developers that want to suppress certain targets that interfere with their therapy’s interactions in vivo currently have to contend with the “massive” size of the CAS protein as well as the chimeric antigen receptor itself, Hart explains. “So there is a need for a very compact system that would allow you to modulate these target genes.” Beyond that one example, Epic has had a “range of conversations” with both Big Pharma and “mid-sized” drug developers about partnering up on their tech.

“What we can do in terms of ex vivo is beyond what cas9 or other approaches towards improving T cells can,” Salzman says. “We don't have to do successive editing because everything can fit within a construct because our molecules are so ultra compact.” Of course, big ambitions require big spending power—beyond the $55 million series A that Epic launched with. “We could be filing a new IND every 12 to 18 months, but that will require more than our initial funding,” Salzman says.

Part of the much-needed extra money could come from those partnerships the biotech is cooking up behind the scenes. But it could also be sourced from a fresh funding round, which the company is already considering. “We've actually had investors reaching in and saying ‘We're interested in pigenetic editing, we've been looking at the field and we think you're in the lead,'” the CEO adds. “So that's been phenomenal.”

Investors: Horizons Ventures and "other leading investors around the globe"

FogPharma

By Max Bayer

Developing polypeptide therapies for hard-to-tackle solid tumors by targeting new intracellular targets.

CEO: Mathai Mammen, M.D., Ph.D. Founded: 2015 Based: Cambridge, Massachusetts Clinical focus: Advanced solid tumors

What makes Fog Fierce: Going into 2023, FogPharma’s future appeared anything but cloudy. The company had raised a $178 million series D round in November that bankrolled a growing pipeline of polypeptides that execs hoped could become first-in-class medicines. The new fundraising haul pushed the company’s total amount raised past $350 million over four rounds. And then Mathai Mammen, M.D., Ph.D., appeared. The former pharmaceuticals R&D head at Janssen was announced as the new CEO of Fog, replacing founder Greg Verdine, Ph.D., who himself is one of the most successful serial biotech entrepreneurs in the last 15 years. It was a seismic hire, one that added a new tier of legitimacy for a company that was on the precipice of the clinic. Mammen was arguably one of the most sought-after executives when he announced his departure from Johnson & Johnson at the end of 2022 and was a finalist to take over Biogen before deciding against it. He’d previously expressed that one of his top priorities was leading a company that was still moldable, rather than trying to overhaul an existing pharma’s R&D machine.

Mammen, now more than three months into the job, says the scientific know-how he was impressed by when he took the job is even more robust than he expected. “Often you do have surprises when you walk into companies,” he said in an interview with Fierce Biotech. “It's not like that; the engine works exactly as it's supposed to. In fact, it's better.” Mammen credits the work of Verdine and the team for leaving him with a biotech that’s hitting on all cylinders. Dosing began in a phase 1 trial for lead asset FOG-001, a beta-catenin inhibitor, earlier this summer, and the therapy is “working exactly as planned.” Fog’s potential centers around its ability to design helicon polypeptides that reach intracellular targets rather than just targets outside of the cell.

Though he’s been impressed with the level of scientific rigor and ophistication, Mammen has also spent his first months enacting change, chiseling Fog’s R&D priorities so that they aren’t too scattered too early. It's a lessen he's learned over his long career in pharma. “I think for the first 10 years, I don't know that I managed this exact process correctly,” he admitted, listing the various ways that business decisions and emotional investment can be intertwined. “And I would say that piece of it went really well within Fog.” The two other projects being elevated to follow-up FOG-001 are preclinical programs targeting ERG and cyclin E1. What’s particularly enticing about the ERG target to Mammen is that it avoids targeting the androgen receptor that’s frequently the focus of potential prostate cancer therapies. Tumors there have proven to have a bewildering ability to both resist treatment on the target and still rely on the receptor. ERG acts downstream of the receptor, with associated gene mutations present in as many as half of prostate cancer cases, according to research published in Cancers last year. Mammen says there are "multiple ways to win on ERG that we have right now.”

That leaves a handful of additional programs available for potential partnerships. Fog has generally received significant inbound interest, according to Mammen, but he has long held a fairly conservative view of partnerships. The company’s financials are currently secure, so Fog doesn’t need external deals at the moment for validation or short-term cash, he says. With respect to the beta catenin inhibitor, Mammen wants to wait until those data mature, maximizing value beyond regional deals he could sign onto now.

The other programs are more individualized, and Mammen is particular about finding the right partner. It’s not just about brand recognition, but how a company’s R&D, commercial or medical affairs teams line up with what Fog is trying to accomplish. Those multitarget research pacts, however? Don’t expect any of those. It’s a lesson Mammen learned from his time leading Theravance.

“That kind of thing is effectively like selling the company without selling the company,” he said.

Investors: Arch Venture Partners, Milky Way Investments, Fidelity Management & Research Company, VenBio Partners, Deerfield Management, GV, Cormorant Asset Management, Invus, Farallon Capital Management, HBM Healthcare Investments, Casdin Capital, PagsGroup, 6 Dimensions Capital, Blue Pool Capital

HiFiBiO Therapeutics

By Max Bayer

Identifying and developing antibodies more efficiently and expeditiously.

CEO: Liang Schweizer, Ph.D. Founded: 2013 Based: Cambridge, Massachusetts

Clinical focus: Fusing a novel microfluid system with machine learning to swiftly discover antibody-based therapies What makes HiFiBiO Fierce: Across any and all therapeutic areas, you’ll likely find monoclonal antibodies playing at least some role in the treatment paradigm. Whether that’s COVID-19, non-small cell lung cancer or Alzheimer’s, the modality, at its simplest, acts as a synthetic biological radar for a given disease target, triggering a broader immune response that may have otherwise been absent.

Despite their wide use, designing antibodies is far from easy. HiFiBiO Therapeutics believes its platform could change all that.

“We think we are the leading antibody single B cell discovery capability,” said CEO Liang Schweizer, Ph.D., in an interview.

The platform fueling that confidence is dubbed Drug Intelligence Science (DIS), a name that Schweizer landed on while waiting for her train at Penn Station in New York City—a notoriously bleak transit hub ripe for ruminating. It’s a broad name for a comparatively specific process. The DIS platform uses machine learning and artificial intelligence to quickly analyze patient samples using a microfluidic droplet system that can rapidly assess single-cell data. The platform can assess 5,000 to 10,000 droplets per second. Schweizer described each droplet as a raindrop that’s reacting with the cells within it, simulating a truncated immune response. Those cells subsequently secrete antibodies, adding more data for the machine learning portion of the platform to sift through and wield for target discovery and antibody construction.

“So basically drug discovery agency—from target to drug to patients—you can use the DIS,” Schweizer said.

HiFiBiO has used this rapid development process to churn out eight clinical candidates, four of which are currently in phase 1 trials, two slated for an IND filing in 2024 and two others handed over to FibroGen. The company has also inked a clinical supply agreement for Novartis’ anti-PD-1 tislelizumab, now being tested in a phase 1 trial alongside HiFiBiO’s BTLA inhibitor HFB200603.

HiFiBiO has also had an extended partnership with Gilead Sciences' Kite Pharma dating back to 2018. The first deal inked then included $10 million upfront from Kite in exchange for HiFiBiO's help identifying neoantigen-reactive T-cell receptors that could turn into cancer treatments. Two years later, the companies linked up again, with the smaller biotech identifying new acute myeloid leukemia targets that Kite could incorporate into its cell therapies. Kite is also an investor in HiFiBio. But the DIS platform is not cemented to the discovery process. Schweizer described how her team is using patient data accumulated in the ongoing phase 1 trials to assess how the drug is impacting immune modulation and which immune cells are reacting. Those are data that not only inform future research and discovery but also biomarker selection for future trials using those assets. Schweizer said it’s “something nobody else [has] ever done in the world."

Future clinical development could look a lot like the ongoing Novartis collab, Schweizer teased, saying she hopes to expand the number of combination therapies. She specifically highlighted the company’s phase 1 OX40 candidate as an asset that could be well suited as part of a combination therapy. Schweizer has firsthand experience wrangling with the target after she spent more than 11 years at Bristol Myers Squibb as a director on the optimization and discovery team. The Big Pharma’s OX40 candidate, BMS-986178, posted lukewarm results as a monotherapy.

“Now, we’ve come up with a second generation, because we think we have a solid hypothesis [for] why the first did not work and why the second would work,” she said. “And having that not only at the mono setting but combination setting.”

Arguably more noteworthy than HiFiBiO’s expeditious sprint to the clinic has been its judicious use of cash. The biotech closed a $75 million series D round more than two years ago and still has two to three years of runway left, according to Schweizer.

“It's not like we're pressing for cash in any way,” she said. That’s allowed her to be a bit more laissez faire about the company’s next financing, but she noted that if HiFiBiO picks up the pace and soon launches into phase 2, potentially registrational trials, it may make the most sense to go public. Her responsibility, she says, is to always ensure that HiFiBiO has at least one year of cash runway.

Investors: Kite Pharma, Mirae Asset Financial Group, B Capital Group, Sherpa, Maison Capital, Trinity Innovation Fund, Grand Mount, HKSTP Venture Fund, IDG, Sequoia Capital China, Legend Star, Hengxu, LYFE Capital, VI Ventures

Orca Bio

By James Waldron

With a precision-focused process, Orca aims to shake up the stale stem cell therapy space and eliminate the scourge of serious adverse reactions from transplants.

CEO: Ivan Dimov, Ph.D Founded: 2016 Based: Menlo Park, California Clinical focus: Acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome What makes Orca Fierce: Stem cell therapies may be nothing new, but Orca Bio’s pitch gives a fresh twist to this much-used process with a mantra of “unprecedented precision.” “What we've been able to do is … actually identify the precise cells that will maximize efficacy, and also the cells that will eliminate the toxicity,” CEO Ivan Dimov, Ph.D., tells Fierce Biotech.

In practice, this means taking donor T cells and stem cells, sorting them into their different subtypes and then combining them in the right mixture to treat disease. The end result is a cell therapy that replaces the need for a conventional bone marrow transplant. The results speak for themselves. In February, phase 2 data for the Bay Area biotech’s lead candidate, dubbed Orca-T, demonstrated an 87% rate of relapse-free survival at 12 months across 71 patients with various blood cancers who had already received a conditioning regimen. While traditional stem cell transplants can effectively cure blood cancers, they can also create problems, including graft-versus-host disease (GVHD). It’s by avoiding this serious adverse event that Orca is expecting to show a real benefit for patients.

“Now that we've accumulated hundreds of patients treated and [given] long-term follow-up, we're actually … seeing less toxicities in general, not just less GVHD,” Dimov says. “We're seeing less non-transplant related mortalities. We're seeing generally really good reconstitution of the immune system. So patients are getting out of the hospital quicker, and that's all driving much better overall survival rates.”

With a readout from an ongoing phase 3 trial expected “sometime next year,” Orca plans to capitalize on the findings by “going very quickly to file” an approval application with the FDA and then launch the candidate, according to Dimov.

While biotechs often need to partner up with the commercial firepower of a Big Pharma to get their drug to market, Orca believes that given the nature of stem cell treatments, it has the resources to take care of everything itself.

“These patients are predominantly treated in a very small number of hospitals across the U.S.,” Dimov explains. “So it's a much more efficient launch process because I don't have to go to about 20,000 physicians.”

Still, phase 3 trials and drug launches are always expensive. With $300 million raised so far in total, including the most recent $192 million series D round in 2020, does the biotech have enough to cover those costs?

The company’s executives are tight-lipped about whether they’re planning on asking investors for more cash. But when it comes to taking the company public, Dimov says Orca is “very opportunistic,” despite refusing to be dawn on a date.

“Markets are very volatile,” the CEO explains. “We want to make sure that we go when it's best for the company, for the shareholders, for the patients. So it's hard to really set a timeline.”

Coming up behind Orca-T is Orca-Q, a “next-generation therapeutic” that fine-tunes the tech used by its predecessor. Where Orca-Q “really shines” is its potential for use among patients for whom a wholly matched stem cell donor can’t be found. Between the two candidates, the company feels it’s resolved some of the biggest issues with standard stem cell transplants.

“One of the things that really excites me is being able to give a lot more patients access,” Dimov says. “Orca-T does that in the sense of less toxicity, so if you have more fragile patients that you wouldn't have treated otherwise, now you can treat them." He added: “And Orca-Q does that in the sense [of] if you don't have the perfect donor match, it's OK, we have an alternative for you.” While the first two candidates are both focused on a variety of blood cancers, a partnership with Lyell Immunopharma penned in 2020 gives an indication of where Orca could swim to next. The aim of that collaboration was to combine Orca’s own precision purification T-cell tech with the expertise at CAR-T developer Lyell to look at new approaches to solid tumors. With solid tumors remaining the holy grail of the next generation of CAR-T therapies, does Orca have its eye in this area as well?

“We’re definitely interested in that space,” Dimov says. “We’ve had several approaches to get into that space that we’re continuing to push in that direction. But we don't have anything specific to mention at this point.”

Investors: Lightspeed Venture, 8VC, DCVC Bio, ND Capital, Mubadala Investment Company, Kaiser Foundation Hospitals, Kaiser Permanente Group Trust, IMRF

Palleon Pharmaceuticals

By Angus Liu

Targeting sugar molecules on cell surfaces to treat cancer and inflammatory disease

CEO: Jim Broderick, M.D. Founded: 2015 Based: Waltham, Massachusetts Clinical focus: Palleon Pharmaceuticals is leveraging the role that cell-surface glycans play in regulating the immune response to treat diseases. What makes Palleon Fierce: The 2022 Nobel Prize in Chemistry awarded to Carolyn Bertozzi, Ph.D., brought a couple biotech companies that she co-founded to the spotlight. One of them is Palleon, which plays at the intersection of glycans and immunology.

Bertozzi earned the Nobel for her work in bioorthogonal chemistry, which allows chemical reactions to proceed in living cells without interfering with existing biochemical processes. This technique enabled scientists to study glycans in live biological systems. These sugar molecules coat all cell surfaces and are involved in key aspects of cell biology, but they are not detected by genomic tools, Palleon’s CEO and co-founder Jim Broderick, M.D., explained.

Bertozzi established the causal relationship between an abnormal glycan pattern on tumor cells marked by the upregulation of sialoglycans—sialic acid-carrying glycans—and immune evasion in cancer, Palleon’s chief scientific officer, Li Peng, Ph.D., said. But sialoglycans can’t be targeted by conventional small-molecule or antibody drugs. The sialoglycans on tumor cells can be recognized by a family of receptors called Siglecs expressed by immune cells. This interaction typically suppresses the immune response in a way similar to that between PD-1 and PD-L1. But unlike the one-to-one binding relationship between PD-1 and PD-L1, 14 functional Siglecs are known to exist in humans, including nine that appear to play an inhibitory role. And there’s an abundance of different sialoglycans. Bertozzi’s third contribution to Palleon’s work, Peng said, is the brilliant idea of using a “nature’s solution,” an enzyme called sialidase, to basically cut off sialic acid in a targeted degradation manner to remove sialoglycans and hence the immune suppression. “There are thousands of sialoglycans, but it doesn’t matter what their structures are; if you remove the sialic acid, the binding doesn’t happen anymore,” Broderick said. In fact, Broderick gathered the first funding for Palleon to work on Siglecs blockade. But that idea simply didn’t work, so the company pivoted to the enzyme approach about a year and half into its existence.

Having recognized the Siglecs redundancy problem, Peng designed Palleon’s lead candidate, E-602, an engineered human enzyme that degrades sialoglycans on tumors and immune cells. In a phase 1 trial coded GLIMMER-01 conducted in patients with various tumor types, investigators found that E-602 can be dosed up to 30 mg/kg with no dose-limiting toxicities. CD8+ T cells in peripheral blood showed sustained desialylation, corresponding to various signs of increase in immune activation in circulation.

The trial didn’t measure tumor response rate like many phase 1 cancer trials would do. To enroll faster, Palleon picked patients that were unlikely to response because of their disease and immune status, including individuals with immune cold tumors, Peng said. The goal of the study was to establish safety and the drug’s ability to remove sialic acid and trigger immune response, she said.

Broderick is confident that the immune biomarker in the peripheral blood could translate into anti-tumor activity in the right patient population based on preclinical findings. “We’re creating a whole new field of immune modulation … It required new tools to measure it and required new therapeutic modalities and new clinical strategies,” Broderick said. “We had to have the innovation every step of the way.” Palleon has recently launched a second part of GLIMMER-01 to combine E-602 with Regeneron’s PD-1 inhibitor Libtayo. The company is now prioritizing the combo study over monotherapy.

Broderick argued that combination is the way to go because if E-602 can activate the immune system, PD-1 is going to be upregulated. If the combo shows it can benefit patients who no longer respond to PD-1 inhibition, then E-602’s contribution can be established, he said.

Moving forward, Peng is working on second-generation molecules that will, like the trending antibody-drug conjugates, have a target arm to help the enzyme—the payload—better localize to cancer cells, which may have relatively low sialoglycans. This multiarm strategy has attracted a lot of business development discussions with other companies “because they have good targets, and they want to overlay this new dimension of glyco-immunology modulation to their targets,” Peng said. Since its founding in 2015, Palleon has raised $147 million.

“There are some Big Pharmas that have recognized the importance of this [immune mechanism], and they are interested in partnering potentially quite broadly,” Broderick said. Because of glycosylation’s role in immune dysfunction, Palleon is also developing glycan-editing and Siglec-targeting programs for inflammatory diseases.

Investors: Matrix Capital Management, SR One, Pfizer Venture Investments, Vertex Ventures, Takeda Ventures, AbbVie Ventures, Surveyor

Proxygen

By Fraiser Kansteiner

Proxygen is discovering molecular glue degraders to build a new avenue toward targeting proteins that were previously considered “undruggable.”

CEO: Bernd Boidol Founded: 2020 Based: Vienna Clinical focus: Molecular glue degraders What makes Proxygen Fierce: With molecular glue degraders the mortar, Proxygen is angling to position itself as a “scientific lighthouse,” the company’s CEO Bernd Boidol said in an interview.

Molecular glue degraders are druglike compounds that stick problematic proteins with ubiquitin ligase, destroying the protein. Glue degraders are like small molecules, but, instead of inhibiting the functions of proteins, they bind two together, one of which is the target protein relevant to the disease, Boidol explained.

“This has a ton of advantages when you think about conservative pharmacology or conservative drugs,” Boidol said. “You can only inhibit 10% to 20% of proteins in the human body because you need some kind of binding pocket on the protein.” “With glue degraders, you don’t need that. You can theoretically target every single protein in the human body.” Historically, however, there haven’t been scalable and systematic discovery strategies for glue degraders—something Proxygen seeks to counter by establishing and continuously improving upon a versatile in-house discovery platform. “What we do is we turn off the entire, let’s say, degradation machinery in the cell,” Boidol said. “With this approach, we can find molecules that have an effect on the target protein." Boidol is a scientist by training who received a Ph.D. in oncology research and did his Master’s thesis at Harvard Medical School in Boston. While getting his Ph.D., Boidol also obtained a business degree in Vienna. Wanting to join those two interests together rather than simply remaining in academia, he joined a management consulting company where he worked with many drugmakers “from the inside.” Then, in 2020, Boidol came back to Vienna to join Proxygen as CEO.

Proxygen has been striking it big in recent months. Back in April, the company signed a licensing agreement worth more than $2.55 billion in biobucks with Merck & Co. How much the biotech is receiving upfront, or how many targets it is offering the Big Pharma, remains undisclosed.

That marked the third licensing deal Proxygen has struck with a major drugmaker since December 2020, when the company teamed up with Boehringer Ingelheim. After Boehringer came German compatriot Merck KGaA, which offered up $554 million in biobucks in exchange for an unknown number of targets.

Boidol couldn’t say much about these ongoing partnerships, except that “each one of these deals is really a very fruitful collaboration.” According to Boidol, it’s not just about “the press release that goes out there” but also the “chemistry” between companies.

“I think having this approach … is something that was for us, a requirement, and I think also a great foundation of the collaborations and the successes we have," he said.

Without divulging more, Boidol said Proxygen is “very, very confident and satisfied with the progress that we have made so far [with each company].”

Proxygen’s pipeline and external workload remain shrouded in mystery. Up next on Proxygen’s radar is its first fundraising round slated for early next year, Boidol said. Proxygen has been able to stay under the radar in part because the biotech hasn’t taken any venture capital money, relying solely on grants and upfront payments received from the trio of deals.

“That’s also not seen and heard of very often in this field—that you have a company like ours that is completely free of external money, of external investments," he said. When it comes to a possible sale or going public, “I think it’s too early to say,” Boidol noted. He said Proxygen is having “a lot of fun” building itself out as a company, but that “I would never say never.” Meanwhile, Big Pharmas like Bristol Myers Squibb have also been getting in on the molecular glue action in recent months. Back in October, BMS teamed up with San Francisco Biotech SyntheX on molecular glue degrader discovery, handing over up to $550 million in potential biobucks. Investors: N/A

RayzeBio

By Conor Hale

Chasing a new generation of radiopharmaceuticals

CEO: Ken Song, M.D. Founded: 2020 Based: San Diego Clinical focus: Cancer radiation therapy What makes RayzeBio Fierce: Radiation has been wielded against cancer cells for decades. But RayzeBio is out to prove it still has plenty of potential left untapped—and, with the right molecular tools, it could become a major treatment option for solid tumors.

Medical radioactive isotopes have typically been designed to cause as little damage as possible when used inside the body: As diagnostics, they emit just enough to help scanners trace their paths through various blood vessels, cells and chemical reactions in the search for disease. Only in recent years have injectable radiopharmaceuticals been approved to not only find cancers but to use their radiation to attack them as well.

This is where RayzeBio hopes to turn up the intensity. The company is designing compounds that bind selectively with targets more likely to line the outsides of cancer cells compared to healthy tissues, while carrying a powerful payload capable of breaking down a tumor’s ability to reproduce.

If that sounds familiar, it’s also the pitch being made by the developers of antibody-drug conjugates—an approach that’s recently garnered billions in biotech investments and been the focus of marquee mega-acquisitions. “Conceptually, radiopharmaceutical therapies and antibody-drug conjugates are similar in that they both involve a binder, a linker and a payload,” said RayzeBio CEO Ken Song, M.D., in an interview. “And the binder is really just a delivery vehicle that gets the payload to the cancer cell.”

But while biotechs of all stripes may be forever searching for those molecules that bind well with a particular cellular target—and, fingers crossed, precipitate some kind of therapeutic effect down the line—to RayzeBio, just making that connection is the all-important task, because once the isotope gets close enough the radiation will do its job.

The payload is also where RayzeBio aims to set itself apart. Novartis currently holds approvals for two radiopharmaceutical cancer treatments: Lutathera and Pluvicto. The former is approved in abdominal neuroendocrine tumors and the latter in prostate cancer, and both have served as the subjects of multibillion-dollar deals. Both drugs are also built around the same isotope—lutetium-177, a beta-particle emitter—but each has it paired up with different binders aimed at distinct cancer targets.

RayzeBio’s chosen champion is actinium-225, which, by contrast, emits alpha particles. This heavier, more destructive radiation is capable of delivering hundreds of times the energy of beta particles while also confining its damage to a radius measuring just a few widths of a cell.

“Beta particles will emit their radiation energy over the span of several millimeters,” Song said. “So when you think about it, you're delivering a more targeted radiopharmaceutical with an alpha particle. It’s really mainly destroying the cell or its adjacent neighbor, with very little risk to causing any off-target or off-tissue effect.” “Alpha particles are also more efficient at causing double-stranded DNA breaks, which is the primary mechanism where you see cell death. So it's a much more potent payload,” he said. The company’s lead candidate, RYZ101, actually relies on the same binder as Lutathera: a peptide chain known as dotatate, which connects with about 80% of the group of gastroenteropancreatic tumors commonly referred to as GEP-NETs. And, in part because dotatate has been so well studied, that has allowed RayzeBio to get creative with its clinical testing.

RYZ101 is currently being studied in a global phase 1b/3 trial—yes, that’s skipping phase 2—and is enrolling patients for the pivotal stage who have inoperable GEP-NETs that have already progressed after lutetium-based therapy. The treatment is also being tested in small cell lung cancer.

In addition, the use of international academic and compassionate use data from combinations of actinium and dotatate let RayzeBio pursue a dose de-escalation study as opposed to an escalating one—where the company was able to start off its trial with a recommended phase 3 dose.

“This is unusual because normally you don't have existing clinical data on a compound when you first file [for a clinical trial with the FDA],” Song said. RayzeBio’s work has triggered intense investor interest since the biotech launched in 2020. After making its debut with a $45 million series A in October 2020, the company counted up another $105 million less than two months later for its series B. The startup went on to absorb yet another $108 million in a June 2021 round before finally collecting $160 million in last year's series D.

That $418 million fundraising haul has helped build a vertically integrated operation, with the goal of establishing in-house drug discovery efforts to design specific binding compounds—including an upcoming, novel peptide that aims to carry actinium into liver cancers—all the way to its own isotope manufacturing. And those binders can also pull double duty by helping identify the tumor cells where the payload will find its mark.

“Your diagnostic can be the exact same binder as your therapeutic—the only difference is you're swapping out isotopes,” Song said. “People have been talking about precision medicine forever. But with radiopharmaceuticals, you're about as precise as you can get.”

Investors: Viking Global Investors, Sofinnova Investments and Wellington Management. Other backers have included Ally Bridge Group, Sands Capital, Laurion Capital Management, Soleus Capital, Venrock Healthcare Capital Partners, Deerfield Management, venBio Partners

SparingVision

By Kevin Dunleavy

The developer of mutation-agnostic gene therapies hopes to create eye disease medicines that can address large patient populations. CEO: Stephane Boissel Founded: 2016 Based: Paris Clinical focus: Genomic medicine, specializing in ocular diseases What makes SparingVision Fierce: The genomic medicines company is leading a step shift in the treatment of optical diseases, going beyond single gene correction therapies to deliver new treatments to patients affected by inherited retinal diseases.

It didn’t take much to convince Stephane Boissel to leave his comfortable position as the executive vice president of corporate strategy at San Francisco biotech Sangamo Therapeutics and gamble with a Paris startup with six employees and one asset.

In the middle of the coronavirus pandemic in 2020, Boissel took the plunge, returning home to become CEO of SparingVision. Three years later, the company is making noise as a gene therapy innovator.

“The science was totally unique,” Boissel said in an interview with Fierce Biotech. “(It was) a fantastic asset that was developed in 20 years by one of the top scientists in the field.” SparingVision traces its roots to co-founder, Jose-Alain Sahel, M.D., now the chairman of the Department of Ophthalmology at the University of Pittsburgh, who devised an innovative gene therapy designed to potentially treat retinitis pigmentosa (RP).

Spark Therapeutics made the first breakthrough in the indication, winning approval for Luxturna in 2017. The traditional gene therapy, however, addresses just one of the 65 mutations that cause RP and can be used by only about 2% of those with the condition. Instead of addressing one of the genetic drivers that cause RP, Sahel focused on a single solution—a mutation-agnostic gene therapy—that could treat each of the 2 million people in the world who have the disorder.

“The beauty of what we’re doing is that theoretically, we can treat everyone,” said Boissel, who was the CEO of regulatory T-cell developer TxCell before Sangamo purchased the company for 72 million euros ($78 million) in 2018.

While SparingVision tempted Boissel with the potential of the RP therapy, it was the company’s broader vision to build an ocular genomic medicine powerhouse that convinced him to take the reins.

“They gave me carte blanche to build a team and carte blanche to build a portfolio by targeting synergistic assets for technologies that will be a good complement to the initial single asset," Boissel said. Two months after Boissel took over as CEO, the company raised 44.5 million euros ($52.5 million) to develop the RP treatment. In September of last year, SparingVision followed with a series B round of 75 million euros ($82 million).

In October 2021, Intellia received a 10% equity stake in SparingVision, in exchange for providing its CRISPR-based gene editing technology for up to three ocular targets. Boissel said the agreement is progressing “extremely well.” SparingVision has advanced one target to the research stage. The company has yet to reveal any indications. While these are long-term projects, there is more urgency with RP. In April, SparingVision kicked off a 33-patient, phase 1/2 trial for SPVN06 dubbed PRODYGY, which is scheduled for an efficacy readout in 2025.

The company has a second RP candidate, which was gained in the 2021 acquisition of Gamut Therapeutics. SPVN20, which also is a mutation-agnostic gene therapy, addresses a later stage of the disease, allowing SparingVision to potentially have two RP drugs on the market simultaneously.

“Ultimately, the goal is to combine the two assets into one single gene therapy,” Boissel said. “But that’s a long shot. We need first to prove the two biologies in development.”

RP causes degeneration of rod photoreceptors in the middle of the eye, leading to night blindness. Over time, cone photoreceptors on the periphery of the retina also degenerate, causing vision to deteriorate to the point that a patient is legally blind. Researchers had long understood how genetic mutations could damage the rods but couldn’t get a handle on why the deterioration of cones followed. Sahel surmised that the loss of rods leads to the destruction of molecules that ensure preservation of the cones. SparingVision’s lead therapy encodes for neutrophil factor RdCVF and an enzyme, enabling it to restore aerobic glycolysis in the cones, protecting them from oxidative stress.

Because SVPN6 is designed to preserve vision and the aim of SVPN20 is to restore it, assessing the effectiveness of the latter treatment in trials will take much less time. If all goes well, SVPN20 could hit the market by 2029, with SVPN6 soon to follow.

Investors: UPMC Enterprises, Jeito Capital, 4BIO Capital, Ysios Capital, Bpifrance, Foundation Fighting Blindness, the RD Fund

Ventus Therapeutics

By Andrea Park

Scoping out the hidden "pockets" on proteins to shape new approaches to inflammatory diseases CEO: Marcelo Bigal, M.D., Ph.D. Founded: 2019 Based: Waltham, Massachusetts Clinical focus: Structural biology and computational chemistry to develop small-molecule candidates in immunology, inflammation and neurology What makes Ventus Fierce: In the spring of 2021, as Ventus Therapeutics closed a funding round totaling $100 million, CEO Marcelo Bigal, M.D., Ph.D., told Fierce Biotech that the series B would help the still-new startup bring its first drug candidate to clinical trials by “late 2022 or early 2023.”

Though slightly off that timeline, two years later, not one but three of Ventus’ compounds are now in or approaching the clinical stage.

“This is remarkable. It would be remarkable for a large company, and it’s certainly remarkable to us,” Bigal said in a recent interview. “There are many things that make our company unique, but I think we can fairly say that Ventus is very productive.”

Ventus develops its small-molecule compounds using its ReSOLVE platform, which is designed to sniff out the “pocket”-like grooves that are found on the surface of some proteins and are the key to binding small-molecule drugs to a target.

“Recently—five, six years ago—there was a sense that we couldn’t drug anything else with small molecules,” Bigal said, resulting in an “undesirable trade” that swapped largely untested, sometimes-risky new therapeutic approaches for the tried-and-true small-molecule modality.

But Ventus’ technology is uncovering “elusive” pockets on proteins that were previously believed to be missing the crucial feature. As the CEO explained, “We can see pockets that only happen in certain conformations of proteins or pockets that are invisible because they’re occupied by water.” The ReSOLVE platform extracts the water structure from those protein pockets and uses it to build a digital blueprint of each pocket—dubbed the hydrocophore—to screen billions of compounds for their protein-binding potential. Ventus screened its first target in 2020—the same year it emerged from stealth with $60 million in series A funding—and came up with three candidates to further develop. One, currently dubbed VENT-03, represents a first-in-class approach. It inhibits the cGAS enzyme to disrupt the mechanisms behind certain inflammatory conditions, including lupus and dermatomyositis. It’s on track to be in clinical studies by December, Bigal said.

The other two are NLRP3 inhibitors, an approach that’s currently being studied as a treatment for other inflammation-causing diseases throughout the body. VENT-01, for example, could be used as a therapeutic across the kidneys, heart and liver, while VENT-02 is focusing on inflammation and degeneration in the brain. The first trial participant was dosed with VENT-02 this month, warranting a party in Ventus’ hometown of Boston, the CEO reported.

The other NLRP3 inhibitor, meanwhile, has caught Novo Nordisk’s eye. Last fall, the Danish drugmaker shelled out $70 million in upfront cash for the exclusive global rights to develop and commercialize VENT-01, with another $633 million on the table in potential milestone and royalty payments down the road. Novo will be looking specifically to develop the compound as a treatment for cardiometabolic conditions including nonalcoholic steatohepatitis and chronic kidney disease.

And while Ventus isn’t explicitly on the hunt for more partnerships like the Novo deal, Bigal said he’s regularly in talks with other pharmas.

“Because of our platform, we have more than we can develop alone,” he said. In addition to its first three candidates, the company has three more compounds in the earlier stages of development plus several other discovery targets—“too much for a single company,” according to Bigal, necessitating new partnerships that will complement and advance Ventus’ existing work.

Indeed, Ventus plans to keep its hands full for the foreseeable future. The chief executive said he expects the company to have multiple compounds in phase 2 and phase 3 studies within the next three years and will be getting ready to submit regulatory paperwork within five years.

“Ventus has been created to endure. We are not in the business of doing something to flip out and sell under any condition or any circumstance,” he said, adding that between Ventus’ current leading candidates alone, “I think we have all the elements to put together an end-to-end company that we can fund and use to develop medications up to the regulatory approval.”

Investors: SoftBank Vision Fund 2, RA Capital Management, Qatar Investment Authority, Andreessen Horowitz, BVF Partners L.P., Casdin Capital, Cormorant Asset Management, Fonds de solidarité FTQ, Alexandria Venture Investments, GV, Versant Ventures

Ref: https://www.fiercebiotech.com/special-reports/introducing-fierce-15-2023