Fierce Biotech: Yale spinout shows how targeting cancer cells’ acidic environment might enhance immunotherapy

Fierce Biotech | Angus Liu

October 7, 2021

Antibody-drug conjugates such as AstraZeneca and Daiichi Sankyo’s Enhertu have shown unparalleled efficacy in certain biomarker-driven tumor types. But those therapies are not as effective at attacking cancer cells that lack the antigen they are designed to target. Yale University spinout Cybrexa Therapeutics is reporting promising early evidence indicating it may have a solution to that shortcoming.

Cybrexa has developed a peptide-drug conjugate (PDC) which, instead of aiming for a specific antigen, targets the acidic environment of cancer cells to deliver a toxic payload. The drug, coded CBX-12, improved the efficacy of immune checkpoint inhibitors in mice with colorectal cancer, Cybrexa unveiled at the AACR-NCI-EORTC virtual International Conference on Molecular Targets and Cancer Therapeutics.

Cybrexa advanced CBX-12 into a phase 1/2 study in May. The phase 1 portion of the trial will examine the safety and tolerability of the PDC at different dosing schedules in patients with solid tumors to determine the best dose for phase 2 testing.

“This is a pan-tumor tumor targeting platform technology,” Vishwas Paralkar, Ph.D., Cybrexa chief scientific officer, told Fierce Biotech Research via email. “For CBX-12 the initial indications we aim to pursue are HER2-[overexpressing] ovarian and small cell lung cancer.”

Antibody-drug conjugates link antibodies specific to surface antigens on cancer cells with a toxic payload. Instead of antibodies, CBX-12 uses a peptide called pHLIP, which was developed by scientists at Yale University and the University of Rhode Island. The peptide targets the acidic environment, which is unique to tumor tissues.

Cybrexa’s propriety alphalex technology allows the peptide to form a corkscrewlike helix when it comes in contact with acidic, or low pH, conditions. It then penetrates the cancer cell membrane and releases a potent cytotoxic agent; in CBX-12’s case, that anti-cancer warhead is a compound called exatecan.

“The novelty of CBX-12 is that it targets acidity, which is a universal feature of all tumors,” study author Sophia Gayle, Ph.D., an associate director of biology at Cybrexa, explained in a statement. “We are, therefore, able to deliver a potent anti-cancer therapeutic selectively to cancer cells in a much broader patient population, as opposed to antibody-drug conjugates that are restricted primarily to patients whose tumors express high levels of a target antigen.”

The company recently showed in different animal models that CBX-12 can selectively kill off tumors without the need to target specific cancer antigens. Because CBX-12 doesn’t seem to suppress bone marrow activity in a phenomenon called myelosuppression, the researchers figured the PDC could be paired with checkpoint inhibitors, immune-boosting drugs that have established themselves as new standard treatment across multiple tumor types.

For the new study, scientists at Cybrexa combined CBX-12 with PD-1 and CTLA4 inhibitors in mouse models of colorectal cancer. Mice that got the combo showed significantly slower tumor growth, complete tumor regressions and improved survival compared with mice treated with checkpoint inhibitors alone. Adding CBX-12 to a PD-1 inhibitor delayed tumor growth by four times and by 10 times when combined with a CTLA4 inhibitor, according to the team.

Rodents that experienced complete tumor regressions showed long-term immunological memory, so, when they were re-challenged with new tumors, the cancer didn’t grow.

The results suggest CBX-12 could potentially be combined with checkpoint inhibitors to help patients whose tumors don’t respond to immunotherapies alone, Cybrexa argues.

Cybrexa was co-founded by Yale scientists Ranjit Bindra, M.D., Ph.D., and Peter Glazer, M.D., Ph.D., in 2016. The New Haven, Connecticut-based company recently raised $25 million in a series B backed by HighCape Capital and Elm Street Ventures to move development of CBX-12 forward.

The company had been working on another drug, CBX-11, which leveraged its alphalex technology to deliver Clovis Oncology’s PARP inhibitor Rubraca. But after seeing encouraging CBX-12 monotherapy data in preclinical studies, “along with the evolving clinical data from both Enhertu and [Gilead Sciences’] Trodelvy demonstrating activity in a wider patient population,” Cybrexa has decided to prioritize the development of CBX-12, Paralkar said. Learnings from CBX-12’s phase 1 trial will guide the development of the rest of Cybrexa’s portfolio, including CBX-11, he added.

The company has said it will explore CBX-12’s potential alongside other therapeutics such as checkpoint inhibitors and PARP inhibitors.

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Flush with cash: Record venture capital funding driving local startups’ demand for CFO talent

Per Hellsund is the CEO of New Haven-based Cybrexa Therapeutics, which recently hired a new chief financial officer.

By Matthew Broderick

For much of the U.S. economy, 2020 was a year best forgotten.

Federal Reserve Bank numbers show more than 100,000 small businesses permanently closed, with many others under duress heading into 2021.

But for venture capital, 2020 was a banner year. According to figures from Pitchbook and the National Venture Capital Association (NCVA), investors poured more than $156.2 billion — or $428 million per day — into U.S.-based startups last year, an 11 percent increase from 2019.

In Connecticut, startups — predominantly technology or life sciences ventures located in Greater New Haven — hauled in more than $707 million in funding in 2020, a 27 percent increase year-over-year, and the most money raised in a single year in the past two decades, according to numbers from a PwC/CB Insights MoneyTree Report.

Connecticut Innovations (CI), the state’s quasi-venture capital arm, invested more than $43 million in nearly 100 startups in the state in fiscal year 2020 alone, a 10 percent increase from the prior year.

And it’s not just a short-term phenomenon. Over the past decade, the median venture capital investment across all phases of startups has increased steadily.

The complexity and size of today’s venture deals have created a growing demand for startup companies to hire a chief financial officer earlier in their life cycle, experts say. In fact, from May 2020 to May 2021, the number of CFOs hired by startups with assets between $10 million to $100 million — a range typical of early or mid-stage companies — has increased by 95 percent, according to S&P Global Market Intelligence data.

Connecticut Innovations CEO Matt McCooe said he is encouraged by the CFO trends emerging among early-stage companies.

In the late 90s, he says, it was common for a startup’s founding team to include a CFO, but many companies over the past decade-and-a-half moved away from that approach to conserve investments and outsource functions like finance.

But as the amount of venture capital and investor expectations increase, and short- and long-term growth strategies develop, CFOs can play a critical role beyond simply balancing the books, he said.

Over the past three years, close to half (43 percent) of first-time CI-funded startups had a CFO in place, McCooe said.

“A [startup] CEO can’t do everything,” McCooe said. “A strong [CFO] can keep an eye on expenses, help craft a vision of the organization, drive product and help raise more capital.”

Shaping strategy

Hiring a CFO is a decision more early-stage startups are making. Last month, New Haven-based Cybrexa Therapeutics, an oncology-focused biotechnology company, founded in 2017 and spun out of Yale’s research-to-startup ecosystem, hired Stephen Basso as its new CFO as the company’s lead therapeutic heads toward its first round of clinical trials.

Per Hellsund, Cybrexa’s CEO, says the company has raised more than $47 million to date but as it gears up for an IPO in 2021 or 2022 — to attract investment for additional trials — hiring a CFO was necessary.

Basso, who previously served finance leadership roles at other pharmaceutical companies including Alexion and Pfizer, says the CFO role has evolved from shepherding the finances to being a strategic business partner.

“One of the things about joining Cybrexa is to partner not just on the finance side, but also helping to shape and frame the clinical strategy in terms of setting the path forward for the organization,” Basso said.

Having that type of business partner earlier in the company’s life cycle has become more important, says John Pacifico, the chief operating officer and CFO of the East Coast for Westport-based venture investor Canaan.

“There’s an appetite from larger strategic companies to get involved earlier in the development cycles and that has created an opportunity for startup companies — particularly in technology, to go public earlier in the life cycle than we would have seen 10 years ago,” Pacifico said.

He noted the re-emergence of special-purpose acquisition companies, or SPACs — which require fewer regulatory hurdles than traditional IPOs and can be a pathway to startups going public via acquisition by a larger company — has accelerated the types of people, including CFO-caliber talent, at the leadership helm for developing companies.

Another driver of the CFO trend, Pacifico says, is the volume of money being funneled into startups.

“[These companies] are raising more money faster than they ever have and there’s planning that needs to be done to really make that work,” he said. “Startups need to be identifying who might be interested in funding the next round of financing, [understanding] the criteria [investors] would require to be interested and working networks to build relationships with prospective investors.”

More money, more responsibility

Frank Milone, who runs the emerging companies and venture capital audit practice for Glastonbury-based accounting and consulting firm FML, says investors’ expectations about progress at certain funding rounds has also accelerated and driven the trends toward CFOs.

Because startups, he says, have more access to early-seed money and larger Series A investment, the expectation from some investors is that scaling the company may be possible in the first funding round.

Growth and scale can create several challenges that a CFO is best equipped to solve, he said.

“If an [early-stage] company needs to pivot to support accelerated growth or change because growth stalls, how do they reallocate funding or conserve cash flow to get further down the development path,” Milone said. “Investors want to know a company has the right individual to address those [situations].”