[Edaily Reporter YU JIN-HEE ] As #PenetriumBio, an innovative new drug development company, unveils its strategy to proceed directly to a U.S. Phase 2 clinical trial for “Penetrium”—its core pipeline candidate for treating intractable solid tumors—similar global success stories are being revisited. Observers are characterizing this as a sophisticated “three-pronged” business strategy that goes beyond the mere time savings of shortening clinical trial phases. By leveraging existing cumulative human safety data, the company aims to increase its chances of approval by the U.S. Food and Drug Administration (FDA) and, furthermore, maximize the drug’s value amid the major shift toward combination immunotherapy expected in 2028.

"Moving Directly to Phase 2 Clinical Trials: A Standard Path Guaranteed by FDA Regulations, Not an Irregularity"

In a shareholder notice on the 15th, PenetriumBio clarified that its plan to enter U.S. Phase 2 clinical trials is not a bypass or omission of the new drug development process, but rather an entirely normal and reasonable path based on scientific evidence.

Generally, in new drug development, Phase 1 clinical trials involve the initial administration of a drug to healthy individuals or a small number of patients to verify safety and pharmacokinetics (PK). However, Penitrium’s active ingredient and the same formulation have already undergone clinical trials during the COVID-19 pandemic, securing real-world human administration data from more than 300 subjects in South Korea alone. Currently, Phase 2 and 3 clinical trials for a dengue fever treatment are also proceeding smoothly in Vietnam. This means that safety and tolerability in humans, as well as pharmacokinetic (PK) indicators such as absorption, distribution, metabolism, and excretion, have already been thoroughly verified.

According to U.S. Food and Drug Administration (FDA) guidelines, it is institutionally permitted to proceed directly to Phase 2 clinical trials—which directly evaluate efficacy—without repeating unnecessary Phase 1 human trials. This applies in cases like Penitrium’s, where sufficient human safety and toxicity data, as well as highly reliable preclinical efficacy data, have already been secured for other indications. This is why a local clinical team led by Kim Taek-sung, President of PenetriumBio’s U.S. Operations, in collaboration with a U.S.-based contract research organization (CRO) specializing in regulatory affairs, conducted an in-depth review of the trial design and concluded that proceeding directly to Phase 2 was justified.

In fact, there are numerous cases where drugs have achieved innovative results by proceeding directly to Phase 2 trials—without conducting separate Phase 1 anticancer trials—based on existing human safety data. According to this publication’s investigation, these drugs have either already been commercialized by global pharmaceutical companies or are currently in global clinical development.

The most representative examples are the combination trials of “Losartan” (originally developed by Organon; commercialization complete), widely used as a hypertension treatment, and “Folfirinox” (Sanofi, etc.; commercialization complete), an anticancer regimen for pancreatic cancer. Focusing on losartan’s mechanisms for regulating the tumor microenvironment and tumor stroma, the research team proceeded directly to a Phase 2 clinical trial in patients with locally advanced pancreatic cancer without conducting a separate, independent Phase 1 trial. This was made possible by the full recognition of human safety data accumulated over decades from patients with hypertension. In that clinical trial, approval was obtained by applying a rational protocol that began administering losartan at a safe, low dose and gradually increased the dosage based on patient tolerance.

“Metformin” (BMS, already on the market)—the gold standard for diabetes treatment—is another textbook example of a drug that advanced directly to a Phase 2 oncology clinical trial through drug repurposing. Based on metformin’s extensive human safety profile, it proceeded directly to a randomized Phase 2 clinical trial—without a separate Phase 1 phase—to evaluate its efficacy in combination with “gemcitabine” (Eli Lilly, commercially available) and “erlotinib” (Genentech/Roche, commercially available) in patients with pancreatic cancer.

In the field of anticancer drugs, there are precedents where pre-commercial candidate compounds have accelerated their development by incorporating safety measures into their Phase 2 clinical trial protocols. One such example is the combination trial of “citravatinib” (Mirati Therapeutics, in clinical development), a targeted anticancer drug candidate in the multi-receptor tyrosine kinase (RTK) inhibitor class, and the immunotherapy “nivolumab” (BMS, commercially available). This clinical trial was also designed as a Phase 2 study but incorporated a “Safety Lead-in” phase, in which the safety and dose-limiting toxicity (DLT) of the combination therapy were first evaluated in an initial cohort of six patients. This is not a case of disregarding early safety; rather, it serves as a precedent demonstrating that a clinical trial design is possible in which safety is thoroughly verified within the Phase 2 framework before rapidly expanding the efficacy evaluation cohort.

The “DART Basket Trial” (NCT02834013), led by Professor Sandip Patel at the Moores Cancer Center at the University of California, San Diego (UCSD), also serves as a solid academic foundation for Penitrium’s multi-cancer basket Phase 2 strategy. The DART trial applied the combination therapy of nivolumab—which already had a well-established safety profile—and “ipilimumab” (BMS, already on the market) to various rare solid tumors. By doing so, it eliminated the inefficiency of conducting separate Phase 1 trials for each rare cancer and instead demonstrated safety and efficacy across multiple cancer types simultaneously in a single Phase 2 trial.

Interpreted as a strategic move to increase clinical success rates and boost market value

PenetriumBio’s current U.S. Phase 2 clinical trial strategy is not aimed solely at “rapid development.” It is underpinned by a multidimensional strategy designed to increase the clinical success rate of new drugs and boost market value amid future shifts in industry trends.

First is speed. By skipping a separate Phase 1 clinical trial, the company can shorten the development period by at least one to two years. While the final optimal dosage for oncology indications will be scientifically determined through the Phase 1 trial currently underway in South Korea, the company is implementing a “Korea-U.S. parallel track” that allows it to proceed directly to Phase 2 efficacy evaluation in the U.S. The dosage to be used in the U.S. Phase 2 trial is designed to be significantly lower than the maximum dose previously proven safe in humans during past COVID-19 and dengue fever clinical trials, which is expected to further accelerate the clinical trial process. Since exceptional anticancer effects were confirmed even at very low doses during animal testing, concerns regarding efficacy are minimal.

Second is maximizing the probability of approval. The leading cause of failure in new drug development is unexpected toxicity during early-stage clinical trials. However, Penitrium has already established a robust human safety profile and pharmacokinetic (PK) data through large-scale cohorts of patients with infectious diseases. Furthermore, the company has added an additional layer of safety through collaboration with world-renowned scholars. Professor Gary S. Firestein, a Distinguished Professor at the University of California, San Diego (UCSD) School of Medicine and a leading global authority in the field of rheumatology and the tissue microenvironment, joined the project after reviewing the preclinical data. Under the leadership of Professor Sandip Patel, the Principal Investigator (PI), and the “Tumor and Autoimmune Microenvironment Advisory Committee”—to be formed with Professor Firestein’s participation—the company plans to introduce the “safety lead-in” approach in the early stages of the Phase 2 clinical trial to maximize the clinical approval rate, which the FDA considers of utmost importance.

Third is a major shift in market value. Based on the “Seed & Soil” hypothesis proposed in 1889 by British surgeon Stephen Paget, Penitrium—unlike existing anticancer drugs that attack cancer cells (the “CIAAT”) directly—employs generative AI to fundamentally normalize the diseased tumor microenvironment (the “soil”). This mechanism has the potential to generate explosive synergies not only as a monotherapy but also when administered in combination with global immuno-oncology drugs.

In particular, the industry anticipates that the expiration of the U.S. substance patent for Merck’s “Keytruda”—the world’s top-selling immuno-oncology drug—in 2028 will mark the beginning of a major shift toward large-scale combination immuno-oncology clinical trials among global pharmaceutical companies. PenetriumBio plans to secure Phase 2 efficacy data as quickly as possible to capitalize on this transition. If this high-speed strategy—skipping Phase 1 and proceeding directly to Phase 2—proves successful, the value of a technology license-out (L/O) to global Big Pharma is expected to rise in tandem with the patent expiration.

Cho Won-dong, Chairman of PenetriumBio, emphasized, “Moving directly to Phase 2 clinical trials in the U.S. is not merely a tactic to save time, but a sophisticated and proven scientific development strategy that maximizes the likelihood of success by leveraging existing, highly reliable data.” He added, “Based on validation by world-renowned scholars and our unique generative AI-based mechanism of action, we will lead the combination therapy paradigm in the global cancer treatment market.”