Hitting triple-negative breast cancer where it hurts
The genesis of a novel inhibitor for breast cancer
By Michael Seringer
Ratna Vadlamudi had a long collaboration with other University of Texas System schools to discover novel drugs to treat breast cancer. During the lead optimization process of designing a drug candidate, Vadlamudi and his team discovered a small molecule that was highly active against solid cancers — ERX-41.
“We made the serendipitous discovery that this small molecule had robust activity against multiple triple-negative breast cancer molecular subtypes,” Vadlamudi said.
The discovery identified a novel therapeutic vulnerability and targeting agent that kills a range of hard-to-treat cancer types in petri dishes and animal models.
Ratna K. Vadlamudi, PhD
Professor and Vice Chair for Research, Department of Obstetrics and Gynecology
Compound: Novel, small molecule — ERX-41
Indication: Breast cancer subtypes
Stage: Completing FDA investigational new drug application studies
Funding: $5.2 million — NIH, SBIR and CPRIT grants
“If you do not know the FDA regulatory process, and most academicians do not, hire an expert.”
“Our studies showed that a new agent, ERX-41, interacts with its molecular target [the protein encoded by the LIPA gene] to induce endoplasmic reticulum stress in cancer cells, leading to cell death. We show targeting LIPA and causing ER stress in cancer cells may be an effective therapeutic strategy,” Vadlamudi explained.
Challenges in formulation and purification
Vadlamudi and his team had a greater challenge in the good manufacturing practice formulation and synthesis of pure ERX-41 than most biotech companies because their initial grant awarded by the Cancer Prevention and Research Institute of Texas required that all the money be spent in Texas. Eventually, Vadlamudi’s team convinced CPRIT to allow the grant to be spent with a lab in Boston. Texas simply lacked an available specialized lab required to formulate and synthesize their compound into pill form, which can be delivered more easily to patients.
“We have very few companies in Texas that have the capability for GMP manufacturing of small molecule inhibitors,” Vadlamudi said. “We sought help from our consultants and they identified a few companies outside of Texas and received quotes. We have chosen a firm that is approved by the [Food and Drug Administration] as a GMP facility and initiated synthesis.”
Formulating the compound is one of the most challenging tasks the company faced, and they are still working on it, Vadlamudi said.
“Our company recruited several consultants, and they are guiding our efforts,” he said. “To save time, we are trying multiple formulations using several different proprietary technologies available with commercial research organizations. This is a very time-consuming and cost-draining process; however, it is an essential step to move forward with clinical translation.”
Vadlamudi said his team underestimated how challenging good manufacturing process formulation and purification would be.
“We are on calls with our chemists every week, working on getting the compound to its purest form,” he said. Not falling victim to the investigational new drug “valley of death” requires extensive planning informed by a complete understanding of the FDA regulatory process. “If you do not know the FDA regulatory process, and most academicians do not, hire an expert.”
Vadlamudi highly recommends young investigators with drug development projects take advantage of the Texas Medical Center’s TMCi Accelerator for Cancer Therapeutics program, which is designed to support scientific founders with the knowledge, resources and connections necessary to successfully advance projects. Hiring knowledgeable consultants has also been essential.
“There is a lot of challenging regulatory work just to get an IND from the FDA,” Vadlamudi said. “We are working with consultants experienced in the IND process, and that has really helped us.”
Not falling victim to the investigational new drug “valley of death” requires extensive planning informed by a complete understanding of the FDA regulatory process.
Vadlamudi’s team was able to source the right good manufacturing process lab in Boston to synthesize the compound in pure form and formulate it into a pill. The lab partner was helpful given its experience in compound development using good manufacturing process standards, which the FDA requires.
Funding and business strategy
Vadlamudi bristles at the cost of getting a novel compound through the FDA investigational new drug process. The founding of EtiraRx and funding of ERX-41’s investigational new drug process earned Vadlamudi a real-world business degree during the development of his novel cancer therapy.
The initial $1.2 million grant provided by CPRIT paid for the screening of the compound among cancers and the successful patent for the novel ERX-41. EtiraRx received $3 million from the National Institutes of Health to fund mechanistic studies, compounding, synthesis, manufacturing in bulk and animal trials. An additional $1 million has been provided by the NIH Small Business Innovation Research grant for the formulation and anticipated transition into human trials.
Vadlamudi and the other founding researchers developed their business plan for EtiraRx with help from their consultants and CPRIT.
“My clinician scientist partner had experience in the business part of the process,” Vadlamudi said. “We relied on that experience a lot.”
EtiraRx is planning to raise a seed investment round once human trials of ERX-41 begin. Control of the company and its development of the molecule are important to the founding team. EtiraRx will focus this new seed investment round on high-net-worth individuals and smaller private equity firms that generally have a longer-term vision for the company and its therapy. By retaining control, EtiraRx can assure the best interests of patients outweigh an exit strategy preferred by larger institutional venture capitalists. By forming a company and licensing the technology from the UT System, EtiraRx not only maintained control over its compound and business plan, but also helped protect its intellectual property while protecting the founders from personal liability.
Lessons learned along the way
Vadlamudi recommends researchers start a company soon after they discover a compound with therapeutic qualities. Once the company is formed, researchers can start raising money through grants, friends and family and small investors. Selling an idea to investors takes a long time, and bootstrapping the business is hard work. Patience pays off — getting across the valley of death to human Phase 1 trials significantly increases the valuation of a company, Vadlamudi said.
To gain insight into both the regulatory and business processes, Vadlamudi suggests taking advantage of resources designed to assist such translational researchers. The NIH, local business incubators, state agencies and nonprofit foundations have numerous, no-cost resources available to biotech entrepreneurs.
“I wish I would have known about all the resources available for free at the NIH earlier in our development of ERX-41,” Vadlamudi said. “It would have helped speed things up in the beginning.”