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Wu J, Liu D, Offin M, Lezcano C, Torrisi JM, Brownstein S, Hyman DM, Gounder MM, Abida W, Drilon A, Harding JJ, Sullivan RJ, Janku F, Welsch D, Varterasian M, Groover A, Li BT, Lacouture ME. Invest New Drugs. 2021 Jan 3. Online ahead of print.

Janku F, Zhang HH, Pezeshki AM, Goel S, Murthy R, Wang-Gillam A, Shepard DR, Helgason T, Masters T, Hong DS, Piha-Paul SA, Karp DD, Klang M, Huang SY, Sakamuri D, Raina A, Torrisi J, Solomon SB, Weissfeld A, Trevino E, DeCrescenzo GA, Collins A, Miller M, Salstrom JL, Korn R, Zhang L, Saha S, Leontovich AA, Tung D, Kreider B, Varterasian M, Khazaie K, Gounder MM. Clin Cancer Res. 2020 Oct 12. Online ahead of print.

Forbes NS, Coffin RS, Deng L, Evgin L, Fiering S, Giacalone M, Gravekamp C, Gulley JL, Gunn H, Hoffman RM, Kaur B, Liu K, Lyerly HK, Marciscano AE, Moradian E, Ruppel S, Saltzman DA, Tattersall PJ, Thorne S, Vile RG, Zhang HH, Zhou S, McFadden G. J Immunother Cancer. 2018;6:78.

Aguirre AJ, Nowak JA, Camarda ND, Moffitt RA, Ghazani AA, Hazar-Rethinam M, Raghavan S, Kim J, Brais LK, Ragon D, Welch MW, Reilly E, McCabe D, Marini L, Anderka K, Helvie K, Oliver N, Babic A, Da Silva A, Nadres B, Van Seventer EE, Shahzade HA, St Pierre JP, Burke KP, Clancy TE, Cleary JM, Doyle LA, Jajoo K, McCleary NJ, Meyerhardt JA, Murphy JE, Ng K, Patel AK, Perez K, Rosenthal MH, Rubinson DA, Ryou M, Shapiro GI, Sicinska E, Silverman SG, Nagy RJ, Lanman RB, Knoerzer D, Welsch DJ, Yurgelun MB, Fuchs CS, Garraway LA, Getz G, Hornick JL, Johnson BE, Kulke MH, Mayer RJ, Miller JW, Shyn PB, Tuveson DA, Wagle N, Yeh JJ, Hahn WC, Corcoran RB, Carter SL, Wolpin BM. Cancer Discov. 2018;8:1096-1111.

Szot C, Saha S, Zhang XM, Zhu Z, Hilton MB, Morris K, Seaman S, Dunleavey JM, Hsu KS, Yu GJ, Morris H, Swing DA, Haines DC, Wang Y, Hwang J, Feng Y, Welsch D, DeCrescenzo G, Chaudhary A, Zudaire E, Dimitrov DS, St Croix B. J Clin Invest. 2018;128:2927-2943

Szot C, Saha S, Zhang XM, Zhu Z, Hilton MB, Morris K, Seaman S, Dunleavey JM, Hsu KS, Yu GJ, Morris H, Swing DA, Haines DC, Wang Y, Hwang J, Feng Y, Welsch D, DeCrescenzo G, Chaudhary A, Zudaire E, Dimitrov DS, St Croix B. J Clin Invest. 2018;128:2927-2943

DeClue AE, Axiak-Bechtel SM, Zhang Y, Saha S, Zhang L, Tung DD, Bryan JN. BMC Vet Res. 2018;14:119.

Mendzelevski B, Ferber G, Janku F, Li BT, Sullivan RJ, Welsch D, Chi W, Jackson J, Weng O, Sager PT. Cancer Chemother Pharmacol. 2018;81:1129-1141.

Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW, Wang-Gillam A, Sznol M, Flaherty K, Buchbinder E, Carvajal RD, Varghese AM, Lacouture ME, Ribas A, Patel SP, DeCrescenzo GA, Emery CM, Groover AL, Saha S, Varterasian M, Welsch DJ, Hyman DM, Li BT.Cancer Discovery. Published online Dec 15, 2017, DOI: 10.1158/2159-8290.CD-17-1119.

Germann UA, Furey BF, Markland W, Hoover RR, Aronov AM, Roix JJ, Hale M, Boucher DM, Sorrell DA, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick MJ, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery CM, Saha S, Welsch DJ. Mol Cancer Ther. 2017;16:2351-2363.

Seaman S, Zhu Z, Saha S, Zhang XM, Yang MY, Hilton MB, Morris K, Szot C, Morris H, Swing DA, Tessarollo L, Smith SW, Degrado S, Borkin D, Jain N, Scheiermann J, Feng Y, Wang Y, Li J, Welsch D, DeCrescenzo G, Chaudhary A, Zudaire E, Klarmann KD, Keller JR, Dimitrov DS, St Croix B. Cancer Cell. 2017;31:501-515.e8.

Zhang XM, Zhang HH, McLeroth P, Berkowitz RD, Mont MA, Stabin MG, Siegel BA, Alavi A, Barnett TM, Gelb J, Petit C, Spaltro J, Cho SY, Pomper MG, Conklin JJ, Bettegowda C, Saha S. Nuclear Med Biol. 2016;43:273-279.

Zheng L, Zhang Z, Khazaie K, Saha S, Lewandowski RJ, Zhang G, Larson AC. PloS One. 2014;9:e116204.

Roberts NJ, Zhang L, Janku F, Collins A, Bai RY, Staedtke V, Rusk AW, Tung D, Miller M, Roix J, Khanna KV, Murthy R, Benjamin RS, Helgason T, Szvalb AD, Bird JE, Roy-Chowdhuri S, Zhang HH, Qiao Y, Karim B, McDaniel J, Elpiner A, Sahora A, Lachowicz J, Phillips B, Turner A, Klein MK, Post G, Diaz LA, Jr., Riggins GJ, Papadopoulos N, Kinzler KW, Vogelstein B, Bettegowda C, Huso DL, Varterasian M, Saha S, Zhou S. Sci Transl Med. 2014;6:249ra111.

Roix JJ, Harrison SD, Rainbolt EA, Meshaw KR, McMurry AS, Cheung P, Saha S. PloS One. 2014;9:e101708.

Tung D, DeCrescenzo G, Welsch D, Cheung PH, Bettegowda C, Saha S. World J Microbiol Biotechnol. 2014;30:3003-3010.

Roix J, Saha S. BMC Nephrol. 2013;14:233.

Tung D, Ciallella J, Hain H, Cheung PH, Saha S. Curr Ther Res Clin Exp. 2013;75:71-76.

Tung D, Ciallella J, Cheung PH, Saha S. Pharmacology. 2013;91:29-34.

Tung D, Cheung PH, Wilson J, Tudor G, Booth C, Saha S. Curr Ther Res Clin Exp. 2012;73:150-164.

Roix JJ, DeCrescenzo GA, Cheung PH, Ciallella JR, Sulpice T, Saha S, Halse R. Diabetes Obes Metab. 2012;14:329-334.

Tung D, Cheung PH, Ciallella J, Saha S. Pharmacology. 2011;88:295-301.

Tung D, Cheung PH, Tudor G, Booth C, Saha S. Curr Ther Res Clin Exp. 2011;72:262-272.

Tung D, Cheung PH, Kaur P, Foreman O, Kavirayani A, Hain HS, Saha S. Pharmacology. 2011;88:100-113.

Kansas City, MO. – BioMed Valley Discoveries (BVD), a clinical stage biotechnology company, announces the receipt of Fast Track designation from the US Food and Drug Administration (FDA) for investigation of the ERK inhibitor ulixertinib (BVD-523) as a treatment for patients with non-colorectal, solid tumors that harbor BRAF mutations G469A/V, L485W, or L597Q. BVD has launched a Phase II multi-center study of ulixertinib for patients with advanced malignancies harboring these atypical (non-V600) BRAF alterations or a MEK alteration.

The Phase II effort builds on a successful Phase Ib evaluating ulixertinib as a novel targeted cancer treatment in cohorts of patients with specific genetic alterations that result in aberrant MAPK pathway signaling. Results from Phase Ib showed that ulixertinib has an acceptable safety profile and early evidence of clinical activity against a wide range of tumor types exhibiting mutations in the MAPK pathway, including atypical alterations in BRAF. 

BVD is pleased to announce that Cmed, Inc., will serve as the contract research organization (CRO) for the Phase IIb study. BVD is also collaborating with Strata Oncology to identify and obtain study patients with Strata’s Precision Oncology Network. This network of trial-ready health systems features a database of matched trial candidates that will allow for rapid and efficient identification of potential patients.

David Chao, PhD, president and CEO of BVD, comments, “We are pleased with the receipt of Fast Track designation for ulixertinib and delighted to collaborate with Cmed and Strata to develop this promising first-in-class ERK inhibitor.”

This study (NCT04488003) is currently expected to begin enrollment in Q3 2020. 

About ulixertinib (BVD-523): Ulixertinib is a first-in class and best-in class small molecule inhibitor of extracellular signal-regulated kinase (ERK) family kinases (ERK1 and ERK2) that is being developed as a novel anti-cancer drug. ERK kinases are downstream components of the mitogen-activated protein kinase (MAPK) signaling cascade (RAS-RAF-MEK-ERK). Ulixertinib has demonstrated promising early efficacy for patients with tumors harboring alterations in the MAPK pathway, including atypical (non-V600) BRAF alterations, for which there are currently no approved targeted agents. 

About Fast Track status: Fast Track is a designation by the FDA of an investigational drug for expedited review to facilitate development of drugs which treat a serious or life-threatening condition and fill an unmet medical need. Fast Track status entails eligibility for Accelerated Approval and Priority Review if certain criteria are met as well as more frequent interactions with the FDA.

About the study: This Phase II study expands upon the ulixertinib Phase I signal to evaluate the utility of ulixertinib to treat patients with tumors harboring an atypical BRAF alteration. Furthermore, the potential to treat MEK1/2 mutant cancers will also be explored. This patient population is rare (<1% of cancers), however a strong scientific rationale exists to treat patients harboring putatively activating MEK1/2 alterations with ERK inhibition. Part A of the trial is tumor histology agnostic, with patients enrolled in one of six groups based on their tumor alteration. Part B of the trial is tumor histology specific, enrolling patients with one of up to three specified tumor histologies based on evolving part A data. 

About Cmed: Cmed, established for 20 years, is a global technology-led full-service CRO specializing in complex disease areas, particularly oncology, immuno-oncology, cell therapy, and other specialty therapeutics areas. Cmed has built a reputation for delivering these clinical trials with expertise, and a personalized, flexible approach, and a mission to contributing to the development of innovative medicines for the benefits of the patients. Cmed has a strong data management and statistics heritage. As well as being a Functional Service Provider of these services, via its Cmed Technology business (part of Cmed Group), Cmed has developed and uses an advanced, enterprise, cloud based clinical data system, encapsia®. encapsia delivers a complete solution to gather and manage multiple live clinical data sources and apply real-time data management, sophisticated visualizations, analytics, and AI. Client benefits include informed trial progress, deep insights into their data to support timely management decisions, and particularly relevant with the disruption caused by the COVID-19 pandemic, able to support remote, decentralized, and virtual trial conduct. For more information, visit www.cmedresearch.com and www.encapsia.com or contact Info@cmedgroup.com.

About Strata Oncology: Strata Oncology, Inc. is a precision medicine company dedicated to transforming cancer care by building a platform to systematize precision oncology across a network of health systems and pharma companies. Strata empowers health systems to deliver a cost-effective, system-wide, precision oncology program, one that integrates cutting-edge molecular profiling and precision therapy trials with routine care, so that all advanced cancer patients have the opportunity to benefit. This large network of trial-ready health systems provides a mechanism to rapidly and predictably enroll precision therapy trials. For more information, visit www.strataoncology.com.

About the Strata Precision Oncology Network: The Strata Precision Oncology Network (“Network”), led by Strata Oncology, is a collaborative network of leading health systems that believe in deploying a clinical-research driven model for precision medicine that enables continuous learning to drive research and clinical care. The Network consists of 25 leading health systems that have demonstrated a commitment to standardizing tumor molecular profiling and precision therapy trials, providing a platform to accelerate drug approvals and catalyze new clinical research opportunities. The Strata Trial serves as the foundation of this approach by providing a standardized genomic testing protocol to deliver precision oncology system-wide.

About BioMed Valley Discoveries (BVD): BioMed Valley Discoveries is a clinical stage biotechnology company focused on addressing unmet medical needs in a variety of therapeutic and diagnostic areas. In addition to the ERK inhibitor, BVD’s portfolio includes an oncolytic bacteria that has completed enrollment for a Phase I study, a selective phosphoinositide 3-kinase gamma inhibitor in late preclinical testing, and two early-stage antibodies targeting the tumor microenvironment.

Operating since 2007, BioMed Valley Discoveries was established by Jim Stowers Jr., founder of the asset management firm American Century Investments, and his wife Virginia, to advance new medical innovations to improve the lives of patients with difficult-to-treat diseases. BVD is owned by a supporting organization of the Stowers Institute for Medical Research, a non-profit, basic biomedical research organization. Since 2000, the endowment of the Stowers Institute has received over $1.5 billion in dividend payments from American Century. The Institute has invested a portion of its endowment in BVD, whose profits accrue to the benefit of the Institute. For more information, visit www.biomed-valley.com.

 

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A phase I clinical trial investigating the use of bacterial Clostridium novyi-NT spores as an injectable monotherapy had manageable toxicities and showed early clinical efficacy in patients with treatment-refractory solid tumor malignancies, according to data presented at the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival, held Sept. 30–Oct. 3.

“Even after a single injection of this bacterial therapy, we see biological and, in some patients, clinically meaningful activity,” said Filip Janku, MD, PhD, associate professor at the Department of Investigational Cancer Therapeutics (Phase I Clinical Trial Program), The University of Texas MD Anderson Cancer Center, Houston. “This strategy is feasible, has manageable adverse effects, and could be clinically meaningful in patients with few therapeutic options.”

While prior anticancer therapies have utilized bacteria, these treatments can cause infection and severe side effects, explained Janku. C. novyi-NT is an attenuated bacterium that requires a hypoxic environment, a feature of cancerous lesions, to survive and proliferate and therefore does not affect healthy cells, he noted. “By exploiting the inherent differences between healthy and cancerous tissue, C. novyi-NT represents a very precise anticancer therapeutic that can specifically attack a patient’s cancer,” Janku said.

Janku and colleagues evaluated the intratumoral injection of C. novyi-NT spores in an open-label, first-in-human study. Between November 2013 and April 2017, the researchers enrolled 24 patients with treatment-refractory solid tumors, with 15 patients having sarcoma, seven patients having diverse carcinoma, and two patients having melanoma. 

Tumors were injected with a single dose of C. novyi-NT ranging from 10,000 to 3 million spores. Two patients treated with 3 million spores displayed dose-limiting toxicities of grade 4 sepsis and/or grade 4 gas gangrene; the maximum tolerated dose was therefore determined to be 1 million spores.

Of the 22 evaluable patients, 21 had stable disease as measured by RECIST for the injected lesion, with tumor shrinkage of greater than 10 percent observed in 23 percent of patients. When both injected and uninjected lesions were included, the stable disease rate was 86 percent. 

Janku noted that RECIST criteria may not accurately capture the results of this trial. “When we inject the tumor, the cells within it die and become necrotic while the remaining tissue becomes inflamed, making the lesion larger in size than the original tumor. Because of this, evaluation via RECIST does not accurately reflect the reduction in tumor burden in these patients.”

Janku and colleagues also evaluated the germination of the bacterial spores through clinical and radiological methods. Of the 24 patients enrolled in the trial, tumors from 46 percent displayed spore germination and resultant tumor cell lysis.

“Despite the absence of clinical signs of germination in some patients, we saw improved tumor-specific immune responses through the increased secretion of T-cell cytokines and increased presence of tumor infiltrating lymphocytes in injected tumors,” noted Janku. “From these preliminary results, it appears that C. novyi-NT is able to activate the immune response besides causing tumor destruction.”

Because C. novyi-NT elicits an innate immune response, Janku believes that this therapy will be synergistic with checkpoint inhibition. The results from this study have led to the initiation of a phase I clinical trial investigating the combination of C. novyi-NT with pembrolizumab (Keytruda).

“We were extremely encouraged by the results of this trial, especially in patients with advanced sarcomas, where immunotherapy hasn’t proven very efficacious,” Janku said. “This bacteriolytic strategy has the potential to be clinically meaningful, especially in combination with checkpoint inhibitors, for patients with advanced solid tumors.” 

Limitations of this study include a short follow-up time for some patients, as many entered into other clinical trials if they became available.

This study was sponsored by BioMed Valley Discoveries Inc. Janku declares no additional conflict of interest.

Provided by American Association for Cancer Research

The novel ERK1/2 kinase inhibitor ulixertinib displayed an acceptable safety profile and had clinical activity in patients whose tumors had mutations in the MAPK cell-signaling pathway, according to data from a phase I clinical trial published in Cancer Discovery, a journal of the American Association for Cancer Research.

"A great number of cancers, including melanoma and lung cancers, have mutations in the MAPK/ERK pathway, and while current therapies target proteins in this cascade, many patients develop resistance to current drugs," said Ryan J. Sullivan, MD, assistant professor of hematology and oncology and member of the Termeer Center for Targeted Therapies at Massachusetts General Hospital. "The common denominator in these failed therapies is that the cancer has found a way to activate ERK. Therefore, the development of ERK inhibitors is a crucial next step to target this aberrant pathway."

The MAPK/ERK pathway is essential for key cellular processes, and mutations along this pathway may result in uncontrolled cellular growth, which can lead to cancer. The RAS gene, an upstream regulator within the MAPK/ERK cascade, is mutated in roughly 30 percent of human cancers. Mutations in BRAF, another gene in this pathway, often occur at codon V600 in malignant melanoma, where combined BRAF/MEK inhibition is the current standard of care. Atypical BRAF mutations (non-V600) are found in a variety of cancers. There is no targeted therapy for patients with atypical BRAF-mutant cancers, said Sullivan.

The ERK gene is the final regulator in the MAPK/ERK pathway, and when upstream inhibition of this protein cascade fails, ERK signaling is reactivated, resulting in renewed MAPK signaling, Sullivan explained. "Targeting ERK for inhibition may allow the opportunity to thwart resistance from upstream mechanisms," he noted. Preclinical studies had shown ERK inhibition to overcome resistance to BRAF and MEK inhibitors.

Sullivan and colleagues tested the ERK inhibitor ulixertinib in an open-label, first-in-human study. They enrolled 27 patients in the dose-escalation phase and 108 in the dose-expansion phase. All patients had advanced solid tumors, and more than 65 percent had BRAF-mutant cancers. Of the patients, 24 percent had received prior BRAF and/or MEK therapy and 51 percent had received prior immunotherapy.

In the dose-escalation phase, the recommended phase II dose (RP2D) of ulixertinib was determined to be 600mg twice daily. The dose-expansion portion of the trial tested the RP2D of ulixertinib in six groups of patients whose tumors had BRAF, NRAS, or MEK mutations, the majority of whom were not treated with prior MAPK-targeted therapy. Partial responses (PR) were seen in 12 percent and 14 percent of evaluable patients in the dose-escalation and dose-expansion cohorts, respectively. PR and/or disease stabilization was seen in all groups, including solid tumors with atypical BRAF mutations.

"It was exciting to see responses in some patients, especially those with non-V600 BRAF mutations," said Sullivan. "We also saw responses in some patients with BRAF V600 mutant melanoma who had progressed on prior BRAF/MEK inhibitor therapy. ERK inhibition may be a potential way forward for these populations."

Patients treated at the RP2D had near-complete inhibition of ERK as verified in blood samples. Side effects were comparable to other MAPK inhibitors, and the most common treatment-related adverse event (AE) was rash. No AEs above grade 3 were observed.

"This study shows that ulixertinib is tolerable and has activity in a subset of patients with mutations in the MAPK pathway," said Sullivan. "The results of this study can be built upon to develop better treatment regimens for these patients."

Sullivan anticipates that ERK inhibitors will likely be used in combinatorial therapies, and they may supplement pre-existing regimens, such as BRAF/MEK inhibition. "I think we'll see very complex combinations tailored to specific cancer subtypes, and ERK inhibitors deserve to be part of the repertoire," Sullivan said.

Based on data from this trial, ulixertinib has received the U.S. Food and Drug Administration's Fast Track designation.

Limitations of the study include a small pool of expansion cohorts, as is consistent with a phase I trial, and lack of tumor pharmacodynamic analysis.

Provided by American Association for Cancer Research

Kansas City, MO. — A preclinical study indicates that ulixertinib (BVD-523) holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting the MAPK pathway. A third of all human cancers are driven by mutations in this pathway.

The study, sponsored by BioMed Valley Discoveries, was published online in Molecular Cancer Therapeutics.Supported by these preclinical findings, clinical trials of ulixertinib were initiated. A Phase 1/2a clinical trial was recently completed and additional trials are currently underway.

“Our findings suggest that targeting ERK activity, the most downstream kinases of the MAPK signaling pathway, may be a rational cornerstone therapy for many tumors,” said Dean Welsch, Ph.D., Head of Pharmacology at BioMed Valley Discoveries and lead study author. “ERK inhibitors may have the potential to address issues of drug resistance that have plagued other targeted therapies.”

The mitogen-activated protein kinase (MAPK) signaling pathway is one of the most well studied pathways in human biology. This pathway behaves like an intracellular series of switches. A signal activates a cell receptor, which in turn activates RAS, which activates RAF, which activates MEK, which then activates ERK. Switched-on ERK activates numerous targets that enable a cell to grow, proliferate, and survive. In this way, ERK plays a key role in communicating extracellular signals that drive key cellular functions. In many types of cancer, this highly coordinated series of cascading events becomes dysregulated, often as a result of mutations. Dysregulation of the pathway causes cells to grow out of control. Because of its established importance in numerous cancers, this pathway has been the focus of drug discovery efforts for many years.

While no compounds have effectively targeted RAS, drugs designed to inhibit RAF or MEK have improved clinical outcomes for patients with metastatic melanoma and other tumor types. Unfortunately, the majority of patients given these targeted therapies eventually develop resistance to the drugs, and their disease progresses. Because ERK resides at the end of the MAPK signaling pathway, ERK inhibition may provide a unique opportunity to extend the duration of response seen with available treatments.

Results in this study characterizing ulixertinib included the demonstration of potential anti-tumor activity in preclinical in vitro assays as well as in vivo models, including studies designed to exemplify the potential for treating patients who had never received a pathway inhibitor and those that had acquired resistance. The authors showed that ulixertinib could arrest the growth of cancer cell lines in the laboratory. Furthermore, they demonstrated that the drug could inhibit the growth of tumors, and even cause them to regress in BRAFand RAS mutant xenograft models. Studies investigating ulixertinib in combination with BRAF inhibitors highlighted the potential for using this agent with existing therapies.

Importantly, cells engineered to be resistant to current therapies were found to retain their sensitivity to ulixertinib. This finding with single-agent ulixertinib was confirmed and extended using in vivo resistance models.

Finally, the researchers studied the emergence of resistance to ulixertinib. They found that single-agent treatment of cancer cells with ulixertinib was quite durable and that it was more challenging to develop resistance to ulixertinib than other agents targeting upstream components of the MAPK signaling pathway.

“Because the ERK inhibitor targets the last step in this pathway, we think ulixertinib has the potential to effectively address aberrant pathway signaling resultant from upstream dyregulation – including those as a consequence of mutations to RAS, RAF, MEK, or ERK,” said Welsch. “These encouraging preclinical studies suggest multiple opportunities for ulixertinib in various cancers. We look forward to the results from ongoing/planned clinical trials to help define how this agent might eventually help cancer patients”.

BioMed Valley Discoveries launched and successfully completed a multi-center clinical trial of the drug in patients with metastatic or advanced-stage cancer. The company also has several investigator-initiated trials planned or underway looking at other indications for ulixertinib, alone and in novel combination therapy regimens.

Ulixertinib received US Food and Drug Administration (FDA) Fast Track designation in September 2015, which allows for an expedited FDA review of drugs and therapies that treat a serious or life-threatening condition and fill an unmet medical need. Vertex Pharmaceuticals Inc discovered ulixertinib. BioMed Valley Discoveries licensed the compound at the clinical candidate stage and has advanced the compound from the late preclinical stage to the completion of Phase 1/2a.

Co-authors of the study include Ursula A. Germann, Brinley F. Furey, William Markland, Russell R. Hoover, Alex M. Aronov, Michael Hale, Diane M. Boucher, Gabriel Martinez-Botella, Matthew Fitzgibbon, and Mark Namchuk of Vertex Pharmaceuticals Inc; Jeffrey J. Roix, Anna Groover, Gary DeCrescenzo, Caroline M. Emery, and Saurabh Saha of BioMed Valley Discoveries; David A. Sorrell of Horizon Discovery Ltd; Paul Shapiro and Ramin Samadani of University of Maryland School of Pharmacy; Michael J. Wick of START; and Kathryn Meshaw of Charles River Discovery Services. The study was funded by BioMed Valley Discoveries.

About BioMed Valley Discoveries (BVD)

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Kansas City, MO. — Deep within most tumors lie areas that remain untouched by chemotherapy and radiation. These troublesome spots lack the blood and oxygen needed for traditional therapies to work, but provide the perfect target for a new cancer treatment using bacteria that thrive in oxygen-poor conditions. Now, researchers have shown that injections of a weakened version of one such anaerobic bacteria — the microbe C lostridium novyi — can shrink tumors in rats, pet dogs, and a human patient.

The findings from BioMed Valley Discoveries and a nationwide team of collaborators demonstrate that C. novyi-NT, a version without the ability to make certain toxins, can act as a new type of “biosurgery” to eat away tumors in hard to reach places. The bacteria excise tumor tissue in a precise, localized way that spares surrounding normal tissue. The study — which represents a new take on an approach first attempted a century ago — indicates that further testing of this agent in selected patients is warranted.

“We have encouraging signs that this bacteria could be used to treat certain inoperable tumors, and that could give hope to some patients who don’t have any other options,” said Saurabh Saha, M.D., Ph.D., a longtime cancer researcher at BioMed Valley Discoveries and senior author of the study. “But we are still in the early stages, and need to further assess the safety and efficacy of the treatment, as well as explore how well it works in combination with other cancer therapies.”

The study was published August 13, 2014, in Science Translational Medicine.

The idea of using bacteria to combat cancer dates back to the 1890’s, when cancer researcher William Coley noticed that some patients who developed postsurgical infections went into remission or were even cured of their disease. Despite the approach’s initial promise, progress was slow for the next century.

Over a decade ago Bert Vogelstein, M.D., a cancer researcher at the Johns Hopkins School of Medicine and one of the study co-authors, tested a number of microbes before identifying a particularly promising one called Clostridium novyi. Because C. novyi is exquisitely sensitive to oxygen, it would grow inside the oxygen-poor core of tumors but stop once it reached healthy tissue. In previous studies, Vogelstein and his colleagues tamed the bacteria further by removing its ability to make toxins and then injected it intravenously into laboratory animals. Though the bacterial treatment had dramatic effects in a third of the mice and rabbits, no complete responses were seen in dogs with naturally occurring cancers.

Dr. Saha and his colleagues at BioMed Valley Discoveries wondered if this failure was due more to the route of administration than to the therapy itself. One issue with intravenous delivery is the small proportion of spores that actually make it to the tumors. The researchers hypothesized that injecting the spores directly into tumors would not only overcome this problem, but might also trigger localized inflammatory and immune responses against tumor cells.

The researchers tested C. novyi-NT via directly injecting the bacteria into tumors in pet dogs with naturally occurring cancers and whose owners volunteered them for the trial. Each dog received between one and four cycles of the new treatment, consisting of a single injection of 100 million spores directly into the target tumor. Of sixteen dogs evaluated after treatment, three had significant shrinkage of their tumors and three had tumors that were completely destroyed.

The next step was to attempt the treatment in humans. The first patient to enroll in this Phase I investigational study was a 53-year old woman with retroperitoneal leiomyosarcoma whose disease, despite eight rounds of chemotherapy and radiation, had spread to her liver, lungs, abdomen, upper arm, and shoulder. The researchers injected 10,000 spores into the patient’s metastatic right shoulder tumor. Within days, CT scans and biopsies demonstrated that the bacteria had infiltrated the tumor and had begun destroying tumor cells. Weeks later, a follow-up MRI showed that a significant amount of tumor had been destroyed. As a result of treatment, the patient’s shoulder pain subsided and she was able to move her arm again.

Studies in other patients are currently underway at multiple sites to test the safety and efficacy of this new approach. Though these results are preliminary, the researchers believe that C. novyi-NT could potentially become part of a new arsenal of immunotherapies that prime a patient’s immune system to fight off cancer.

“Earlier pre-clinical studies showed that in the process of destroying cancer tissue, C. novyi-NT generates a potent innate immune response which also contributes to the localized tumor destruction,” said Dr. Saha. “The hope is that C. novyi-NT will be a useful adjuvant to the new immune checkpoint inhibitors that can block the ability of tumors to evade a host mediated immune response. It will be interesting to see if a combination of the two approaches could destroy tumors not just at the injection site, but also at any other sites where the cancer may have spread to throughout the body.”

Study co-authors from BioMed Valley Discoveries are: Linping Zhang, Amanda Collins, David Tung, Maria Miller, Jeffrey Roix, Halle H. Zhang, and Mary Varterasian. Other co-authors include Nicholas J. Roberts, Yuan Qiao, Luis A. Diaz Jr., Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Chetan Bettegowda, and Shibin Zhou of the Johns Hopkins Kimmel Cancer Center’s Ludwig Center; Filip Janku, Thorunn Helgason, Ravi Murthy, Robert S. Benjamin, Ariel D. Szvalb, Justin E. Bird, and Sinchita Roy-Chowdhuri of The University of Texas MD Anderson Cancer Center; Ren-Yuan Bai, Verena Staedtke, and Gregory J. Riggins of the Johns Hopkins Medical Institutes Department of Neurosurgery; Anthony W. Rusk and Kristen V. Khanna of Animal Clinical Investigation, LLC; Baktiar Karim and David L. Huso of the Johns Hopkins University Department of Molecular and Comparative Pathobiology; Jennifer McDaniel and Gerald Post of The Veterinary Cancer Center; Amanda Elpiner of VCA Great Lakes Veterinary Specialists; Alexandra Sahora of The Oncology Service, Friendship Hospital for Animals; Joshua Lachowicz of BluePearl Veterinary Partners; Brenda Phillips of Veterinary Specialty Hospital of San Diego; Avenelle Turner of Veterinary Cancer Group of Los Angeles at City of Angels Veterinary Specialty Center; and Mary K. Klein of Southern Arizona Veterinary Specialty and Emergency Center.

The study was funded by BioMed Valley Discoveries, Inc., the Virginia and D.K. Ludwig

Fund for Cancer Research, the Maryland Cigarette Restitution Fund, the Commonwealth Fund, Swim Across America, the Burroughs Wellcome Career Award for Medical Scientists, Voices Against Brain Cancer, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins Clinician Scientist Award, and National Institutes of Health (National Cancer Institute award numbers CA129825 and CA062924, and National Institute of Neurological Disorders and Stroke award number R25NS065729) funded the research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

About BioMed Valley Discoveries

BioMed Valley Discoveries, Inc. is a for-profit, disease-related research and development organization, whose mission is to address unmet medical needs in areas that are considered too early, too unconventional or too unprofitable for traditional biotech and pharmaceutical companies. Operating since 2007, BVD advances its mission with commercial capabilities and resources typically unavailable to academic institutions. As a member of the Stowers Group of Companies, BVD receives its funding principally from an endowment supporting the Stowers Institute for Medical Research, a non-profit 550-person basic biomedical research organization. One hundred percent of the profits from BVD will also accrue to the benefit of the Stowers Institute. James Stowers, Jr., founder of American Century Investments, and his wife Virginia established BioMed Valley Discoveries and the Stowers Institute for Medical Research. Together, Jim and Virginia Stowers have endowed the Institute with over $2 billion in donations, including a controlling interest in American Century Investments. Since it began operations in 2000, the Institute has received and spent over $1 billion in dividends from its ownership stake in American Century Investments.

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