On February 3, 2020 CytomX Therapeutics, Inc. (NASDAQ: CTMX), a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics based on its Probody therapeutic technology platform, reported the appointment of Alison L. Hannah, M.D., as senior vice president and chief medical officer (Press release, CytomX Therapeutics, FEB 3, 2020, View Source [SID1234553772]).

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"Alison brings to CytomX broad and deep experience in guiding clinical stage therapies to registration," said Amy Peterson, M.D., chief development officer of CytomX Therapeutics. "She will be a tremendous asset to our company given her extensive and successful track record in clinical drug development."

Dr. Hannah brings 30 years of experience in the development of investigational cancer therapies having most recently served as a consultant to nearly 30 pharmaceutical and biotechnology companies. In this capacity, Dr. Hannah has successfully filed over 40 regulatory applications for First-in-Human clinical testing and has played significant roles in the broad marketing approval of 8 therapeutics (talazoparib, enzalutamide, defibrotide, carfilzomib, sunitinib, toceranib, irinotecan and filgrastim) including extensive experience interacting with global health and regulatory authorities. Earlier in her career, Dr. Hannah held the role of Senior Medical Director at SUGEN, Inc. (acquired by Pharmacia & Upjohn, now Pfizer) where she had oversight of clinical development, clinical operations, and pharmacovigilance. At SUGEN, she specialized in the development of tyrosine kinase inhibitors, including sunitinib (SUTENT) for kidney cancer. Dr. Hannah began her career at Quintiles, a global contract research organization, where she specialized in overseeing early to registrational-stage oncology clinical trials. Dr. Hannah currently serves on the board of NeoGenomics, a publicly traded cancer diagnostic company. Dr. Hannah received her B.A in biochemistry and immunology from Harvard University and her M.D. from the University of Saint Andrews.

"CytomX’s Probody technology represents a truly innovative approach to cancer drug development," said Alison Hannah, M.D., chief medical officer of CytomX Therapeutics. "I am pleased to be joining at a time where the advancement to Phase 2 with both of our wholly owned assets, CX-072 and CX-2009, and continued progress within our partnered programs, marks our dedication to helping oncology patients with serious unmet needs."

On February 3, 2020 Applied BioMath (www.appliedbiomath.com), the industry-leader in applying systems pharmacology and mechanistic modeling, simulation, and analysis to de-risk drug research and development, reported a collaboration with Gritstone Oncology, Inc. for semi-mechanistic systems pharmacology modeling (Press release, Applied BioMath, FEB 3, 2020, View Source [SID1234553789]). Applied BioMath created a semi-mechanistic pharmacokinetic, receptor occupancy model for a Gritstone Oncology, Inc. bispecific antibody. Gritstone plans to leverage this model for clinical candidate selection for its work in treating solid tumors. "Our collaboration with Applied BioMath helped us explore the impact of various drug properties such as affinity and half life," said Jonah Rainey, Vice President of Antibody Therapeutics at Gritstone Oncology, Inc. "Their modeling efforts provided a framework for identifying optimal bispecific design for lead selection."

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Applied BioMath employs a rigorous fit-for-purpose model development process which aims to quantitatively integrate knowledge about therapeutics with an understanding of its mechanism of action in the context of human disease mechanisms. Their approach employs proprietary algorithms and software that were designed specifically for mechanistic PK/PD modeling. "When you are designing a bispecific therapeutic, or any complex therapeutic, it’s extremely difficult to assess ideal drug properties without the aid of modeling," said Dr. John Burke, PhD, Co-Founder, President, and CEO of Applied BioMath. "Specifically, it’s the mechanistic component of our systems pharmacology modeling that enables us to closely replicate therapeutic and disease biology which in turn helps our clients quickly answer critical questions about their project."

On February 3, 2020 Portola Pharmaceuticals, Inc. (Nasdaq: PTLA) reported the appointment of Rajiv Patni, M.D., as executive vice president and chief medical officer, effective immediately (Press release, Portola Pharmaceuticals, FEB 3, 2020, View Source [SID1234553790]). Dr. Patni brings to his new role two decades of clinical development and approval experience as a biopharmaceutical industry leader. As a member of the Executive Committee, Mr. Patni will report to Scott Garland, president and chief executive officer, and will be responsible for leading Clinical Development, Clinical Operations, Medical Affairs, Regulatory Affairs, Biometrics, Pharmacovigilance, and Data Management.

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"Rajiv brings deep clinical development experience to Portola that will be invaluable as we work to establish Andexxa as the standard of care for Factor Xa patients with life-threatening or uncontrolled bleeding," said Scott Garland, Portola’s president and chief executive officer. "He will focus on leading our post-market clinical studies, including label expansion, along with driving our European regulatory activities. These are key elements of our long-term growth strategy, and we look forward to his leadership in strengthening our healthcare community engagement in the U.S. and Europe further establishing the clinical and economic differentiation of Andexxa."

During his career, Dr. Patni has contributed to 8 approvals, across multiple therapeutic areas, including cardiology and neurology, in both established and growing companies. Before joining Portola, Dr. Patni was chief medical officer at Adamas Pharmaceuticals, Inc., a fully-integrated, development and commercial company focused on neurological diseases. In this role, he built out the R&D and medical affairs departments. These efforts resulted in the FDA approval of GOCOVRI. Prior to Adamas, Dr. Patni was Chief Development Officer at Ocera Therapeutics. Earlier in his career, he held senior roles in clinical development and medical affairs in Actelion Pharmaceuticals (US affiliate), Roche and Pfizer.

"I am excited to join Portola at this pivotal time of growth," said Dr. Patni. "The Company is uniquely positioned with the first and only reversal agent for Factor Xa inhibitors, a large and rapidly growing class of medications. I am eager to contribute to Portola’s mission and further enhance awareness of the potential life-saving benefits and value of Andexxa."

Dr. Patni received his M.D. from the Mount Sinai School of Medicine, and completed his training in internal medicine and cardiology at the Albert Einstein College of Medicine, where he remained as an attending physician before joining industry.

Jeff Myers, M.D., Ph.D., who has served as Portola’s interim chief medical officer since May 2019, will continue in his role as the Company’s senior vice president of medical affairs.

On February 3, 2020 The University of Texas MD Anderson Cancer Center reported that circulating tumor cells (CTCs), a form of liquid biopsy, was independently associated with melanoma relapse, suggesting CTC assessment may be useful in identifying patients at risk for relapse who could benefit from more aggressive therapy following primary treatment (Press release, MD Anderson, FEB 3, 2020, View Source [SID1234553774]).

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Results from the study were published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). Although CTCs can be detected in melanoma patients, there is limited data regarding their significance in stage III (node-positive) disease. This prospective study was based on earlier research that found CTCs in a significant number of breast cancer patients, which was associated with relapse, independent of other existing methods for determining prognosis.

"Our findings are significant, given that there is a need for blood-based biomarkers to guide clinical decision making for stage III melanoma patients," said Anthony Lucci, M.D., professor of Breast Surgical Oncology and Surgical Oncology, and study lead. "There currently are no blood tests available to help doctors accurately tell which patients are likely to relapse, and should be given therapy, and which are low risk, and could be observed."

The researchers assessed CTCs during the patient’s first clinic visit, and relapse-free survival was compared between patients with one or more CTCs, versus those with no CTCs. CTCs were observed in 90 out of 243 patients enrolled in the study.

"Our analysis demonstrated that CTC detection was significantly associated with a decrease in relapse-free survival at six months, and persisted at a 54-month longer-term follow-up," said Lucci. "The data from this study provides support for the future pursuit of liquid biopsy techniques to help identify patients most likely to benefit from adjuvant systemic therapy."

Lucci added that this is vital given that there currently is no clear consensus on when to recommend immunotherapy for node-positive melanoma patients. Despite the development of new targeted and immune therapies to treat melanoma, many patients either do not respond to these therapies or develop resistance to therapy within six to eight months. Because such therapies also can have side effects, avoiding treatment in patients at low risk for relapse may prevent overtreatment.

The study was funded by Sheila Prenowitz, Debbie and Craig Kiefer, the Simon and Linda Eyles Foundation, the Sam and Janna Moore family, and the Wintermann Foundation. Lucci reported no disclosures.

On February 3, 2020 Nektar Therapeutics (NASDAQ: NKTR) reported the publication of preclinical data on its lead immuno-oncology candidate, NKTR-214, bempegaldesleukin (bempeg) in two manuscripts in Nature Communications (Press release, Nektar Therapeutics, FEB 3, 2020, View Source [SID1234553791]). Bempeg is an investigational CD122-preferential interleukin-2 (IL-2) pathway agonist designed to provide activation and proliferation of cancer-killing immune cells, known as CD8+ effector T cells and natural killer (NK) cells. The published data demonstrate that bempeg, in combination with immune-based therapies including checkpoint inhibition (CPI), antigen-specific vaccination and adoptive cell transfer (ACT) therapy, enhanced T-cell mediated tumor control by selectively expanding effector T cells (Teffs) over T regulatory cells (Tregs) in the tumor microenvironment.

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The first manuscript, titled "Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy," was published online and can be accessed here. The research was conducted by a team at MD Anderson Cancer Center, led by former tenured professor, Willem W. Overwijk, Ph.D., who currently serves as Vice President, Oncology Research at Nektar Therapeutics.

"Using preclinical models, we were able to demonstrate how bempeg potentiates both CPI and vaccination strategies by expanding and maintaining tumor infiltrating T cells and depleting intratumoral Tregs by a novel mechanism of cytokine release to drive efficient intratumoral Treg depletion," said Dr. Overwijk. "Our findings further define the mechanism of action of bempeg and highlight the rationale for its clinical application in combination with immune-based therapies for patients with cancer."

In the study, the activity and mechanism of action of bempeg was evaluated in combination with PD-1 and CTLA-4 CPI therapy and also with antigen-specific vaccination in preclinical animal models. The researchers concluded that bempeg in combination with PD-1 CPI therapy resulted in a higher response rate, prolonged disease control and yielded more complete responses in a variety of preclinical tumor types including colon cancer, melanoma, bladder cancer, lung cancer and breast cancer. In addition, bempeg supported the expansion and long-term maintenance of vaccination-induced anti-tumor Teffs; and bempeg treatment mediated selective depletion of intratumoral but not of peripheral Tregs, suggesting that in patients with cancer, bempeg-containing regimens could increase tumor control without exacerbating systemic inflammation. This preferential depletion of intratumoral Tregs was also observed in a small cohort of patients with renal cell cancer and melanoma receiving bempeg monotherapy, suggesting the results in mice may extend to patients receiving bempeg-based therapies.

Key findings are summarized below:

Bempeg with anti-PD-1 CPI as combination therapy demonstrated superior efficacy over anti-PD-1 monotherapy in 8 different mouse tumor models.
Anti-PD-1 monotherapy did not change TIL frequency or clonality, while addition of bempeg increased both TIL frequency and clonality.
To delve deeper into the immune-mediated mechanism, the B16 melanoma model was used with gp100 antigen-specific CD8+ (pmel-1) T cells to track T cell numbers and persistence.
Combination of gp100 vaccination and bempeg markedly suppressed tumor growth and prolonged mouse survival.
Long-term tumor control directly correlated with the magnitude and persistence of vaccination-induced, gp100-specific CD8+ Teff in the circulation. Aldesleukin (IL-2) also synergized with vaccination but did not achieve similar potency of bempeg as measured by tumor control or T cell responses.
While bempeg increased systemic and intratumoral levels of melanoma-specific CD8+ T cells, intratumoral numbers of Tregs plummeted.
Similar depletion of intratumoral but not systemic Tregs was also observed in patients with renal cell cancer and melanoma treated with bempeg (NCT02869295).
The authors present data that CD8+ Teff-derived IFN-ɣ and TNF-α synergize to deplete intratumoral Tregs by directly inhibiting local Treg proliferation.
In the second manuscript, published this week in Nature Communications, a research team led by Antoni Ribas, Ph.D. at the UCLA Jonsson Comprehensive Cancer Center evaluated bempeg in combination with adoptively transferred T cell therapy (ACT) in melanoma models. The studies found ACT therapy supported by bempeg increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in the B16 melanoma model.

Bempeg + ACT showed preferential activation of tumor-specific CD8 T cells over Tregs in spleen and tumors of mice, increased immune-related gene expression in the tumor microenvironment, and greatly increased animal survival compared to IL-2 + ACT.
Bempeg + ACT increased tumor-specific T cell polyfunctionality (secreting multiple (>2) cytokines per cell) both intratumorally and peripherally compared to IL-2 +ACT in mice.
Analysis of peripheral blood samples from patients treated with bempeg monotherapy in a Phase 1 trial (NCT02869295) also showed enhanced polyfunctionality of T cells and NK cells.
The authors conclude that bempeg may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion, tumor infiltration and polyfunctionality of the adoptively transferred T cells.
The second manuscript titled "Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist," was published online and can be accessed here. The UCLA announcement of the publication can be accessed here.

Bempeg in combination with checkpoint inhibitors and other immune-mediating agents is being evaluated in clinical trials. For more information, visit the Pipeline page on nektar.com.