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.

On February 3, 2020 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that Rubraca (rucaparib) is now available and reimbursed in France (Press release, Clovis Oncology, FEB 3, 2020, View Source [SID1234553756]). Rubraca (rucaparib) is an option for monotherapy maintenance treatment for adults with relapsed, platinum-sensitive high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy.2 Rucaparib is indicated for eligible patients regardless of BRCA status, which means it can be prescribed for women who harbor a BRCA mutation or who are BRCA wild-type.2

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"This is excellent news as this represents an important new option for patients with relapsed ovarian cancer who have responded to platinum-based chemotherapy," said a spokesperson for IMAGYN, the only French network of patient associations involved in the fight against ovarian cancer and gynecological tumors. "For too long, ovarian cancer treatment options beyond chemotherapy, surgery and anti-angiogenic therapy have been limited, and today’s announcement means that eligible women with ovarian cancer have more choice in their treatment than ever before."

Approximately 5,000 women are diagnosed with ovarian cancer in France every year, which equates to roughly 14 every day.3 Ovarian cancer is the eighth most common cancer in women and the fourth most fatal cancer in France.4 In addition, approximately 25 percent of ovarian cancer patients harbor a BRCA1/2 mutation in the tumor, correlating to improved outcomes to platinum and PARP inhibitors therapy.5,6 The majority of women diagnosed with ovarian cancer are BRCA wild-type; these patients typically have a worse prognosis.5,6 Of those treated with surgery and first line chemotherapy, approximately 70 percent of patients will relapse within the first three years.7

"The availability of rucaparib is good news, as ovarian cancer is a disease often diagnosed at an advanced stage and many women may have a poor prognosis," said Professor Isabelle Ray-Coquard, President of the GINECO Group, which specializes in clinical and translational research in the field of women’s cancers, and sets up and coordinates clinical trials in France and abroad. "Patients with relapsed ovarian cancer may have many debilitating symptoms, and it is important that new treatments such as rucaparib are made available to the eligible patients that may benefit from them."

The European Union (EU) authorization is based on data from the pivotal phase 3 ARIEL3 clinical trial, which found that rucaparib significantly improved PFS in all ovarian cancer patient populations studied.1 ARIEL3 successfully achieved its primary endpoint of extending investigator-assessed PFS versus placebo in all patients treated (intention-to-treat, or ITT), population, regardless of BRCA status (median 10.8 months vs 5.4 months).1,2 In this population, the risk of progression or death has been decreased by 64%.1 In addition, it successfully achieved the key secondary endpoint of extending PFS by independent radiological review versus placebo in all patients treated (ITT), regardless of BRCA status (median 13.7 months vs 5.4 months).2 The overall safety profile of rucaparib is based on data from 937 patients with ovarian cancer treated with rucaparib monotherapy in clinical trials.2

"The fact that rucaparib is now reimbursed and available in France means there is a new treatment for patients with platinum-sensitive relapsed ovarian cancer," said Dr. Anne Floquet, President of the SFOG, the French Society for Gyneco-Oncology. "I am very proud to have been able to participate in the ARIEL3 study, which demonstrates the effectiveness of rucaparib in improving patients’ progression-free survival. I am also delighted to be able to prescribe this treatment as it may offer benefits for eligible patients."

"We are working to make Rubraca available in multiple countries across Europe, and with the reimbursement and availability of Rubraca in France, it is now a treatment option for eligible patients in Germany, England, Italy, and in France," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "Rubraca is effective across a broad population of women with relapsed ovarian cancer and is an important step in the ovarian cancer treatment pathway for eligible patients."

About Rubraca (rucaparib)

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 that is being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancer (mCRPC), as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca (rucaparib) European Union (EU) authorized use and Important Safety Information

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Rubraca is indicated as monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with ≥2 prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.

Efficacy of Rubraca as treatment for relapsed or progressive EOC, FTC, or PPC has not been investigated in patients who have received prior treatment with a PARP inhibitor. Therefore, use in this patient population is not recommended.

Summary warnings and precautions:

Hematological toxicity

During treatment with Rubraca, events of myelosuppression (anemia, neutropenia, thrombocytopenia) may be observed and are typically first observed after 8–10 weeks of treatment with Rubraca. These reactions are manageable with routine medical treatment and/or dose adjustment for more severe cases. Complete blood count testing prior to starting treatment with Rubraca, and monthly thereafter, is advised. Patients should not start Rubraca treatment until they have recovered from hematological toxicities caused by previous chemotherapy (CTCAE grade ≥1).

Supportive care and institutional guidelines should be implemented for the management of low blood counts for the treatment of anemia and neutropenia. Rubraca should be interrupted or dose reduced according to Table 1 (see Posology and Method of Administration [4.2] of the Summary of Product Characteristics [SPC]) and blood counts monitored weekly until recovery. If the levels have not recovered to CTCAE grade 1 or better after 4 weeks, the patient should be referred to a hematologist for further investigations.

MDS/AML

MDS/AML, including cases with fatal outcome, have been reported in patients who received Rubraca. The duration of therapy with Rubraca in patients who developed MDS/AML varied from less than 1 month to approximately 28 months.

If MDS/AML is suspected, the patient should be referred to a hematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged hematological toxicity, MDS/AML is confirmed, Rubraca should be discontinued.

Photosensitivity

Photosensitivity has been observed in patients treated with Rubraca. Patients should avoid spending time in direct sunlight because they may burn more easily during Rubraca treatment; when outdoors, patients should wear a hat and protective clothing, and use sunscreen and lip balm with sun protection factor of 50 or greater.

Gastrointestinal toxicities

Gastrointestinal toxicities (nausea and vomiting) are frequently reported with Rubraca, and are generally low grade (CTCAE grade 1 or 2), and may be managed with dose reduction (refer to Posology and Method of Administration [4.2], Table 1 of the SPC) or interruption. Antiemetics, such as 5-HT3 antagonists, dexamethasone, aprepitant and fosaprepitant, can be used as treatment for nausea/vomiting and may also be considered for prophylactic (i.e. preventative) use prior to starting Rubraca. It is important to proactively manage these events to avoid prolonged or more severe events of nausea/vomiting which have the potential to lead to complications such as dehydration or hospitalization.

Embryofetal toxicity

Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of Rubraca to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 600 mg twice daily (see Preclinical Safety Data [5.3] of the SPC).

Pregnancy/contraception

Pregnant women should be informed of the potential risk to a fetus. Women of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of Rubraca (see section 4.6 of the SPC). A pregnancy test before initiating treatment is recommended in women of reproductive potential.

On February 3, 2020 Calibr, the drug discovery and development division of Scripps Research, reported that the U.S. Food and Drug Administration has given clearance to the Investigational New Drug (IND) application for Calibr’s "switchable" CAR-T cell therapy, which is being evaluated for the treatment of certain cancers, including relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma and chronic lymphocytic leukemia (Press release, The Scripps Research Institute, FEB 3, 2020, View Source [SID1234553776]).

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Having achieved this regulatory milestone, Calibr can begin clinical trials for its novel cell therapy candidate, CLBR001 + SWI019. The therapy leverages a patient’s own immune cells to treat cancer, putting them under the control of a novel molecular "switch" that seeks to eliminate life-threatening side effects that have hampered the use of cell therapies to date.

"CLBR001 + SWI019 is a first-in-class switchable CAR-T cell platform designed to confer the efficacy associated with engineered T cell therapies, while potentially affording greater safety and versatility through the incorporation of a control switch," says Travis Young, PhD, Calibr’s vice president of biologics and leader of its CAR-T development program. "If successful, this approach holds promise to be universally applied to other types of cancer, including solid tumor cancers that have yet to reap the benefits of CAR-T therapies."

CAR-T, short for chimeric antigen receptor T-cell, is a relatively new form of cancer therapy that has achieved remarkable responses in patients with blood- or bone marrow-based diseases such as leukemias and lymphomas. It works by genetically engineering a patient’s own T cells—which play a key role in immune response—to seek and destroy cancer within the body. However, some patients who receive T-cell therapies experience an adverse effect, which can be severe, called cytokine release syndrome, which occurs when the immune system reacts too strongly and causes dangerous inflammation.

Calibr’s switchable CAR-T cell platform incorporates an antibody known as SWI019 that acts as a switch, activating the engineered cell and directing it to engage the cancer target. This may allow doctors to more precisely regulate the potency of the therapy and is expected to provide a significant safety advantage. In preclinical studies, the approach proved highly effective at eliminating tumors while controlling the level of cytokines produced in response to treatment.

"AbbVie continues to be impressed by Calibr’s progress on advancing this innovative switchable cell therapy technology," says Mohit Trikha, Ph.D., vice president, head of Oncology Early Development and Bay Area site head at AbbVie. "This milestone is an important step forward for this potential CAR-T therapy and our recently expanded collaboration with Scripps Research, which holds promise to rapidly advance additional treatment options for patients."

The launch of the clinical study—the third being run independently by the institute and the fifth study to originate from Calibr’s research—is another major landmark for Scripps Research’s pioneering nonprofit drug development model. News of the FDA’s decision comes on heels of another recent IND acceptance for Calibr’s first-in-class bispecific antibody for prostate cancer; that drug candidate, CCW702, is now being tested in a phase I trial for patients with metastatic, castrate resistant prostate cancer.

The switchable CAR-T cell platform was invented at Scripps Research and progressed to the Investigational New Drug stage with support from the Wellcome Trust. Calibr recently partnered its platform with biopharmaceutical company AbbVie, which holds certain rights to commercialization.

"AbbVie has been an outstanding partner for Scripps Research on this CAR-T cell program," says Scripps Research President and CEO Peter Schultz, PhD. "We look forward to continuing to bring novel therapies to the clinic through this collaboration."

Clinical development of CLBR001 + SWI019 will be led by Calibr’s Chief Medical Officer Pamela D. Garzone, PhD. Calibr expects to begin enrolling patients for the phase 1 clinical trial in the first half of 2020, with the potential to expand the platform to solid tumors in coming years.