On January 15, 2020 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, reported that the first patient has been dosed in a Phase 2 study evaluating the investigational agent alvocidib, a potent CDK9 inhibitor, in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with a hypomethylating agent (HMA) (Press release, Tolero Pharmaceuticals, JAN 15, 2020, View Source [SID1234553246]). The open-label, randomized study has two parts and will evaluate the safety and efficacy of alvocidib in monotherapy or in combination with low-dose cytarabine.

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"Patients with AML who are resistant to or progressed following treatment with the BCL-2 inhibitor venetoclax in combination with an HMA have limited treatment options, and it has been well established in the literature that a key potential mechanism of resistance to BCL-2 targeted therapy is the switch to a dependence on MCL-1," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals, Inc. "The initiation of this study marks an important step toward understanding the potential of alvocidib as a monotherapy or in combination with low-dose cytarabine for these patients. We believe that patients whose cancers have progressed following treatment with venetoclax may be sensitive to alvocidib and this trial will help us to better understand this hypothesis."

The primary objective of the Phase 2 study is to determine the rate of combined complete remission (CR) and CR with incomplete hematological recovery (CRi), of alvocidib and alvocidib in combination with low-dose cytarabine in patients with AML. Secondary objectives include establishing the recommended treatment regimen for the second part of the study and evaluating the median overall survival (mOS) and CR rate. Additional secondary outcome measures include evaluating event-free survival (EFS), duration of composite CR (CRc), safety and tolerability of the regimen and mortality.

In the first part of the study, patients who are refractory to or have relapsed on venetoclax in combination with an HMA will be randomized into two arms. In Arm 1 of the study, patients will receive combination therapy of alvocidib and low-dose cytarabine. In Arm 2 of the study, patients will receive alvocidib monotherapy. In the second part of the study, patients will receive the regimen based on the outcome of the first part.

The trial is being conducted at sites in the United States. Additional information on this trial, including comprehensive inclusion and exclusion criteria, can be accessed at www.ClinicalTrials.gov (NCT03969420).

About Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the Phase 2 studies, Zella 202 in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with azacytidine or decitabine (NCT03969420) and Zella 201 in patients with relapsed or refractory MCL-1 dependent AML, in combination with cytarabine and mitoxantrone (NCT02520011). Alvocidib is also being evaluated in Zella 101, a Phase 1 clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with cytarabine and daunorubicin (7+3) in newly diagnosed patients with AML (NCT03298984), and Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with decitabine (NCT03593915). In addition, alvocidib is being evaluated in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555).

About CDK9 Inhibition and MCL-1
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.1 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.2 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.1,3 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).4,5 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.4 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.1

On January 15, 2020 Crescendo Biologics Ltd (Crescendo), the drug developer of novel, targeted, T cell enhancing therapeutics, reported the publication of a paper that demonstrates greater tissue penetration and in vivo efficacy of Humabody VH therapeutics compared to conventional antibody formats, in the scientific journal Cancer Research a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Crescendo Biologics, JAN 15, 2020, View Source [SID1234553230]).

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The full paper by Nessler et al can be accessed online HERE.

The study run by Dr Greg M. Thurber at the University of Michigan demonstrates that the level of tissue penetration by Humabodies plays a major role in therapeutic efficacy and illustrates the benefits of using an albumin-binding domain to extend serum circulation time.

Humabodies are small, in vivo matured human VH domain building blocks that can be easily assembled into multifunctional molecules. They can be configured for optimal target engagement in ways which can be challenging for regular antibody formats. Dr Thurber’s results confirm that the smaller size and specifically tailored binding configuration achievable with Humabody molecules can result in improved penetration into the tumour microenvironment and a greater cancer-killing effect using a preclinical in vivo model of prostate cancer.

Dr Greg M. Thurber, an associate professor of chemical engineering and biomedical engineering at the University of Michigan, said:

"The tissue and cellular distribution of biologics is an important but understudied area in drug development. In collaboration with Crescendo, we demonstrated that the distribution of these drugs within the tumor was as significant as the total tumor dose in determining response. Importantly, this work shows how antibody engineering strategies can be used to design therapeutics with improved distribution to maximize efficacy."

Dr James Legg, SVP R&D at Crescendo Biologics, noted that:

"We’re delighted to be working with Greg Thurber’s team at the University of Michigan; they have developed a deep mechanistic understanding and expertise in the in vivo distribution of therapeutic agents. We look forward to continuing our collaboration."

On January 15, 2020 The HealthWell Foundation, an independent non-profit that provides a financial lifeline for inadequately insured Americans, reported that it has opened a new fund to provide copayment and premium assistance to Medicare patients living with small cell lung cancer (SCLC) (Press release, HealthWell Foundation, JAN 15, 2020, View Source [SID1234553247]). Through the fund, HealthWell will provide up to $8,000 in financial assistance for a 12-month grant period to eligible patients who have annual household incomes up to 500 percent of the federal poverty level.

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About Small Cell Lung Cancer (SCLC)

SCLC, a type of neuroendocrine tumor, typically starts in the bronchi, the major airways in the center of the chest that lead to the lungs. SCLC is an aggressive cancer that grows and spreads rapidly, according to LUNGevity, a leading national lung cancer organization. SCLC represents approximately 15 percent of all lung cancers and about two-thirds of those diagnosed have extensive-stage disease, cancer that has metastasized or spread to other lymph nodes or organs, at the time of diagnosis. Treatment options vary depending on the stage of the disease and typically include one or more types of therapy, such as surgery, chemotherapy, radiation therapy or palliative care.

"A lung cancer diagnosis can leave patients feeling overwhelmed and worried about next steps in managing their condition. Many patients, especially those on Medicare, are concerned about their treatment options and whether they will be able to afford the proper care," said Katie Brown, OPN-CG, Vice President Support and Survivorship Programs at LUNGevity. "Eliminating as much stress as possible is critical to overall wellbeing and positive outcomes when navigating a lung cancer diagnosis. We applaud the HealthWell Foundation for recognizing the financial challenges people living with small cell lung cancer face and for assisting this patient community in accessing critical medical treatments without the stress of having to worry about covering the cost of their treatments."

"A diagnosis of small cell lung cancer can be devastating for the patient and their family. Treatment options often consist of chemotherapy and radiation, high-cost therapies that can create financial hardship and additional stress, especially for those on Medicare," stated HealthWell Foundation President, Krista Zodet. "We are honored that our dedicated donors understand the underlying challenges SCLC patients and their families face in accessing and affording treatment. We are excited to be able to assist Medicare patients living with SCLC with their out-of-pocket treatment costs and to be able to relieve some of the financial burden associated with those costs."

To determine eligibility and apply for financial assistance, visit HealthWell’s Small Cell Lung Cancer Fund page. To learn how you can support this or other HealthWell programs, visit HealthWellFoundation.org.

On January 15, 2020 Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS), a clinical-stage biopharmaceutical company focused on developing immunotherapies based on gene-edited allogeneic CAR T-cells (UCART), reported the first patient dosing in AMELI-01, the Phase 1 dose escalation clinical trial evaluating a new UCART123 product candidate in relapsed/refractory acute myeloid leukemia (AML) (Press release, Cellectis, JAN 15, 2020, View Source [SID1234553232]). This trial, sponsored by Cellectis, is part of an Investigational New Drug (IND) from the US Food and Drug Administration for a new UCART123 construct and an optimized production process, and will evaluate the safety, expansion, persistence and clinical activity of the product candidate in patients with relapsed/refractory AML. AMELI-01 replaces the first US clinical trial assessing the UCART123 product candidate.

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"Cellectis invented and has pioneered the allogeneic approach for many years," said Dr. André Choulika, Chairman and CEO, Cellectis. "Being a leader of the space, it’s important for us to consistently improve our technology and manufacturing expertise to remain at the forefront. With this new IND, we are delivering on our promise of continual innovation in order to advance the efforts of our clinical trials. We hope that with this optimized production process, our UCART123 product candidate will be well equipped to help people living with AML."

This clinical trial is led by Gail J. Roboz, M.D., Professor of Medicine at Weill Cornell Medicine and New York-Presbyterian (New York, USA), in collaboration with Naveen Pemmaraju, M.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center (Texas, USA), David Sallman, M.D., Assistant Member in the Malignant Hematology Department at H. Lee Moffitt Cancer Center (Florida, USA), and Daniel DeAngelo, M.D., Ph.D., Institute Physician and Director of Clinical and Translational Research of Adult Leukemia at Dana Farber Cancer Institute (Massachusetts, USA).

About UCART123

Our wholly controlled product candidate, UCART123, is a gene-edited T-cell investigational drug that targets CD123, an antigen expressed at the surface of leukemic cells in AML. In July 2019, the US Food and Drug Administration (FDA) accepted an Investigational New Drug (IND) for Cellectis to conduct a Phase 1 clinical trial with an optimized version of the UCART123 product candidate in patients living with AML. This IND includes a new UCART123 construct and an optimized production process, and replaces our previous IND on UCART123.

On January 15, 2020 GenScript, a world leading biotechnology company, reported its support of Avidea Technologies’ efforts to develop a groundbreaking peptide-based personalized cancer vaccine (Press release, GenScript, JAN 15, 2020, View Source [SID1234553248]).

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Research published in Nature Biotechnology on January 13, 2020 describes the systematic development of Avidea’s personalized cancer vaccine (SNP-7/8a) based on a self-assembling nanoparticle technology (referred to as "SNAP"), which was shown to more efficiently induce T-cell responses against tumor neoantigens compared to traditional vaccines. Developing and validating SNP-7/8a as a personalized cancer vaccine required synthesis of hundreds of unique neoantigen peptides, which were successfully synthesized by Genscript in support of this work.

"Screening hundreds of neoantigens in mice to validate the generalizability of SNP-7/8a was a tremendous undertaking that could not have been possible without the diligent efforts of GenScript’s peptide chemists who were able to rapidly synthesize even the most challenging sequences at the high purity required," said Avidea Technologies’ CEO Geoffrey Lynn, PhD, a primary author of the study.

The publication is particularly timely as personalized cancer vaccines are garnering increasing attention among the scientific and medical community as important components to enabling precision immuno-oncology. While traditional cancer treatment is largely based on "one size fits all" approaches such as chemotherapy and radiation, which can be limited by off-target effects and low efficacy for treating certain advanced cancers, precision immuno-oncology promises to reduce off-target toxicity and improve efficacy by training a patient’s own immune response, particularly T cells, to attack cancerous cells.

Key to enabling precision immuno-oncology is focusing the immune response against tumor-specific peptide antigens, particularly neoantigens, which are mutant peptides that are unique to cancerous tissue and are not found in healthy tissue. Current vaccines using neoantigen peptides have shown promise in initiating neoantigen-specific T-cell responses. However, the response itself is often not as robust as may be required for tumor regression, which may be in part due to the inability of conventional vaccine platforms to account for the broad variability of neoantigen peptide properties.

In order to address challenges associated with neoantigen peptide variability, Avidea Technologies, working in close collaboration with the Vaccine Research Center at the National Institutes of Health (NIH), developed a personalized cancer vaccine platform (SNP-7/8a) that ensures any neoantigen peptide, irrespective of the underlying amino acid sequence, can be self-assembled into uniform nanoparticles of an optimal size and composition for inducing T-cell responses.

To support this work, GenScript synthesized hundreds of challenging neoantigen peptides that were selected to have a wide range of properties, including neoantigen peptides with extremes of net charge and hydrophobicity, which was instrumental to enabling Avidea and NIH scientists to validate the generalizability of the SNP-7/8a platform as a personalized cancer vaccine. In order to accomplish these challenging syntheses, the GenScript team utilized their 15 years of experience in complex and hydrophobic peptide synthesis, high throughput LPS/SPS/microwave synthesis platforms, and patented quality control program.

"We are honored that Avidea chose to partner with GenScript to synthesize the hundreds of difficult peptides required for this study. As neoantigens can have quite variable properties, working on this project has strengthened our ability to manufacture large quantities of these difficult peptides," said Xin Zhang, associate director of GenScript’s peptide services. "We look forward to our continued collaboration with Avidea on future breakthrough neoantigen peptide vaccines to advance the precision immuno-oncology field."

Leveraging GenScript’s core strength in difficult peptide synthesis, Avidea and the NIH were able to demonstrate the utility of SNP-7/8a for improving formulation consistency and increasing the magnitude and breadth of neoantigen-specific T-cell responses in mice as compared with two gold-standard cancer vaccine technologies. Additionally, the SNP-7/8a platform was also shown to induce CD8 T-cell responses in non-human primates, which is predictive of responses in humans. Based on these encouraging data, Avidea is planning to advance SNP-7/8a to clinic in 2020.

GenScript was pleased to support these studies and hopes that such efforts and continued cooperation with Avidea and others in this space will lead to more efficacious precision immuno-oncology treatments and ultimately improved outcomes for patients.