On April 11, 2018 Aileron Therapeutics (NASDAQ:ALRN), the clinical stage leader in the field of stapled peptide therapeutics for cancers and other diseases, reported the publication of nonclinical results in Science Translational Medicine demonstrating the anti-cancer potential of ALRN-6924 in models of Acute Myeloid Leukemia (AML) (Press release, Aileron Therapeutics, APR 11, 2018, View Source;p=RssLanding&cat=news&id=2342163 [SID1234525472]). ALRN-6924 is designed to reactivate p53-mediated tumor suppression by targeting the two primary p53 suppressor proteins, MDM2 and MDMX. ALRN-6924 is being evaluated in Phase 1 and Phase 2 clinical trials in patients with AML, myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL).

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In AML, blood-forming stem cells in the bone marrow produce abnormal red and white blood cells as a result of damage to DNA. P53, a natural tumor suppressor, is inactive in AML, allowing cancer cells to grow unimpeded. Reactivating p53 with ALRN-6924 appears to slow or stop the growth of both mature and immature cancer cells. As demonstrated by the researchers at Albert Einstein in their nonclinical studies, treatment with ALRN-6924 increased the median survival rate in an animal model of human AML (mice transplanted with human leukemia cells) from 50 to about 150 days. In addition, about 40% of the animals were cured, meaning they were tumor-free at one year.

"These data further support our belief that p53’s function may be more effectively restored when both MDMX and MDM2 are blocked. ALRN-6924, a stapled peptide therapeutic shown to inhibit both protein targets, has the potential to deliver on the long-held promise that restoring apoptosis through the p53 pathway may be critical in treating certain cancers," said Manuel Aivado, M.D., Ph.D., Chief Medical and Scientific Officer of Aileron.

"This is a very striking response. Most experimental drugs for leukemia in our experience achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40 percent of the treated mice," said study leader Ulrich Steidl, M.D., Ph.D., Professor of the Departments of Cell Biology and of Medicine and the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research at Albert Einstein College of Medicine, and Associate Chair for Translational Research in Oncology at Montefiore.

The study in Science Translational Medicine is titled, "Dual inhibition of MDMX and MDM2 as a Therapeutic Strategy in Leukemia."

About ALRN-6924
ALRN-6924 is a first-in-class product candidate designed to reactivate wild type p53 tumor suppression by disrupting the interactions between the two primary p53 suppressor proteins, MDMX and MDM2. Aileron believes ALRN-6924 is the first and only product candidate in clinical development that can equipotently bind to and disrupt the interaction of MDMX and MDM2 with p53. Based on preclinical data and preliminary evidence of safety and anti-tumor activity in its ongoing clinical trials, there may be a significant opportunity to develop ALRN-6924 as a monotherapy or combination therapy for a wide variety of solid and liquid tumors. ALRN-6924 is currently being evaluated in multiple clinical trials for the treatment of acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL). For information about its clinical trials, please visit www.clinicaltrials.gov.

On April 11, 2018 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 that three posters regarding the Company’s allogeneic, off-the-shelf, CAR-T product candidates will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting to be held from April 14 to 18, 2018, in Chicago, Illinois (Press release, Cellectis, APR 11, 2018, View Source [SID1234525258]).

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April 16, 2018, 8:00 AM – 12:00 PM Central Time
Section 45

Repurposing endogenous immune pathways to improve chimeric antigen receptor T-cells potency
M. Sachdeva1, B. Busser1, S. Temburni1, A. Juillerat1, L. Poirot2, P. Duchateau2, J. Valton1;
1Cellectis, New York, NY, 2Cellectis, Paris, France

April 16, 2018, 1:00 PM – 5:00 PM Central Time
Section 24

Preclinical efficacy of allogeneic anti-CD123 CAR T-cells for the therapy of blastic plasmacytoid dendritic cell neoplasm (BPDCN)
T. Cai1, K. L. Black2, A. Naqvi2, R. Galetto3, A. Gouble3, J. Smith4, A. Cavazos1, L. Han1, Q. Zhang1, V. Kuruvilla1, S. N. Sergej Konoplev1, S. S. Neelapu1, A. A. Lane5, M. L. Guzman6, H. Kantarjian1, A. Thomas-Tikhonenko2, N. Pemmaraju1, M. Konopleva1;
1UT MD Anderson Cancer Ctr., Houston, TX, 2The Children’s Hosp. of Philadelphia, Philadelphia, PA, 3Cellectis SA, Paris, France, 4Cellectis Inc, New York, NY, 5Dana-Farber Cancer Inst., Boston, MA, 6Weill Cornell Med. Coll., New York, NY

April 18, 2018, 8:00 AM – 12:00 PM Central Time
Section 31

Prediction of immunotherapy outcome by multimodal assessment of minimal residual disease and persistence of allogeneic anti-CD123 CAR T-cells (UCART123) in pre-clinical models of acute myeloid leukemia
M. Sugita1, N. Mencia-Trinchant1, N. Ewing-Crystal1, G. Suppa1, R. Galetto2, A. Gouble2, J. Smith3, G. J. Roboz1, D. C. Hassane1, M. L. Guzman1;
1Weill Cornell Med., New York, NY, 2Cellectis SA, Paris, France, 3Cellectis Inc, New York, NY

Abstracts are available on the AACR (Free AACR Whitepaper) website. The three posters to be presented at the 2018 AACR (Free AACR Whitepaper) Annual Meeting will be available on the Cellectis website after April 18, 2018.

On April 11, 2018 Molecular Partners AG (ticker: MOLN), a clinical-stage biopharmaceutical company developing a new class of drugs known as DARPin therapies*, reported that Molecular Partners and AstraZeneca (LON: AZN) will collaborate on Molecular Partners’ ongoing phase 1b/2 clinical study of MP0250 with osimertinib (Tagrisso) for the treatment of patients with EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) pre-treated with osimertinib (Press release, Molecular Partners, APR 11, 2018, View Source [SID1234525260]). Under the collaboration, AstraZeneca will supply osimertinib (Tagrisso) required for the clinical study. The clinical study is planned to enroll approx. 40 patients and is taking place in the United States.

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"We are delighted to welcome AstraZeneca as collaboration partner for our second phase 2 study of MP0250. This underlines the growing interest in MP0250 and nicely documents the potential value of MP0250 in EGFR-mutated NSCLC," said Dr. Andreas Harstrick, Chief Medical Officer at Molecular Partners.

MP0250 offers the possibility of targeting two main tumor escape pathways by blocking both hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) simultaneously while continued treatment with osimertinib suppresses EGFR-mutated NSCLC tumor cells.

Osimertinib is a third generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with clinical activity against CNS metastases, which demonstrated significant benefit in untreated EGFR-mutated NSCLC patients in a global phase 3 trial last year. Osimertinib is currently marketed globally, as Tagrisso, for the treatment of locally advanced or metastatic EGFR T790M NSCLC.

The clinical study[1] consists of two parts: the dose-escalation phase (Part A), to establish a safe
recommended dose for MP0250 in combination with osimertinib. In the subsequent treatment
expansion phase (Part B), patients will be further evaluated for efficacy and safety.

[1] ClinicalTrials.gov identifier NCT03418532

About the DARPin Difference
DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multi-specificity and multi-functionality. DARPin candidates are potent, specific, safe and very versatile. They can engage in more than 5 targets at once, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.

With their good safety profile, low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapies have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology, and is advancing a proprietary pipeline of DARPin drug candidates in oncology. The most advanced global product candidate is abicipar, a molecule currently in Phase 3, in partnership with Allergan.

Several DARPin molecules for various ophthalmic indications are also in development. The most advanced systemic DARPin molecule, MP0250, is in Phase 1 clinical development for the treatment of solid tumors and in Phase 2 development for hematological tumors. In addition, Molecular Partners intends to further evaluate MP0250 for solid tumors in a phase 1b/2 trial for EGFR-mutated NSCLC. MP0274, the second-most advanced DARPin drug candidate in oncology, has broad anti-HER activity; it inhibits HER1, HER2 and HER3-mediated downstream signaling via Her2, leading to induction of apoptosis. MP0274 has moved into Phase 1. Molecular Partners is also advancing a growing preclinical pipeline that features several immuno-oncological development programs. DARPin is a registered trademark owned by Molecular Partners AG.

On April 10, 2018 Trillium Therapeutics Inc. (Nasdaq/TSX: TRIL), a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported its TTI-621 and TTI-622 clinical programs (Press release, Trillium Therapeutics, APR 10, 2018, View Source [SID1234525242]). TTI-621 and TTI-622 target CD47, a protein commonly found on the surface of cancer cells. CD47 emits a "do not eat" signal to the immune system, allowing cancer cells to evade detection.

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TTI-621 Program

TTI-621 (SIRPa-IgG1 Fc) is a decoy receptor that blocks CD47 and delivers an activating signal to effector cells such as macrophages through its IgG1 Fc region. It is being evaluated in two multi-center clinical trials using intravenous or intratumoral administration and preliminary data from both studies were reported at last year’s American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. Notably, weekly infusions of TTI-621 were shown to be well tolerated and intratumoral injection was observed to reduce local lesions in 9 out of 10 patients with mycosis fungoides, a common type of cutaneous T-cell lymphoma (CTCL). Building upon these monotherapy results, Trillium has refined and focused its TTI-621 clinical program.

"Our thorough signal-seeking efforts in the TTI-621 program have successfully identified T-cell lymphoma as an indication of interest," said Dr. Niclas Stiernholm, President and CEO of Trillium Therapeutics. "Consequently, we are now moving forward with a more focused TTI-621 program that reflects our commitment to vigorously pursue this signal in both the intravenous and intratumoral trials."

Recent key modifications to the intravenous dosing study (TTI-621-01, NCT02663518) include:

Focusing near-term efforts on patients with CTCL and peripheral T-cell lymphoma (PTCL). These patients are being enrolled in separate cohorts that will be evaluated using a Simon 2-stage design, with a maximum of 35 subjects in each cohort.
Introducing a standardized intra-subject dose intensification schedule for all newly enrolled subjects to increase drug exposure.
Instituting a number of phase 2-like design elements, such as an independent data monitoring committee and central review of diagnostic pathology as well as radiographic disease imaging.
Recent key changes to the intratumoral dosing study (TTI-621-02, NCT02890368) include:

Increasing the duration of treatment to allow for weekly continuation therapy.
Ability to increase the size of each cohort from 12 to 40 patients based on early signs of clinical benefit.
Establishing new cohorts to study intratumoral TTI-621 in combination with a PD-1 or PD-L1 inhibitor, pegylated interferon-alpha 2a, talimogene laherparepvec (T-vec) or radiation therapy.
TTI-622 Program

TTI-622 (SIRPa-IgG4 Fc) is the second SIRPaFc decoy receptor that Trillium is advancing into the clinic. TTI-622 consists of the same CD47-binding domain of human SIRPa as TTI-621 but linked to an IgG4 Fc region, which has a more restricted ability to engage activating Fc receptors. It is expected to have a different pharmacologic profile than TTI-621 and is being developed primarily for combination therapy. Like TTI-621, TTI-622 has the advantage of minimal binding to human red blood cells, thereby reducing the risk of anemia and a large antigen sink effect.

"TTI-622 allows us to deepen our presence in the CD47 space," added Dr. Stiernholm. "With this agent we now have two SIRPaFc decoy receptors being evaluated in clinical trials, each with a different level of Fc receptor engagement. We are excited to compare and contrast the activity of these molecules and determine if each has unique applications that could benefit cancer patients."

A two-part, multicenter, open-label, phase 1a/1b study of TTI-622 in patients with advanced relapsed or refractory lymphoma or multiple myeloma is being initiated, with the first patient expected to be dosed in Q2 2018. In the phase 1a dose-escalation part, patients will be enrolled in sequential dose cohorts to receive TTI-622 once weekly to characterize safety, tolerability, pharmacokinetics, and to determine the maximum tolerated dose. In the phase 1b part, patients will be treated with TTI-622 in combination with rituximab, a PD-1 inhibitor or a proteasome inhibitor-containing regimen

On April 10, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported that the first patient was dosed in a global Phase 2 clinical trial of tislelizumab, an investigational anti-PD-1 antibody, in patients with previously treated advanced hepatocellular carcinoma (HCC or liver cancer) (Press release, BeiGene, APR 10, 2018, View Source;p=RssLanding&cat=news&id=2341754 [SID1234525244]).

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"We have made great progress in the development of tislelizumab with three global Phase 3 trials now enrolling patients. Along with our partner, Celgene, we are encouraged by this progress and excited for the development opportunity of tislelizumab globally," commented John V. Oyler, Founder, Chief Executive Officer, and Chairman of BeiGene.

"This potentially registration-enabling trial of tislelizumab is expected to help us further understand its safety and efficacy with respect to the line of treatment in which it is administered to patients with advanced liver cancer. For these patients, as well as for patients in the concurrent front-line Phase 3 study of tislelizumab as compared to sorafenib, we are hopeful that tislelizumab will provide a new treatment option for a patient population with significant unmet needs," commented Amy Peterson, M.D., Chief Medical Officer for Immuno-Oncology of BeiGene.

The Phase 2, multi-center trial is designed to evaluate the efficacy and safety of tislelizumab in patients who were previously treated for unresectable HCC. Approximately 225 patients will be enrolled at approximately 75 cancer centers internationally including Greater China (including Taiwan), the United States, and Europe. Patients will receive a 200 mg dose every three weeks.

The trial’s primary endpoint is overall response rate (ORR) evaluated by an Independent Review Committee (IRC), and secondary endpoints include duration of response (DOR), progression-free survival (PFS), disease control rate (DCR) and clinical benefit rate (CBR) assessed by IRC, and overall survival. Additional secondary endpoints include investigator assessed ORR, DOR, PFS, DCR and CBR, safety and tolerability and health-related quality of life.

"I look forward to evaluating tislelizumab for patients with advanced liver cancer, for whom the expected median survival is typically less than one year. Patients who have either not seen benefit from their front-line or even second-line treatments, or who may have lost an initial response, could potentially respond to tislelizumab. We are excited to build upon the knowledge base we have from the dose expansion cohort of patients with HCC from its Phase 1 trial," said Professor Ann-Lii Cheng, M.D., Ph.D., Distinguished Professor and Superintendent of the Cancer Center of National Taiwan University and principal investigator of the trial.

For more information about the trial, patients and physicians should email BeiGene at [email protected].

About Hepatocellular Carcinoma

HCC is a major global health problem, accounting for 85-90 percent of all reported cases of liver cancer.i Liver cancer is the sixth most common type of cancer, with an estimated 782,000 new cases per year worldwide; it was also the second most common cause of cancer-related mortality, responsible for an estimated 746,000 deaths.ii China accounts for approximately 50 percent of both new HCC cases and HCC-related deaths worldwide.ii

About Tislelizumab

Tislelizumab (BGB-A317) is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. It is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. Tislelizumab has demonstrated high affinity and specificity for PD-1. It is potentially differentiated from the currently approved PD-1 antibodies in an engineered Fc region, which is believed to minimize potentially negative interactions with other immune cells, based on preclinical data. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumor cancers outside of Asia (except Japan).