Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On October 30, 2017 Siamab Therapeutics, Inc., a biopharmaceutical company developing novel cancer immunotherapies, reported the presentation of new preclinical data demonstrating the safety of its novel anti-Sialyl-Tn (STn) antibody drug conjugates (ADCs) in multiple animal models, including non-human primates (NHPs) (Press release, Siamab Therapeutics, OCT 30, 2017, View Source [SID1234521303]). These results add to the company’s efficacy data findings showing that its anti-STn antibody therapeutics inhibit tumor progression in cell-line-derived and patient-derived xenograft (PDX) ovarian cancer and pancreatic cancer mouse models, with complete regression observed in some treatment arms. The preclinical efficacy and safety data were presented in a poster presentation at the 2017 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), held October 26-30, 2017, in Philadelphia.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Siamab’s platform enables the development of highly specific monoclonal antibody (mAb) therapeutics that target cancer cell surface glycans called tumor-associated carbohydrate antigens (TACAs), a novel class of cancer-specific antigens. TACAs are implicated in immune suppression, chemoresistance, and a cancer stem cell (CSC) phenotype.

“Our lead ST1 program shows compelling efficacy and safety across a range of PDX and xenograft studies, underscoring the promise of our anti-STn antibody approach to treat chemoresistant solid tumors,” said Jeff Behrens, president and chief executive officer of Siamab. “The new data from a pilot pharmacokinetic/toxicity study in primates demonstrate the favorable safety and tolerability of ST1 in large animals. The NHP results are extremely encouraging and provide an important step to de-risk IND-enabling GLP toxicity studies, which we plan to initiate in 2018.”

The poster presentation, titled “Humanized anti-Sialyl-Tn monoclonal antibody-drug conjugates (ADCs) inhibit tumor growth in vivo and in vivo,” was presented during the Therapeutic Agents: Biological poster session. In the poster, Siamab scientists and collaborators reported data demonstrating anti-tumor effect in vitro utilizing humanized anti-STn ADCs as well as inhibition of tumor progression in vivo in both cell line and PDX ovarian cancer models with complete regressions observed in some treatment groups. No significant weight loss was observed for any of the treatment groups in these models indicating the therapy was well tolerated by all the groups. In addition, the poster featured new safety data demonstrating Siamab’s anti-STn ADC has an excellent safety profile through the completion of a non-GLP pilot pharmacokinetic/toxicity study in non-human primates. Two doses were administered at days 1 and 22. Dose levels were 1mg/kg, 3mg/kg, and 6mg/kg. No weight loss or deaths occurred in the study and no gross pathology changes were observed in all organs examined. All clinical chemistry results (liver, kidney function, etc.) were normal throughout the study.

ST1, Siamab’s lead antibody program targeting STn, is in late stage preclinical development for the treatment of solid tumors. The elevated presence of STn—a key TACA observed in a number of solid tumors, including ovarian, prostate, pancreatic, gastric, and colon—is associated with metastatic disease, poor prognosis, and reduced overall survival. Elevation of STn expression is linked to chemotherapy resistance and enables tumors to evade the host immune system. Siamab has also identified the presence of STn on myeloid-derived suppressor cells (MDSCs), which are major regulators of immune response in cancer and influence the tumor microenvironment by suppressing T cells. STn is a major reported constituent of two established CSC biomarkers, CD44 and MUC1, which reside on both CSCs and mature malignant cells in some cancer types.

Siamab is utilizing STn-selective antibodies to develop both tissue- and serum-based biomarker assays with the potential to become companion diagnostics for both the stratification of patients as well as tools for assessing the pharmacodynamic action of the anti-STn therapeutic in the clinic.

Siamab recently announced it has entered into a strategic discovery collaboration with Boehringer Ingelheim with the goal of developing anti-cancer therapeutics targeting TACAs. Siamab will apply its proprietary technology platform to generate TACA-specific antibodies for use in multiple solid tumor applications. Financial terms of the agreement were not disclosed.

New data show that switching patients with Crohn’s disease (CD) to INFLECTRA (infliximab CT-P13) from REMICADE (infliximab) led to comparable efficacy, safety and tolerability to treatment with REMICADE over a 24 week period (Press release, Pfizer, OCT 30, 2017, View Source [SID1234521318]). The full 54-week results of the randomized controlled trial comparing INFLECTRA and REMICADE in biologic-naïve patients with active CD support the long-term effectiveness of treatment with INFLECTRA.1 The results also show that INFLECTRA was well-tolerated, with a similar safety profile to REMICADE.1 Pfizer Inc. (NYSE:PFE) and Celltrion Healthcare jointly announced the secondary outcomes from the phase III trial of INFLECTRA in CD at the 25th United European Gastroenterology (UEG) Week.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

*INFLECTRA is marketed as INFLECTRA (infliximab-dyyb) in the United States (U.S.) and under other brand names in some countries. In the EU, INFLECTRA is marketed as INFLECTRA (infliximab CT-P13)
**REMICADE is a U.S. registered trademark of Janssen Biotech, Inc.

"The data announced today show that 24 weeks (six months) after switching from REMICADE to the Infliximab biosimilar CT-P13, patients with Crohn’s disease continue to experience similar efficacy, safety and tolerability compared to staying on REMICADE," said Stephen B Hanauer, M.D., Professor of Medicine-Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, US. "These data support previous findings which demonstrate the importance of CT-P13 as a treatment option for patients with Crohn’s disease, providing healthcare professionals further confidence when stable patients switch to CT-P13 from REMICADE."

"These new data add to the considerable body of evidence, including real-world studies and the NOR-SWITCH trial, for the switching of stable patients to INFLECTRA," said Sam Azoulay, M.D., Senior Vice President, Chief Medical Officer, Pfizer Essential Health. "Today’s announcement further highlights Pfizer’s commitment to biosimilars and provides additional evidence supporting use of INFLECTRA in Crohn’s disease."

The study previously reported its primary endpoint at six weeks, demonstrating non-inferiority of INFLECTRA compared to REMICADE in the treatment of CD.2

More than 50 real-world studies in IBD have been conducted with INFLECTRA, evaluating over 7,500 IBD patients in real-world settings.2,3,4,5,6,7,8,9,10,11,12,13,14 There is an important and growing body of evidence for the switching of stable REMICADE patients to INFLECTRA. Clinical studies supporting this switch include NOR-SWITCH,15 BIO-SWITCH,16 PROSIT-BIO3 and now CT-P13 3.4.1,2,17 For example, the NOR-SWITCH study published earlier this year showed that switching from REMICADE to INFLECTRA was not inferior to continued treatment with REMICADE when measured across all adult indications.15

About the trial

This is a randomized, double-blind, parallel-group, phase III study conducted over 54 weeks in 220 patients with active CD to compare overall safety and efficacy between INFLECTRA and REMICADE as determined by the Crohn’s Disease Activity Index (CDAI)-70 response rates†.1 The primary endpoint of the 54 week study was collected at week 6 to demonstrate that INFLECTRA is non-inferior to REMICADE in the treatment of CD.2 From Week 30, patients on REMICADE were randomized to either continue on the same treatment or switch to INFLECTRA while patients on INFLECTRA were randomized to either continue on the same treatment or switch to REMICADE.1 Final study results were collected at 54-weeks.1

The pre-specified secondary endpoints reported today include CDAI-70 response rates after week 6, clinical remission,[1] Short Inflammatory Bowel Disease Questionnaire (SIBDQ)[2] results, and safety endpoints including adverse events and immunogenicity. While not powered to draw definitive conclusions, these new data add to the body of evidence supporting use of INFLECTRA in the Crohn’s Disease indication, including switch to INFLECTRA from REMICADE.1 Comparable efficacy, as measured by CDAI-70 response and clinical remission after week 6 was observed, and these response rates were maintained and observed to be similar in all study arms at week 54.1 One-year data including adverse drug reactions, serious adverse events and infections were observed to be similar among all treatment groups.1 There were no clinically meaningful differences in immunogenicity results throughout the study period among treatment groups up to week 54.1

† CDAI: Crohn’s Disease Activity Index, a recognised measure for the evaluation of disease activity. A response to treatment is measured as a decrease of 70 points or greater (CDAI-70).
[1] Clinical remission: decrease in CDAI >150 points
[2] Short Inflammatory Bowel Disease Questionnaire, a health-related quality of life tool measuring physical, social, and emotional status, and has been predominantly used in trials for Crohn’s disease.

ABOUT INFLECTRA: IMPORTANT SAFETY INFORMATION AND INDICATIONS FROM THE U.S. PRESCRIBING INFORMATION

Only your doctor can recommend a course of treatment after checking your health condition. INFLECTRA (infliximab-dyyb) can cause serious side effects such as lowering your ability to fight infections. Some patients, especially those 65 years and older, have had serious infections caused by viruses, fungi or bacteria that have spread throughout the body, including tuberculosis (TB) and histoplasmosis. Some of these infections have been fatal. Your doctor should monitor you closely for signs and symptoms of TB during treatment with INFLECTRA.

Unusual cancers have been reported in children and teenage patients taking TNF-blocker medicines. Hepatosplenic T-cell lymphoma, a rare form of fatal lymphoma, has occurred mostly in teenage or young adult males with Crohn’s disease or ulcerative colitis who were taking infliximab products and azathioprine or 6-mercaptopurine. For children and adults taking TNF blockers, including INFLECTRA, the chances of getting lymphoma or other cancers may increase.

You should discuss any concerns about your health and medical care with your doctor.

What should I tell my doctor before I take INFLECTRA?

You should let your doctor know if you have or ever had any of the following:

Tuberculosis (TB) or have been near someone who has TB. Your doctor will check you for TB with a skin test. If you have latent (inactive) TB, you will begin TB treatment before you start INFLECTRA.
Lived in a region where certain fungal infections like histoplasmosis or coccidioidomycosis are common.
Infections that keep coming back, diabetes, or an immune system problem.
Any type of cancer or a risk factor for developing cancer, for example, chronic obstructive pulmonary disease (COPD) or had phototherapy for psoriasis.
Heart failure or any heart condition. Many people with heart failure should not take INFLECTRA.
Hepatitis B virus (HBV) infection or think you may be a carrier of HBV. Your doctor will test you for HBV.
Nervous system disorders (like multiple sclerosis or Guillain-Barré syndrome).
Also tell your doctor if you:

Use the medicines Kineret (anakinra), Orencia (abatacept), or Actemra (tocilizumab) or other medicines called biologics used to treat the same problems as INFLECTRA.
Are pregnant, plan to become pregnant, are breast-feeding, or have a baby and were using INFLECTRA during your pregnancy. Tell your baby’s doctor about your INFLECTRA use. If your baby receives a live vaccine within 6 months after birth, your baby may develop infections with serious complications that can lead to death.
Recently received or are scheduled to receive a vaccine. Adults and children taking INFLECTRA should not receive live vaccines or treatment with a weakened bacteria (such as BCG for bladder cancer) while taking INFLECTRA.
What should I watch for and talk to my doctor about before or while taking INFLECTRA?

The following serious (sometimes fatal) side effects have been reported in people taking INFLECTRA.

You should tell your doctor right away if you have any of the signs listed below:

Infections (like TB, blood infections, pneumonia)—fever, tiredness, cough, flu, or warm, red, or painful skin or any open sores. INFLECTRA can make you more likely to get an infection or make any infection that you have worse.
Lymphoma or any other cancers in adults and children.
Skin cancer—any changes in or growths on your skin.
Heart failure—new or worsening symptoms, such as shortness of breath, swelling of your ankles or feet, or sudden weight gain.
Reactivation of HBV—feeling unwell, poor appetite, tiredness, fever, skin rash, and/or joint pain.
Liver injury—jaundice (yellow skin and eyes), dark brown urine, right-sided abdominal pain, fever, or severe tiredness.
Blood disorders—fever that doesn’t go away, bruising, bleeding, or severe paleness.
Nervous system disorders—numbness, weakness, tingling, changes in your vision, or seizures.
Allergic reactions during or after the infusion—hives, difficulty breathing, chest pain, high or low blood pressure, swelling of face and hands, and fever or chills.
Lupus-like syndrome—chest discomfort or pain that does not go away, shortness of breath, joint pain, rash on the cheeks or arms that gets worse in the sun.
Psoriasis—new or worsening psoriasis such as red scaly patches or raised bumps on the skin that are filled with pus.
The more common side effects with infliximab products are respiratory infections (that may include sinus infections and sore throat), headache, rash, coughing, and stomach pain.

INFLECTRA is a prescription medication used to treat:

Crohn’s Disease

Can reduce signs and symptoms and induce and maintain remission in adult patients with moderately to severely active Crohn’s disease who haven’t responded well to other therapies
Paediatric Crohn’s Disease

Can reduce signs and symptoms and induce and maintain remission in children (ages 6-17) with moderately to severely active Crohn’s disease who haven’t responded well to other therapies
Ulcerative Colitis

Can reduce signs and symptoms, induce and maintain remission, promote intestinal healing, and reduce or stop the need for steroids in adult patients with moderately to severely active ulcerative colitis who haven’t responded well to other therapies
Rheumatoid Arthritis

Can reduce signs and symptoms, help stop further joint damage, and improve physical function in patients with moderately to severely active rheumatoid arthritis, in combination with methotrexate
Ankylosing Spondylitis

Can reduce signs and symptoms in patients with active ankylosing spondylitis
Psoriatic Arthritis

Can reduce signs and symptoms of active arthritis, help stop further joint damage, and improve physical function in patients with psoriatic arthritis
Plaque Psoriasis

Approved for the treatment of adult patients with chronic severe (extensive and/or disabling) plaque psoriasis under the care of a physician who will determine if INFLECTRA is appropriate considering other available therapies
Please see full Prescribing Information for INFLECTRA (infliximab-dyyb).

On October 30, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported preclinical data supporting the ongoing clinical development strategy for its Chk1 inhibitor, SRA737 (Press release, Sierra Oncology, OCT 30, 2017, View Source [SID1234521304]). The results were presented in a poster on October 29th at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) held in Philadelphia, Pennsylvania.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

“The data generated from these experiments are consistent with recent findings from our research and demonstrate that a potent and selective Chk1 inhibitor such as SRA737 can effectively synergize with sub-therapeutic doses of gemcitabine to induce replication catastrophe and tumor cell death,” said Dr. Alan R. Eastman, Professor at the Geisel School of Medicine at Dartmouth and the founding Director of the Molecular Therapeutics Research Program of the Norris Cotton Cancer Center at Dartmouth-Hitchcock. “I look forward to results from the clinical study Sierra is conducting which translates this novel strategy for the treatment of patients with advanced cancers.”

“Chk1 is essential for managing replication stress (RS), which is intrinsically elevated in certain oncogene-transformed tumors, and can also be further enhanced by chemotherapeutic drugs like gemcitabine. While gemcitabine likely causes RS by depleting deoxynucleotide (dNTP) and damaging DNA, Chk1 protects against RS through a variety of molecular mechanisms. Consequently, tumor cells become highly reliant on Chk1 to manage replication stress and its downstream consequences in order to survive and continue to proliferate,” added Dr. Christian Hassig, Senior Vice President of Research at Sierra Oncology. “Through our research, we have demonstrated that SRA737 has the potential to synergize with several clinically important chemotherapeutic inducers of RS to kill tumor cells in vitro at low concentrations. We also demonstrated that the combination of SRA737 and gemcitabine may prove efficacious in gemcitabine-resistant clinical settings and that SRA737 can be potentiated by sub-therapeutic doses of gemcitabine in animal models of cancer.”

“Replication stress has been recognized as a potent driver of genomic instability, a fundamental hallmark of cancer, and is rapidly emerging as an area of dynamic scientific research,” stated Dr. Nick Glover, President and CEO of Sierra Oncology. “Tumors harboring high levels of intrinsic or exogenous forms of replication stress are potential candidates for therapeutic intervention using SRA737. We are actively leveraging these concepts in our ongoing monotherapy and low-dose gemcitabine combination clinical trials.”

About the Poster
Title: The Chk1 inhibitor, SRA737, demonstrates chemical synthetic lethality with replication stress-inducing agents, including novel low-dose gemcitabine, in preclinical models of cancer.
Poster #181; Abstract #B181:
The Poster is available on the company’s website at www.sierraoncology.com.

Data reported in the Poster demonstrated that:

The combination of SRA737 with a range of RS-inducing agents was highly synergistic in a panel of 15 cell lines of diverse tissue lineages, with the strongest synergy observed with gemcitabine.
Profound synergy between SRA737 and gemcitabine was observed in several bladder cancer cell lines as well as in human patient-derived bladder cancer 3D cultures, further supporting the clinical development of this RS-inducing combination.

Significant anti-tumor activity and increased survival (vs. control) were observed when SRA737 and gemcitabine were dosed in combination in a highly aggressive gemcitabine resistant bladder carcinoma PDX model. These findings suggest that the combination of SRA737 and gemcitabine may be efficacious in gemcitabine-resistant clinical settings.
Strikingly, anti-tumor activity was observed when SRA737 was combined with a sub-therapeutic dose of gemcitabine in xenograft models of colorectal adenocarcinoma and osteosarcoma. This combination was shown to increase RS markers by three to five-fold over the change noted with gemcitabine alone. These findings support i) the development of SRA737 in combination with low, sub-therapeutic doses of gemcitabine and, ii) the broader application of this unique combination in tumor indications where gemcitabine is not standard of care.

On October 30, 2018 Xynomic Pharma, a clinical stage US oncology drug development company, reported that it has acquired exclusive global rights to develop, manufacture and commercialize BI 882370, a 2nd-generation RAF inhibitor, from Boehringer Ingelheim, a top-20 global pharmaceutical company (Press release, Xynomic Pharmaceuticals, OCT 30, 2017, View Source [SID1234527683]). Under the terms of the agreement Xynomic will pay upfront, milestone and royalty payments up to approximately $502 million.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

BI 882370 is a potent and selective RAF inhibitor uniquely binding to the DFG-out conformation, whereas marketed BRAF inhibitors occupy the DFG-in conformation. BI 882370 inhibited proliferation of BRAFmut melanoma cell lines with 100x higher potency (EC50 1 – 10 nM) than vemurafenib (VEM), a marketed BRAF inhibitor.

In the colorectal cancer (CRC) animal models, BI 882370 was superior to VEM in both the Colo-205V600V/E model and HT-29V600V/E model. BI 882370 in combination with cetuximab induced tumor regressions in the less sensitive HT-29 model.

In melanoma’s G-361V600V/E model, BI 882370 was superior to VEM, marketed BRAF inhibitor dabrafenib (DAB), marketed MEK inhibitor trametinib (TRA) and DAB-TRA combination. In a second melanoma model A375V600E in which tumors developed resistance to VEM, the TRA-BI 882370 combination demonstrated superior efficacy over TRA-DAB combination.

There were no relevant findings in exploratory toxicology studies at exposures delivering efficacy superior to VEM, DAB and TRA.

"BI 882370, with an impressive efficacy and safety profile demonstrated in animal models, is well positioned to become a best-in-class 2nd-generation Pan-RAF inhibitor for the treatment of B-RAF mutant cancers including CRC and melanoma. We are honored to partner with BI, a global leader in oncology, and will move this asset into clinical testing expeditiously," said Y. Mark Xu, Chairman, CEO and President of Xynomic.

RAF inhibitors have attracted resurged and strong interest in oncology. Compared to 1st-generation, BI 882370 may provide an improved therapeutic window, enabling more pronounced and longer-lasting pathway suppression and thus resulting in improved efficacy.

Xynomic’s pipeline also includes Abexinostat, a potentially best-in-class HDAC inhibitor entering global pivotal Ph 3 trials against Non-Hodgkin’s lymphoma and renal cell carcinoma.