On December 13, 2017 Stemline Therapeutics, Inc. (Nasdaq:STML), a clinical-stage biopharmaceutical company developing novel therapeutics for difficult to treat cancers, reported detailed data from its SL-401 pivotal trial in BPDCN, as well as results from other ongoing trials in additional indications, at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, held in Atlanta, GA (Press release, Stemline Therapeutics, DEC 13, 2017, View Source [SID1234522625]). Presentations are available on the Stemline website, www.stemline.com, under the Scientific Presentations tab.

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SL-401: Pivotal Trial in BPDCN – Primary endpoint met; Median overall survival (OS) not reached in first-line patients; BLA submission preparation underway

We believe the SL-401 pivotal trial in BPDCN is the largest multicenter prospective study ever conducted in this indication. The trial enrolled 45 BPDCN patients (32 first-line, 13 relapsed/refractory) and consisted of 3 Stages: Stage 1 (lead-in, dose escalation), Stage 2 (expansion), and Stage 3 (pivotal, confirmatory)

Key outcomes in Stages 1, 2, and 3 (ASH ’17 data)
– Across all 3 stages, 42 patients received SL-401 at 12 ug/kg/day
– In first-line BPDCN, SL-401 (12 ug/kg/day)
– 90% (26/29) overall response rate (ORR)
– 72% (21/29) rate of CR + CRc + CRi (complete response + clinical CR [CR with residual skin abnormality] + CR with incomplete bone marrow recovery)
– 45% (13/29) of patients were bridged to stem cell transplant (SCT)
– In relapsed/refractory BPDCN, SL-401 (12 ug/kg/day)
– 69% (9/13) ORR
– 38% (5/13) CR + CRc + CRi rate; 1 patient bridged to SCT
– Median overall survival (OS) not reached in first-line BPDCN (Stages 1-2, and 3), SL-401 (12 ug/kg/day)
– 71% 12-month OS in Stages 1 and 2; follow-up ongoing for 12-month OS in Stage 3
– Most common treatment-related adverse events (TRAEs) were: alanine aminotransferase increase (52%), aspartate aminotransferase increase (50%), hypoalbuminemia (50%), and thrombocytopenia (38%). TRAEs included capillary leak syndrome (19%), which was grade 5 in 2.4% (1/42) of BPDCN patients at 12 ug/kg/day, 2.6% (4/153) of all patients across all trials at all doses, and 1.7% (2/119) of patients across all trials at 12 ug/kg/day

Stage 3 pivotal cohort (first-line, 12 ug/kg/day)
– Met its primary endpoint with a 54% (7/13) CR + CRc rate (95% CI: 25.1, 80.8)
– The lower bound of the 95% confidence interval (CI) exceeded the pre-specified rate of 10%
– 77% (10/13) ORR
– 46% (6/13) of patients bridged to SCT

Next steps for BPDCN
– A BLA submission is in preparation
SL-401: Phase 1/2 Trial in myeloproliferative neoplasms (MPN): chronic myelomonocytic leukemia (CMML) and myelofibrosis (MF)

Key outcomes (ASH ’17 data)
– SL-401 Phase 1/2 trial consists of a Stage 1 (lead-in, dose escalation) and Stage 2 (expansion); has enrolled 24 patients
– No dose limiting toxicities (DLT) were identified and a maximum tolerated dose (MTD) was not reached. Most common TRAEs include hypoalbuminemia (33%), thrombocytopenia (33%), and fatigue (29%). Most common TRAEs (grade 3 or higher), include thrombocytopenia (24%) and anemia (19%)
– Durable CR (14+ months) in CMML patient
– 65% (11/17 evaluable) of CMML and MF patients had spleen reductions >25% (range 29% to 100%)
– Durable SD in 4 patients (2 CMML, 2 MF) for 5+ to 8+ months. Three ongoing SD patients enrolled with baseline platelet counts <100,000, including 1 patient platelet count <50,000 are on treatment

Next Steps in MPN
– Continue enrollment and patient follow-up
– Favorable tolerability and preliminary signs of activity support both single agent and combination development strategies, including JAK-inhibitors and hypomethylating agents
SL-401: Phase 1/2 Trial in Acute Myeloid Leukemia (AML) in CR with Minimal Residual Disease (MRD)

Key outcomes (ASH ’17 data)
– SL-401 Phase 1/2 trial consists of Stage 1 (lead-in, dose escalation) and Stage 2 (expansion); has enrolled 16 patients
– No DLTs or MTD identified in Stage 1; Most common TRAEs (Stage 1 and 2) include hypoalbuminemia (44%), ALT increase (38%), AST increase (38%), and thrombocytopenia (38%). Most common TRAEs, grade 3+, include ALT increase (31%), AST increase (25%), and thrombocytopenia (19%). 2 cases (13%) of grade 3 CLS were noted
– Five patients, including one who went to SCT at 3+ months, were relapse-free for at least 5+ months (range 5+ to 14+), including 2 ongoing (8+ months [on SL-401] and 14+ months [SCT])

Next Steps for AML/MRD
– Patients enrolling and being followed for MRD alterations and response duration
– Given preclinical data indicating potential synergies between SL-401 and azacitidine in AML and high-risk MDS, and that a clinical trial is underway assessing that combination in AML, a transition to combination therapy in this indication is under active consideration
Ivan Bergstein, M.D., CEO of Stemline, commented "The remarkable data presented at ASH (Free ASH Whitepaper) from our pivotal trial with SL-401 in BPDCN sets the stage for our upcoming BLA submission and a successful 2018. In conjunction with these efforts, we kicked off our BPDCN disease awareness campaign at ASH (Free ASH Whitepaper), which includes outreach to hematologist-oncologists, dermatologists, and pathologists, including highlighting the BPDCN diagnostic signature triad of CD123, CD4 and CD56 (an easy to remember: 1, 2, 3, 4, 5, 6). We believe this endeavor is critical for the proper and timely diagnosis of BPDCN, a historically underappreciated and underdiagnosed malignancy. Additionally, we and our investigators believe SL-401 is beginning to demonstrate encouraging signs of clinical activity in indications beyond BPDCN, including CMML and MPN, as presented at ASH (Free ASH Whitepaper)."

On December 12, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported the first results from the pivotal phase III MURANO study evaluating Venclexta/Venclyxto (venetoclax) plus MabThera/Rituxan (rituximab) compared to bendamustine plus MabThera/Rituxan (BR) for the treatment of people with relapsed or refractory chronic lymphocytic leukaemia (CLL) (Press release, Hoffmann-La Roche, DEC 12, 2017, View Source [SID1234522580]). The results showed that a fixed duration of treatment with Venclexta/Venclyxto plus MabThera/Rituxan significantly reduced the risk of disease progression or death (progression-free survival; PFS, as assessed by investigator) by 83% compared with BR (HR=0.17; 95% CI 0.11-0.25; p<0.0001). No new safety signals were observed. Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

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"The MURANO study results indicate that Venclexta/Venclyxto plus MabThera/Rituxan has the potential to provide an important new chemotherapy-free option for people with previously treated chronic lymphocytic leukaemia," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are particularly encouraged by the magnitude of benefit observed across key efficacy measures compared to a current standard of care, and we look forward to discussing these results with health authorities."

Results from the study were featured in the official press programme of the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta on Monday, 11 December, and will be presented during the Late-Breaking Abstracts Session on Tuesday, 12 December, at 7.45am EST by John F. Seymour, MD, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia (Abstract #LBA-2).

Data from the MURANO study will be submitted to global health authorities, including the US Food and Drug Administration (FDA), which has granted Breakthrough Therapy Designation for Venclexta in combination with Rituxan for the treatment of relapsed or refractory CLL based on promising results from the phase Ib M13-365 study.

Venclexta was granted accelerated approval by the FDA in April 2016 for the treatment of people with CLL with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. The MURANO study is part of the company’s commitment in the United States to convert the current accelerated approval of Venclexta to a full approval.

A robust clinical development programme for Venclexta/Venclyxto is ongoing, and additional results across multiple blood cancers including acute myeloid leukaemia (AML) and multiple myeloma (MM) were also presented at the ASH (Free ASH Whitepaper) Annual Meeting.

About the MURANO Study
MURANO (NCT02005471) is a phase III open-label, international, multicentre, randomised study evaluating the efficacy and safety of Venclexta/Venclyxto in combination with MabThera/Rituxan compared to bendamustine in combination with MabThera/Rituxan (BR). All treatments were of fixed duration. The study included 389 patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who had been previously treated with at least one, but not more than three, lines of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta/Venclyxto plus MabThera/Rituxan (Arm A) or BR (Arm B). The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints include PFS assessed by independent review committee (IRC), overall response rate (ORR), complete response rate (with or without complete blood count recovery, CR/CRi), overall survival (OS), minimal residual disease (MRD) status, duration of response, event-free survival and time to next CLL treatment.

The results showed:

Patients in the study who received Venclexta/Venclyxto plus MabThera/Rituxan lived significantly longer without their disease worsening (PFS, as assessed by investigator) compared to those who received BR (HR=0.17; 95% CI, 0.11-0.25; p<0.0001; median PFS: not reached vs. 17.0 months, respectively).
At two years, 84.9% of patients in the Venclexta/Venclyxto plus MabThera/Rituxan arm had not experienced disease progression, compared to 36.3% of patients in the BR arm.
Consistent benefit was observed in all patient subgroups for Venclexta/Venclyxto plus MabThera/Rituxan compared to BR, including high-risk and low-risk groups.
IRC assessment was consistent; as assessed by IRC, Venclexta/Venclyxto plus MabThera/Rituxan reduced the risk of disease progression or death by 81% compared to BR (HR=0.19; 95% CI 0.13, 0.28; p<0.0001).
Clinical benefit observed for Venclexta/Venclyxto plus MabThera/Rituxan compared to BR was consistent across key secondary endpoints, including OS (HR=0.48, 95% CI 0.25-0.90; medians not yet reached), ORR as assessed by investigator (93.3% vs. 67.7%), CR/CRi as assessed by investigator (26.8% vs. 8.2%). These results were not statistically significant. In addition, higher rates of MRD-negativity at any time were observed with Venclexta/Venclyxto plus MabThera/Rituxan compared to BR (83.5% vs. 23.1%). MRD negativity was defined as less than one CLL cell in 10,000 leukocytes.
No new safety signals were observed with the treatment combination of Venclexta/Venclyxto plus MabThera/Rituxan. The most common Grade 3-4 adverse events with Venclexta/Venclyxto plus MabThera/Rituxan compared to BR, respectively, were low white blood cell count (57.7% vs. 38.8%), low red blood cell count (10.8% vs. 13.8%), low platelet count (5.7% vs. 10.1%), low white blood cell count with fever (3.6% vs. 9.6%), pneumonia (5.2% vs. 8.0%) and infusion reactions (1.5% vs. 5.3%).
About Venclexta/Venclyxto
Venclexta/Venclyxto is a small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). Overexpression of the BCL-2 protein in CLL has been associated with resistance to certain therapies. It is believed that blocking BCL-2 may restore the signalling system that tells cells, including cancer cells, to self-destruct. Venclexta/Venclyxto is being developed by Roche and AbbVie. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

Together, the companies are committed to further research with Venclexta/Venclyxto, which is currently being evaluated in phase III clinical trials for the treatment of CLL, along with studies in several other types of cancers. In the United States, Venclexta has been granted four breakthrough therapy designations by the FDA: in combination with Rituxan for people with relapsed or refractory CLL, as a monotherapy for people with relapsed or refractory CLL with 17p deletion; in combination with hypomethylating agents (azacitidine or decitabine) for people with untreated acute myeloid leukaemia (AML) ineligible for intensive chemotherapy, and in combination with low-dose cytarabine (LDAC) for people with untreated AML ineligible for intensive chemotherapy.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world.1 CLL mainly affects men and the median age at diagnosis is about 70 years.2 Worldwide, the incidence of all leukaemias is estimated to be over 350,0001 and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.3

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera /Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), and Venclexta / Venclyxto (venetoclax) in collaboration with AbbVie, Roche’s pipeline of investigational haematology medicines includes Tecentriq (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule antagonist of MDM2 (idasanutlin/RG7388). Roche’s dedication to developing novel molecules in haematology expands beyond malignancy, with the development of Hemlibra (emicizumab), a bispecific monoclonal antibody for the treatment of haemophilia A.

On December 12, 2017 Immutep Limited (ASX: IMM; NASDAQ: IMMP) (Immutep or the Company), reported update on the Company’s two ongoing clinical trials with eftilagimod alpha (LAG-3Ig or IMP321). Immutep is pleased to advise that clinical studies of eftilagimod alpha are progressing well (Press release, Prima Biomed, DEC 12, 2017, View Source [SID1234522623]).
In line with previous guidance, the third cohort of TACTI-mel (Two ACTive Immunotherapeutics in melanoma), the Company’s Australian melanoma clinical trial, has now been fully recruited. The sixth and last patient of that cohort received their first treatment yesterday, bringing the total number of patients recruited for the trial to 18.

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The patients eligible to participate in the TACTI-mel Phase 1 clinical trial are those with unresectable or metastatic melanoma who have either had a suboptimal response or had disease progression with pembrolizumab (KEYTRUDA) monotherapy as a first-line of treatment. These patients are dosed with eftilagimod alpha in combination with pembrolizumab. To date, no dose limiting toxicity has been observed in any patient at any dose level. Data shows the combination to be safe and well tolerated. Data from all three cohorts is expected in H1 2018.

AIPAC (Active Immunotherapy PAClitaxel), the Company’s European clinical trial started recruitment of the randomized part of the study in January 2017. In addition to centres in Belgium and the Netherlands, competent authorities’ approvals have been received and patient recruitment has also now commenced in Poland, Hungary, United Kingdom and Germany, with France following in due course. In total, 29 out of 34 clinical sites have been activated with the outstanding site activations expected to occur in early 2018. The study is expected to be fully recruited by mid-2018.

As announced earlier in June, data from the open-label safety run-in cohort of 15 patients, who received 6mg and 30mg doses of eftilagimod alpha in combination with paclitaxel, were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL, USA. Final results received in December 2017 confirm the data presented at ASCO (Free ASCO Whitepaper). Data shows that the combination of eftilagimod alpha plus weekly paclitaxel in patients with metastatic breast cancer is safe and well tolerated, leading to an overall response rate of 47% in the safety run-in. Pharmacodynamic parameters on primary and secondary target cells confirmed the proof of principle in patients.

Eftilagimod alpha Partnering Update
Immutep’s Chinese partner for eftilagimod alpha, EOC Pharma, an oncology focused affiliate of Eddingpharm, applied in the first quarter of 2017 for an Investigational New Drug (IND) in China, in preparation before starting clinical trials. Recent positive changes in the Chinese regulatory environment are likely to speed up development of eftilagimod alpha in China.

CYTLIMIC, the Japanese NEC spin off with which Immutep has a collaboration agreement, presented a poster at ASCO (Free ASCO Whitepaper) (View Source) which showed the results of their T-cell based therapeutic cancer vaccine with eftilagimod alpha as a vaccine adjuvant. A new material transfer agreement with CYTLIMIC regarding their purchase of additional vials of eftilagimod alpha from Immutep was concluded in September 2017.

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IMP761 Update
IMP761 is the first humanized antibody which acts as an agonist to one of the three immune checkpoint molecules targeted in oncology, namely CTLA-4, PD-1 and LAG-3. Consequently, Immutep is the first company to translate the vast amount of clinical data and biologic knowledge from oncology to the field of auto-immune diseases. The preclinical development of our agonist anti-LAG-3 antibody has now been successfully advanced following an extensive cross-reactivity study on a series of 30 FDA-approved human tissues sections, a prerequisite before entering the clinic.

On December 12, 2017 Palleon Pharmaceuticals, a company focused on developing Glycoimmune Checkpoint Inhibitors to treat cancer, reported an agreement with King’s College London to license intellectual property developed in the laboratory of Joy Burchell, Ph.D., Professor of Glyco-Oncology at the university. This agreement gives Palleon the exclusive rights to a patent portfolio that will facilitate the development of drugs that target Glycoimmune Checkpoints, a novel approach to overcoming resistance to first-generation immuno-oncology drugs.

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Professor Burchell has been a leader in the field of aberrant glycosylation in breast cancer for over 25 years. Earlier in her career she developed tools that demonstrated that more than 90% of breast cancers, and many other carcinomas, carry glycans that are different from those carried by proteins on normal cells. She was the first to show that a mucin known as MUC1 is present in the sera of breast cancer patients. This discovery enabled the development of the CA15.3 test, a serum assay used to measure the response to breast cancer treatment and to monitor recurrence of breast cancer. More recently, Professor Burchell has been investigating how aberrant glycosylation of MUC1 plays a significant role in immunosuppression and allows the cancer to thrive.

Jim Broderick, M.D., Chief Executive Officer and Founder of Palleon, commented, "Professor Burchell’s research is at the forefront of understanding how tumors use glycans to evade the immune system. We now know that tumor cells down-regulate a wide spectrum of immune cell types by cloaking themselves in certain glycan patterns, and that this mechanism of immunosuppression can be targeted by a new class of drugs. This licensing agreement strengthens Palleon’s position as the leader in this new approach to defeating cancer’s suppression of the human immune system."

Dr. Burchell added, "We have known about the alteration of glycans on the surface of malignant cells for decades. However, recent discoveries in the field of glycoscience have demonstrated the role of glycans in immunosuppression. Glycobiology is now emerging as a major axis of immunosuppression in cancer. We expect these findings to provide the foundation for developing immuno-oncology drugs that will have a significant impact on the lives of patients."

On December 12, 2017 Innovation Pharmaceuticals, (OTCQB:IPIX) ("the Company"), a clinical stage biopharmaceutical company, reported that the European Patent Office has granted a European patent for Brilacidin, the Company’s first-in-class defensin-mimetic, in the prevention and control of Oral Mucositis (OM) (Press release, Innovation Pharmaceuticals, DEC 12, 2017, View Source [SID1234522572]). Brilacidin-OM is being developed under an FDA Fast Track designation for this indication.

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The European patent supplements other Brilacidin-OM patents that have been granted in the United States, Asia (Japan, Taiwan, China), Oceania (Australia) and South Africa. All currently issued patents have an expiration date of 2032. Additional Brilacidin-OM patent applications are pending in other key markets including Russia and South Korea.

The European patent is part and parcel to the Company’s strategy to develop and commercialize Brilacidin-OM internationally through licensing agreements. An estimated 700,000 (source: GLOBOCAN) Head and Neck Cancer (HNC) patients worldwide will develop OM this year, with the figures expected to climb to over one million annually by 2023. In spite of OM incidence rates ranging as high as 100 percent in HNC, there currently are no FDA-approved drugs for the prevention and treatment of OM in these types of cancer patients receiving chemoradiation.

"We are looking at a global product opportunity with OM that is extremely attractive and intellectual property protection is critical. With no approved drugs for our initial target indication in preventing OM in HNC, the first company to commercialize a safe and effective drug would undoubtedly command a significant portion of the market, which is estimated to be at least $1 billion worldwide," said Leo Ehrlich, Chief Executive Officer at Innovation Pharmaceuticals.

"The topline data released yesterday from our Phase 2 trial showed a meaningful reduction in the incidence of severe OM even compared to a rate somewhat lower than historic norms in the placebo arm, demonstrating Brilacidin-OM’s clear effect in preventing this extremely painful, and at times even deadly, consequence of chemoradiation in a majority of HNC patients treated with the drug. I can’t imagine a physician not wanting to prescribe, and a patient not wanting to use, a simple oral rinse like Brilacidin-OM if it would mean cutting the chance of developing severe OM by as much as 38.7 percent, as observed in patients who adhered to the requirements of the trial protocol," Mr. Ehrlich continued.

"Given the positive topline data, the Company is compelled to aggressively seek a development path that will most efficiently bring Brilacidin-OM to patients in need," said Arthur P. Bertolino, MD, PhD, MBA, President and Chief Medical Officer at Innovation Pharmaceuticals. "We intend to work diligently with the FDA and other health authorities, on a worldwide basis, and ideally in collaboration with interested potential partners, to achieve this goal. We have a potential "game changer" asset with Brilacidin-OM, able to make a big impact on a cancer patient’s well-being, and we are in the privileged position of planning wholeheartedly for the next stage of development as we strive to be the first to fill a wide void in oncology as quickly as possible."