On September 28, 2017 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, today presented preliminary data from the dose-verification portion of the ongoing Phase 1/2 trial of its investigational anti-PD-1 antibody BGB-A317 in Chinese patients with advanced solid tumors at the 20th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO) in Xiamen, China (Press release, BeiGene, SEP 28, 2017, View Source [SID1234520678]). The preliminary data suggest that BGB-A317 was generally well tolerated and exhibited preliminary evidence of anti-tumor activity in a Chinese study population with advanced solid tumors. BeiGene and Celgene Corporation have a global strategic collaboration for BGB-A317 for solid tumors; BeiGene retains exclusive rights to BGB-A317 in China.

“BGB-A317 was generally well tolerated and showed preliminary activity in a heavily pretreated study population with advanced solid tumors. At the time of the data cut-off, no dose-limiting toxicities were observed. The pharmacokinetic profile in Chinese patients was consistent with that reported in global trials of BGB-A317 at the registrational dose,” commented Professor Lin Shen of the Peking University Cancer Hospital and Beijing Institute for Cancer Research, Beijing, China, the lead author of the abstract.

“This dose-verification trial is an important step as we advance BGB-A317 along China’s domestic innovative drug development pathway. Two registrational trials of BGB-A317, in urothelial cancer and classical Hodgkin lymphoma, are currently ongoing in China. The Celgene partnership allows us to increase our investment in BGB-A317, and we intend to initiate Phase 3 trials supporting approval in China for each of the four most common tumors in the country including lung, stomach, liver, and esophageal cancers, with the initial studies expected to start in the fourth quarter of 2017 or first quarter of 2018,” commented Amy Peterson, MD, Chief Medical Officer, Immuno-oncology at BeiGene.

Summary of Results from the Ongoing Phase 1/2 Trial

The multi-center Phase 1/2 trial of BGB-A317 consists of a Phase 1 dose-verification portion and a Phase 2 portion of indication expansion in disease-specific cohorts. Data presented at CSCO include patients enrolled in the Phase 1 portion of this study, who received BGB-A317 at 200 mg once every three weeks (Q3W).

As of June 16, 2017, 20 patients had enrolled in the trial. The median duration of therapy in these patients was 53 days (range 21–171 days).

Adverse events (AEs) assessed by the investigator to be related to treatment occurred in 19 patients (95%). The most common treatment-related AEs (TRAEs) were related to changes in clinical laboratory value; TRAEs occurring in 15% or more of patients included increased blood bilirubin (45%), anemia (35%), proteinuria (30%), increased aspartate transferase (AST) (25%), increased alanine transferase (ALT) (20%), leukopenia (15%), neutropenia (15%), pyrexia (15%), and vomiting (15%). All of the TRAE cases were grades 1 or 2 except for one case each of grade 3 increased blood bilirubin, leukopenia, and neutropenia. Increased AST (25%) and ALT (20%) were the most common AEs that were potentially immune related.

At the time of the data cutoff, 11 patients had at least one post-baseline imaging assessment, and three patients had at least two imaging assessments. The efficacy-evaluable population (measurable disease at baseline and at least one post-baseline tumor assessment, or progression or death) consisted of 12 patients, including three patients with microsatellite-instability-high (MSI-high) colorectal cancer (CRC), two patients with gastric cancer (GC), two patients with hepatocellular carcinoma (HCC), two patients with urothelial cancer (UC), two patients with melanoma, and one patient with gastrointestinal stromal tumor (GIST). Partial responses (PR) were observed in one patient with UC (confirmed) and one with GC (unconfirmed). Stable disease was observed in two patients with melanoma and one with MSI-high CRC. In the remaining eight patients who were not evaluable as of the data cutoff, a third unconfirmed PR was observed in a patient with esophageal cancer 11 days after the data cutoff. At the time of the data cutoff, 15 patients remained on treatment.

About BGB-A317

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. BGB-A317 has high affinity and specificity for PD-1. It is 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. BGB-A317 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 BGB-A317 for solid tumors.

On September 28, 2017 Galena Biopharma, Inc. (NASDAQ:GALE), a biopharmaceutical company developing hematology and oncology therapeutics that address unmet medical needs, reported that two clinical trials evaluating NeuVax (nelipepimut-S) in combination with trastuzumab (Herceptin; Genentech/Roche) for the prevention of recurrence in breast cancer patients have enrolled the protocol-defined number of patients to complete enrollment (Press release, Galena Biopharma, SEP 28, 2017, View Source [SID1234520677]). The milestones were reported by the clinical research organization conducting both trials – a Phase 2b clinical trial in HER2 1+/2+ patients and a Phase 2 clinical trial in HER2 3+ patients.

“Completing enrollment in both of these trials represents a major milestone for NeuVax development,” said Bijan Nejadnik, M.D., Executive Vice President and Chief Medical Officer of Galena. “The combination of trastuzumab and NeuVax has been shown to be synergistic in preclinical investigation, and we believe could be an effective treatment to prevent breast cancer recurrence in patients with no other treatment options. We would like to thank our investigators and patients who are participating in these trials as we look forward to the interim results next year for the Phase 2b trial and the primary endpoints for both trials in 2019.”

Phase 2b Clinical Trial in HER2 1+/2+ Patients

The Phase 2b clinical trial has enrolled the necessary 300 patients to complete enrollment. The clinical trial is a randomized, multicenter, investigator-sponsored, study enrolling HER2 1+ and 2+, HLA A2+, A3+, A24 and/or A26, node positive, and high-risk node negative breast cancer patients. Eligible patients are randomized to receive NeuVax + GM-CSF + trastuzumab or trastuzumab + GM-CSF alone. Once enrolled, all patients receive the standard trastuzumab dosing for 12 months. One cohort also receives six doses of NeuVax given as a primary vaccine series starting with the third dose of trastuzumab and then goes on to receive a NeuVax booster inoculation once every six months for up to 36 months. The next milestone for the trial will be the interim efficacy analysis that is scheduled to be performed by the Data Safety Monitoring Board (DSMB) in the first quarter of 2018. The primary endpoint of the study is disease-free survival after 24 months, with results expected from that milestone in the fourth quarter of 2019. Genentech/Roche is providing the trastuzumab and partial funding for this trial.

Data presented in October 2016 demonstrated that this novel combination of trastuzumab and NeuVax with HER2 low-expressing patients is well tolerated and the cardiac effects of trastuzumab are not impacted by the addition of NeuVax. In February 2017, the DSMB reported that there were no safety concerns with the trial and the trial is not futile. The recommendation from the DSMB was to continue the trial with one revision to the statistical analysis plan regarding the timing of the pre-specified interim analysis. Given the lengthy duration of enrollment for the trial, the DSMB determined that the pre-specified interim efficacy analysis be moved up from 12 months to 6 months after the last patient is enrolled. Therefore, the DSMB expects to perform the interim efficacy analysis in the first quarter of 2018.

Phase 2 Clinical Trial in HER2 3+ Patients

The Phase 2 clinical trial has enrolled the necessary 100 patients to complete enrollment. This multi-center, prospective, randomized, single-blinded trial enrolled patients with a diagnosis of HER2 3+ breast cancer who are HLA A2+ or HLA A3+ and are determined to be at high-risk for recurrence. High-risk is defined as having received neoadjuvant therapy with an approved regimen that includes trastuzumab but not obtaining a pathological complete response at surgery, or underwent surgery as a first intervention and was found to be pathologically node-positive (≥ 4 positive lymph nodes, or having 1-3 positive lymph nodes (pN1) if hormone receptor negative). These high-risk patients are known to have higher recurrence rates than other HER2 3+ breast cancer patients. Eligible patients are randomized to receive NeuVax + GM-CSF + trastuzumab or trastuzumab + GM-CSF alone. Once enrolled, all patients receive the standard trastuzumab dosing for 12 months. One cohort also receives six doses of NeuVax given as a primary vaccine series starting with the third dose of trastuzumab and then goes on to receive a NeuVax booster inoculation once every six months for up to 36 months. The primary endpoint of the study is disease-free survival after 24 months, with results expected from that milestone in the fourth quarter of 2019. Partial funding for this trial was awarded through the Congressionally Directed Medical Research Program funded through the Department of Defense, via a Breast Cancer Research Program Breakthrough Award.

In February 2017, the DSMB reported that there were no safety concerns with the trial and the trial is not futile. The pre-specified interim safety analysis was completed on n=50 patients and demonstrated that the agent is well tolerated with no increased cardiotoxicity associated with giving NeuVax in combination with trastuzumab. The recommendation from the DSMB was to continue the HER2 3+ trial unmodified.

About NeuVax (nelipepimut-S)

NeuVax (nelipepimut-S) is a first-in-class, HER2-directed cancer immunotherapy under evaluation to prevent breast cancer recurrence after standard of care treatment in the adjuvant setting. It is the immunodominant peptide derived from the extracellular domain of the HER2 protein, a well-established target for therapeutic intervention in breast carcinoma. The nelipepimut-S sequence stimulates specific CD8+ cytotoxic T lymphocytes (CTLs) following binding to specific HLA molecules on antigen presenting cells (APC). These activated specific CTLs recognize, neutralize and destroy, through cell lysis, HER2 expressing cancer cells, including occult cancer cells and micrometastatic foci. The nelipepimut-S immune response can also generate CTLs to other immunogenic peptides through inter- and intra-antigenic epitope spreading. In clinical studies, NeuVax is combined with recombinant granulocyte macrophage-colony stimulating factor (GM-CSF).

NeuVax is currently in two breast cancer studies in combination with trastuzumab (Herceptin; Genentech/Roche): a Phase 2b trial in node positive and triple negative HER2 IHC 1+/2+ (clinicaltrials.gov identifier: NCT01570036); and, a Phase 2 trial in high risk, node positive or negative HER2 IHC 3+ patients (clinicaltrials.gov identifier: NCT02297698). A Phase 2 clinical trial is also ongoing with NeuVax in patients with ductal carcinoma in situ (DCIS) (clinicaltrials.gov identifier: NCT02636582), and a Phase 2 trial is planned in patients with gastric cancer.

About Breast Cancer

New cases of breast cancer occur at an annual rate of 125 per 100,000 women in the U.S., with over 250,000 new cases and 40,000 deaths expected in 2017. Approximately 89.7% of breast cancer patients are expected to survive five years after diagnosis. Approximately 12.4% of women will be diagnosed with breast cancer at some point during their lifetime (2011 – 2013 data). The prevalence data from 2013 showed an estimated 3,053,450 women living with breast cancer in the United States.

According to the National Cancer Institute (NCI), only about 25% of breast cancers diagnosed are HER2 positive (IHC 3+). NeuVax targets approximately 50%-60% of these women who are HER2 low to intermediate (IHC 1+/2+ or FISH < 2.0) and achieve remission with current standard of care, but have no available HER2-targeted adjuvant treatment options to maintain their disease-free status. Sources: National Cancer Institute and NCI Surveillance, Epidemiology, and End Results Program

On September 28, 2017 Starpharma (ASX: SPL, OTCQX: SPHRY) reported that AstraZeneca has this week presented its first DEP candidate utilising Starpharma’s DEP delivery platform, AZD0466, at the 3rd AstraZeneca-MedImmune-CRUK Cambridge Centre Symposium 2017 in Cambridge, UK (Press release, Starpharma, SEP 28, 2017, View Source [SID1234520676]).

AZD0466 is a highly optimised nanomedicine formulation[1] of a novel dual Bcl2/xL inhibitor which utilises Starpharma’s DEP delivery technology. AstraZeneca describes AZD0466 as a best-in-class drug with a broad combination opportunity in solid and haematological tumours[2].

The Bcl family of proteins are important in the regulation of cell death, known as apoptosis. Bcl2 is an anti-apoptotic protein which allows cancer cells to live indefinitely and remain resistant to many treatments. Bcl2 is a clinically validated oncology target with venetoclax (VenclextaTM – AbbVie/Genentech) being approved by the US FDA in 2016. Peak global sales of venetoclax are projected to be greater than US$7 billion[3]. However despite its significant market potential, it is considered that there are gaps in the therapeutic potential of these first generation Bcl2 inhibitors[4]. Venetoclax may not maximise the inhibition of Bcl2 proteins, with surviving cancer cells potentially able to exploit the combined Bcl2/xL pathway as a parallel survival mechanism[5].

Starpharma’s CEO, Dr Jackie Fairley, said: “We’re very excited to be able to confirm the first oncology target for our DEP licence with AstraZeneca. AZD0466 has the potential to be a best-in-class drug with a broad combination opportunity in solid and haematological tumours, due to its broader Bcl2/xL profile. There are currently no marketed drugs which target this dual Bcl2/xL pathway and we are pleased that our DEP platform can play a part in filling this gap.”

Dr Fairley added: “Having recently announced the successful results of our DEP docetaxel phase 1 clinical trial and commencement of phase 2, this news further builds on the momentum of our DEP platform. Today’s announcement further highlights the broad applicability and depth of enhancement offered by our DEP platform. Furthermore, the reproducible benefits across multiple internal and external drug candidates provide additional validation of our DEP platform as we move multiple candidates into the clinic. We look forward to AstraZeneca progressing AZD0466 into the clinic to improve the lives of cancer patients around the world.”

Under the AstraZeneca multiproduct DEP licence, Starpharma is eligible to receive potential development, launch and sales milestones of US$124 million for AZD0466, and US$93.3 million for each subsequent qualifying product under the multiproduct licence. Starpharma will also receive tiered royalties on net sales on AZD0466 and any other resultant DEP AstraZeneca products, and AstraZeneca funds development costs of AZD0466 and other DEP AstraZeneca products.

On September 28, 2017 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology Company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology, reported release of an abstract from a clinical study evaluating poziotinib in EGFR Exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) by scientists from The University of Texas MD Anderson Cancer Center, the sponsor of the trial (Press release, Spectrum Pharmaceuticals, SEP 28, 2017, View Source [SID1234520674]). This abstract contains limited data as of the submission deadline of June 21, 2017. Additional data from their clinical experience and the ongoing Phase 2 study will be released in an oral presentation at the 18th International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in Yokohama, Japan, October 15-18, 2017.

Wednesday, October 18th, 2017:

Abstract # Type Title First Author/Presenting Author Time

10369 Oral The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC Elamin, Heymach 11:00 AM-11:10 AM JST

Abstract #10369: The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC

Background

Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients EGFR exon 20 mutations from an ongoing phase II study.

Methods

We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).

Results: In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3rd generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to > 85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH).

To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.

Conclusion: Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.

About Poziotinib

Poziotinib is a novel, oral pan-HER inhibitor that irreversibly blocks signaling through the Epidermal Growth Factor Receptor (EGFR, HER) Family of tyrosine-kinase receptors, including HER1 (erbB1; EGFR), HER2 (erbB2), and HER4 (erbB4), and importantly, also HER receptor mutations; this, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer. Spectrum received exclusive license to develop, manufacture and commercialize worldwide excluding Korea and China from Hanmi Pharmaceuticals.

On 28 September 2017 Evotec AG (Frankfurt Stock Exchange: EVT, TecDAX, ISIN: DE0005664809) and Exscientia Ltd (“Exscientia”) reported that Evotec has made a EUR 15 m investment to take a minority stake in Exscientia (Press release, Evotec, SEP 28, 2017, View Source [SID1234520672]). Through this investment, Evotec becomes the first strategic shareholder in the UK-based company. Exscientia is focused on Artificial Intelligence (“AI”)-driven drug discovery and design. With more than 1,800 scientists, Evotec has one of the largest and leading drug discovery platforms in the industry.

Exscientia and Evotec have cooperated since early 2016 to advance small molecules and bispecific small molecules in immuno-oncology. The ongoing success of this partnership was the basis of this expanded and deepened corporate relationship. Exscientia is the world leader in developing and applying AI approaches specifically to design new and better therapeutic molecules in a faster and more cost-effective manner. Exscientia’s approach fuses the power of AI with the discovery experience of seasoned drug hunters and chemistry experts. This investment will enable Exscientia to drive higher value partner programmes and expand discovery on its automated design platform.

Dr Werner Lanthaler, Chief Executive Officer of Evotec, said: “Our investment in Exscientia represents Evotec’s single biggest equity placement to date and in, what we feel, is the world leading AI technology company. Working with Exscientia on a joint immuno-oncology project over the past year, we have experienced first-hand how its AI approaches, along with our medicinal chemistry platform, can positively and radically impact drug discovery. We are very excited about the joint potential to leverage AI in chemistry. This investment is also the first time that we can efficiently use our recently awarded EUR 75 m loan facility from the European Investment Bank to bring down cost of capital for such an investment.”

Commenting on the investment, Prof. Andrew Hopkins, Chief Executive Officer of Exscientia, added: “Exscientia and Evotec have built a close relationship over the past year sharing mutual interest in agile innovation. We are delighted that Evotec has made this investment for a minority equity stake, allowing Exscientia to deliver more drug discovery projects in a rapid and capital efficient manner. I’m also delighted that Dr Mario Polywka, Chief Operating Officer of Evotec, will join Exscientia’s Board of Directors, allowing us to benefit from his strong operational expertise in growing successful biotech companies.”