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.”