Aug 31, 2018

AstraZeneca’s DEP Bcl2/xL inhibitors show compelling efficacy and synergy in combination

AstraZeneca’s DEP Bcl2/xL inhibitors show compelling efficacy and synergy in combination

 

  • AstraZeneca’s first of several patent applications on Starpharma’s DEP® dendrimer with AstraZeneca’s Bcl2/xL inhibitors has been published, showing compelling results
  • DEP® Bcl2/xL conjugates demonstrate better anti-cancer activity than Bcl2/xL inhibitor alone in multiple cancer models
  • DEP® Bcl2/xL conjugates in combination with leading current anti-cancer treatments provide substantial improvements in efficacy in multiple leukemia models

 

Melbourne, Australia; Starpharma (ASX: SPL, OTCQX: SPHRY) today announced AstraZeneca’s first patent application on DEP® Bcl2/xL conjugates has been published by the World Intellectual Property Organisation. These DEP® Bcl2/xL conjugates combine Starpharma’s innovative DEP® delivery technology with AstraZeneca’s novel Bcl2/xL inhibitor for treating various cancers, including leukemias.

The published patent application shows compelling efficacy data on DEP® Bcl2/xL conjugates, both alone and in combination with other leading current anti-cancer treatments, in various preclinical human tumour models.

As announced on 28 September 2017, AstraZeneca describes its DEP® Bcl2/xL conjugate, AZD0466, as “best-in-class” with a broad combination opportunity in both solid and haematological tumours (blood cancers)[1].  Bcl2 is a clinically validated oncology target with the leukemia drug venetoclax (Venclexta® - AbbVie/Genentech) approved by the US FDA in 2016. Peak global sales of venetoclax are projected to be greater than US$7 billion[2]. However, venetoclax has only anti-Bcl2 activity and its efficacy may be limited because cancer cells are potentially able to exploit a parallel survival mechanism[3]. Therefore, targeting both Bcl2 and Bcl/xL (as AstraZeneca’s novel DEP® Bcl2/xL conjugate AZD0466 does), and using it in combination with other therapies, are attractive strategies that may overcome problematic drug resistance which occurs in many human cancers and thereby provide better efficacy.

Starpharma CEO, Dr Jackie Fairley commented: “AstraZeneca’s impressive data published today demonstrates that the DEP® Bcl2/xL conjugates are highly effective across a range of cancer types both alone and in combination with other anti-cancer agents. Especially exciting for Starpharma is the combination with blockbuster products such as Rituximab, where the DEP® Bcl2/xL conjugates, including AZD0466 showed a strong synergistic effect. Given the synergy appears to also occur with other leading anti-cancer drugs this could represent an important additional benefit for the DEP® platform”.

The publication of this patent application results from the highly successful collaborative research effort between Starpharma and AstraZeneca and names inventors from both companies.

Under the AstraZeneca multiproduct DEP® licence, Starpharma is eligible to receive potential development, launch and sales milestones of US$124 million for the first DEP® product, and US$93.3 million for each subsequent qualifying product. Starpharma will also receive tiered royalties on net sales, and AstraZeneca funds development costs of DEP® AstraZeneca products, including these DEP® Bcl2/xL conjugates.

Summary of the Published Data

In one study utilising an Acute Lymphoblastic Leukemia model, AstraZeneca compared its Bcl2/xL inhibitor alone to two DEP® Bcl2/xL conjugates. The model uses the human Acute Lymphoblastic Leukemia cell line RS4;11. Figure 1 shows that DEP® Bcl2/xL inhibitor conjugates were more efficacious than the Bcl2/xL inhibitor alone.

 

Figure 1 In vivo anti-tumor activity of DEP® Bcl2/xL conjugates in a human Acute Lymphoblastic Leukemia model


Combination therapy is extremely common in cancer treatment to improve efficacy outcomes.  The recently published patent also explored the performance of the novel DEP® Bcl2/xL conjugates in combination with leading anti-cancer drugs including Rituximab and AstraZeneca’s acalabrutinib (Calquence) in lymphoma models. The efficacy of the DEP® Bcl2/xL conjugates in combination with these widely used cancer drugs was extremely impressive, showing significant synergistic effects compared to the drugs alone. This finding is significant, particularly given the fact that this strongly synergistic effect is seen reproducibly.

In a study utilising a B cell Lymphoma model (SuDHL-4), DEP® Bcl2/xL conjugates in combination with Rituximab performed much better than Rituximab alone. The combination significantly inhibited tumor growth and resulted in complete tumor regression in most animals, whereas none was seen with single drug treatment (Figure 2).

Rituximab is a leading leukemia therapy sold under the brand names Rituxan and Mabthera. In 2017 Rituximab had sales of approximately US$7.5 billion and is primarily used to treat non-Hodgkin's lymphoma and chronic lymphocytic leukemia[4].

 

Figure 2 In vivo anti-tumour activity of DEP® Bcl2/xL in combination with Rituximab in a human lymphoma model


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[1] 3rd AstraZeneca-MedImmune-CRUK Cambridge Centre Symposium 2017 presentation

[2] http://www.fiercepharma.com/marketing/abbvie-roche-look-for-blockbuster-boost-from-110k-leukemia-med

[3] https://www.astrazeneca.com/content/dam/az/Our-Science/IMED-Biotech-Unit/IMED_Annual%20Review_2016.pdf

[4] Medtrack Database, August 2018

 

 This contains certain forward-looking statements.