Posts Tagged Preclinical

Anti-angiogenic/ Anti-Vasculogenic Therapy for Triple Negative Breast & other Cancers


Rathin Das, Founder and CEO of Synergys Biotherapeutics talked about antibody fusion therapy for cancer treatment at http://www.bio2devicegroup.org event.

Synergys is a preclinical stage biotherapeutics company, developing polyfunctional antibody drugs.  It has established an antibody-linked biological payload system called Antibody-Targeted Anti-vasculogenic Payload (A-TAP). The Company’s most advanced product candidate generated from this system is Anti-EGFR-TAP that is being developed as a new generation anti-angiogenic/anti-vasculogenic biotherapeutic for Triple Negative Breast Cancer (TNBC) and other EGFR+ malignancies.

Angiogenesis is the development of new vasculature from preexisting blood vessels and/or circulating endothelial cells, and is essential for neoplastic proliferation, progression, invasion and metastasis. VEGF (vascular endothelial growth factor), PDGF (Platelet-derived growth factor ), bFGF (basic fibroblast growth factor) are among the most prominent of various growth factors and their signaling pathways that support angiogenesis. Due to the commercial success of the anti-angiogenic antibody drug bevacizumab (Avastin®) by Genentech/Roche, the field of angiogenesis has been generating significant interest as potential target for possible anti-cancer therapy. Bevacizumab is an anti-VEGF MAb which blocks angiogenesis by inhibiting VEGF-A . The MAb interacts nonselectively with its receptors VEGFR1 and VEGFR2.

However, bevacizumab suffers from several safety and efficacy issues, despite its approval for various cancers, including colorectal, renal, cervical carcinoma, glioblastoma, and head and neck and others. It failed to delay the growth of metastatic breast cancers, failed to improve the quality of life of the patients, and its side effects were significant, leading to reversal of the drug’s FDA approval in 2011. Another anti-angiogenic MAb , Ramucirumab (Cyramza) from ImClone, (recently acquired by Eli Lily), targets VEGFR2, and has been recently approved. Ramucirumab has been approved for gastric cancer and NSCLC, but it failed at clinical Phase III for metastatc breast cancer.

Earlier to the development of bevacizumab, Endostatin, a 20 kDa fragment of collagen XVIII, was identified as a naturally occurring inhibitor of endothelial cell proliferation in vitro and angiogenesis in vivo. Although highly efficacious in decreasing tumor burden in animal models, and safe in humans in very high doses, no consistent evidence of antitumor activity for recombinant human endostatin (huEndo) was observed in human trials. Several explanations have been advanced for huEndo’s efficacy failure in humans, including its rapid clearance, low potency and sub-optimal presentation as the monomeric form . Despite these limitations, a proprietary formulation of endostatin (EndoStarÒ) has completed Phase III and IV testing and is now approved in China, providing further evidence of its safety and potential for efficacy, said Das.

Synergys is utilizing an anti-EGFR monoclonal antibody as a targeting domain to facilitate the delivery of a mutant form of human endostatin, huEndo-P125A (where Alanine substitution of Proline 125, significantly increases anti-angiogenic potency of endostatin), as a biological anti-angiogenic payload, for the treatment of cancer. Most importantly, unlike earlier failures of endostatin used as an anti-angiogenic in clinical trials, where monomeric form of endostatin with N-terminal amino acid deletions was used, “ in our approach a ‘dimeric’ fusion of a full-length endostatin-P125A mutant to a targeted antibody is utilized”, said Dr. Das. The “dimeric”endostatin-P125A generated by linking two molecules of endostatin-P125A to two heavy chains of an antibody molecules shows excellent inhibition of endothelial cell angiogenesis and profound inhibition of vasculogenic mimicry or VM. VM is the formation of an alternative tumor vasculature assembled directly from tumor cells and not from vascular endothelial cells.

Synergys is developing Anti-EGFR-TAP for the treatment of Triple-negative breast cancer (TNBC), which is an especially deadly subtype of breast cancer, said Das. It comprises approximately 15% of newly diagnosed breast cancer and is overrepresented in young women, in patients with BRCA1/2 mutations and in women of African ancestry (1). At present, TNBC has the poorest survival outcome of all breast cancer subtypes. TNBC lacks the three most commonly targeted receptors in human breast cancer: the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)/neu. However, the expression of epidermal growth factor receptor 1 (EGFR, HER1) is reported in greater than 60% of TNBC. Although no approved targeted therapy is currently available for the treatment of this highly aggressive subtype of breast cancer, several recent clinical studies involving agents for DNA repair by poly (adenosine disphosphate-ribose) polymerase (PARP inhibitors) have shown promising results in some BRCA1 and BRCA2 mutated TNBC patients. However, the role of PARP inhibitors in unselected TNBC patients is still uncertain and newer more effective targeted therapies are urgently needed for TNBC .

In addition to tumor induced angiogenesis, TNBC readily exhibits VM. Indeed Anti-EGFR-TAP demonstrated excellent inhibition of endothelial cell angiogenesis and profound inhibition of VM of TNBC cells.  Anti-EGFR-TAP treatment also showed significant inhibition of growth of triple negative breast cancer xenografts relative to those treated with cetuximab (Anti-EGFR MAb).  Various published studies have shown that none of the approved angiogenesis inhibitors inhibit VM. Indeed, not all anti-angiogenic antibodies show anti-VM activities. To this end, in a head to head comparison, three other anti-angiogenic antibodies were negative in VM assays relative to Anti-EGFR-TAP. The inhibitory effects of Anti-EGFR-TAP for both angiogenesis and vasculogenic mimicry , therefore, is both interesting as well highly promising as a potential drug for progressive cancers, said Das.  Further Das observed, it is important to inhibit both angiogenesis and VM, not just angiogenesis, to inhibit overall tumor growth.

Synergys is attempting to collect more safety and efficacy data with significant animal studies and also looking at other EGFR+ malignancies . Das said that the A-TAP technology is a new generation of cutting-edge biological payload system that is capable of generating highly efficacious polyfunctional biotherapeutics , with multibillion dollar market potential.  Currently, they are seeking financing for rapid product development. The company is also open to negotiations around partnering and structuring deals around out-licensing business model.

(Edits by Rathin Das).

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Aligning value proposition: From Preclinical to Market for Medical Devices


Tim Pelura, CEO, Surpass Preclinical CRO talked on how medical device companies can align their strategy, from preclinical to market, with a focus on the value proposition, at www.bio2devicegroup.org event.

We are operating under a new reality now where power has shifted to the payers and the providers, said Pelura.  Medical device companies are evaluated based on safety and procedural efficacy as well as cost and value.  Increasingly heightened regulatory scrutiny and tightening FDA regulations have led to increase in audits (which were up 40% in the last year) and warning letters are (which were up 24% over the last 2 years).  Due to regulatory and reimbursement challenges, medical device companies are focusing their R&D efforts on improving already approved devices, rather than developing innovative new products.  Meanwhile startups are finding the landscape challenging due to funding challenges and increasing costs of bringing new products to market.

Healthcare Infostep

Healthcare Infostep (Photo credit: Wikipedia)

Inkeeping with the reality of pressures on payers that are transmitted down, new healthcare delivery models are emerging, and therefore, patient pathways are being modified to obtain to obtain better outcomes, with less cost.  Medical device companies will need to work with new business models, that solve significant problems and reduce overall costs.  Companies seeking growth will need to expand their offerings to target underserved populations and lower socioeconomic classes.

In essence, it is about the value proposition offered by the new product or service, “what benefit you provide for who and how you do it uniquely well”, said Pelura.  He advised, these “must-haves” in a business pitch, “describe your target buyer, the problem you are seeking to solve, and why you do it better than the alternative”.

Pelura walked the audience through the process of arriving at the value proposition.  First, companies must define the problem they are seeking to solve and identify correctly the need to solve the problem.  Next, they should try to go after obvious problems, rather than aspirational or “good to solve” problems.  And finally, they should try to address acute or critical problems.

In defining a solution, they should try to generate many ideas and then measure the viability of customer adoption of each idea using gain/pain ratio; what the customer stands to gain versus the cost of adoption of the new solution.  The best solutions are those that offer game-changing benefits, with minimal modifications to the existing process or environments, said Pelura.  Go for “Disruptive Innovations, that are Non-Disruptive to Adopt”, advised Pelura.   Medical device companies must visualize the entire process or patient pathway to ensure that the new solution would cause minimal disruptions, in the whole process.

While new technologies often emerge with a focus on engineering and progress to bench testing and then plan preclinical, and clinical strategies and only then consider navigating regulatory, market, and reimbursement challenges; in actuality, they should invert the process.  They should begin with considering reimbursement challenges, analyze the competitive landscape, study the market opportunity, give thoughtful consideration to the regulatory challenges, then consider clinical and preclinical strategy, before embarking on prototype and bench testing.  Because if the value proposition is wrong then a company can end up with a product that no one wants or needs, resulting in considerable waste of precious innovation dollars and time, said Pelura.

Speaking of Surpass, Pelura shared that preclinical Contract Research Organization, Surpass is doing things differently.  While having deep expertise as a preclinical CRO in helping medical device companies with their preclinical in vivo and human cadaveric studies, Surpass also seeks to impact the system, by probing and assisting their clients with questions that go to the value proposition.  Surpass assists the clients in designing the most translatable preclinical study by understanding issues of clinical end points, product’s desired features and characteristics, all the while keeping in mind who would be operating the device, studies and activities that might need to be completed to demonstrate the products, performance, safety, and efficacy, as well as data that would be required to drive reimbursement and more.  This novel process ensures that any preclinical testing performed is aligned to the new product’s value proposition, hence helping save valuable healthcare innovation dollars.  

The session was followed by Q&A.

 

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