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).

Genetically Engineered Oncolytic Virus to Treat Glioblastoma

Glioblastoma or GBM is the most aggressive brain tumor for which currently there exists no cure.  Michelle Chen talked about targeted oncolytic virus therapy for these tumors.  These tumors are highly malignant because the cells reproduce quickly and they are supported by a large network of blood vessels.  There are approximately 25,000 new cases in Europe and US, each year.  Median survival in newly diagnosed patients who receive the best treatments is less than 14 months.  Most patients experience quick relapse and survival after 5 years is very dim.

Following the diagnosis, the current standard of care consists of surgery, radiotherapy, and chemotherapy with temozolomide.  FDA has recently also approved Avastin for recurrent GBM.  But new therapies for GBM are urgently needed.  There is a lot of activity in this space but currently active drugs have lot of safety concerns.

English: TAC_Brain_tumor_glioblastoma-Coronal_plane Italiano: Immagine TAC della zona cerebrale, identificando un tumore di tipo glioblastoma (Photo credit: Wikipedia)

DNX-2401 may be an elegant genetic engineered solution.  DNX-2401 is an engineered virus that is capable of selectively and effectively killing a broad range of tumor cells with defects in the retinoblastoma (Rb) pathway.  The virus enters cells by binding to specific types of integrins highly expressed on tumor cells and tumor endothelial cells.  Once it gets in, the virus replicates rapidly and the replicating viruses in turn kill host tumor cells.  Further cell killing is done by triggering of anti tumor immune response which is capable of eliciting tumor destruction.

DNX-2401 therapy has shown to improve survival in animal models.  Relapse of GBM is attributed to recurrence and persistence of tumor stem cells.  Is it possible that the virus kills the stem cells as well?  Indeed, results indicate that brain tumor stem cells are also susceptible to being killed by DNX-2401, said Chen.  Additionally, Delta 24 RGD + temozolomide seem to provide enhanced therapeutic benefit in combination therapy.

Early safety profile of DNX-2401 looks very good and early indication suggests it to be very efficacious and capable of selectively and effectively killing a broad range of tumor cells.  Expectations are that DNX-2401 will demonstrate therapeutic effects in a wide variety of cancers.  Currently DNX-2401 is delivered by direct injection into the tumor bed, guided by the MRI through the cranium or through surgical resection, into the walls of the resection cavity to kill residual tumor cells.

Chen went into more detailed explanation of the mechanism of action, and her talk was followed by Q&A.

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Other information and events below.

Jobs: There is a huge uptick in JOBS.  Check out new jobs posted for May at http://bit.ly/1o85CTM .

TiEcon: If you are a professional  in #healthIT, #digital health,  #internetofthings, #cloud, #bigdata or related, I would say this is the conference, you don’t want to miss – It gives fabulous opportunity to network with 4000+ professionals. Check out great agenda, top notch speakers & panelists at www.tiecon.org.  Register for #TiEcon (May 16 & 17 at Santa Clara Convention Center) at link http://tinyurl.com/kr2hkcw  as my guest & enter promo code tievalue to get $100 discount.

Healthtechnology conference & Code-a-thon http://www.healthtechnologyforum.com, focused on exploring pathways to sustainable health, is on May 20 in SF. Please register for the conference as my friend, with the discount code “HTF14-FriendOfOrganizer” and send me your first & last name at wd_darshana at hotmail dot com, to get $150 off the price of the ticket. There are $20K+ in prizes at the code-a-thon.

Dr. Sarvajna Dwivedi, founder of Pearl Therapeutics will talk on Tuesday, May 6.  Notice venue change & pre-register at  http://www.eppicglobal.org . Pearl Therapeutics was acquired by Astra Zeneca last year, for $1.15 B and was a winner of TiEcon’s TiE50 awards, two years in a row. It will likely be sold out event, so please pre-register.

http://www.bio2devicegroup.org meets every Tuesday in Sunnyvale, CA.  Morning meetings are free, wealk-ins welcome. Dr. Alan Jacobs, Founder & CEO, PerceptiMed will talk on “Preventing Drug-Related Patient Injury and Death With Advanced, Cost-Effective Technology Systems“.

Feel free to send me an email for any of these events at wd_darshana at hotmail dot com and you can follow my updates on Twitter @DarshanaN.

Prognostic Biomarkers in Diffuse Large B-cell Lymphoma

Jason Yonehiro, founder and CEO of CombImmune Inc., talked about diagnostic biomarkers in lymphoma and their application in clinical utility and drug discovery, at www.bio2devicegroup.org event.

Non-Hodgkin’s Lymphoma refers to any of a large group of cancers of lymphocytes (white blood cells) and is often marked by lymph nodes that are larger than normal, accompanied by fever and weight loss.  They can be aggressive or fast growing and indolent or slow growing.  NHL is steadily growing over past few years.  While there were 115,000+ cases of NHL in 2002, worldwide, over 140,000 cases of NHL are anticipated in 2019.  NHL is more common in women.

Currently R-CHOP, a combination therapy that adds the drug Rituximab, a monoclonal antibody to standard combination called CHOP, consisting of four chemotherapy drugs, is considered a standard regimen for Diffuse Large B-Cell Lymphoma, the commonest type of NHL.  Bone marrow transplant is considered to be the second line of treatment.  Rituxan can lead to serious, including fatal, adverse effects and not all patients respond to this mode of treatment.  There is a significant unmet need for effective therapies for treatment of T-cell lymphomas, said Yonehiro.  There are several drugs in the pipeline.  Avastin failed in the trials, Revlimid is showing promise, but likely to be pushed further in treatment paradigm and Rituxan continues to remain gold standard in treatment.  Rituxan is not cheap.  A 28 day regimen with Revlimid, costs up to $10,000.  Rituxan is expected to come off patent and price may come down but its efficacy remains the same.

Thus far, it has been observed that Diffused Large B Cell Lymphoma (DLBCL) patients do poorly with the current standard of care, the R-Chop therapy.  But there do not exist any molecular diagnostic tests that predict patient outcome.  About 75% of patients respond to the standard of care but about 30-40% of patients relapse and die within 5 years.  The challenge is to identify high risk patients who might benefit from more aggressive chemotherapy.  It is important to minimize overtreatment of all patients, offer more treatment options, individualize treatment plans, identify high risk patients, make better clinical assignment, and optimize treatment.

Studies indicate that distinct patterns of chromosomnal abnormalities characterize NHL and there is need to better understand how these differences impact the response to certain therapies, said Yonehiro.  The field of personalized medicine is growing.  About $9.7B went into this area but this is expected to double by 2017.  The tool currently used is International Prognostic Index or IPI.  It is a clinical tool developed to aid in predicting the prognosis of patients with aggressive non-Hodgkin’s lymphoma.  In addition to the Ann Arbor Stage, IPI added certain other factors deemed significant, including age, elevated serum LDH, performance status, and number of extranodal sites of diseases.  However, this tool does a poor job, said Yonehiro.

CombImmune’s mission is to utilize prognostic and predictive biomarkers that enhance understanding of immune dysfunction to tumor infiltration and combine that with therapeutics that restore immune function and destruction of the tumor.  CombImmune prognostic test is based on Two Gene Score (TGS) to identify high risk patients.  TGS + IPI give a significantly more accurate patient profile, said Yonehiro.  Originally, they developed a 300 gene assay and now it is distilled down to 2 genes.  TGS has been vetted through study of 692 patients and there is an ongoing 215 patients prospective study.  TGS is based on PCR (Polymerase Chain Reaction) standardized molecular diagnostic genetic technique.

Genomic information is critical to improving management of hematologic cancers, said Yonehiro.  Two Gene Test, based on LMO2 and CD 137 expressions are robust independent prognostic determinants in DLBCL.  All studies thus far clearly indicate that TGS and IPI capture more high risk patients than IPI alone.  The clinical utility and value would be in its ability to pick out patients in need of more aggressive therapy, while others are put on “wait and watch” list.  The talk was followed by Q&A.

English: Micrograph of a diffuse large B cell lymphoma, abbreviated DLBCL. Lymph node FNA specimen. Field stain. See also Image:Large b cell lymphoma – cytology small.jpg (Photo credit: Wikipedia)

Wet AMD – Leading Cause of Blindness: Symptoms, Causes, & Innovative Treatment Options

Dr. Mark Shusterman, Medical Director at Oraya Therapeutics, discussed new treatment options for Wet Age Related Macular Degeneration, at http://www.bio2devicegroup.org .

AMD is a leading cause of blindness for seniors, worldwide. In the US, it impacts more people than cataracts and glaucoma combined. It affects 9.1 million people in the U.S. and 10 to 30 million people worldwide. Almost entire medical budget could be consumed by AMD, if the current paradigm for AMD is not solved, said Shusterman.

Biology of the eye is interesting. Normal human eye has two chambers, the anterior and the posterior chamber. Retina has photoreceptors, with the highest concentration of cons that allow us to see color. These are lined at the back of the eye and create electrical impulses that travel through the optic nerve to the brain. The Macula is an oval shaped spot near the center of the retina and is responsible for high resolution central vision. More specifically, it is the fovea, a dimple shaped central part of the macula that produces the highest resolution vision. Retina is the thinnest at this region and most serious forms of macular degeneration affects this area. Risk factors for macular degeneration include, age (60+ years), race (Caucasians and Asians are at greater risk), gender (women are at higher risk), genetics (probability increases, if someone in the family has it), and life style issues (smoking, diet, obesity, and high blood pressure).

Wet form of macular degeneration is a more serious form which is preceded by Dry AMD. Dry AMD is characterized by drusen in the retina and takes years or even decades to develop. It can remain stable or can progress to Wet AMD. About 10-15% of Dry Amd converts to Wet AMD. In Wet AMD, abnormal blood vessels behind the retina start to grow under the macula and these vessels are very fragile and leaky. The oozing blood and fluids accumulate, eventually scarring the rods and the cons. If untreated, it progresses to loss of central vision within 2 years. Signs and symptoms of AMD include, wavy appearance of straight lines, foggy or blurry central vision, difficulty distinguishing colors, development of central blind spot, difficulty reading, and difficulty recognizing faces. Some of the possible ways to prevent AMD are, eating diet rich in vitamins C & E, selenium and carotenoids, taking prescription vitamins indicated for eye health that includes antioxidants and zinc, exercise, not smoking, and maintaining normal BP, weight, and cholesterol.

Often however, there is a disease progression and until now few viable and cost effective treatment options existed. Initially, there were attempts to treat AMD with laser. But it seemed that laser did not just burn scarred tissue, but some good tissue and nerves as well. It appeared, that with laser, slightly less vision loss in the immediate future was traded with more significant vision loss, a year or two later. Another photodynamic therapy or PDT is still around but only seems to work well in certain forms of AMD, but is not effective for most forms of AMD. Anti-VEGF injections, Lucentis, Avastin, Macugen, and Eylea are all in use and have been a standard form of suggested treatment for AMD, since Lucentis was introduced in 2006. Anti-VEGF drugs work by targeting VEGF (Vascular Endothelial Growth Factor), a protein responsible for creation of new blood vessels. But cost and frequency of injections required are major inhibiting factors. For instance, an injection of Avastin costs $50. An injection of Lucentis costs between $1200 and $1400. Most of these anti-vitreal injections work best when given routinely on a monthly basis. Eylea can be given bi-monthly. While the efficacy of anti-VEGF compounds has prolonged and saved the eyesight of millions of patients worldwide, it has also placed a huge new burden on patients who require costly, regular injections, as well as on the ophthalmic practice and on the healthcare systems. And cost constraints render this form of treatment unavailable to many people, across the world. Additionally, although greatly beneficial in stabilizing the progression of wet AMD, and decreasing resulting vision loss, the use of anti-VEGF agents carries significant known risks, such as infection (endopthalmitis), increase in intraocular pressure (glaucoma), stroke and others.

Oraya therapy is a new breakthrough treatment, intended as one-time, non-invasive procedure for Wet AMD. Oraya Therapy uses highly targeted, low-voltage X-rays to inhibit and prevent the growth of abnormal blood vessels under the macula (choroidal neo-vascularization) that is most often associated with wet AMD. Radiation is a useful modality because it targets rapidly proliferating and late responding tissues and cells and unlike ablative therapies like laser photocoagulation, it can deliver small amount of energy to the targeted area like the Endothelium (anti-angiogenic), Fibroblasts (anti-fibrotic), and Inflammatory cells (anti-inflammatory). Non-mitotic cells (such as nerve cells) are left largely unaffected. Slowly replicating cells (such as normally proliferating vascular endothelial cells) generally have time to repair the damage or to be replaced by recruitment from outside the target region.

Oraya Therapeutics I-Ray System comprises of Precision-controlled X-ray tube, Patient interface, patented Eye stabilizing device, Eye tracking module, and Intuitive operator interface. The IRay System is designed to deliver three overlapping X-ray beams to the macula, each 4 mm in diameter. The beams are directed into the eye while the patient sits comfortably in a chair, with the head positioned on a chin rest. The entire procedure takes about 20 minutes and the patient can go home after the appropriate post-treatment evaluations are made. Clinical data indicates that the use of radiation in conjunction with existing pharmacologic therapies may have beneficial results in terms of improved disease control with a decreased need for recurrent intra-ocular injections. Examination of the effects of radiotherapy on wet AMD, in more than one thousand patients, indicated that patients treated with radiotherapy were two times more likely to require no further injections and were overall more likely to require fewer than 4 treatments in a year. The radiotherapy was delivered using high-energy external beam systems (with the exception of one study that used brachytherapy), and doses ranged from 7.5 to 24 Gy. The analysis also determined that no patients suffered radiation retinopathy, optic neuropathy, or malignancy. The presentation was followed by Q&A.