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  • Halozyme PegpH20 Works Best On High Hyaluronan- But How High Is High?

    Hyaluronan (NASDAQ:HA) is a substance or GAG which fills the extracellular space. In tumors that secrete HA, overfilling increases intratumor pressure, constricting arterioles which deliver chemotherapy to cancer cells. PegpH20 has its own antitumor activity, but more importantly it removes HA, reducing pressure and increasing the flow of chemotherapy. The tumor most susceptible to this effect is Pancreatic ductal adenocarcinoma. Recent interim results from Halozyme study 202 demonstrated a 67% increase in Progression Free Survival due to the addition of PegpH20 to the current standard of care Gemcitabine-Abraxane (9.2 mos in Study 202 vs 5.5 mos in MPACT Study).

    The Peg-Gem-Abraxane PFS value was achieved in High Hyaluronan patients. Just what percentage of patients are in fact High in Hyaluronan depends on the cut off and method of measuring Hyaluronan chosen. Two main techniques have been used by Halozyme- earlier immunohistochemistry using bionyated HA binding protein and HTI 601 or Stainmap (tm) a bionyated recombinant immunoadhesin. The former required 25% HA positive staining for High Status. The latter is given a Digital Image Score (currently in Study 202 by GE Medical) according to Halozyme's recently issued US Patent 8846034:

    "In one example, a method of diagnosis utilizes a sample of tumor tissue, tumor cells or a bodily fluid containing proteins from a patient. In the method, the presence and level of expression of HA can be determined using an HABP, for example a TSG-6-LM, TSG-6-LM-Fc or variant or mutant thereof, as provided herein. The level of expression of the HA is determined and/or scored and compared to predetermined HA phenotypes associated with disease. As described below, these predetermined values can be determined by comparison or knowledge of HA levels in a corresponding normal sample as determined by the same assay of detection and using the same HABP reagent. It is within the level of one of skill in the art to determine the threshold level for disease diagnosis depending on the particular disease, the assay being used for detection of HA and/or the HABP detection reagent being used. For example, in bodily fluids such as plasma, HA levels greater than 0.015 .mu.g/mL, and generally greater than 0.02 .mu.g/mL, 0.03 .mu.g/mL, 0.04 .mu.g/mL, 0.05 .mu.g/mL, 0.06 .mu.g/mL or higher correlates to the presence of a tumor or cancer. In another example, in immunohistochemistry methods of tumor tissues with a score of HA.sup.+2 or HA.sup.+3 can be determinative of disease. If the level is indicative of disease, then the patient is diagnosed with having a tumor."

    So, each sample is compared to the expected HA value for the tissue involved- not to a preset cut off. The 87% value for High Hyaluronan status in Pancreatic Cancer is based on the old technique and 25% positive staining per field. The 63% value for High Hyaluronan status in the same tumor is based on HTI 601, a value which will be presented at AACR 15. Halozyme gives only a 40-60% estimate of High Haluronan PDA in their interim analysis of study 202. Why the hedge? Well since PegpH20 works better in high Hyaluronan tumors, the higher the cut off set for entrance into the high Hyaluronan group the better for showing a separation from the current standard of care. I predict accelerated approval, based on the 40% cutoff and 67% (or better with the subsequent addition of LMW Heparin to the combination) PFS advantage, then medical oncologist expansion of the treatment group in this most aggressive cancer.

    So High is as High as needed to provide maximal added quality of life to these patients in desperate need of same.



    Presentation Title:Development and analytical validation of a novel assay for tissue detection of hyaluronan in the tumor microenvironment to select patients for molecularly targeted pancreatic cancer therapies
    Presentation Time:Sunday, Apr 19, 2015, 1:00 PM - 5:00 PM
    Location:Section 24
    Poster Board Number:19
    Author Block:Arnold B. Gelb, Ping Jiang, Laurence Jadin, Daniel C. Maneval, H. Michael Shepard. Halozyme Therapeutics, Inc., San Diego, CA

    A recently described biotinylated recombinant immunoadhesin (HTI-601, Jadin 2014) was adapted for use in an immunohistochemistry-based assay on formalin-fixed paraffin-embedded tissue. Sensitivity, specificity, and within-laboratory precision studies were performed in a research mode and then at a central laboratory on a validation set of approximately 200 tumor and normal tissues under GCP conditions. Both pathologist scoring and operator-assisted image analysis (positive pixel count for strong positive pixels) were evaluated.
    Results: Analytical sensitivity studies identified an optimal probe dilution of 0.417 µg/mL on an immunostainer based on dynamic range in 4 human tumor xenografts containing differential levels of HA. The frequency of high HAobserved was 62.7% of archival PDA (N=75).

    Mar 19 10:58 PM | Link | 3 Comments
  • The Breakthrough Case For Halozyme PEGPH20 - Round Peg Round $HALO

    FDA- "On July 9, 2012 the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed. FDASIA Section 902 provides for a new designation - Breakthrough Therapy Designation. A breakthrough therapy is a drug:

    • intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition and
    • preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development."

    1. "The Keytruda Breakthrough Therapy Designation in advanced NSCLC is supported by data from the ongoing Phase 1b KEYNOTE-001 study, and updated findings were recently presented at the European Society of Medical Oncology (ESMO) 2014 Congress. The FDA's Breakthrough Therapy Designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. KEYTRUDA was previously granted breakthrough status for advanced melanoma."
    ***Overall Response Rate of 66 Percent Observed in KEYTRUDA-treated Patients Whose Cancer Progressed on Brentuximab Vedotin.

    2. On March 6, 2013, FDA granted ceritinib breakthrough therapy designation based on preliminary evidence of clinical activity in patients with metastatic ALK-positive NSCLC previously treated with crizotinib.

    The primary endpoint supporting approval was objective response rate (ORR) according to RECIST v1.0 as evaluated by both investigator and a Blinded Independent Central Review Committee (BIRC). Duration of response (DOR) was also assessed.

    3. Imbruvica is the second drug with breakthrough therapy designation to receive FDA approval. The Food and Drug Administration Safety and Innovation Act, passed in July 2012, gave the FDA the ability to designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases.

    The FDA is approving Imbruvica under the agency's accelerated approval program, which allows the FDA to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. The FDA also granted Imbruvica priority review and orphan-product designation because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease, respectively.

    Imbruvica's accelerated approval for MCL is based on a study where 111 participants were given Imbruvica daily until their disease progressed or side effects became intolerable. Results showed nearly 66 percent of participants had their cancer shrink or disappear after treatment (overall response rate). An improvement in survival or disease-related symptoms has not been established.

    So, based on PRELIMINARY Data just short of or equivalent to Halozyme's PegpH20 Study 202 P2 interim data, the FDA recently granted Breakthrough Status to two solid tumor and one blood cancer therapies. As far as "demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development," the 71% ORR in the high hyaluron group clearly does, in comparison to the 23% ORR seen with FDA approved Abraxane-Gemcitabine in the same population in the MPACT study.

    Aduro BioTech's GVAX, a cancer vaccine previously halted in the clinic, is finding new life in a combination treatment that the Berkeley-based company is testing in patients with pancreatic cancer. With a grim overall 5-year survival rate of about 6%, pancreatic cancer has long remained one of the toughest targets in the oncology field.

    Aduro was granted a coveted breakthrough therapy designation from the FDA for the combo approach, made up of its CRS-207 and GVAX, which it acquired from Biosante ($BPAX) last year.

    The designation was awarded based on findings from a Phase II trial in metastatic pancreatic cancer patients. In a randomized study of 93 patients who failed or refused prior therapy, patients receiving the combination of GVAX Pancreas and CRS-207 cancer vaccines lived 6.1 months compared to those receiving GVAX Pancreas vaccine alone, who lived 3.9 months.

    So, Aduro was recently granted Breakthrough designation specifically for the same target population -Previously untreated patients with Pancreatic Cancer Stage 4b, in which they achieved an Overall Survival data 50% shorter than Halozyme Progression Free Survival. This comparison in layman's terms is: Take Halozyme and stay out of the hospital for 9 months (in high Hyaluronan High Patients representing>50%) or take Aduro and survive 6months- including time in the hospital.

    The choice is simple. Halozyme is Expecting Breakthrough status in the coming months.

    Tags: HALO
    Jan 18 12:31 PM | Link | 3 Comments
  • HALOZYME Final (Not Just Mature) PegpH20-Gemcitabine Foundation Phase 1B Data

    HALO has told us in Sept 2013 that the Median Overall Survival for the High Hyaluronan group was 529 days- "not mature"- meaning more than 1/2 of the 6 pts in this group were still alive almost 18 mos into the study (Folfirinox had been the leader in MOS with 11.1 mos but in a Ph3 trial- 8.5 for Abraxane-Gem). Progression Free survival was set at 219 days or 7.3 mos vs 6.6mos with Folfirinox and 5.5mos with Abraxane-Gem- but this won't change. What will change is MOS- Greg frost announced on 11/5/13 that the MOS was still "not mature" so then around 570 days. In Jan 2014, Helen Torley said that HALO was preparing the data for publication. Did she mean the Mature data (in other words, were there then 2 mos later 3 or fewer alive?) or the Final data (all passed on)? It has certainly taken a while to now present the final data. There was one "complete biochemical responder"- so, did he or she live the bulk of this time? Did they live right up to the deadline for ASCO GI data submission? Anything longer than 570 days - 19 mos- will be a very pleasant surprise for me. Given the current numbers for Panc Ca Stage 4b, if these numbers are approached on Ph2, we're talking breakthrough status and early approval. The PPS reaction should be substantial--but only if the 71% of institutional owners allow it. They won't be able to contain Ph2 results- if similar. Lastly, just the presentation at ASCO GI is testament to the fact that everything about this study was top notch and a feather in HALO's cap- had it not been so, the abstract would have been rejected. Torley and Joshi came to HALO to build an oncology company, putting their substantial reputations on the line. Their first step was crucial and a success.

    Dec 03 10:27 AM | Link | Comment!
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