Roche’s GA101 (obinutuzumab): Engineering an antibody to beat Rituxan
Jul29

Roche’s GA101 (obinutuzumab): Engineering an antibody to beat Rituxan

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog. Survival rates for people with B-cell driven blood cancers, such as non-Hodgkin’s Lymphoma and chronic lymphocytic leukemia, have vastly improved in the last decade thanks to the introduction of Rituxan, marketed by Biogen Idec and Genentech. But the drug, a chimeric monoclonal antibody targeting CD-20, a protein that sits on the surface of B-cells, has its limitations: not all patients respond at first, and others become resistant to the drug over time. As a result, companies are tinkering with the sugar molecules that decorate antibodies in hopes of coming up with a drug that binds better to its target and, ultimately, is more effective at battling cancer. At the American Society of Clinical Oncology annual meeting, held earlier this year in Chicago, Roche offered Phase III data showing its glycoengineered antibody GA-101 worked better than Rituxan at delaying the progression of CLL. If all goes well with FDA, the drug could be approved by the end of the year. BACKGROUND: Although the CD20 antigen is expressed on both normal and malignant cells, it has proven to be a useful target therapeutically.  Rituximab, ofatumumab and most of the anti-CD20 antibodies in earlier development are Type I monoclonal antibodies, which means that they have good complement-dependent cytotoxicity (CDC) and Ab-dependent cell mediated cytotoxicity (ADCC), but are weak inducers of direct cell death. In contrast to Type I monoclonal antibodies, next generation monoclonals are increasingly Type II, such as GA101 (obinutuzumab) in CLL and NHL and mogamulizumab (anti-CCR4), for T-cell leukemias and lymphomas.  They have little CDC activity, but are much more effective at inducing ADCC and also direct cell death, at least based on in vitro studies performed to date. How does glycoengineering make a difference? Glycoengineering is the term used to refer to manipulation of sugar molecules to improve the binding of monoclonal antibodies with immune effector cells, thereby increasing ADCC. Obinutuzumab is a very different molecule from rituximab, in that it is a novel compound in its own right (originally developed by scientists at Glycart before being bought by Genentech).  It is not a biosimilar of rituximab.  It is also a glycoengineered molecule designed specifically to improve efficacy through greater affinity to the Fc receptor, thereby increasing ADCC activity. The overall intent with the development of obinutuzumab was to significantly improve efficacy over rituximab and Type I monoclonal antibodies in B-cell malignancies using glycoengineering techniques. At the recent ASCO annual meeting, data from a phase III trial was presented to evaluate rituximab or obinutuzumab in combination with the chemotherapy...

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New Targets in Advanced Prostate Cancer

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog. Much hullabaloo has been in the medical news over the past year over new options for the treatment of metastatic castrate resistant prostate cancer (CRPC). FDA approval for two new drugs, abiraterone acetate (J&J’s Zytiga) and enzalutamide (Astellas/Medivation’s Xtandi), has meant a sharp focus on drugs that target the androgen receptor. But at the the American Society of Clinical Oncology Genitourinary (ASCO GU) symposium, held last month in Orlando, intriguing data on new targets for CRPC emerged. Zytiga and Xtandi target the androgen receptor (AR) in very different ways, but the overall effect is similar, in that they can effectively reduce the levels of prostatic serum antigen (PSA), which is reactivated in tumors with advanced disease. Zytiga acts high up in the steroidogenic pathway and one side effect associated with monotherapy is the development of mineralcorticosteroid effects, leading to over stimulation of the adrenal glands and hypokalaemia.  This toxicity must therefore managed with concomitant prednisone therapy. Xtandi, meanwhile, more directly targets the androgen receptor, which tends to be amplified in advanced prostate cancer. The drug doesn’t have same effect on cortisol production as Zytiga, and can therefore be taken without steroids. The androgen receptor isn’t the only valid target in CRPC, however.  Aldo-keto reductase 1C3 (AK1C3), an enzyme that can facilitate androstenedione conversion to testosterone, is also over-expressed in advanced prostate cancer. Several new agents in early development appear to specifically target AK1C3. At ASCO GU, a couple of abstract particularly caught my eye and are worth highlighting here: 1) Bertrand Tombal et al., presented the initial data on Xtandi monotherapy in advanced prostate cancer in the hormone-naive setting, that is prior to CRPC.  Traditionally, Androgen Deprivation Therapy (ADT) is given to patients with high risk disease.  In the US, LHRH antagonists are used first-line, followed by AR antagonists such as bicalutamide, giving a basis for the rationale testing Xtandi, which is a more complete antagonist of the AR than bicalutamide. In this trial, the single arm design sought to determine whether not enzalutamide would have activity in patients who had not received standard ADT therapy. The waterfall plots in this study (n=67) were impressive. The results showed that: a) Ninety-three percent of study participants experienced a ≥80% PSA decrease at week 25. b) Median change in PSA was -99.6% (range -100% to -86.5%). In other words, most of the men in this trial responded well to Xtandi, suggesting that a randomized trial is well worth pursuing next. You can read more about the specifics of this new development and what Dr Tombal had to say...

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New Developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 1

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog. The cancer research conference season kicked off in earnest in 2013 with the American Society of Clinical Oncology (ASCO)’s Gastrointestinal Symposium, held in San Francisco in late January. Some of the most anticipated data to be presented at ASCO GI was for drugs that treat pancreatic cancer, with three drugs—Celgene’s Abraxane, AB Science’s masitinib, and Sanofi’s S1, generating the most interest. With this post, we’ll take a closer look at the most advanced of the three agents, Abraxane, which generated encouraging results in a Phase III study. Later this week, we’ll tackle masitinib and S1. Abraxane is a nanoparticle albumin-bound form of the breast cancer drug paclitaxel, and is designed to improve the activity of the active ingredient. Abraxane is already approved in the US for advanced breast and lung cancers, and recently showed signs of activity in metastatic melanoma. At ASCO GI, Daniel Von Hoff, director of the Translational Genomics Research Institute, presented data from a randomized phase III study called MPACT that compared the effects of Lilly’s Gemzar, the current standard of care, to a once weekly combination of Gemzar and Abraxane in patients with metastatic adenocarcinoma of the pancreas. With 861 patients, this was a large global study that sought to determine whether the combination would outdo the regulatory standard of care. A note on the trial design: Although this study uses Gemzar as the standard of care, in practice, many leading oncologists prescribe FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) for advanced pancreatic patients. But because FOLFIRINOX is generic, and is not formally approved by FDA for advanced pancreatic cancer, Phase III studies tend to match new drug candidates up against Gemzar. As Hedy Kindler, director of gastrointestinal oncology at the University of Chicago, explained, FOLFIRINOX is widely used because the regimen has “the higher response rate, and that has the longer median survival.” However, FOLFIRINOX also has unpleasant side effects, and in private practice settings, oncologists prefer to use less toxic combinations based on Gemzar—namely, Gemzar alone, GemOx (with oxaliplatin), or GemErlotinib (with Tarceva, an EGFR TKI). To provide context, FOLFIRINOX typically has an improved survival of approximately 11 months, while gemcitabine or gemcitabine plus erlotinib elicit a 6-7 month improvement in median overall survival (MOS).  Erlotinib added 12 days of extra survival over gemcitabine alone, but unfortunately we have no way of selecting those advanced pancreatic patients most likely to respond to EGFR therapy. Celgene is exploring the combination of Abraxane and Gemzar based on preclinical work that suggests Abraxane can knock out the...

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#FoodChem Carnival: A bit o’ science on your Thanksgiving tippling

In my family, the first thing that happens when you walk in the door to my Aunt Kim’s house on Thanksgiving is you find yourself on the receiving end of the world’s best hug. The second thing that happens is a glass of champagne is thrust into your hand. So when I sat down to consider how to contribute to this week’s Thanksgiving-inspired #foodchem carnival, the science of champagne seemed a natural fit. And since some might consider champagne medicinal, it can squeeze by at the Haystack, right? Anything you want to know about the science of champagne can pretty much be learned from Gérard Liger-Belair, a professor of chemical physics at the University of Reims Champagne-Ardenne. Liger-Belair has possibly the best job in existence: he spends his days trying to decipher the chemistry and physics of champagne. We covered some of his tips for champagne serving here (most practical for every day imbibing: don’t use soap to wash your flutes. Instead, rinse with hot water and wipe with a towel. The cellulose fibers left behind from your swipe promote effervescence.). More recently, Liger-Belair has come out with evidence that size does matter—bottle size, that is. The smaller the bottle, the lower the concentration of dissolved CO2 in each successive glass poured. The message here: forget those wimpy splits, and go magnum. But if you do have a smaller bottle (okay, or a normal 750mL bottle), you can maintain some of the effervescence by keeping nice and frosty. Meanwhile, if you want to enjoy that nose-tickling fizz at the top of your glass for longer, this study suggests you should pick a flute over a coupe. This family prefers a flute, anyway. Less spillage. So there you have it. Happy Turkey Day, all! For more on the science of champagne, check out: What’s that Stuff: Champagne: http://pubs.acs.org/cen/whatstuff/stuff/8201champagne.html Unraveling different chemical fingerprints between a champagne wine and its aerosols: http://www.pnas.org/content/106/39/16545 Uncorked: The Science of Champagne:...

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Cantley Talks Pfizer CTI Collaboration

As drug companies forge closer ties with academic researchers, the value of pharma-academia partnerships continues to be cause for much debate (see here, here,  here, and here for more on that). We’ve watched the evolution of these collaborations with interest, and as part of our ongoing coverage, this week’s issue brings an in-depth look at the mechanics of Pfizer’s Centers for Therapeutic Innovation, its network of academic partners centered on hubs in San Francisco, New York, Boston, and San Diego. But much of our focus has been on what drug companies can gain from deeper ties with academia. There’s another side to the coin: what the academic lab gains from teaming up with industry. While visiting Pfizer’s Boston CTI, I was glad to have a long chat with Harvard’s Lewis Cantley, known in cancer research circles for the discovery of the PI3K pathway, about why it made sense to link up with Pfizer. Cantley has had many pharma partnerships, was a founder of Agios Pharmaceuticals, and has sat on the boards of other start-ups. As such, I was curious what made him want to turn to Pfizer for this particular project—developing a drug against a cancer target discovered in his lab–rather than go at it alone, or try to spin out another company. Cantley conceded that his lab could have plugged away at the target for several years and eventually come up with something promising. But the target requires an antibody, and his lab is more experienced at discovering small molecules. Pfizer, meanwhile, could step in with expertise and technology that they otherwise would never have access to, significantly speeding up the drug discovery process. Further, Pfizer made teaming up easy. “The legalities of conflict of interest issues and IP issues had all been addressed with negotiations between Harvard and Pfizer before they even solicited proposals,” Cantley says. “To me, this was huge.” He notes that past partnerships with industry have involved at least a year of negotiating before anyone gets down to doing business—or, as it may be, science. Another positive was that working with Pfizer meant researchers in his lab could continue to be involved with the project. When Cantley became a founder of Agios, which focuses on developing drugs that interrupt cancer cell metabolism, he could no longer ethically allow students in his lab work on that aspect of the science. But under the Pfizer pact, post-docs can continue to explore the drug development as well as any basic biological questions that may arise. Lastly, Cantley was attracted by the facility with which Pfizer and academic scientists could interact. As it turns out, Cantley’s labs are...

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Sanofi’s MS Pill Aubagio Wins FDA Approval

Another pill for multiple sclerosis has gotten FDA’s stamp of approval. Sanofi’s Aubagio is expected to hit the market in a few weeks, making it only the second oral drug available to people with MS. Novartis’ MS pill Gilenya, which works by a different mechanism of action than Aubagio, has been on the market for two years. Aubagio will cost roughly $45,000 a year, strategically priced below the leading MS drugs on the market. As Leerink Swann analyst Seamus Fernandez pointed out today in a note, that puts it at about 6.5% lower than Teva’s Copaxone, 8% less than Biogen Idec’s Avonex, and 28% below the price of Gilenya. “We continue to be surprised by the magnitude of price increases within the MS market overall and view Sanofi’s slight discount as reasonable,” he added. As we described back in 2009, MS is a problem of an immune system gone awry, with lymphocytes first attacking myelin, the protective sheath on nerve fibers, and eventually breaking down the fibers themselves. The first wave of MS drugs—beta-interferons like Avonex and Copaxone–intercept T-cells to slow down the body’s immune response. But that approach is promiscuous—the beta-interferons also prompt widespread gene expression, and cause flu-like side effects. The latest wave of MS treatments take a more refined approach to reining in the immune system. Biogen’s Tysabri, for example, blocks alpha-4-beta-1 integrin, which signals immune cells to leave the bloodstream and enter the brain and spinal cord. Gilenya keeps some T-cells out of the bloodstream by binding to sphingosine-1-phosphate receptor, thereby preventing some white blood cells from leaving the lymph nodes. Aubagio, meanwhile, inhibits dihydroorotate dehydrogenase, a critical enzyme in the synthesis of pyrimidine, which activated white blood cells need to survive. Whereas the beta-interferons have a sweeping effect on the immune system, some pathways are maintained with Aubagio’s activity. Aubagio has a few advantages over Gilenya and Tysabri: namely, it does not carry the same safety risks associated with those drugs (see here and herefor more on that), and is taken orally just once a day. But Aubagio also has its downsides. On the efficacy front, its milder interaction with the immune system renders it less effective than the more hard-hitting treatments. And it can cause hair loss and birth defects, a serious limitation for women of childbearing age—as Fernandez points out in his note, a large population in the MS...

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