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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Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA
Apr04

Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA

Bookmark this page now, folks. On Wednesday, April 10, I will be here, liveblogging the public debut of five drug candidates’ structures. The “First Time Disclosures” Session at the ACS National Meeting in New Orleans runs from 2PM-4:55PM Central time. I am not able to conjure up a permalink to the session program, so here’s a screengrab instead. 1:20PM I’m in hall R02, where the session’s set to begin in about 40 minutes. Found a seat with a power outlet nearby, so I’m good to go! 2:29PM BMS-906024 Company: Bristol-Myers Squibb Meant to treat: cancers including breast, lung, colon, and leukemia Mode of action: pan-Notch inhibitor Medicinal chemistry tidbit: The BMS team used an oxidative enolate heterocoupling en route to the candidate– a procedure from Phil Baran’s lab at Scripps Research Institute. JACS 130, 11546 Status in the pipeline: Phase I Relevant documents: WO 2012/129353 3:02PM LGX818 Company: Novartis Institutes for Biomedical Research and Genomics Institute of the Novartis Research Foundation Meant to treat: melanoma with a specific mutation in B-RAF kinase: V600E Mode of action: selective mutant B-RAF kinase inhibitor Status in the pipeline: Phase Ib/II Relevant documents: WO 2011/023773 ; WO 2011/025927 3:47PM AZD5423 Company: AstraZeneca Meant to treat: respiratory diseases, in particular chronic obstructive pulmonary disease Mode of action: non-steroidal glucocorticoid receptor modulators Medicinal chemistry tidbit: This compound originated in part from a collaboration with Bayer Pharma. Status in the pipeline: Phase II Relevant documents: WO 2011/061527 ; WO 2010/008341 ; WO 2009/142568 4:17PM Birinapant (formerly known as TL32711) Company: TetraLogic Pharmaceuticals Meant to treat: cancer Mode of action: blocks the inhibitor of apoptosis proteins to reinstate cancer cell death Status in the pipeline: Phase II Relevant documents: US 8,283,372 5:00PM MGL-3196 (previously VIA-3196) Company: Madrigal Pharmaceuticals, acquired from VIA Pharmaceuticals, licensed from Roche Meant to treat: high cholesterol/high triglycerides Mode of action: mimics thyroid hormone, targeted to thyroid hormone receptor beta in the liver Medicinal chemistry tidbit: this molecule was discovered at Roche’s now-shuttered Nutley site. Status in the pipeline: completed Phase I trials Relevant documents: WO 2007/009913 ; WO 2009/037172 And that’s it, folks! Watch the April 22nd issue of C&EN for more on this...

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New Targets in Advanced Prostate Cancer
Mar18

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 2
Mar01

New developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 2

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog. In my last post on The Haystack, we discussed the phase III data from the Abraxane MPACT trial in advanced pancreatic cancer that was presented at the recent ASCO GI meeting in San Francisco. Two other late-stage studies in pancreatic cancer caught my eye—fresh data for AB Science’s kinase inhibitor masitinib and Sanofi’s multidrug pill S1. Masitinib is an oral tyrosine kinase inhibitor from AB Science that targets KIT, PDGFR, FGFR3 and has shown activity in gastrointestinal stromal tumours (GIST). A different version of the drug (Masivet, Kinavet) is also approved in France and the US for the treatment of a dog mast cell (skin) cancers, which are also known to be KIT-driven. S1 is multidrug pill from Sanofi and Taiho that consists of tegafur (a prodrug of 5FU), gimeracil (5-chloro-2,4 dihydropyridine, CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) enzyme, and oteracil (potassium oxonate, Oxo), which reduces gastrointestinal toxicity. Previous Japanese studies have demonstrated effectiveness of this agent in gastric and colorectal cancers, so a big unaswered question is whether it is effective in pancreatic cancer. So what was interesting about the latest data at this meeting? At the ASCO GI conference in 2009, French oncologist Emmanuel Mitry presented data from a small Phase II study of the effect of combining masitinib and Eli Lilly’s Gemzar in advanced pancreatic cancer. The study had just 22 patients, but the median overall survival of 7.1 months in was not a large improvement over what is often seen with the standard of care, Gemzar given alone, or with a combination of Gemzar and Genentech’s Tarceva. Over the years, many combination therapies based on Gemzar have failed to show superiority over single agent therapy. It’s both a high unmet medical need and a high barrier to beat.  Thus, the phase III data for the combination of masitnib and Gemzar was highly anticipated at this year’s ASCO GI meeting. Gael Deplanque and colleagues compared masitinib plus Gemzar to Gemzar plus placebo.  Although the overall trial results for median overall survival were slightly higher than in the phase II study, they were not significant (7.7 versus 7.0 months, P=0.74; HR=0.90). Some promising data was observed, however, in a subset of the population identified by a profile of biomarkers that the authors vaguely described as, “a specific deleterious genomic biomarker (GBM) consisting of a limited number of genes.” No other details on the actual genes or biomarkers were was provided, but the subset was described as having an improved MOS to 11.0 months compared to the Gemzar...

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New Developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 1
Feb26

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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#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma
Jun29

#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog. Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation. However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months. At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them? An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research–this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic. One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone. Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent. Jeffrey Weber from Moffitt Cancer Center in Tampa presented the results of the complex phase I/II study, which included melanoma patients with either the BRAFV600 E or K mutation who had not undergone treatment of any kind. The hope was that by suppressing the MAP kinase-dependent resistance mechanisms, patients would enjoy three kinds of improvements over current treatment: 1) Improved progression-free survival (PFS), response rate, and survival 2) Prolonged duration of response 3) Decreased incidence of BRAFi-induced proliferative skin lesions An impressive waterfall plot of tumor shrinkage for patients (n=77) with the BRAFV600K mutation drew gasps from the audience – only four patients failed to respond to the combination, while the majority had a response of 30% or better. This isn’t something you see every...

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