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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.GA101

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 chlorambucil versus chlorambucil alone in newly diagnosed CLL.  Patients elderly and had co-existing co-morbidities, excluding them from standard chemotherapy with fludarabine and cyclophosphamide (FC).

This two part trial sought to compare both combinations to the chemotherapy initially, and then against each other in a head-to-head comparison once the survival data matured in the second phase.  Data from the first phase of the study was reported at this meeting.

What did the results show?

When looking at the response rates, both obinutuzumab and rituximab combinations had a higher overall response rate (ORR) than chemotherapy alone (75.5% and 65.9% vs. 30.2% and 30.0%).  Importantly, the combinations had a great proportion of complete responses (CR) i.e. 22.2% and 8.3% compared to 0% in the chlorambucil arms.

Minimal residual disease (MRD), a measure of the number of leukemia cells remaining in the blood, was 31.1% in the peripheral blood of the obinutuzumab combination compared with 0% in the chemotherapy arm.  Corresponding values in the rituximab and chlorambucil arms were 2.0% and 0%, respectively.

Median progression-free survival (PFS) i.e. the length of time during which people lived without their disease worsening for the obinutuzumab plus chlorambucil arm were impressively higher than chemotherapy alone.  PFS was more than doubled (23 months compared to 10.9 months, HR=0.14, p <.0001) when compared to chlorambucil alone.  The corresponding outcome data for the rituximab combination were 15.7 versus 10.8 months for chlorambucil alone (HR=0.32, p <.0001).

Since ASCO, Roche have announced that the FDA granted Priority Review for obinutuzumab in CLL (in addition to the Breakthrough Designation already received in May, when the company filed a new drug application for obinutuzumab), meaning that the PDUFA date is set as December 20th.  In addition, the Data Monitoring Committee decided that the interim data analysis was sufficient to meet the primary endpoint of the trial, ahead of schedule.  The data confirms that obinutuzumab was superior to rituximab in terms of the disease worsening (PFS).  The full data will be presented at ASH in December, when overall survival data (ie did the patients live longer) may be available.

The adverse event profiles were slightly different between the monoclonal antibodies.  Patients in the obinutuzumab arm experienced more infusion site reactions, and a slightly higher degree of myelosuppression (thrombocytopenia and neutropenia), but lower infection rates.

Overall findings

The study demonstrated that both obinutuzumab and rituximab were more beneficial to elderly patients living with CLL and co-existing medical conditions than chemotherapy alone.  The final head to head analysis of the two combinations will be available once the second stage of the study has mature data.  Based on the progress to date, the signs are very encouraging that the chemical engineering behind the development of obinutuzumab may potentially have produced a superior compound to rituximab for treatment of B-cell malignancies.

Should the mature outcome data show a positive survival advantage in obinutuzumab’s favour over rituximab, we may well see similar glycoengineering techniques applied to other monoclonal antibodies in the near future, potentially leading to further improvement in outcomes.

 

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.
NOLAblog-program
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
IMG_3813
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
IMG_3810
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
IMG_3812
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
IMG_3811
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
IMG_3814
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 session.

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 here.

2) Ramesh Narayanan et al., presented an intriguing poster on a new preclinical compound from GTX Inc that specifically targets AK1C3. The results demonstrated some nice inhibitory activity of AKR1C3, with reduced androgen signaling and CRPC tumour growth. It is important to selectively inhibit C3 and not the C1 and C2 isoforms, since the latter are involved in production of the sex hormones.  Inhibition of C1 and C2 is also counter-productive because it can increase the androgenic signal and deprive ERβ of its ligand. To date, the challenge has been to develop a C3 isoform specific inhibitor, making GTX-560 a compound that may be worthwhile watching out for in the clinic.

Recently, Adeniji et al., (2011) observed that, “AKR1C3 plays a pivotal role in prostate tumor androgen biosynthesis, inhibitors of this enzyme have the potential to be superior to abiraterone acetate, a CYP17/20 hydroxylase/lyase inhibitor.”

Clearly, this is a promising development in CRPC, however, it is early days yet and we will have to wait and see how the clinical trials progress with this new agent.

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 protective stroma surrounding the tumor, thereby providing better penetration of the tumor.  The phase II data led to a promising 12.2 months improvement in median overall survival.

In general, results from randomized phase III trials tends to be lower than that reported in the smaller studies. This is exactly what happened in the MPACT trial, with the Abraxane combination showing a MOS of 8.7 months versus 6.7 months for Gemzar alone, a highly statistical significant finding (P<0.000015). The hazard ratio (HR) was 0.72, suggesting that the combination gave a 28% reduction in the risk of death versus gemcitabine.

Kindler is eager to use and learn more about the combination and notes that it will be another option for oncologists rather than a new standard of care.

This is encouraging data and met the primary endpoint. Celgene is expected to file for approval for Abraxane in advanced pancreatic adenocarcinoma in the second half of the year. Data on a previously identified biomarker (SPARC expression) was not yet available and is expected to be presented at the annual ASCO meeting in June.  The audience at the GI meeting were clearly expecting survival to be higher in those patients with high SPARC expression, but we will see what happens.

Advanced pancreatic cancer is a particularly devastating disease – the incidence and prevalence are approximately equal, with patients typically having a year of life left.  The symptoms are vague and insidious plus there are no useful screening approaches approved for earlier detection, so the emergence of potential biomarkers for selecting patients most likely to respond to Abraxane or Tarceva in combination with gemcitabine would be a most welcome advance, especially given the toxicities associated with FOLFIRINOX.

 

 

Francis Collins At TEDMED – Repurposing Drugs, Replacing Animal Models, Rocking Out


You know you’re at an interesting conference when the director of the NIH starts off his presentation with a guitar duet, and shares a session with Cookie Monster.

But the organizers of TEDMED made a very deliberate decision in opening this year’s conference with Francis Collins. This is the first year that the gathering of medical luminaries, artists, and design gurus (TED stands for Technology, Entertainment, Design) is taking place in Washington, DC, after moving from San Diego. It marks a philosophical shift for the organization, from TEDMED as idea incubator to TEDMED as inserting itself into the national conversation on health and medicine. What better way to do that then bringing in the head of the biggest biomedical funding agency?

Collins wants to compress the time it takes to get a drug development pipeline, and make the pipeline less leaky. This isn’t news to folks around the pharma blogosphere, including here at the Haystack, Ash at Curious Wavefunction and Derek Lowe, who’ve followed last year’s announcement of NIH’s venture for drug discovery, the National Center for Advancing Translational Sciences.

Folks have expressed some concerns about the concept, and its emphasis on the promise of gene-based drug discovery. But, as Derek noted, the fact of the matter is that everyone in drug discovery wants the things Collins wants, so there’s a measure of goodwill for the venture too.

Collins spent his time on the TEDMED stage emphasizing two things: drug repurposing and developing high-tech cellular solutions to supplement and replace often-imperfect animal models.

On the tech side, Collins showcased the Harvard-based Wyss Institute’s lung-on-a-chip, which combines tissue engineering and electronics to mimic the interface between the lung’s air sacs and capillaries (Science, DOI: 10.1126/science.1188302). He said that technologies like this suggest viable alternatives to animal testing are possible.

When New Scientist reported on the lung-on-a-chip in 2010, researchers praised it as a step in the right direction, but cautioned that immortalized cell lines, such as those on the chip, don’t neccesarily behave like primary cells from patients. Collins also noted that it might be possible to use such devices with patients’ own cells someday.

On the repurposing side, Collins cited an article on the topic in Nature Reviews Drug Discovery (DOI: 10.1038/nrd3473), and alluded to lonafarnib (SCH 66336), a farnesyltransferase inhibitor that was originally designed to be part of cancer-treatment cocktails. It didn’t pan out as a cancer drug, Collins said, but now clinical trials are underway to test whether the drug is effective at countering a rare mutation that causes Hutchinson-Guilford progeria, an ailment that leads to rapid aging in children. Collins shared the stage with 15-year-old Sam, a progeria patient.

Francis Collins (right) and Sam. (TEDMED)

To bridge the massive gap between ideas and applications in medicine “we need resources, we need new kinds of partnerships, and we need talent,” he told the audience.

In a conversation with reporters after his talk, Collins provided another repurposing story published last month– bexarotene, a retinoid X receptor agonist intended for lymphoma that was just shown to clear amyloid-beta and reverse cognitive deficits in a mouse model of Alzheimer’s (Science, DOI: 10.1126/science.1217697)

At that chat, I asked Collins how the repurposing effort and his call for talent squares with massive layoffs in industry and flat or declining funding.
“It would help if we had a strong foundation of support,” Collins said. He said his agency’s purchasing power has decreased 20% over the last 8 years.

Another reporter asked what was the main obstacle to getting repurposing become habit. “IP,” Collins said. He told reporters that a model intellectual property sharing agreement with pharmaceutical companies has been drafted. Asked if companies had signed on to it, Collins said “we’re working on it.”

UPDATED 3:30PM 4/12: Here’s the scoop on Cookie Monster, for Muppet devotee Robin:
he spoke later in the session with ultramarathoner Scott Jurek about nutrition.

ARIAD Presents PACE Data; Provides Potential Gleevec Backup

Sufferers of chronic myeloid leukemia (CML), a rare and tough-to-treat blood cancer, received some good news at the 2011 Americanponatinib Society of Hematology meeting in San Diego this week. On Monday, ARIAD Pharmaceuticals disclosed new results from the Phase 2 PACE trial of its lead drug ponatinib (AP24534). The data (covered by FierceBiotech, Xconomy, and TheStreet), indicate major responses to the drug in ~40% of recipients, even in advanced or refractory (resistant to treatment) CML .

With these numbers in hand, ARIAD enters a tight race, already populated by headliners like Gleevec (imatinib), which in 2001 made a splash as a first-line CML therapy. Drugs such as Gleevec and ponatinib belong to the family of tyrosine kinase (TK) inhibitors, which dock with a mutated protein called Bcr-Abl. This protein (actually a fusion of two distinct proteins via a chromosomal mishap) triggers disease by accelerating blood cell creation, leading to uncontrolled growth and eventually CML.

imatinibSince cancers constantly evolve, new mutations in the TK active site had rendered Gleevec ineffective for certain variations of CML. Many of the PACE trial patients had previously tried newer TK inhibitors, such as Sprycel (dasatinib, BMS) and Tasigna (nilotinib, Novartis), and found that their CML had become resistant due to a single amino acid mutation in the kinase active site, which swapped a polar residue (threonine) for a carbon chain (isoleucine). So, ARIAD chemists decided to develop a drug that borrowed the best points from the earlier therapies, but capitalized on this mutation (A pertinent review in Nature Chemical Biology covers early examples of “personalized” cancer drugs developed for disease variants).

So, how did they accomplish this particular act of molecular kung-fu?  For that, we hit up the literature and go all the way back to . . . 2010. As explained in a development round-up (J. Med. Chem., 2010, 53, 4701), most approved Bcr-Abl inhibitors share several traits: densely-packed nitrogen heterocycles linked to a toluyl (methyl-phenyl) amide, then a highly polar end group, such as piperazine or imidazole. Since the mutation axed a threonine residue, the hydrogen-bond donor adjacent to the ring in earlier drugs was no longer necessary. So, chemists replaced it with a vinyl group.

A computer analysis designed to achieve better binding and drug-like properties suggested an alkyne linker might fit into the mutated active site even better than a vinyl group, so that’s ultimately what ARIAD installed. The program also suggested moving an exocyclic amino group into the aromatic (forming an uncommon imiadzo-[1,2-b]-pyridazine, green in picture). Borrowing the best stuff from other therapies, ARIAD’s chemists also wove in the “flipped” amide and -CF3 motifs (both blue) from nilotinib, as well as the methylpiperazine (red) from imatinib.Binding overlay

With computational rendering (Cancer Cell, 2009, 16, 401) ARIAD scientists could overlay both imatinib and ponatinib in the mutated enzyme’s active site (see picture, right). Notice that unlike imatinib, ponatinib avoids bumping into isoleucine 315. Ponatinib also gets a little extra binding oomph by poking its CF3 group into a hydrophobic pocket near the bottom of the active site.

Using Gene Expression Patterns to Repurpose Drugs

Late last month, researchers from many different fields gathered at the Computer History Museum in Mountain View, California, to discuss the benefits of open science and data sharing. One of the best talks from that event, the Open Science Summit, was delivered by Joel Dudley, the co-founder of NuMedii, a firm that aims to find new indications for medications.

Dudley has repeatedly found new uses for old drugs by picking through public data sets about the gene expression profiles of different diseases. He then looks for medications that are known to reverse those profiles.

Much of the data that Dudley uses comes from the Gene Expression Omnibus, which he regards as a gold mine.

Life Sciences in the Era of Big Data from Open Science Summit on FORA.tv

A full list of videos from the Open Science Summit is also available.