Category → Big Pharma
Today’s issue examines the surge of interest in rare disease drugs, which in the past few years have attracted significant interest from biotech firms, big pharma, and venture capitalists alike. In addition to exploring the business and policy drivers behind increased investment in orphan drugs, the multi-part story looks at the critical role patient organizations play in drawing attention to rare diseases. As such, it seemed worth highlighting advice from various stakeholders on what patient groups can do to entice drug developers to work on their disease:
–Organize yourselves. Find as many patients as possible, and establish a registry that will make it easy for a drug firm to begin a clinical trial. “Beginning to identify people, getting them into a registry, and collecting natural history data is one of the most valuable things a developer can have when they’re thinking about a program,” says Genzyme’s CEO David Meeker. “Among the most helful things that patient advocates can do is to help us to understand the natural history of disease,” agrees Kevin Lee, CSO of Pfizer’s rare disease unit. “Without that understanding of how the disease progresses, and what the endpoints can be, its almost impossible to do drug development.”
–Find a way to collaborate with one another. In even the smallest of diseases, patient groups tend to proliferate. And while its natural and understandable for advocates to want to do all they can to help their own child or family member, it can lead to duplicative efforts. The disparate groups can also make it tougher for drug developers to access. “We all need to give everybody a lot of space here to do what they think is best, but in an optimal world, there are tremendous advantages to being coordinated,” Meeker says.
–Be connectors. Patient organizations have the amazing ability to bring together academics who had previous not collaborated. “What I have found over and over again is that patient advocates know the investigators in their field far better than the investigators themselves do,” says Christopher Austin, director of NIH’s National Center for Advancing Translational Science (NCATS). “They can be instrumental there.”
–Get the right researchers interested. Often only a handful of academic researchers are working on a given rare disease, and drug developers say attracting new scientists into the field, while also giving careful consideration about who to fund is key. Patient groups should look for someone who can use advocacy funds to attract larger grants. “If they can get some grant support, you’ll get more done,” says Emil Kakkis, CEO of Ultragenyx. “If they can’t get any grant support, you’ll have to wonder if it was just because the disease is rare, or another reason.”
–Don’t cut corners. As more patient groups directly fund and organize natural history studies and early clinical trials, they need to make sure the work they support is of the same caliber as that done by biotechs or pharma. “Every data point they generate may some day be helpful in getting a drug approved,” says Philip Reilly, venture partner at Third Rock Ventures.
–Take the reins. With the passage of FDASIA last year, FDA committed to allowing patients more of a seat at the table during regulatory discussions. But the role patient groups will play—how they will be allowed to particulate and how much influence they have—is still to be determined. Ritu Baral, analyst at Canaccord Genuity, thinks there’s opportunity in that vagueness. “Give an inch, take a mile. If they’re going to define it, then we can define it as a patient group,” Baral, who also sits on the board of a disease foundation, says. “We can set the markers where we want to set them.”
–Help drug developers understand your needs. Drug companies are partnering with patient organizations earlier on in the drug process than in the past, convening patient advisory boards to understand how best to design a clinical trial, says Amy Waterhouse, vice president of regulatory affairs at Biomarin. That design ins’t just about regulatory practicalities, but about what families need out of the design in order to participate—a three day visit to a hospital instead of four, for example, can make all the difference. “We learn so much from discussions [with patient groups] that we wouldn’t get from the literature,” Waterhouse says.
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!
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
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
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
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
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.
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.
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 and placebo arm.
They also noted that patients with high pain, who usually do poorly on standard chemotherapy, also saw improvement with the masitinib combination. AB Science might have found a particularly aggressive subset that respond to masitinib, in which case, a biomarker would be useful in selecting those patients most likely to respond, as opposed to a catch-all approach where everyone is treated regardless of the predictive value.
AB Science has asked European regulatory authorities for approval, but the Phase III data will not be sufficient for US approval. The company will need to validate the biomarker panel in a large-scale randomized study, and a new phase III trial is now recruiting patients. The outcome of that study won’t be known for awhile, but the hope is for more insight into how to choose the right patients to respond to masitinib in combination with Gemzar.
The other compound featuring late-stage results in pancreatic cancer was Sanofi’s S1. The compound is interesting, but so far its development has been limited to Asian patients, particularly people of Japanese origin. Studies in caucasians have not seen any benefit over standard 5FU therapy.
Katsuhiko Uesaka, medical deputy director at Shizuoka Cancer Center Hospital in Japan, presented encouraging data for the use of S1 as adjuvant therapy in combination with Gemzar after surgical resection (relevant in stage I-III pancreatic cancer). They compared S1 and Gemzar in a head to head non-inferiority trial (with 385 patients. In the interim analysis reported at this year’s ASCO GI meeting, the hazard ratio for S-1 to Gemzar was 0.56, while the 2-year survival rates were 53% for Gemzar and 70% for S-1. The percentage of serious side effects were similar to previously reported studies with Gemzar and S-1, including fatigue (4.7/5.4), anorexia (5.8/8.0), leukopenia (38.7/8.6), thrombocytopenia (9.4/4.3), anemia (17.3/13.4), and elevated AST (5.2/1.1).
Overall, the authors concluded that S-1 adjuvant chemotherapy was shown to be as good as, perhaps even better than Gemzar, even suggesting that S-1 could be considered the new standard treatment for resected pancreatic cancer. It should be noted, however, that this data is only applicable to patients of Japanese origin since no caucasian data was included in this analysis.
We’re almost at the end of National Chemistry week, folks, and the Haystack is finally kicking in to blogger SeeArrOh’s now rampant #ChemCoach carnival. The goal of any carnival is to get a lot of different bloggers to post on the same topic–in this case, to write about how they got to where they are today as a way of educating young chemists on their career options. Round-ups of the dozens of posts this week can be found here, here, and here. Since the science writing field has been well covered here and by our own Carmen Drahl, and because the Haystack is focused on all things pharma, I thought I’d enlist the help of someone with a much more illustrious career than my own. Without further ado, I give you some words of career wisdom from TB Alliance‘s chemistry guru Christopher Cooper:
What you do in a standard “work day.”
What kind of schooling / training / experience helped you get there?
How does chemistry inform your work?
Finally, a unique, interesting, or funny anecdote about your career*
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 in the same building as Pfizer’s Boston CTI. “It’s literally two minutes to get from my lab to theirs,” he notes. The seamless exchange of reagents and technologies occurs at a “speed which just doesn’t happen with other industry collaborations,” he says.
Indeed, as the story discusses, Pfizer is banking on that proximity to enable good targets or lead molecules to be quickly moved from the bench to the bedside. The goal is to have three to four compounds in human trials in the next 18 months—a swift turnaround considering the first CTI, a partnership with UCSF and labs in San Francisco, was announced just two years ago.
Just months after announcing it would close its storied Nutley, N.J., R&D site, Roche said today that it will open a translational clinical research center at New York City’s Alexandria Life Sciences Center. The move means three big pharma firms will soon be enjoying a view of the East River: Lilly was the flagship tenant when two years ago it moved some 140 scientists from ImClone’s lower Manhattan labs into the sparkling new site. Pfizer later chose the Alexandria center for the New York hub of its Centers for Therapeutic Innovation, a unit that teams Pfizer scientists with academic scientists.
When Roche said it was shutting down the Nutley site, it said it was in search of an East Coast location for a much smaller research footprint. Some had initially speculated that Cambridge, Mass., would be the obvious choice for Roche, as most pharma companies have shifted their main East Coast R&D to the Boston area. More recently, it emerged that Roche was deciding between two locations in NY and N.J. Today’s release indicates that Roche plans to stick around N.Y. for awhile: it has signed an 11-year lease at the Alexandria Center.
Does this mean NYC, which has long struggled to attract pharma and biotech researchers to its fair streets, is starting to see some momentum in the life sciences?
In a blow to the Hepatitic C drug development arena, Bristol-Myers Squibb last night pulled the plug on BMS-986094, an NS5B inhibitor in mid-stage trials. The decision comes just weeks after the company reported a patient suffered from heart failure during a Phase II study of the compound. Nine patients were eventually hospitalized, with varying symptoms of kidney and heart toxicity, according to BMS’s release (See more coverage by Adam Feuerstein at The Street and by Andrew Pollack at the NYT)
BMS-986094? You might know this molecule better as Inhibitex’s former nucleoside INX-089. The molecule came to BMS through its $2.5 billion purchase of Inhibitex in 2011, as we wrote last year here at the Haystack.
The molecule belongs to a family of new nucleosides with fairly common structural motifs: a central sugar appended to a nitrogen heterocycle (usually purine- or uracil-based) and an elaborate phosphoramidate prodrug. These new drugs’ similarities may also prove to be their Achilles heel – Idenix Pharmaceuticals announced an FDA-requested partial clinical hold on their IDX-184 lead. This cautious approach aims to protect patients; though the drugs are similar, 184’s main structural difference – a thioester-based, slightly more-polar prodrug – seems to be enough to distance it from the cardiac side-effects seen with BMS-986094.
For a fairly in-depth look at the chemistry behind these inhibitors, as well as dozens of other analogues that never made it to prime time, check out US Patent 7,951,789 B2, issued to Idenix just last year.
The spectacular—and largely anticipated—failure of the Alzheimer’s treatment bapineuzumab has caused an outpouring of stories questioning what went wrong and what it means about pharma’s approach to R&D. Pfizer, Johnson & Johnson, and Elan, the developers of bapineuzumab, are taking a beating in the press for investing so heavily, not to mention raising the hope of so many patients, in a therapy that had not shown strong signs of efficacy in early trials.
Most stories are focused on the implications for Alzheimer’s research and, more generally, the pharma business model given the hundreds of millions of dollars the three companies sank into bapineuzumab. But news of its failure also resonated in research communities focused on other neurogenerative diseases, like Parkinson’s disease and Huntington’s disease, marked by protein aggregation.
I checked in with Todd Sherer, CEO of the Michael J. Fox Foundation to understand what Parkinson’s researchers might learn from the disappointing data from bapineuzumab. Sherer believes there are scientific and business ramifications of the results, both of which might have a chilling effect on neuroscience research.
From a scientific perspective, some are declaring the failure of bapineuzumab the nail in the coffin of the amyloid hypothesis, the theory that the beta-amyloid, the protein responsible for the plaque coating the brains of people with Alzheimer’s disease, is the primary cause of neuron death in the disease. Bapineuzumab, which blocks beta-amyloid, was one of a handful of treatments to test the hypothesis in the clinic. So far, every drug to reach late-stage trials has failed.
Sherer isn’t convinced bapineuzumab is the nail in the amyloid hypothesis coffin. “Obviously the results are very disappointing given the level of interest and investment that’s been put forward for this therapy,” Sherer says. “I don’ think that the result is a definitive answer to the amyloid hypothesis because there are many different ways to target amyloid aggregation therapeutically.”
Parkinson’s researchers are also trying to learn from the setbacks in Alzheimer’s and apply that to studies of drugs targeting alpha synuclein, the protein that clumps together in the brains of people with Parkinson’s disease. “One of the things that is a learning for us in Parkinson’s is really to try to be as smart and informative as we can be in the early clinical trials,” he says.
In Alzheimer’s, for example, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a collaboration between government, academic, and industry scientists, was formed in 2003 to identify biomarkers that can be used both in the diagnosis of the diseases and in the clinical development of Alzheimer’s drugs. However, Sherer points out that while progress in the ADNI initiative has been promising, it was started too late for many companies, which had already jumped into larger clinical trials of Alzheimer’s therapies.
The Fox Foundation already has a biomarker initiative for Parkinson’s ongoing. The goal is that when the first clinical trial for a vaccine alpha-synuclein, to be led by the Austrian biotech Affiris with support from the non-profit, starts later this year, the tools will be in place to conduct a highly informative study.
On the business side, Sherer worries about the impact of more bad news in Alzheimer’s at a time when many companies are already moving out of drug discovery in many areas of neuroscience. “One of the concerns I have is that investors like big pharma companies and others are already showing a trend towards risk aversion,” Sherer says. “That will just get reinforced by these large trials not succeeding.”
Although basic research is uncovering new therapeutic avenues in diseases like Alzheimer’s and Parkinson’s, companies may decide the bar for understanding the biological relevance for each drug target needs to be set much higher. But when it comes to Parkinson’s disease, he adds, “we are not going to have the luxury of knowing everything about the disease and the biochemical pathways before we need to push forward with therapies.”
One hope Sherer has is that companies will make much of the data from these failed trials available to the research community to try to understand what didn’t work, and what the results really mean. “It’ll be a goldmine of information for other Alzheimer’s trials, but also for other genetic diseases like Parkinson’s disease and Huntington’s disease.”
The ax is falling on more pharma R&D jobs. Earlier today, Derek Lowe brought word from readers that research jobs were being cut at Bristol-Myers Squibb. The company just confirmed that “fewer than 100″ positions were being eliminated in the U.S. Here’s the official word from BMS:
“Bristol-Myers Squibb is strategically evolving the company’s Research focus to ensure the delivery of a sustainable, innovative drug pipeline in areas of serious unmet medical need and potential commercial growth.
The Company is aligning and building internal capabilities to support the evolution of its Research focus. In doing so, certain research areas will be streamlined and there will be investment and growth in other areas. This strategic evolution has resulted in job eliminations in the short term to allow longer term investment. This initiative will result in a reduction in employee headcount of fewer than 100 people in an R&D organization of more than 7,000 employees. Impacted employees were notified on August 1, 2012 and transitions will take place within two weeks of this date.”
The company will not confirm whether they are, as Derek’s sources suggest, in the metabolic disease area or limited to New Jersey. If indeed they are all coming out of its N.J. labs, today’s announcement will add to challenging times for the state. As we wrote last month after Roche announced plans to shutter its Nutley site, costing some 1,000 jobs, the number of drug industry jobs in N.J. fell by 22.4% between 2007 to 2010, according to a report by Battelle and the Biotechnology Industry Organization.