"If you plan to be around five or 10 years from now, you have to have a Chinese strategy." That poignant comment in a BioWorld Todayarticle came from Joshua Boger in 2011. The founder and former CEO of Vertex Pharmaceuticals Inc., and now executive chairman of Alkeus Pharmaceuticals Inc., had just returned from China where Shanghai Syntheall Pharmaceuticals Co. Ltd., a manufacturing subsidiary of Wuxi Apptec Co. Ltd., is the manufacturing site for starting materials for Vertex's hepatitis C drug Incivek (telaprevir).
A combined massive government investment, a growing appetite for capitalism, and a shift from pharmaceutical industry service provider to growing innovator mean China has emerged as a key player.
"You need friends in China,” Boger told BioWorld. “That's how we think about our partnership [with Wuxi Apptec]. If you say, 'I'll wait until I get big enough to sail in and build a facility,' that's last century. You'd better start it by becoming important to companies in China. You help them, they help you.”
BioWorld, focused mostly on U.S. and European biotech markets for the last two decades, has been slowly adding coverage of news from China. We’re tapping into news from Hong Kong, Taiwan’s healthy biotech sector, and South Korea which has intentions of dominating the biosimilars market. We’re keeping an eye on a joint regulatory scheme cooking between Australia and New Zealand.
Earlier this month BioWorld reported a key turning point for Chinese biotech: a company from Sichuan province earned coveted pre-qualification status from the World Health Organization for its Japanese encephalitis vaccine. It’s the first time a Chinese vaccine maker has earned a WHO seal of approval, which opens up markets worldwide.
Then there is this: In 2012 it was reported that, for the first time, there were more pharmaceutical sales representatives in China than the U.S.
Right Site Asia, an industrial real estate specialist, estimated that there are more than 1,000 biotech industrial parks across China. BioWorld already highlighted what are likely the top 10 largest, most successful and best known of these parks.
There’s so much news from this part of the world that we can no longer treat it as being secondary to the robust U.S. and European sectors. These are no longer emerging markets. They have arrived.
Thus, the launch of BioWorld Asia. This weekly news source will aim to provide in-depth coverage of Asia’s biopharma sector, with trademark BioWorld analysis and perspective on licensing deals, M&A and financings. Preview our launch issue and then let us know what you think.
Warning: Asian firms don’t have strong publication relations mechanisms in place, so depending on press releases or lay press reports won’t cut the mustard for serious biopharma players. Yes, the big pharma firms will issue statements when they partner or build a new facility. But there are literally thousands of other biopharmas in Asia with products and pipelines brewing. Get in on the action. Tune into BioWorld Asia for news of the most innovative drug development efforts in Asia.
As I write this, I’m sitting in the University of British Columbia/Vancouver General Hospital (UBC/VGH) Eye Care Centre, where my husband, Chuck, is completing post-tests at the conclusion of a six-month study on prosopagnosia, otherwise known as face blindness. The condition isn’t treatable with drugs – not yet, at least – but it’s nonetheless disabling, prompting researchers at several centers in North America and Europe to work collaboratively and seek to help patients carry on with their lives.
Clinical studies of prosopagnosia have, so far, informed researchers more about the causes and structural manifestations of the disease than about potential treatments. “Acquired” face blindness can result from lesions associated with various types of brain disease or injury, such as stroke, traumatic brain injury or – as in my husband’s case – complications from brain surgery. Researchers also have discovered that some individuals are born with “congenital” or “developmental” prosopagnosia – the lifelong inability to distinguish among faces, with the possible exception of their closest family members. Many of these cases seem to run in families, prompting scientists to suspect an as-yet-undiscovered genetic component.
While not life-threatening, prosopagnosia involves visual impairments beyond the inability to recognize faces. Like many chronic illnesses, living with the condition is isolating and exhausting. Close friends and family members know they must introduce themselves every time they encounter Chuck or they’ll appear to him as a stranger. But it’s not easy to explain prosopagnosia to casual acquaintances and expect them to understand its limitations.
My husband has braved the effects of face blindness for nearly 20 years. Recently, he began treatment for depression – another outcome he has in common with many patients who turn to clinical trials seeking a fresh alternative for a chronic physical or mental illness.
All of this got me thinking about patient experiences before, during and following clinical trials and the movement to incorporate those experiences into the regulatory decision-making process.
The FDA’s Patient Focused Drug Development program, mandated in the Food and Drug Administration Safety and Innovation Act, could be a move in the right direction, provided the agency’s 20 planned public meetings over the next five years, each designed to address a different indication, offer patients more than lip service. Individuals with chronic fatigue syndrome (CFS) – the first condition selected by the FDA to gather patient perspectives – are still waiting for a therapy to combat their Illness after the agency gave Philadelphia-based Hemispherx Bioscience Inc. a complete response letter (CRL) for Toll-like receptor 3 modulator Ampligen (rintatolimod) following the drug’s Arthritis Advisory Committee (adcom) meeting in December 2012, despite pleas for approval from patients and treating physicians. The drug is the only one in late-stage development for CFS.
The CFS community is not the only one feeling bruised following an adcom. In May, Aveo Oncology Inc.’s tivozanib got a 13-1 thumbs down from the FDA's Oncologic Drugs Advisory Committee (ODAC) – and, subsequently, a CRL from the FDA – in renal cell carcinoma (RCC) based on concerns about the adequacy of the drug’s single Phase III trial, despite no overt arguments about safety. In fact, the lone ODAC vote to support the adequacy of the data came from the committee’s patient representative, who argued for approval based on the tolerability of tivozanib in RCC. A patient who testified during the ODAC public hearing said tivozanib was the first of eight drugs that had worked for him since his diagnosis four years earlier and asked committee members to keep an open mind. They didn’t.
Earlier this month, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 9-2 against expanding the lipid-lowering agent Vascepa (icosapent ethyl) in combination with a statin drug to reduce triglycerides, non-high density lipoprotein cholesterol, apolipoprotein B, low-density lipoprotein cholesterol, total cholesterol and very low density lipoprotein cholesterol in adults. Although the drug, developed by Amarin Corp. plc, of Dublin, is already approved as monotherapy for severe hypertriglyceridemia, the committee voted to wait for results of an ongoing cardiovascular outcomes trial – not scheduled for completion until 2016 – rather than using a surrogate endpoint to recommend approval. Although the FDA has yet to issue its decision on the drug, observers worry the discussion and adcom vote could signal a deleterious shift in how the agency views efficacy requirements for chronic therapies.
Anecdotally – a word that sends shivers through FDA reviewers – the outcome of adcoms seems almost as capricious as the drugs alleged to underperform in clinical studies. Such fickleness comes at a huge cost to subjects, who join clinical trials not just in the hope of gaining pain-free days or additional months of life but also to help the larger patient community.
Chuck did not participate in the UBC/VGH clinical study with the goal of being “cured” of prosopagnosia. He volunteered so the lessons learned from his disability might help researchers develop therapies for those newly diagnosed with the disorder. Individuals who participate in drug trials do no less. Their experiences, their suggestions and their testimony before FDA adcoms deserve at least the same regard as the opinions of professionals paid to decide the fate of drugs and devices – especially when a compelling case can be made for conditional approval and post-marketing studies.
When Chuck was diagnosed with prosopagnosia 20 years ago, the first thing he asked doctors was how to treat the condition. The question was met with blank stares. Many patients suffering from disabling, disfiguring and life-threatening conditions still face similarly bleak responses. Treatments that may help even a small number of these individuals without causing greater harm than their disease deserve balanced hearings that incorporate both clinical and personal experience. Instead, adcom panels and the questions they deliberate often appear stacked for or against a particular drug, seemingly based on the preliminary judgment of FDA reviewers.
Although sponsors bear the financial costs of drug development, patients literally pay with their blood, sweat and tears. When drugs come before regulators, patients and their family members similarly deserve to be at the heart of the discussion. Certainly, clinical objectivity is necessary along the road to drug development, but so is real-world experience. Patient testimonies often inform as much or more than the experts, and their voices should not be relegated to the peanut gallery.
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) rocked the biotech industry last week by voting 9 to 2 against approval of Amarin Pharmaceuticals Inc.’s fish-oil derived omega-3 supplement Vascepa in the supplemental indication of mixed dyslipidemia. The drug is already approved for lowering triglycerides and its efficacy and safety results from the Phase III ANCHOR trial for the new proposed indication were just about as good as it gets, so it was widely expected the EMDAC would rubber stamp the new indication with perhaps a couple of holdouts.
The voting reversal was due to pointedly worded discussion and voting questions, which put the committee on the spot not only to decide whether the ANCHOR trial had met its goals of showing efficacy and safety in reducing the targeted lipid values, but whether the use of those lipid changes as a surrogate endpoint was valid for approval.
The committee ultimately decided to recommend against immediate approval, asking the company to resubmit its application after the results of its ongoing cardiovascular outcomes trial, REDUCE-IT, are available some time in 2017. Whether that’s even going to happen is now in doubt, as Amarin was counting on increased revenues from the expanded indication to keep the lights on through the end of that trial.
Meanwhile, folks have been wondering if the FDA couldn’t provisionally approve Vascepa for mixed lipidemia, and in some way make its continued approval contingent on a positive outcome from REDUCE-IT.
That question was raised in the adcom discussion. The answer given was that the FDA can give provisional approval in four situations: in the event of accelerated approval, in the case of deferred pediatric studies, using the animal rule, and if there’s a specific safety concern.
Accelerated approval, deferred pediatric studies, and the animal rule do not apply in the case of Vascepa, and the committee agreed that there was no safety concern with Amarin’s application.
So although at least some on the committee would have liked to recommend approval of Vascepa in mixed dyslipidemia, with some option to take it away if REDUCE-IT didn’t pan out, the FDA’s regulations did not provide a mechanism for it. The panel only had the option to recommend approval or not.
Of course, the agency is not bound to the panel’s recommendation.
Remember the heady days about eight years ago when Amgen Inc. and Genentech Inc., prior to its acquisition by Basel, Switzerland-based Roche AG, both vied for top spot in terms of market capitalization? At that time, both companies briefly commanded impressive $100 billion market caps and their collective valuation represented a significant chunk of the whole sector’s worth. Between then and now the industry took a nose dive in the wake of cratering global financial markets. As a result valuations declined and Genentech, now a unit of Roche, no longer factors into the industry’s current performance statistics.
Well, thanks to an amazing run that the sector has been on for almost 24 months the prestigious $100 billion market cap is again within sight.
It might have been attained, too, but for the U.S. government shutdown and looming debt ceiling uncertainties that have spooked the markets putting biotech valuations on a reverse trajectory as company stock prices fall.
We will have to wait and just marvel at the numbers that were put up by biotech. Prior to the government machinations, Gilead Sciences Inc. reached a market cap of almost $97 billion with Amgen Inc. not too far behind sporting a market cap of $88 billion.
The difference between the Amgen/Genentech era and now is the fact that the gap between the valuations of Gilead/Amgen and other “blue chip” biotechs is not as wide as it was back then when Amgen/Genentech represented almost 50 percent of the total sector’s value.
The incredible performances that many firms have been exhibiting on the capital markets have served to drive the sector to lofty new valuation heights – more than $500 billion at the end of the third quarter.
According to our ongoing analysis, 54 biotech companies developing therapeutics, with market caps greater than $1 billion, collectively saw their share prices jump by an average of 27 percent and finished up by a whopping 92 percent at the close of the third quarter.
The statistics are equally impressive when the 257 public biotechnology companies that are developing biotherapeutics are taken into account. According to the BioWorld Stock Report, they collectively recorded an average 28 percent share price increase in the quarter and a 51 percent increase since the beginning of the year.
This stellar performance may become a distant memory if the shutdown in Washington drags on for a significant period. Already the biotech sector has slipped 6 percent since the end of the quarter giving fuel to those pundits who believe that the industry’s “bubble” has burst.
I am not in that camp. This is a mere temporary hiatus as investors take the opportunity to lock in profits from biotech’s great run. The fundamental underpinnings of the sector are still strong and while biotech’s “run” may slow down to a “trot” during the fourth, it is still on a trajectory for even higher valuations in 2014.
I’m terrified of hospitals.
Not so many years ago, this would have been an absurd remark. With doctors and high-tech medical care all around, a hospital seemed like one of the safer places in the world to be.
But then, not so many years ago, age-related macular degeneration likely would have blinded many patients, as it did my late grandfather, pre-Macugen, pre-Lucentis.
Things change, and not always for the better. The rise of resistant infections, especially the hospital-haunting and deadly methicillin-resistant Staphylococcus aureus (MRSA) has kept drug developers scrambling for new weapons against this bug and others.
Until lately, the FDA hasn’t helped much. “Basically, we took a five-year hiatus on antibiotic development,” noted Paul Edick, CEO of Durata Pharmaceuticals Inc., who spoke with me on the phone last week, after the company submitted the new drug application for dalbavancin.
Durata is asking the FDA to approve dalbavancin first for acute bacterial skin and skin structure infections caused by gram-positive microorganisms, including MRSA.
The drug – a second-generation, semisynthetic lipoglycopeptide – came from Pfizer Inc., which spun out Durata with dalbavancin in 2009, having lost interest in developing anti-infectives since gaining the asset in the takeover of Vicuron Pharmaceuticals Inc. in 2005.
By the time dalbavancin fell into Durata’s hands, it had garnered three “approvable” letters from the FDA. The first involved “check the box” things that “were no real big deal,” Edick said.
Pfizer also wanted to move manufacturing in house. Setting up for this, the pharma company found that its assay for endotoxin was more sensitive than regulators insisted on, so the firm asked that the FDA restate the parameters in such a way that Pfizer’s test fit the bill.
“The FDA said, ‘Thank you very much,’” and sent another “approvable” letter re-specifying the stricter endotoxin measures, Edick said. Everything seemed ready to go.
Dual Endpoint Plucked from 1930s
Pfizer then, “surprisingly, got a third ‘approvable’ letter, saying, ‘Please justify the non-inferiority margins in your trials,” he said – margins that had been set by the agency itself. “What they were in essence asking a sponsor to do is to justify their own guidance, which makes no sense.”
All antibiotics in development had to do the same thing in order to continue.
Times had grown hard for antibiotics. When problems – liver toxicity, mainly – arose with Sanofi SA’s Ketek (telithromycin), the FDA was “under a lot of pressure to either go to placebo-controlled trials or find a surrogate marker,” Edick said. “They were basically pushing back on the industry and saying, ‘You guys figure it out.’”
Pfizer put the drug on the shelf. At about the same time Durata took over dalbavancin, the FDA withdrew its guidance altogether. So, until the summer of 2010, there wasn’t any at all. “We met with them in June, and they issued the new guidance in August,” Edick said. In September, Durata gained a special protocol assessment for its experiments.
Today, “there’s a bunch of antibiotics, all of a sudden making it through the development process,” he said, including candidates from Trius Therapeutics Inc., The Medicines Co., and Cempra Inc.
“You can’t do placebo-controlled trials in studies like this, because people die,” Edick pointed out – but the FDA found a pair of studies, conducted in the UK in the 1930s, that did just that. These trials with erysipelas patients, comparing “the cephalosporin of that day” against placebo, formed the basis for the surrogate statistical endpoints on which the agency finally decided, he said.
In the patients who survived, skin lesions were seen to have stopped growing at about the third or fourth day. Among those who had arrived with fevers, temperatures had returned to normal in the time frame as well.
Hence, the new, primary dual endpoint – a statistical one that only projects a clinical cure, which must be verified (secondary endpoint) by a physician at day 14. The FDA also changed the margin of error on non-inferiority, reducing it to ±10 percent, from the old guidance of ±12.5 percent.
Upside: solid rules. Downside: The antibiotic must “prove” efficacy in just a few days.
‘A Reasonable Thing to Do’
“It’s actually worse than that,” Edick said, mainly because of the fever measurement.
“The physicians take a Magic Marker and outline the lesion,” he said. “After three days, if the lesion has stopped growing – cessation of spread, is what they call it – you’ve hit that first endpoint. If you had fever at baseline, you need to have three readings of no fever between a certain period, like 48 to 72 hours. That’s what makes these studies extremely difficult. You’re taking a temperature every six hours,” though ordinarily, nurses do so at their shift changes.
Worst of all, for antibiotics developers, is that “missing data equals failure,” Edick said. “If you don’t have all of those fever measurements at day three, the patient is automatically a failure, even though, by day 14, they could be absolutely cured.”
Durata set the bar even higher for itself, enrolling much sicker patients than those tested by other sponsors – larger lesions, higher white blood cell counts. “Also, we didn’t use lymphadenopathy as a criteria for systemic disease, because European regulators don’t consider it accurate as a measure for that,” Edick said. (The development plan in general is different for Europe, where the primary endpoint is the doctor exam at 14 days.)
Even with the more severely afflicted patients, “we still hit all the endpoints” with dalbavancin given in two doses, spaced a week apart, he said. What’s more, the doses do not require anything like the five to nine-day hospital stay for intravenous infusion that “the vast majority” of patients need now, Edick said.
“This, we think, is going to be extremely important from a clinician’s standpoint,” he said.
All the turmoil ahead of nailing down the regulatory guidelines for antibiotics – including a weird endpoint based on ancient, unethical experiments – seems likely to turn out worthwhile. “If you step back from it, now that we’ve done these studies, one could argue, this is a reasonable thing to do,” Edick said.
And maybe, just maybe, hospitals could become safe places once again.
What’s in a biosimilar name? That depends on whether the vial is half empty or half full.
Seeing it as half full, many generic makers focus on the similarities between a follow-on and its reference biologic. Because of those similarities, they say biosimilars and their reference product should share the same international nonproprietary name (INN) – as is the practice with traditional generic drugs. That’s the argument the Generic Pharmaceutical Association (GPhA) made in the citizen petition it submitted to the FDA earlier this month.
Used to cashing in on the success of a small molecule brand drug by sharing its INN and through automatic substitution with little marketing effort, generic makers frame their argument as one of access to cheaper biologics. The more biosimilars are seen as the same as the innovator drug, the easier their job will be in selling them to the market at discounted prices.
On the other side of the debate are brand makers, joined by several patient advocates, who see the vial as half empty. In demanding unique names for each biosimilar, they highlight the differences between biosimilars and the innovator biologic.
Used to having a corner on the biologic market, the innovators, some of whom are developing their own biosimilars, frame the argument as one of safety. The more patients and prescribers are aware of the differences and exactly which version of a drug is being dispensed, the easier it will be to track adverse events – and perhaps maintain the innovator’s marketing edge.
Either way, the truth is likely found somewhere in the middle of the vial.
As with all follow-on, generic and me-too drugs, there are both similarities and differences. But given the complexity of some biologics, there are questions patients will want answered before they trust their health to a new version of a biologic that’s working for them. Exactly how similar is the “highly similar” standard set by the FDA for biosimilars? Is it simply a matter of “we’ll know it when we see it”?
And given the potential differences, no matter how slight, the FDA’s stance that biosimilars don’t need to demonstrate safety also raises a few questions. What is the certainty that minor manufacturing differences won’t become a major clinical difference in a subset of patients, especially if the mechanism of the innovator biologic isn’t fully understood? Short of massive clinical trials, how can drugmakers demonstrate that those differences are truly minor? And, contrary to the FDA’s current position, should biosimilar makers have to demonstrate the safety of their products?
Patients don’t care if the vial is half full or half empty. They want to know that the biologic they’re given is as safe and effective as the one they’ve used before.