The Big Red Biotech Blog

Innovation Tip: Avoid Putting "Stars upon Thars"

I love Dr. Seuss!  I hope everyone else loves Dr. Seuss too.  So I cannot resist passing this post on from Scott Anthony on the Harvard Business Review blog. It deals with innovation and what not to do when setting up an innovation group.

For this lesson, Scott refers us to the Dr. Seuss parable about the Sneetches - some with and some without "stars upon thars".  Many companies make the mistake of confering innovation groups with "stars upon thars" which naturally leads to resentment from those without stars.  Unfortunately, those without stars reside in the base business and must play a key support role if the innovation group is to succeed.

If you create a sense of have and have not with regard to the confirmation of "stars upon thars" for some, you make a big mistake at the beginning that will likely doom the innovation effort.

Posted by Bruce Lehr August 31st 2010.

President's Council Calls for Government Help for Vaccine Overhaul

The President's Council of Advisors on Science and Technology (PCAST) recently reviewed the response to manufacturing vaccines for the H1N1 pandemic.   The group concluded that there are shortcomings in the existing technologies for producing vaccines and the government coudl serve an important role by funding research areas that could provide needed solutions.   See in-Pharma Technologist.com.

Key areas where PCAST said the government could help with research funding include:

• Cell-culture based or recombinant DNA based methods of vaccine production to replace eggs
• Development of optimized seed viruses and potency assays, and investigation of the immune response to live attentuated influenza virus (LAIV)
• Backing of clinical trials for LAIV
• Incentives and pathways for development of recombinant DNA technologies - movement of at least 3 recombinant vaccines into proof of concept trials within 3 years
• Increased use of adjuvants by overcoming regulatory barriers with FDA guidance
• Investigation of possible universal flu vaccine to conserved areas of the virus

Certainly, from my selfish perspective, I would like to see more cell culture based production systems and use of more adjuvants.  It is two areas where SAFC currently is active in the vaccine market.  We support flu production in cell lines like MDCK and EBx.  We also operate a CMO business that produces virus and vaccines for clients - for diseases like influenza, AIDs, malaria, and gene therapeutic applications.

We also supply various adjuvants including squalene into final flu vaccine preparations - particularly for European manufacturers who are less restricted on adjuvant use than their US counterparts. SAFC could also play a role in recombinant DNA vaccines in the future I'm certain.

I think the PCAST recommendations make sense.  There has been a tremendous resurgence interests in vaccines - see Bill & Melinda Gates Foundation emphasis for example.  Vaccines are now being developed for not only the traditional communicable and childhood diseases, but are booming in areas like cancer prevention. The production processes and regulatory processes have not really kept pace.  There certainly is a golden opportunity now to upgrade our technoloiges to take advantage of these advances as well as to further advance the field. Government investment in this area should be welcomed and is important to public health.

Posted by Bruce Lehr August 31st 2010.

 

 

Patent Doc Blog Revisits Gene Patenting

The Patent Doc blog this morning comments on a good editorial in the Financial Times on Gene Patenting - written by Duke Law Professor, James Boyle, author of The Public Domain: Enclosing the Commons of the Mind.

Professor Boyle writes that we are moving to a new understanding on the issue - - one where competing groups give up property right in a "pre-competitive commons" - a pool of information from which all can draw.

He conceeds the process is complex.  "How does one guarantee that all can benefit? At what point do we stop sharing and allow privatization and property rights?"  Acknowledging that these properties are also necessary features of a working solution.

But he notes, we also now have tools that help better understand the complexities of commons construction -- Elinor Ostrom won 2009 Nobel Prize in Economics for this type of analysis. He concludes that we should view this not as an ideological war but as a pragmatic process of design.

It's an argument for restraint, for formation of shared data pools, and public-private ownership and cooperation. Yet still recognizes that companies will profit from products developed as a result of these efforts.

Posted by Bruce Lehr August 31st 2010.

Genzyme Rejects Sanofi Offer

As indicated yesterday, Genzyme's board quickly rejected the $18.5 B bear hug letter offer it received from Genzyme on Sunday. Genzyme spokemen cited the offer as undervaluing their company. As reported in the WSJ Health blog this morning, they cite examples such as their Campath treatment for MS - which is in phase III trials and which they expect to realize annual sales of more than $3 B - as a reason why the offer is low ball.

This however may be slight of hand at play as some analysts doubt the drug will ever reach $1 B. Its commercial fate is by no means a certainty and it will not reach the market until at least 2012 if all goes well from Genzyme point of view.

Posted by Bruce Lehr August 31st 2010.

DIPP Discussion Document into Compulsory Licensing and Price Controls

As posted late last week, India's Department of Industry Policy and Promotion (DIPP) proposed changing compulsory licensing to ensure drug availability and affordability in the country.  This action is arising out of fears by some that the India Pharma Industry is becoming rapidly consolidated amongs larger firms and in particular multi-nationals.  The result has been a rapid rise in exported drugs -- from 18% of revenues in 94-95 to more than 52% in 08-09.  Foreign owners now account for 3 of the top 10 Indian drug companies.

DIPP published its discussion document last week for comment. See here Download DIPP CL-DraftDiscussion[1].

Posted by Bruce Lehr August 30th 2010.

Buy, Buy, Buy Marco says Buy IMGN!

I don't know who Marco is and whether he knows anything about stocks or not. However, in his post on Seeking Alpha today, he recommends buying up ImmunoGen stock as it drops precipitously in price in the wake of the FDA Refuse to File letter sent to Roche/Genentech last week. This involves ImmunoGen as they have licensed their TAP technology to Genentech for use with its trastuzumab (Herceptin) molecule. The resulting molecule, T-DM1, is what Roche sought to get accelerated approval from the FDA for the treatment of advanced HER2 positive breast cancer.  The FDA says "Nyet" based on data submitted.

However, there is no indication that the drug is in trouble for ultimate approval.  Genentech is starting its phase III trials as scheduled and is seeking to file with the FDA again in mid-2012.  The drug is still expected to be a winner. 

ImmunoGen doesn't get its milestone payment now though -- and this has led to its 35% drop in stock price since August 27th.  Marco says this is a buying opportunity (where have you heard that before on Wall Street). However, in this case, T-DM1 does seem to me to be a viable therapy.  As Marco, points out the IMGN stock appears to have stabilized after its "market correction" and is seemingly backed by some substantial institutional investors.  This also tends to be stabilizing.  So, if you have the stomach (and extra cash) for it - buy low and wait to sell high sometime after mid-2012 when Genentech makes its next filing.

Posted by Bruce Lehr August 30th 2010.

 

 

New Medicines Plummet to All-time Low since the Second World War

This comes to us from the Independent via the PharmaGossip blog.  It is another article documenting the patent cliff -- $142 B worth of drugs falling down over the next 5 years.  This time, not only detailing what's coming off patent, but reiterating the lack of new drugs that are making it through the approval process.

PharmaGossip: "The number of new medicines is at an all-time low and is as low as it has been since the Second World War," - The Independent.

Pharma companies will be losing 14 to 41 per cent of their existing revenues in that 5 year span. There is debate as to whether pharma should continue to invest so heavily in R&D for new "blockbusters". A new PricewaterhouseCoopers (PWC) report, Pharma 2020: The Vision, notes that in the six years from 2001 to 2007, the FTSE pharmaceutical index grew only by 1.3% versus Dow Jones World index rise of 34.9%.  Only 5 of the top Big Pharma generate more than 10% of their revenue from drugs introduced since 2001.  Yikes! The industry is spending 2x as much on R&D and only getting 2/5 as many products to market as a decade ago.

The PWC report isn't all gloom (a few rays of sunshine).  PWC does point out that the global pharma market is still expected to grow from its current $518 B size to as much as $1.3 trillion by 2020. Growth in pharmerging countries is expected in strong double digits. World population is still expected to grow to 7.6 billion by 2020 and there will be an increase in people over the age of 65 from $477 M to more than $719 M during that time.  This population are big users of prescription drugs -- 75% of whom take at least 1 prescription, and 33% take more than 4 prescriptions (especially in my family).

Check out another closely related topic, regarding "Why in-licensing is not the cure", from Seeking Alpha. This speaks heavily to a Morgan Stanley and Accenture reports that urge big pharma companies to follow an "Integrated Therapeutics" model.  A model not dependent solely on producing innovative medicines.  Rather, the companies focus on producing a "suite of medical solutions that include risk-sharing pricing contracts, drug delivery devices, companion diagnostics, or care management services."  This way meaningful value is added to the product, beyond solely the molecule, and benefits are generated for the many parties involved including patients, payers and drug makers.

Posted by Bruce Lehr August 30th 2010.

 

 

Axe Me Again? says Roche

The Pharmalot blog reports this morning that Roche may be planning a large new round of job cuts.  Large being a relative term but in this case meaning in the thousands. 

Pharmalot blog on Roche job cuts.

Cuts will not only come after sales and marketing jobs but will also touch research and development and administration according to management sources. Cuts will be spread across the world (why limit the fun?) and involve different company facilities and countries. Formal announcement of the plan is expected to happen later this week according to Sonntag.

Roche says any announcement will not happen that soon.

Posted by Bruce Lehr August 30th 2010.

"Non-Inferiority" Trial Rationale may be Inferior - FDA Reviews Policy

I had never heard the term "non-inferiority trial" before.  So I have to thank the Pharmalot blog and Outsourcing-Pharma.com for educating me a bit on the subject.  It seems one avenue to gain FDA approval is to show your product is NO WORSE than the next guy's licensed product for the same indication.

Except, you can actually be a little bit worse if your drug is cheaper, or perhaps safer, or has fewer drug interactions or maybe is just easier to take.  If taken to the extreme, I suppose over time that you could see downward drift in "same performing" drugs using this route if you offer it cheap enough for 3rd party payers.  Not too cynical a view - couldn't help myself.

 Well, it turns out the maybe someone woke up at the FDA in March and the agency has decided (and in fact is) getting tougher on the use of non-inferiority trials. In a new report by the GAO, the FDA is cited as setting more limitations on the types of trials where these studies can be applied. Secondly, the agency is reportedly being more rigorous in its review of trial data.

Congress has accepted the fDA has imporved of late but still believes there is work to be done in the non-inferiority arena.  Some have called for a placebo to be included in all non-inferiority trials. 

"The GAO report shows that these so-called 'non-inferiority' trials have often proved to be an inferior means of reviewing the safety and efficacy of new drugs," said Congressman Ed Markey, MA. 

"...no one benefits from ineffective drugs---and so I encourage FDA and industry to continue to collaborate to do everything possible to ensure that safe and effective drugs are developed, " said Congressman Henry Waxman, CA.

It's funny.  I would think Congressmen would be experts at non-inferiority trials given their campaign proclivities.  Maybe someday we can focus on superiority trials?

Posted by Bruce Lehr August 30th 2010.

 

Now I "Get It" from Sanofi’s Courtship with Genzyme

By now, you've read articles in WSJ, in-Pharma Technologist, Pharmalot or elsewhere that Genzyme has received a "bear hug" letter from Sanofi's CEO Chris Viehbacher.  Read more in the PharmTech Talk blog below. It appears Sanofi will go directly to the Genzyme shareholders to pressure its management for a deal or may even escalate proceedings to a hostile takeover situation should that not work. We'll see.

PharmTech Talk » Sanofi’s Courtship of Genzyme in Limbo.

Derek Low also posted on this topic this morning in his In the Pipeline blog  - entitled "How about the same price you turned down before? Hmm?"  One might wonder why Sanofi would go back to Genzyme with the same $69/share price offered back in a letter on July 29th to the Genzyme board. The answer came to me from the History Channel. It's really quite simple. 

I've become addicted in past month watching "American Pickers" and "Pawn Stars".  Both are shows with an eccentric cast of real-life characters who buy things - buy assets.  Pickers find their rusty, dusty, hidden treasures in barns, outbuildings, old churches and factories throughout the MidWest and South.  Pawn Stars operate in the only slightly less glamorous confines off the Las Vegas strip.  Both have something else in common - they only buy what they believe they can make a profit on!  Yes. No matter how intriguing or "neat" the item, you are limited in the price you can afford to pay for it by the price you can get selling it - and thus turn a profit.

So it hit me, between Derek's post and this article from Expatica explaining that Viehbacher is in no hurry to speed the Genzyme deal to an unworkable conclusion.  Sanofi can only afford to pay as much as will allow it to earn a profit for its shareholders!  What a concept?  The assets, products and pipeline from Genzyme need to support its sales price.  It's pretty simple isn't it.  Just ask Pickers and Pawn Stars.  By the way, there is another similarity here - the Sanofi offer is an all cash deal - for $18.5 B.

However, at this writing, the WSJ and Xconomy reports that Genzyme has formally rejected today's offer from Sanofi and is holding out for its $80/share ask price.

 

 

 

Posted by Bruce Lehr August 30th 2010.

FDA rejects the Roche Immunogen T-DM1 accelerated approval filing

Really nice explanation by Sally Church's Pharmastrategyblog as to why the FDA likely decided to reject Roche's application for accelerated approval with T-DM1.

via www.pharmastrategyblog.com

Re-Posted by Bruce Lehr August 27th 2010.

FDA to Genentech "No Fast Track for You" on T-DM1

The FDA has informed Roche/Genentech that it will not grant accelerated approval of the BLA submitted in support of their T-DM1 therapy for breast cancers.  The phase II trial did not meet the agency's criteria for approval because all treatment choices approved for metastatic breast cancer were not included in the study.

Roche/Genentech will still take the drug into Phase III and will resubmit a BLA in mid-2012. Due to the FDA's decision, Immunogen will now have to wait for its next milestone payment. If the BLA had been accepted, Immunogen would have earned a payment from Genentech.

Trials will go on and there is no reason to believe the drug is in trouble.  It just won't get accelerated status. See Fierce Biotech story.

Posted by Bruce Lehr August 27th 2010.

9 out of 10 Vaccum Cleaner Salesmen are for Genzyme-Sanofi Deal

This wry commentary from Derek Low's In the Pipeline blog this morning.  It too analyzes real possibility that Sanofi will walk away from Genzyme deal if Genzyme board cannot accept the offer on table - said to be $70/share. 

Walking away may be much better alternative to overpaying just to "make a deal happen".

Posted by Bruce Lehr August 27th 2010.

How Many Senior Executives Does It Take to Innovate? Is Answer Zero!

A couple of interesting blog posts on Innovation this morning.  The first comes to us from the Innovate on Purpose blob written by Jeffrey Phillips. It examines the "innovation gap" between senior executives and their teams.  Basically, it argues that senior executives become locked in with their current processes to a large degree and also become doubtful that their ogranizations have the wherewithal to be nimble enough to innovate. Mr. Phillips woudl argue that they are underestimating their Company's employees abilities and perhaps even more importantly - willingness to innovate. The post contains the rather provocative statement that firms that had experienced innovation success "had as little involvement from senior management as possible." Wow! 

Seth Godin also writes on the topic of senior management in his blog today.  He notes that senior managers tend to remember what got them where they are - but [too] slowly discover that the things that got you into power are no longer dependable.  The paradox, he notes, is that by the time you are senior, the decisions that matter the most would best be made by people who are junior (more close to the action and trends).

Like I say, provocative.

Posted by Bruce Lehr August 26th 2010.

 

 

Pharma News from India

The WSJ advises this morning that Abbott will become the largest drug company in India when its deal with Piramal closes next month. This is part of Abbott's plan to expand its presence in the 17 so-called 'pharmerging' markets.  These markets have grown from $42 B in 2000 to more than $126 B in 2009. IMS predicts these markets will account for 70% of pharmaceutical growth in the next 5 years.

As such Abbott's CEO Miles White was eager to outbid rivals like Cipla Ltd, Daiichi Sankyo Co., Ranbaxy Labs and GSK PLC to gain the top spot in India - even if some analysts say he overpaid. The India market is expected to swell from $11 B in 2009 to more than $30 B by 2020. Abbott is looking for more than $8 B in sales from pharmerging markets in 2010 and wants to exceed $14 B over the next 5 years. A lot of this needs to come from India.

Fierce Biotech this morning reports on Cipla Ltd plans for expansion in India. The company says it is making investment plans for more biotechs in the region and is looking to spend up to $200 M toward this effort. Cipla has acquired Stempeutics in the recent past and wants to invest more in biosimilars -- particular in HIV/AIDS therapeutic area.

Posted by Bruce Lehr August 26th 2010.

 

Senators Ask Why Provenge Being Reviewed for On-Label Use?

As detailed in Ed Silverman's Pharmalot blog, two US Senators are asking questions with regard to Medicare's review of Provenge.   They note that it is not standard by any means to review a drug for an approved use.  Off-label? Yes.  Approved on-label? No.

Senators Ask Why Medicare Is Reviewing Provenge // Pharmalot.

The Senators suspect that Medicare may wish to restrict coverage - presumably due to its high cost.  Such a review is NOT common for new drugs and price is NOT supposed to be part of the analysis. Stay tuned.

Posted by Bruce Lehr August 26th 2010.

PhRMA Fires Back at AARP Report

Here is PhRMA's analysis and response to the AARP report issued yesterday on drug price increases.  Not surprisingly, PhRMA is critical of the AARP analysis and responds that drug prices have grown slowly in the past the year.

Full statement.

Posted by Bruce Lehr August 26th 2010.

Drug Prices Rose 8 Percent Last Year

From Pharmalot blog this morning, the AARP reported that on average drug prices increased by 8.3% in 2009 - despite world wide recession and a drop in inflation.

Drug Prices Rose 8 Percent Last Year: AARP // Pharmalot.

For the most popular drugs, that increase was a whopping, eye-popping 41.5% as compared to a 13.3% increase in the Consumer Price Index.  Consultants criticized the study as focusing only on branded medications and noted that generics are widely available in the US and very competitively priced with rapidly growing market share.

By contrast a US Bureau of Labor Statistics study found an overall price increase for drugs at much more modest 3.4%.  We may have another case of lies, damn lies and statistics. 

Posted by Bruce Lehr August 25th 2010.

 

Sanofi Offering Walk-Away Price?

 

A Bloomberg report via Fierce Biotech indicates that Sanofi has upped its offer to Genzyme to $70/share from $69 but is not inclined to go higher.  This is according to the famous "inside source".  Sanofi is rumored to be ready to walk away if Genzyme does not become more serious about this offer.  As widely reported, Genzyme insiders are seeking an offer at or north of $80/share.  Sanofi is said to be calling their bluff with the Genzyme stock currently trading at $66 and with prospects of a deeper drop should Sanofi pick up its toys and go elsewhere to play.

Here's an article from HBR that promotes wisdom of having a firm walk away price.

Posted by Bruce Lehr August 25th 2010.

 

 

 

 

India DIPPs into Compulsory Licensing and Price Controls

As reported in in-Pharma Technologist.com, the Indian Department of Industrial Policy and Promotion (DIPP) is considering greater compulsory licensing provisions for drug makers.  These provisions could be applied, if necessary, to 3rd party drug (MNC) companies that takeover local generic competitors.  Indian regulators fear the upsurge in this type of activity in the recent past could result in pricing local populations out of the market in key therapeutic areas -- like cancer treatments where pricing often makes drugs too expensive for patients to access.

DIPP is careful to emphasize that compulsory measures would be used "when a single critical drug is either unavailable per se or unavailable at reasonably affordable prices".  DIPP is inviting public comment on when compulsory measure should be invoked and how compensatory royalties should be handled.

Posted by Bruce Lehr August 25th 2010.

Where are the cures?

Follow the link to Derek Low's In the Pipeline for a blog post of the same title today.  In it, he highlights the balance that needs to be struck in reporting progress with difficult diseases like Parkinson's, Alzheimer's, etc and reporting that cures are imminent.  There is often a large gap between medical science offering us a glimmer of hope in unraveling the next step toward a cure for one of these complex diseases and an actual clinical therapy - which can be years (or even decades off). You need to be responsible when reporting on progress to strike that proper balance.

However, I was struck by Derek's headline, and somewhat by the irony that this week's stem cell ruling will temporarily (hopefully) derail one promising avenue for the treatment of these disorders - namely stem cell therapies.  Clearly, these are years off but constant political wrangling and start/stops to research are not particularly helpful in reaching a cure. 

Where are the cures?  Apparently not with stem cells for the moment as a result of Lamberth's ruling.

Posted by Bruce Lehr August 25th 2010.

Lamberth Stem Cell Ruling Stems Research Pending Appeal

Judge Royce Lamberth's ruling that federally funded human embryonic stem cell research violates the Dickey-Wicker Law has thrown stem cell research in the USA into temporary (though immediate) disarray. According to stem cell researchers, Lamberth's temporary injunction has halted research at dozens of labs. The University of Wisconsin alone has 34 approved stem cell projects -- 21 of which are federally funded and affected by the ruling.

The ruling calls into question not only research done with 75 new stem cell lines approved by the Obama administration since 2009, but even research with previous cell lines considered to be acceptable by the Clinton and Bush administrations could be at risk under this ruling.

The NIH announced that researchers who are currently working on $131 M worth of grants in 2010 can continue their work.  However, the NIH has suspended all review of new grant applications.  There is currently up to $74 M in new funding requests in 50 grant applications before the NIH - $54 M in renewed funding requests and $20 M in completely new research.  All of this is suspended.

Francis Collins, director of the NIH, expressed concern that the suspension of stem cell funding could do great harm to research in the US - "It has the potential to do serious damage just at a time when we were gaining momentum."  Tim Kamp says, director of the University of Wisconsin Stem Cell and Regenerative Medicine Center, the ruling "will put us at a huge competitive disadvantage to other countries" including programs in Japan, the UK, Australia and China.

The Justice Department stated on Tuesday that it would appeal the ruling. It has asked the district court to put its ruling on hold while the appeals court considers the case.  Beyond that, Democratic Leaders in the Congress are deciding whether to pursue additional legislation to restore stem cell research or to remove Dickey-Wicker from this year's spending bill.  Leaders are exploring legal and political ramifications.

Seeking Alpha reports that a basket of stem cell stocks that they follow were down 5.5% in Tuesday's trading following the ruling. Ironically, several of the companies affected do not work with embryonic stem cells and have programs centered on use of adult stem cells from autologous adipose tissue or bone marrow.  Cytori Therapeutics, Aastrom Biosciences, StemCell Inc, and International Stem Cell Corp are 4 companies who saw their stock drop more than 5% but DO NOT work with embryonic stem cells. Geron IS a company that works with embryonic stem cells that saw its stock drop.  Osiris Therapeutics is a company that works with adult stem cells that actually saw its stock rise. 

Read here for more gory details:  WSJ Health blog, WSJ, Fierce Biotech, Seeking Alpha, and Seeking Alpha (Zacks).

Posted by Bruce Lehr August 25th 2010.

 

 

Roche Signs $1.1 B Deal with Aileron

Aileron Therapeutics today announced that it had reached a deal with Roche, getting $25 M upfront with milestones that could reach $1.1 billion, for access to its stapled peptide platform.  This technology enables delivery of peptide based drugs by maintaining structural configurations that are resistant to proteases, filtration from the blood stream, and enable peptides to enter cells -- all while preserving the peptides bioactivity. Stapled peptides can also recognize extracellular and intracellular targets with specificity.

Roche is making a "...significant commitment....betting they're finally going to unlock the power of peptides as a superclass of drugs," siad Aileron CEO Joseph A. Yanchik III.  Roche will initially take 5 targets to the clinic. See Fierce Biotech.

Posted by Bruce Lehr August 24th 2010.

Amyloid Smamyloid!

A good post from Derek Low In the Pipeline reporting on interview of Mark Smith, Case Western, in Forbes.  Dr. Smith is a long time opponent of the theory that amyloid is a cause of Alzheimer's disease. He has long argued that amyloid is actually a sign of the brain trying to protect itself and that therapies geared toward removing amyloid will actually make things worse.

The recent Lilly trial seems to add some marks to his side of the ledger.  Of course, several other anti-amyloid drugs (gamma secretase inhibitors) are being tested by major pharma companies as we speak in Phase II trials.  We shall see if these trials bear similar results to that experienced by Lilly.

In the meantime, Dr. Smith predicts the field will stick with apporaches aimed at reducing amyloid until more patients are treated with other modalities not aimed at reducing amyloid plaques.

Posted by Bruce Lehr August 24th 2010.

Genzyme Looks to Extract More Value from Sanofi

As reported in the WSJ and in Fierce Biotech, Genzyme is balking at the price that has been offered by Sanofi to acquire it. Sanofi cannot begin any due diligence into the proposed deal until the two sides have agreed on a starting price that is acceptable to Genzyme's board and shareholders.  A

As noted yesterday, at least one Genzyme shareholder has already filed suit to try to block any sale from occurring at a perceived "low price" - if an $18.4 billion offer can be construed as low. Genzyme wants to see the offer at a figure a lot closer to $80 per share - up considerably from the current $69 per share.  It's current stock price is running at $68 per share.

 

Posted by Bruce Lehr August 24th 2010.