invivo@live.com
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
your study-to-study comparisons [of Telaprevir vs Boceprevir] are very unscientific.
--------------------------------------------------------------------------------
Of course they are.
Sorry you would be laughed out of the FDA.You know it is not an accepted scientific practice to compare non head to head trials. You are one of the brightest people i have met on the internet.You are much smarter than me but if you stand by the statement i have lost some of the high regard i have for you as probably the brightest person i have conversed with on the net.
I am not going to continue to argue i know you will not cede .
All of your points make logical sense but we will see when and if both drugs get labeled and what the label says .
Investors will of course make exactly the kinds of comparisons that you’re dismissing as irrelevant. By now, I think there’s enough data to say that Telaprevir is the clear frontrunner (#msg-54317080).
I think investors have already given VERTEX a 7 bil market cap in terms of MRK its not as big a deal as it is with VERTEX.That is the main reason they have not shown all of their data.VRTX needed money and loudly announced their data at every point in this process. You need to see the label . I am not saying they are irrelevant but in the real world things are not so black and white .
BTW your study to study comparisons are very unscientific.You continue to post these comparisons like its gospel.I know you are a smart man but what you are doing is not an accepted practice comparing non head to head studies.It is not allowed in the real world.
In terms of the Vertex drug and Merck drug i know that many people including my self are waiting for the full data from both companies so we can compare the data. I have to tell you that these comparisons will not have the impact that some on this board and on wall street think they will have. If you have any experience actually marketing drugs in front of the FDA you know that non label comparisons will not only not be allowed and they will be closely monitored. Unless there is a head to head trial both companies when marketing will not be allowed to discuss the other product . The FDA has been very strict in this area in the last two years. The so called experts will not be allowed to approach that area when being paid by one of the companies.That is about the only time these mouthpieces talk is when they are getting paid.
If the drugs are even close they will be considered me too drugs except in the case in several critical tie breakers.
Most important area is who will pay for it.Insurance coverage will be the most important factor.Now Merck has vast resources and that could be an advantage but if Telepravir receives a shorter course than than the Merck product that will make it significantly less expensive and add in the EPO and that could seal it.That is why the drugs labels are going to be critical in terms of treatment duration.We are still very far away from the label
But do not get so hung up on comparing one study to a completely different non head to head trial.It is just not allowed in the real world
I got you. I thought you were referring to the untreated total population group
We will see what they report at AASLD
The other half of the bolus of patients we’re talking about consists of those who have never been treated
The problem with treating this group is that most do not even know they have the virus.Its not going to be easy to mine them . This was the great hope of the Orasure product for use in the General medicine office.The only time these patients are even flagged are when elevated ALts show up . That happens in about 50 % of patients . Its too bad most GP Dr's don't even catch that
Null responders 31%
There is a large piece of the pie in the general population that are non responders . This is where Merck's AASLD data will be critical .
I bet they beat this number easily
Isn't it true if the primary endpoint was not met therefore the study shows no statistical significance then you begin to look at confidence intervals ? Which is a much weaker endpoint.
]Three healthy volunteers testing a combination of the drugs IDX184 and IDX320 showed elevated liver enzyme levels in a routine post-study safety test, the Cambridge, Massachusetts company says.
Although liver function returned to nearly normal levels in all three subjects, the FDA placed a clinical hold on the study until it can discuss the results and other relevant data with Idenix.
I am just curious if any knows the extent of the elevation in the enzyme levels ? The elevation must have been at a high rate . The presentation at AASLD will be telling .
Idenix CEO and chairman Jean-Pierre Sommadossi says the company remains “committed to the future potential of these drug candidates,” based upon the safety and antiviral activity it has measured in other studies in which the drugs were tested alone, instead of in combination
It looks like they already are developing strategies to overcome this set back.
Idenix Hopes to Resume Course With Hepatitis C Drugs by Year's End
http://seekingalpha.com/article/224650-idenix-hopes-to-resume-course-with-hepatitis-c-drugs-by-year-s-end
By Michael Fitzhugh
Idenix Pharmaceuticals (IDIX) halted a mid-stage study of two hepatitis C drugs after the U.S. Food and Drug Administration ordered it to suspend the trial over safety concerns. The news led investors to sink the company's shares on worries about the program's future.
Three healthy volunteers testing a combination of the drugs IDX184 and IDX320 showed elevated liver enzyme levels in a routine post-study safety test, the Cambridge, Massachusetts company says.
Although liver function returned to nearly normal levels in all three subjects, the FDA placed a clinical hold on the study until it can discuss the results and other relevant data with Idenix. The company is preparing that information now in hopes of expediting the agency's review and resolving the matter as quickly as possible. It says it is aiming for submission by the end of the year.
Idenix CEO and chairman Jean-Pierre Sommadossi says the company remains “committed to the future potential of these drug candidates,” based upon the safety and antiviral activity it has measured in other studies in which the drugs were tested alone, instead of in combination.
But investors chopped the value of Idenix shares nearly in half when news of the clinical hold hit. The price of Idenix shares fell to $3.18 from $5.99 on the day it was announced. On top of that punishment, the hold will also likely make Idenix's ongoing search for an outside partner to advance its hepatitis C program more difficult.
Idenix plans to present full data from studies of Idenix's IDX184, IDX320, and IDX375, the company's third experimental hepatitis C drug, at the annual meeting of the American Association for the Study of Liver Diseases in Boston at the end of October.
Hepatitis C treatment has been an active area for development this year. Bristol-Myers Squibb (BMY) moved to acquire ZymoGenetics, its partner on a promising mid-stage Hepatitis C drug, for $885 million in early September. Vertex Pharmaceuticals (VRTX) reported that telaprevir, its late-stage hepatitis C drug, can help some people tackle the virus in half the time the current treatment takes while minimizing side effects. There's also a GSK-Regulus Therapeutics partnership on miR-122, as well as a new drug application due from Merck (MRK) for its hepatitis C medicine boceprevir.
About 70 percent to 80 percent of the estimated 3.2 million people in the United States who have chronic hepatitis C virus infection don't know it because they are asymptomatic, according to the Centers for Disease Control and Prevention. But the disease can result in long-term health problems, including liver damage, liver failure, liver cancer, and even death.
Patent Docs blog
http://www.patentdocs.org/2010/09/second-circuit-denies-en-banc-reconsideration-in-cipro-case.html
« Goeddel v. Sugano (Fed. Cir. 2010) | Main | USPTO Updates Obviousness Examination Guidelines »
September 08, 2010
Second Circuit Denies En Banc Reconsideration in Cipro® Case
In re Ciprofloxacin Antitrust Litigation
By Kevin E. Noonan --
The Second Circuit on Monday denied plaintiffs' petition for rehearing en banc of its decision that the "reverse payment" agreement between Bayer and Barr over ciprofloxacin hydrochloride (Cipro®) was not anticompetitive under the antitrust laws. One judge, Rosemary S. Pooler, dissented from the decision, as she had dissented from the original panel decision. And her dissent illustrates the point of disagreement, if not the flaw in her arguments (and that of others, including the Federal Trade Commission) that such agreements should be per se illegal.
To recap, Bayer holds U.S. Patent No. 4,670,444 claiming generically certain antibiotic drugs, and specifically ciprofloxacin hydrochloride that Bayer sells as Cipro®. Barr filed an Abbreviated New Drug Application (ANDA) containing a Paragraph IV certification that the '444 patent was invalid and unenforceable. Before trial, Bayer and Barr settled the litigation, entering into agreements providing that none of the defendants would challenge the validity or enforceability of the '444 patent, and that Barr would convert its Paragraph IV certification to a Paragraph III and not market its generic Cipro® until the '444 patent expired. Importantly, the agreements contained a provision that Bayer would sell Cipro® to Barr for resale or make quarterly payments ("reverse payments") until December 31, 2003. In return, Barr agreed not to sell a generic version of Cipro® until at least six months before the '444 patent expired. It is undisputed that Bayer had paid Barr a total of $398 million under this agreement. Similar agreements were also made between Bayer and other generic drug makers, including The Rugby Group and Watson Pharmaceuticals, Inc.
The Federal Circuit heard a portion of this case under a Walker Process antitrust claim, based on the willful assertion of an unenforceable patent, pursuant to Walker Process Equip., Inc. v. Food Mach. & Chem. Corp., 382 U.S. 172, 177 (1965), finding that the "reverse payment" agreement was not per se illegal under antitrust law. A coalition of patient groups, trade unions and pharmacies brought suit in the Eastern District of New York sounding solely in antitrust. The Court, bound by the Second Circuit's precedential Tamoxifen decision (In re Tamoxifen Citrate Antitrust Litigation, 466 F.3d 187, 208-12 (2d Cir. 2005)), that such reverse payments were not per se illegal, granted summary judgment to defendants. The original appellate panel, similarly bound by the Tamoxifen precedent, affirmed, in a decision that urged the plaintiffs to petition for rehearing en banc. That petition has now been denied, setting the stage for a certiorari petition to the Supreme Court.
Judge Pooler raises the many public policy positions taken by the FTC and others, regarding the effects on consumers and drug prices occasioned by such reverse payment agreements. Her dissent notes that, in the five years prior to the Court's Tamoxifen decision, there were no settlement agreements containing reverse payment provisions, while since that decision there had been a "dramatic surge." She cites the FTC Report (see "FTC Disapproves of 'Pay-for-Delay' Drug Deals") for the datum that there have been 53 reverse payment-containing agreements that had cost consumers "approximately $3.5 billion per year" (by FTC estimates, which may be flawed; see Patent Docs report).The significant statement in the dissent, that illustrates the underlying (flawed) rationale behind much of the opposition to reverse payment agreements, is this:
Further, such settlements serve no obvious redeeming social purpose. Put simply, what the patent holder purchases by means of an exclusion payment settlement is the continuation of a patent the patent holder must have thought had some significant probability of being declared invalid.
And in a footnote, continuing:
Nor, it should be noted, are exclusion payments a patent holder's only means of hedging against this probability. Instead, the probability of invalidation could be reflected in a settlement by means of which the patent holder agrees to some reduction in the unexpired term of the patent.
There are several assumptions behind this statement, not the least of which is contrary to the statutory presumption of validity (the dissent quotes an amicus brief by "the United States" to the effect that "[t]he presumption of patent validity is simply a procedural device that assigns burdens in litigation challenging the validity of an issued patent. There is no basis for treating that presumption as virtually conclusive and allowing it to serve as a substantive basis to limit the application of the Sherman Act"). What is missing is the concept of risk and reward in the current Hatch Waxman regime, by which generic drug makers are in a position to attack a patent protecting a valuable pharmaceutical franchise while themselves taking no risk. Indeed, the skewed nature of this relationship has been noted by courts (including the Second Circuit in this case: "the Hatch-Waxman Act redistributes the relative risks between the patent holder and the generic manufacturer, allowing generic manufacturers to challenge the validity of the patent without incurring the costs of market entry or the risks of damages from infringement") and by a recent study in the journal Science, questioning the utility of the litigation provisions of Hatch Waxman (see "Maybe Hatch-Waxman Data Exclusivity Isn't So Good For Traditional Drugs After All"). It should be noted that these misgivings may be shared by members of Congress, who did not include Hatch Waxman-like litigation provisions in the recently-enacted follow-on biologics bill, instead opting for complicated negotiation provisions seemingly aimed at discouraging Hatch Waxman type litigation over biologic drugs (see "A First Look at the Abbreviated Follow-on Biologic Regulatory Pathway" snippets, pages 1-4).
The dissent also notes that while the Hatch Waxman Act does not prohibit reverse payment agreements, it also "does nothing to change the general rule that market-sharing agreements violate the antitrust laws." This notion ignores the several decisions by other courts of appeal that reverse settlement agreements are not anticompetitive, when analyzed by the rule of reason (see "Reverse Payments in Generic Drug Settlements" - Part I, Part II, Part III). Indeed, the dissent's position (and the FTC's and others) is that these agreements should be per se illegal under the Sherman Act. The problem with this argument is that it is contrary to the legal determinations of several other courts of appeal that not only are these agreements not anticompetitive but, in many instances, result in generic versions of patented drugs being available to consumers earlier than they would have been if the patentee had prevailed at trial.
The dissent also (disturbingly) cites the several sources of "criticism" of the Court's Tamoxifen decision, including "the majority of State Attorneys General, the Federal Trade Commission, the American Medical Association, and an impressive array of consumer groups and academic commentators." This is legal decision by plebiscite, not law, and is possibly the worst way for this type of question to be decided. The careful balancing of risks, rights, and responsibilities required to address this issue is not something that should be left to various interest groups with their various axes to grind. This may be a question for Congress or the Supreme Court to address, but it is irresponsible for the dissent to suggest that popular opinion is the best way to come to the correct decision.Posted at 11:55 PM in Food and Drug Administration | Permalink
TrackBack
TrackBack URL for this entry:
http://www.typepad.com/services/trackback/6a00d83451ca1469e201348724eb57970c
Listed below are links to weblogs that reference Second Circuit Denies En Banc Reconsideration in Cipro® Case:
Comments
The agreement between innovator and generic companies may look as though it is within the exclusive zone of patent law. This is so because the certification on product patent which claims per se the said drug is converted into para IV into Para III and constitutes well within the ambit of patent law. However,such agreement per se violates the trade principles and constitutes anti competitiveness.
Posted by: senthil kumar | September 09, 2010 at 04:33 AM
Any agreement between innovator and generic companies which denies affordability of generic drugs is against the public interest and contravenes and negates the competitive spirit and forms the basis for anti-trust violations.Any such agreement against public interest becomes anti-competitive and seen as a violation of anti trust priniciples.
Posted by: K.M.Senthil Kumar | September 09, 2010 at 06:34 AM
Kevin,
Again, another nice article on the "reverse-payment" issue. I especially like your comment that the reliance in Pooler's dissent on the "forum of public opinion" is "legal decision by plebiscite, not law." Or as others would say "judicial activism," not "judicial reasoning based on law."
Posted by: EG | September 09, 2010 at 10:03 AM
Dear Kumar:
Please read the opinions in the "Part I, Part II, and Part III" posts referenced in this one. The simple calculus you espouse simply does not comport with reality.
Thanks for the comments.
Posted by: Kevin E. Noonan | September 09, 2010 at 05:18 PM
Dear Kevin,
Thanks for your comments. Though, it may not go well with the reality, such agreements needs scrutiny through judicial review.
Posted by: K.M.Senthil Kumar | September 10, 2010 at 01:38 AM
Dear Kumar:
Agreed. But Judge Pooler and others believe these agreements are pet se illegal. Thus, no judicial review would be necessary. Tamoxifen and other decisions apply a rule of reason, which provides just the like of judicial scrutiny you support.
Thanks for the comment.
India becomes a hub for fake medicines
http://www.washingtonpost.com/wp-dyn/content/article/2010/09/10/AR2010091006700.html
"When we bust one operation, two more spring up elsewhere," says private investigator Suresh Sati, sitting. Pankaj Dutt works with Sati. (Rama Lakshmi) Network NewsX Profile
By Rama Lakshmi Washington Post Foreign Service
Saturday, September 11, 2010
IN NEW DELHI Private investigator Suresh Sati rattled off the popular brand names listed on the boxes of cough syrup, supplements, vitamins and painkillers sprawled across the desk and shelves in his basement office.
"They look real, but all these are fakes," said Sati, head of a New Delhi-based agency that helps police conduct raids against counterfeit-drug syndicates across the country. "A regular customer cannot make out if a drug is fake. . . . The biggest giveaway is when someone is selling medicines very cheap. It is almost always fake."
India, the world's largest manufacturer of generic drugs, has become a busy center for counterfeit and substandard medicines. Stuffed in slick packaging and often labeled with the names of such legitimate companies as GlaxoSmithKline, Pfizer and Novartis, the fake drugs are passed off to Indian consumers and sold in developing nations around the world.
Experts say the global fake-drug industry, worth about $90 billion, causes the deaths of almost 1 million people a year and is contributing to a rise in drug resistance.
Estimates vary on the number of these drugs made in India. The Indian government says that 0.4 percent of the country's drugs are counterfeit and that substandard drugs account for about 8 percent. But independent estimates range from 12 to 25 percent.
Indian officials say the clandestine industry has hurt the image of India's booming pharmaceutical industry and its exports, worth $8.5 billion a year, mostly to African and Latin American countries.
To clamp down on the illegal trade, the health ministry launched a reward program this year offering $55,000 to those who provide information about fake-drug syndicates.
Last year, the ministry also strengthened its drug law to speed up court trials. Suspects found guilty of manufacturing and selling fake drugs can be sentenced to life in prison.
The number of people arrested for manufacturing and selling fake drugs rose from 12 in 2006 to 147 last year, and drugs worth about $6.5 million were seized over this period.
"It is very difficult to dismantle the entire operation," Sati said. "When we bust one operation, two more spring up elsewhere. Convictions are rare."
The tricks of the trade include sticking fraudulent labels on expired products, filling vials with water, stuffing small amounts of real ingredients in packages of popular licensed brands and putting chalk power in medicine packets.
But more than the concern for public safety, officials here have been particularly alarmed about recent incidents that discredit India's image abroad.
In June, officials at Nigeria's Abuja airport caught a shipment of fake antibiotics, containing no active ingredients, with a "Made in India" label.
Nigerian investigators later said that a Chinese company shipped the drugs via Frankfurt. In a similar incident last year, a shipment of fake anti-malaria drugs from China arrived in Nigeria with an Indian tag.
Last year, Sri Lanka banned imports from four Indian companies after officials discovered substandard medicine in shipments.
Over the years, drug companies have used holograms or embossed their logo on the packaging to protect their brands, but these have also been counterfeited in India.
One company, MSN Labs, is using a technology developed by U.S.-based start-up firm PharmaSecure that allows consumers to check the authenticity of medicines by sending in a text message of the code written on them.
But many Indian companies are "apprehensive of pursuing the cases for fear of bad publicity and possible loss of confidence among consumers," said Barun Mitra, director of the New Delhi-based think tank Liberty Institute.
Co-writing a report on a recent survey, Mitra said that 12 percent of sampled drugs from the capital's pharmacies were substandard. "We are behaving like ostriches with our heads in the sand and pretending that nothing is amiss even as the problem keeps growing and affecting Indian patients."
On a recent morning in the northern city of Varanasi, a young man named Ashish waited for a shipment of painkillers and postpartum pills to arrive by train.
He said his order of pills that controlled postpartum bleeding contained chalk powder but came with the brand name Methergine in a Novartis package.
The painkiller had insufficient ingredients and carried a Bidanzen Forte label inside a knockoff GlaxoSmithKline package.
"There is a lot of profit in this," said Ashish, 28, describing the extent of counterfeit drugs in Varanasi. He declined to give his surname because his operation is illegal.
"I do not think about right or wrong," he said. "I am not killing anybody. The worst is that these medicines will not show any result and the patient may have to check into a hospital."
Well you raise a good point about Roche-Vrus . When you consider that VRTX has a 7 Billion market cap and Vrus has less than 1 billion i think it has more potential to be acquired than VRTX.Although we know what they say about a bird almost in the hand.VRTX has much already baked into its price. I fancy many are thinking they will capture 70% of the DAA market in the first two years.That may be as much as 4 billion. Whats the other 3 billion in market cap for ? I think other more advanced DAAs can hit the market within a 2 to 3 year time period. Who says they get 70% of that early DAA market even if they are approved ? We have caught a glimpse of Merck's data.At AASLD we will see all the data.I don't believe MRK and VRTX are going to initiate any more pivotal studies until post approval its too risky. They need approval but approval is not etched in stone.One leading research hepatoligist thinks its likely the FDA asks for for safety data on the Rash and Anemia that each drug has shown.Nothing is absolute with the FDA. Another fly in the ointment is insurance coverage.One drug may show 10 or 15 % higher efficacy so the other company may low ball insurance companies.These are going to be very pricey medications.Nothing is assured. I still think VRUS has a good chance of getting bought out. I have no position . I know this board contains many VRTX bulls and my Cheese presented today may of the Swiss variety but i do present some potential logical pitfalls with the current value of VRTX. All of my Bio tech money is in MNTA in my opinion with the approval of Enox Mnta is much less dicey than your typical bio tech.Heck they are printing money at this split second .I did not notice a Friday Enox approval for Teva.For all one knows minus Bernstein it will transpire in short order ?
You have to love Teva . The really know how to play both sides. The are the leader in the Bi-pharmaceutical category
Teva's only arguments are based on feelings of fairness in that they argue it is unfair to let Merck enforce the patent against them. However, once it's realized that the patent here was really on something new, that this is the only patent Merck has listed in the Orange Book on the drug, that Teva wants to make the same exact drug, and that CRT (the patent applicant and actual owner) was a small non-profit cancer research organization at the time it applied for the patent, then it starts to actually seem quite unfair to take the patent away if they did not do anything clearly wrong. Again, the fairness bias has to lie with Merck, not against them.
A Prescription For Growth?
( Good to see MNTA getting this kind of press )
On Friday September 10, 2010, 6:24 pm EDT
Observers have been saying for years that large drugmakers weren't ready for the era when billions of dollars' worth of patents would expire. That era is now.
Generic-drug makers are set to take as much as 80% of the market once held by brand-name pharmaceuticals as blockbuster patents expire, triggering a flurry of deals.
Case in point: Sanofi-Aventis' (NYSE:SNY - News) $18.5 billion bid Aug. 29 for profitable biotech Genzyme (NMS:GENZ).
Days earlier, Sanofi, the world's sixth-largest by market cap, lost a court bid to protect the patent on its biologic anticoagulant Lovenox, which wasn't supposed to expire until 2012.
The court upheld an earlier Food and Drug Administration ruling that allows Momenta Pharmaceuticals (NMS:MNTA) to sell a generic version of Lovenox. Unless Sanofi wins on further appeal, it will lose a big piece of Lovenox' sales — $2 billion in the U.S. in 2009.
The big kahuna of patent expirations is Pfizer (NYSE:PFE - News), still the largest drugmaker by market cap despite a share price that has fallen more than 67% since 2000. Nine of Pfizer's drugs, including famous blockbusters Lipitor and Viagra, will lose their U.S. markets to generics by 2015. Together, their U.S. sales accounted for 13% of Pfizer's overall revenue last year.
The list of patent losses goes on and on, and the dollars of lost revenue pile up. That explains not just Sanofi's bid for Genzyme, but previous mega-acquisitions. Pfizer bought Wyeth for $68 billion in 2009. Months later, Merck (NYSE:MRK - News) paid $41 billion for Schering-Plough.
All the big pharmas are beating the bushes for biotechs whose promising technology they can partner with on, license or buy.
Specialty drugs appear to be in a better position, pumping out a narrow range of products aimed at specific groups of patients. The products may be branded or generic, and range from skin lotions and prescription anti-acne pills to oral contraceptives and colitis medicine.
Strong performance from the likes of Valeant Pharmaceuticals (NYSE:VRX - News), Warner Chilcott (NMS:WCRX), Endo Pharmaceutical Holdings (NMS:ENDP), Medicis Pharmaceutical (NYSE:MRX - News) and Paladin Labs have helped propel IBD's Ethical Drug Industry Group. As of Friday, the collection of 50 stocks ranked No. 14 among IBD's 197 Industry Groups, up from No. 104 six months ago.
1. Business
The drug business is all about two things: development and marketing.
The Big Pharma companies are great at marketing. Development is harder, as evidenced by some spectacular flops in recent months.
Pfizer had hoped it had found a successor to Lipitor with Torcetrapib. It canceled the project in 2007 after phase three trials showed a higher-than-acceptable risk of death.
Eli Lilly (NYSE:LLY - News) last month gave up on semagacestat for Alzheimer's, also in phase three. It made patients worse.
All those failures cost piles of money.While Big Pharma has traditionally "swung for the fences," specialty drug companies make money by "hitting singles," says Damien Conover, strategist and senior pharmaceutical analyst for rating firm Morningstar.
For the most part, specialty drugmakers don't have huge research and development costs, he says. Many of their products are adapted from long-approved drugs available as generics, and they depend on a few drugs that carry high margins.
Specialty drugmakers also don't have the heavy marketing overhead, says Les Funtleyder, manager of the soon-to-launch Miller Tabak Health Care Transformation Fund.
Big Pharma, which is still focused on a mass market, needs armies of salespeople to persuade primary-care physicians to prescribe their products. The smaller, more focused companies don't need giant sales forces to reach specialists.
"The big companies are more influenced by general market conditions," Funtleyder said. That's because they are diversified and are trying to find new, expensive-to-develop products for their pipelines.
Shares of the specialty drug companies have appreciated well over the last 12 months, led by Valeant, up 122%. Sanofi and Roche (OTC:RHHBY.ob - News), by contrast, are each down 16%, and Pfizer is down 5%. The best performer among the Big Pharma companies is Bristol-Myers Squibb (NYSE:BMY - News), up 17%.
Name Of The Game: For Big Pharma, the keys are developing new drugs and marketing them well. Failing that, they buy up smaller, innovative companies with promising drug pipelines. For specialty drugmakers, success hinges on finding lucrative niches.
2. Market
The U.S. remains the biggest market for pharmaceuticals in the world, but the industry is a global one, with some of the fastest growth in emerging countries such as China and India.
Big Pharma depends on foreign sales for about half its revenues, and the industry is turning its attention to emerging markets.
As people become wealthier, they can afford better medical care and more medicine.
Latin America, Eastern Europe, India and China are target markets for big- and small-cap pharmas to sell their generic products with brands they can advertise and promote. "There's more growth there than here," Funtleyder said.
Valeant has been more selective, focusing abroad on two therapy classes: dermatology and neurology. It limits itself to the U.S., Canada, Australia, New Zealand, Mexico, Brazil and Central Europe. It goes only where no competition exists for its products.
Valeant has a market cap of $4.4 billion on expected sales this year of $1 billion. Paladin has a market cap of $486 million and more than $121 million in expected sales this year.
Pfizer's projected sales are $62 billion, and Sanofi's are $43 billion.
For specialty pharma, the future is rosy. More generics give it more opportunity to make new formulations that don't need to be blockbusters to be profitable.
3. Climate
Pharma was at the center of the debate over ObamaCare, the industry everyone loved to hate.
Yet, as a proportion of all health costs, U.S. spending on pharmaceuticals was nowhere near as high as critics might think.
Data firm IMS Health puts the 2009 U.S. expenditure on drugs at $322 billion. That's just 13% of the total $2.5 trillion spent on health in the U.S. in 2009.
ObamaCare has not hurt drugmakers — and likely will help them, Funtleyder says. Part D, the Medicare drug benefit signed into law by former President George W. Bush, has meant more revenue for pharma, both branded and generic, and has cost taxpayers less than expected.
The Obama legislation filled a coverage gap. With the Obama-Care subsidy, more seniors should stay on their medications longer, increasing drug sales.
In 2014, millions more people will start to come into the insurance system, if all goes according to plan. That means new customers for drugs.
As for fears that the government will impose price controls on drugmakers, that's not likely, Funtleyder says.
"Our reading of the reform bill finds no mechanism for the government to impose price controls," he said. "That may hurt taxpayers but not drug companies."
4. Technology
Experts see promise on multiple fronts.
Biologic drugs, made of proteins rather than chemicals, will better target specific diseases vs. the hit-or-miss approach of conventional drugs.
And the era of the "me-too" drug — drugs that treat what's already being treated well enough — is over, Funtleyder says. Cholesterol is one area well-covered by statin-class medicines, he says.
Alzheimer's, cancer, diabetes and other life-threatening or chronic diseases are where the "unmet medical need" lies, he said.Genetic testing is a growing diagnostic field. It already lets doctors predict a patient's predisposition for certain diseases such as breast cancer.
Within a few years, mapping a person's entire genetic structure could be affordable, helping doctors determine what ailments may be treated or even pre-empted with what drugs.
5. Outlook
In both North America and Europe, markets for many drugs have stopped growing, Funtleyder says. People who need today's drugs aren't getting sick at a faster rate.
As for big mergers of drugmakers, they probably won't resume until middecade, he says.
The prospects for the future in drug development "always comes back to the pipeline," Funtleyder said.
That depends on pharma funding enough science to generate medical breakthroughs. A few of those and the "tide will lift all ships," Morningstar's Conover said.
Upside: ObamaCare should bring new drug customers. An aging population will need drugs to treat chronic conditions. And genetics may open up a whole new wave of innovative treatments.
Risks: A wave of expiring patents will pressure big-name drugmakers in the short term, hitting sales and margins as cheaper knockoffs flood the market.
They will probably go on a mini buying binge acquiring smaller Biotechs and start cutting costs in marketing and sales and reload the pipeline.
Idenix is exciting for similar reasons. It will be presenting a combination study of two of its antiviral drugs at the AASLD
Considering it was published today makes one wonder
It doesn't take much to get " published " today
Four Biotech Takeout Candidates
http://blogs.forbes.com/matthewherper/2010/09/10/four-biotech-takeout-candidates/
By MATTHEW HERPER
Inspired by recent mergers in the biotech sector, Sanford C. Bernstein biotechnology analyst Geoffrey Porges screened 10,000 companies to come up with a list of 25 that look like possible takeout candidates — and then picked four of those he thinks are most likely to get scooped up.
Some of Porges’ criteria are obvious: buyers like newly launched products, drugs that don’t face a lot of regulatory uncertainty, and lately large drug companies have been making plays for smaller ones whose stocks have been depressed by some surprise bad news — Porges points out that Sanofi’s bid for Genzyme and Celgene’s purchase of Abraxis Bioscience as evidence.
More important, Porges kept in mind two forces that are shaping the pharmaceutical industry. First, drugs are increasingly a specialty business, with companies focusing on treatments for genetic diseases, uncommon cancers, and other rare ailments. Big, broad, blockbuster treatments are out, and narrowly focused and very expensive treatments are in. Drugs are for sick people.
Second, large drug companies are trying to avoid traditional small molecule drugs that will face large generic uptake after their patents expire. They prefer proteins, cell therapies, and other newer types of medicines that will continue to generate revenue even if patents expire and generics emerge. Here’s the list:
ViroPharma
Makes Cinryze, a recently launched treatment for hereditary angioedema, an ultra-orphan disease. Currently demand for the product is exceeding supply. Downsides to an acquirer: the stock price is near a 52-week high, and there is risk of competition.
Geron
The developer of drugs aimed at processes involved in aging and embryonic stem cell treatments has always been long on promise but short on results. But its treatments against cancer and spinal cord injury represent “high risk, high reward” opportunities for potential acquirers.
Allos
Sells the highly focused, very expensive cancer drug Folotyn. The stock has not performed well, but the ultra-orphan cancer niche and the idea that the acquirer could do better that current management might appeal to buyers.
Pharmacyclics
An exception, it makes small molecule drugs, but for cancer. Porges writes that the most promising program is in Bruton tyrosine kinase (Btk) inhibitors. Its lead compound showed what Porges says was “intriguing” activity in a form of lymphoma. Most interesting: the promising drugs came from gene-mapper Celera when it decided to get out of drug development — they could be proof genomics works for drug development after all.
Matt, are there any other rare genetic disease companies that should be on the list. What about Alexion?
Matthew Herper
The Medicine Show
Porges ranked Alexion, Dendreon, United Therapeutics and Onyx as being somewhat likely of a near-term takeout. They’re all perennial buyout candidates, and I think any of them would make sense for a large pharmaceutical company at some point.
But Dendreon has the overhang of the Medicare coverage decision, Onyx is partnered with Bayer, and I’m not sure Martine Rothblatt would sell United — and that’s one case where investors would stand behind her. Alexion probably similar in that regard,
Biotech Stocks
Biotech Busts And Breakthroughs
Matthew Herper, 09.10.10, 10:05 AM ET
http://www.forbes.com/2010/09/10/biotech-busts-breakthroughs-business-healthcare-august-2010.html?boxes=businesschannelsections
ZymoGenetics bulls are having a big party. The Seattle biotech was the second-best-performing biotechnology stock in August, rising 22% on heightened hopes for the hepatitis C drug it is developing with Bristol-Myers Squibb. Then, after market close on Sept. 7, Bristol said it would buy ZymoGenetics for $750 million--an 85% premium over its previous close. End result: The company shares have blasted up 124% since Aug. 1.
Idenix, another hepatitis drug developer, was the third-best-performing stock among biotechs in August. Its stock popped after it released abstracts for a medical meeting to be held by the American Association for the Study of Liver Diseases in October, and investors liked what they saw.
Wall Street is bracing for one of the biggest new drug categories in a decade: the launch of a series of antiviral medicines that could dramatically improve the cure rate for hepatitis C, a viral disease that slowly attacks the liver and is often fatal. Four million people in the U.S. are infected with this virus, according to an estimate from the Centers for Disease Control & Prevention, and the virus is associated with 20,000 deaths. It is spread by sexual contact, intravenous drug use and transfusions. Actress Pamela Anderson, country singer Naomi Judd and Aerosmith singer Steven Tyler have publicly said they contracted the illness.
In Pictures: Biotech Busts And Breakthroughs, August 2010
The current treatment for hepatitis C combines interferon drugs sold by Roche and Merck with an antiviral medicine called ribavirin in an 11-month course. The combo causes flu-like symptoms and anemia, but cures 40% of patients. Now new drugs that could be approved within a year could increase the cure rate to 70% for newly diagnosed patients.
The new pills are being developed by Merck and the team of Vertex Pharmaceuticals and Johnson & Johnson. Full trial data on both drugs is coming at a big meeting of liver specialists next month. Just about everyone on Wall Street expects Vertex to win this duel, as its results have looked best so far. Even bearish analysts seeing U.S. sales of Vertex's telaprevir hitting more than $2 billion in 2013. Last week, Vertex released a press release showing it could reduce infection in patients who had not been helped by interferon therapy, including tough-to-treat patients drug companies often leave out of clinical trials.
Vertex shares popped, but analysts at Needham & Co. downgraded the company from "buy" to "hold" because of the risk that investors are going to now turn their attention to the next big thing--combinations of drugs that could supplant the current regimen. The argument goes that even though Vertex is going to sell a ton of telaprevir over the next few years, sales could crater when even newer drugs hit the market and completely change things again--hence the excitement about both Zymogenetics and Idenix.
Zymogenetics' drug is a new version of interferon, called pegylated interferon lambda, that could have fewer side effects. Bristol is testing it in combination with two other experimental drugs code-named BMS-790052 and BMS-650032 that are in mid-stage trials, and also two earlier-stage compounds. Bristol's studies include a regimen that eliminates ribavirin, which will reduce side effects such as anemia and depression. Mark Schoenebaum, an analyst at ISI, calls Bristol Vertex's "toughest competitor."
Not all Zymo fans are partying. Biotech Stock Research Chief Executive David Miller, who had listed ZymoGenetics as one of the top picks in his monthly newsletter, argues that ZymoGenetics was "gutless" and "math-challenged" for taking the Bristol deal. He pointed out that ZymoGenetics could have made as much as $1.1 billion from its pre-existing Bristol collaboration without the merger; it has other collaborations with Merck and Seromo. He blames the sale on big Zymo investors Akzo Nobel and Warburg Pincus, who apparently want a payout sooner rather than later.
--------------------------------------------------------------------------------
Idenix is exciting for similar reasons. It will be presenting a combination study of two of its antiviral drugs at the AASLD, and if it comes out positive it will start a follow-up trial. Vertex has started a combo-drug strategy, too, but it could still lose its early advantage. Many biotech watchers expect the hepatitis C market to follow a similar trajectory as the HIV drug market, where breakthrough first-generation drugs were relatively quickly supplanted by more convenient second-generation versions with fewer side effects. A decade ago, GlaxoSmithKline and Bristol-Myers Squibb ruled the market for AIDS drugs. Glaxo launched the first HIV drug that combined multiple drugs in one pill. But Gilead Sciences came along with a better once-a-day combo and it has stolen the entire market.
So how should investors play this market? It would be great to pick the next Gilead. But a smarter strategy might be to buy a basket of stocks including Vertex, Idenix, Pharmasset and Intermune. Bristol might be a good pick, too. It has outperformed its Big Pharma brethren over the past couple years, has a solid strategy of shrinking to focus on niche markets and has a 6% dividend yield.
In Pictures: Biotech Busts And Breakthroughs, August 2010
The New World of Biosimilars: What Diabetologists Need to know about Biosimilar Insulins
www.medscape.com
[CLOSE WINDOW]
Authors and Disclosures
Irene Krämer,1 and Thomas Sauer2
1Pharmacy Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany
2Industrial Affairs, Chemistry and Biotechnology, sanofi-aventis Germany, Frankfurt, Germany
From The British Journal of Diabetes and Vascular Disease
The New World of Biosimilars: What Diabetologists Need to know about Biosimilar Insulins
Irene Krämer; Thomas Sauer
Posted: 09/01/2010; British Journal of Diabetes and Vascular Disease © 2010 Sage Publications, Inc.
Abstract and Introduction
Abstract
Biosimilar pharmaceuticals are emerging as patent protection on the original biopharmaceutical products expires. However, biopharmaceuticals are particularly complex molecules, and biosimilar insulins present special challenges. In part this reflects their structure and chemical modification after synthesis to attain a biologically active form. Their therapeutic window is narrow and the accuracy of their dosing is highly dependent on the formulation and quality of the administration device. For these reasons, the European Medicines Agency has issued stringent guidelines that must be fulfilled in order to receive approval as a biosimilar soluble insulin. Prescribers should therefore consider issues of manufacture, protein quality, formulation, reliability of supply, and other factors that might affect efficacy, safety and tolerability when making choices regarding the selection of biosimilar products.
Introduction
Biopharmaceuticals are biological medicinal products derived from recombinant DNA and expressed by genetically engineered organisms to produce the target therapeutic proteins in large quantities. The first biopharmaceutical introduced into clinical use was recombinant human insulin (Humulin, Eli Lilly) in 1982. Since then, hundreds of biopharmaceuticals, including cytokines, enzymes, antihaemophilic factors and monoclonal antibodies have received marketing authorisation in various jurisdictions.
As patents for the early biopharmaceuticals have already expired, requests for marketing authorisation of 'similar' biological medicinal products (so-called biosimilars) have been submitted in the EU, and various biosimilars such as epoetin alfa, somatotropin and GCSF are already available. The EMA was the first regulatory authority to implement a regulatory framework for the marketing authorisation of biosimilars. This requires the submission and approval of a dossier that, while comprehensive, is less detailed than that of the innovator product. Comparable procedures are in place in other jurisdictions including Malaysia, Taiwan and Australia. In the USA, the Food and Drug Administration is also preparing a regulatory framework; products assessed by this new licensing procedure will be referred to as follow-on biologics (FOBs).
In Europe, several human insulins are available, each with an independent marketing authorisation based on a full dossier. The different brands are authorised for use with specific administration devices (generally a single-use or reusable pen). In some countries where patent regulations are less rigorous human insulin and insulin analogues are available that are (by definition) neither innovator products nor biosimilars and are therefore called 'other insulins'. In 2007, an application to the EMA for marketing authorisation of three biosimilar insulins was withdrawn after the CHMP issued a provisional opinion that the products could not be approved for human use.[1]
Biosimilars are not interchangeable with originator molecules or with each other as are traditional small-molecule generic drugs.[2] In fact, the EMA has stressed that because biosimilars and their reference molecules are not identical, the interchange of a reference medicine for a biosimilar medicine should be based on the opinion of a healthcare professional.[3] Hence, it is essential for prescribers to appreciate these issues in order to make informed choices about the biosimilars they will encounter. This article discusses key aspects to consider when evaluating a biosimilar, with a special focus on biosimilar insulin.
Complexities in the Manufacture of Insulin Biopharmaceuticals
Protein molecules have molecular weights which may be orders of magnitude higher than those of traditional small molecule drugs. Their structures are also far more complex, requiring consistency of their primary structure (amino acid sequences), secondary and tertiary structures (three-dimensional folding patterns), and quaternary structure (stable association of two or more identical or different subunits).
In the case of recombinant human insulin, the precursor protein is synthesised by genetically modified organisms and must be proteolytically cleaved to produce active insulin (figure 1). The insulin preparation must also be formulated to control the formation of discrete hexamers (complexes of six insulin monomers), to confer the required absorption characteristics (figure 2). The more recent insulin analogues contain additional or substituted amino acid residues or other functional groups introduced by genetic engineering or by biochemical modification. These changes alter the speed of bioavailability and thereby modify the PK and PD profiles of the molecule.
Figure 1. The biosynthesis of insulin
The insulin precursor preproinsulin contains a signal sequence that is proteolytically cleaved to yield proinsulin, whose C chain links the future A and B chains of mature insulin. Cleavage of the C chain converts proinsulin to insulin.
Adapted from Joshi SR et al. J Assoc Physicians India 2007;55(suppl):19–25[14]
Figure 2. Association of insulin monomers in the presence and absence of zinc and phenolic excipients
Insulin readily associates into dimers, aggregates and (in the presence of divalent cations such as zinc), into hexameric forms. The presence of phenolic excipients causes these hexamers to undergo conformational changes that increase their stability.
Key: R6 = hexamer with insulin molecules whose B1–B8 residues are in an a-helical (R) conformation; T6 = hexamer with insulin molecules whose B1–B8 residues are in an extended (T) conformation.
Adapted from Beals et al. Informa Healthcare: New York, 2008;265–80[22]
Given their structural complexities biopharmaceuticals are far more difficult to manufacture than small-molecule drugs. The use of living organisms introduces an inherent variability in the manufacturing process. To guarantee the quality and compliance of each production batch, absolute consistency of the manufacturing process is required. Even apparently slight changes in any of the manufacturing or formulation steps can have major clinical consequences.[4–8] Manufacturers of biosimilar products must develop proprietary expression systems and processing steps independently. Thus biopharmaceuticals can never be identical copies of originator molecules, even when they have demonstrated comparable physicochemical and biological properties to a reference product using currently available tests. The most they can achieve is 'biosimilarity'.[5,9,10] For non-glycosylated products such as human insulin, PK and PD differences are most probably caused by differences in formulation, while for glycosylated products (e.g. epoetin), the glycosylation pattern is probably the major source of PK/PD variations. The essential steps in the manufacture of a biopharmaceutical and the loci of potential variability in their manufacturing processes are shown in figure 3.[11]
Figure 3. Manufacture of a biopharmaceutical: opportunities for variation between manufacturers[11]
Adapted from Mellstedt H et al Ann Oncol 2008;19:411–9[11]
The first commercial insulins, extracted from beef and pork pancreata, became available shortly after the discovery of insulin in 1921, and the first long-acting insulins, PZI and NPH, had been developed by the 1940s. However, patients using animal insulin products that were not highly purified often had local injection site reactions or more rarely, systemic reactions such as IgE-mediated anaphylaxis.[12] Highly purified products and recombinant insulins are associated with decreased levels of anti-insulin antibodies. Nonetheless, there is little evidence that antibody formation affects glucose control or causes other complications of insulin therapy.[13] The more recent recombinant insulin analogues contain additional or substituted amino acid residues. The first short-acting analogues, insulin lispro and insulin aspart, were introduced in the late 1990s, and the first long-acting analogue insulin glargine in 2000. Each of these innovations was made with a view to improved onset and duration of action,[14–16] to reduce hypoglycaemia and hyperglycaemia and to improve tolerability. The history of developments in insulin is summarised in figure 4 and a summary of available insulins is given in figure 5.
Figure 4. The development of therapeutic insulin: a timeline[14–16]
Since the discovery of native insulin in 1921, successive discoveries have improved the production of therapeutic insulins as well as their pharmacokinetic and pharmacodynamic properties. Work on therapeutic insulins has garnered three Nobel Prizes.
Key: NPH = neutral protamine Hagedorn; PZI = protamine zinc insulin.
Figure 5. Insulin medicinal products currently available: a summary
In the manufacture of recombinant human insulin, the recombinant organism that actually expresses the precursor protein is generally Escherichia coli or a yeast such as Saccharomyces cerevisiae. The engineered gene encoding for the precursor protein must be inserted into a suitable stable expression vector. The choice and the characteristics of this construct will affect key aspects, such as the degradation characteristics of soluble proteins and the yield of the process. The recombinant cells are screened, and a well characterised master cell bank is established from a single clone. This master cell bank is used to create uniform working cell banks that are used to cultivate the cells and produce the desired product. During product synthesis the culture and fermentation conditions are tightly controlled in order to optimise yields and avoid formation of unwanted by-products.[17] Generally, impurities come from either the growth medium (especially for products isolated from cell culture supernatant) or the host cells. These impurities can be host-related (e.g. endotoxins, HCPs, DNA, viruses), product-related (e.g. denatured protein, aggregates, protein fragments, deamidated species, conformational isomers), or process-related (e.g. growth medium components, metals, column material). When the product is recovered, modified and purified the formation of inclusion bodies (for example in high-yield E. coli processes), requires the disruption of the cells to release preproinsulin. This is then isolated, purified and folded, and then enzymatically cleaved to produce the mature insulin molecule.[18–20] In the case of insulin, impurities such as desamido forms may arise as by-products of conversion from proinsulin to insulin by removal of the C-peptide and regeneration of the three-dimensional form of the molecule.[21]
After numerous purification steps, the insulin is crystallised or lyophilised and formulated. The insulin molecule is negatively charged at neutral pH, and readily associates into dimeric complexes or into zinc-containing hexamers (figure 2). Thus, zinc may be added to trigger aggregation into soluble discrete hexameric structures containing two zinc ions per hexamer.[14] Phenolic excipients, added as antimicrobial agents, also bind to specific sites on hexameric insulin, changing its conformation to a more stable form (so-called T–R transition). Other agents added at the formulation stage may include physiological buffers (to maintain pH) and agents that maintain isotonicity (to minimise injection pain and tissue damage).[22]
Any variations in the entire process of insulin synthesis and formulation may result in a product which may be physicochemically very similar to an appropriate reference product, but which differs subtly in its clinical PK or PD characteristics.[9,14] The steps in the manufacture of insulin are summarised in figure 6.
Figure 6. A highly complex process: steps in the manufacture of insulin
Reproduced with kind permission from sanofi-aventis group.
Insulin Devices: An Added Complexity
For biosimilar insulins, the additional dimension of the administration device should also be considered. Stringent regulatory requirements for insulin administration devices specify use of durable labels and distinguishing marks, visibility of the dose and accuracy with which it is dispensed after storage and handling under a variety of environmental conditions, including having been physically dropped. For example, cartridges, syringe/needle systems, disposable and reusable pens and pumps must be tested with each insulin formulation and concentrations that will be used. Since the combinations of insulin and device may differ widely in their dosing characteristics, it cannot be assumed that an insulin biosimilar will be compatible with an existing administration device. For this reason the EMA requires that compatibility is demonstrated.[23,24] Insulin pen injectors and cartridges (3.0 ml cartridge in the U-100 strength is the current market standard) provide more accurate and reproducible dosing than syringes and vials. They are also more convenient, easier to transport and may improve safety and adherence,[25–27] suggesting that the availability of pen injectors should be a requirement for insulin biosimilars.
Regulatory Requirements for Insulin Biosimilars
In recent years the EMA has produced an overarching guideline on biosimilars[28,29] as well as guidance documents addressing quality issues, 30 non-clinical and clinical issues, 31 and guidelines for specific biosimilars, including soluble recombinant human insulin.[21]
As mentioned earlier[9] the EMA requires that biopharmaceuticals undergo comprehensive comparability studies of both the drug substance and product to provide evidence that the biosimilar is indeed similar in quality, safety and efficacy to a single appropriately chosen reference product that has the same pharmaceutical form, strength and route of administration that is already approved in the EU. In general, required preclinical data include primary pharmacology and repeat-dose toxicology data. The EMA requires toxicological studies that focus on potential immunogenicity, as well as in-vitro affinity bioassays, assays for insulin and IGF-1 receptor binding, and tests for intrinsic activity.[28–31]
One of the main concerns when switching or substituting insulin products is hypoglycaemia caused by differences in activity of different brands. Therefore, it is obligatory to ensure that the effects of any insulin product in clinical use are highly consistent and predictable. The EMA requires at least one PK single-dose crossover study that compares the biosimilar insulin with the reference product, using subcutaneous administration, preferably in patients with type 1 diabetes. Clinical activity must be determined in a comparative PD study, designed as a double-blind, crossover, hyperinsulinaemic, euglycaemic clamp study, to demonstrate the product's hypoglycaemic response profile. Current EMA guidelines for soluble insulin biosimilars do not require a clinical efficacy trial, but do require a clinical safety study. The product's immunogenicity must be investigated through clinical studies of at least 12 months, including a comparative phase lasting at least 6 months. Finally, the manufacturer must also design a pharmacovigilance programme that will rapidly detect any clinically significant immunogenicity that may emerge over extended time periods.[21,28–30] The application for marketing authorisation of three biosimilar insulin formulations in March 2007 suggested deficiencies in long-term efficacy and inadequate immunogenicity testing.[32–34] The details of these applications were recently reviewed by Kuhlmann and Marre in this journal.[35]
What Clinicians Should Know Before Selecting a Biosimilar Insulin
When contemplating biosimilar insulins, it is important to consider the manufacturer, protein quality and formulation, batch consistency and reliability of supply (table 1).[36,37] Reassurance can be gained from full disclosure of information to the healthcare community about the manufacturing process and about safety testing.
[ CLOSE WINDOW ]
Table 1. A checklist of issues to consider when selecting a biosimilar insulin product[36]
Manufacturer
v R eputation, reliability, experience with biopharmaceuticals
v Location of manufacture of the medicinal product
v Location of the manufacture of the active drug substance (are third parties involved?)
v Dissemination of safety updates and changes in manufacturing process
Protein quality and formulation
v Bioassays: appropriateness, comparisons with reference product
v Levels of foreign proteins, DNA, pyrogens, endotoxins, aggregates
v Formulation: choice of excipients, stabilisers and preservatives
v Administration device or technique; teaching materials for use of a different administration system
v Shelf life, susceptibility to degradation
v Consistency between batches; appropriate quality controls
Reliability of supply
v Stock position
Clinical efficacy
v Clinical trials carried out with different batches of the biosimilar product itself: adequacy of design, results, consistency and generalisability of results
Clinical safety and tolerability
v Comparison of safety and tolerability profile with reference product
v Precautions or contraindications for use of the biosimilar
v Serious adverse events
v Immunogenicity (especially as compared to reference product); selection of antibody tests
v Post-marketing risk management programmes: required laboratory tests, antibody testing, pharmacovigilance programmes to detect infrequent adverse events
With regard to quality suppliers should be asked for a written statement that covers aspects such as the purity of the biosimilar protein, the upper limits for impurities such as aggregates or endotoxins, differences in isomer pattern, and clinical consequences of any potential differences. In the case of insulin impurities such as desamido forms may arise as by-products of conversion from proinsulin to insulin by removal of the C-peptide and regeneration of the three-dimensional form of the molecule.[31] Moreover, with regard to formulation any differences between the biosimilar and the originator molecule plus choice of excipients, stabilisers and preservatives should be provided, Additionally administration (either device or technique) should be explicit. If the biosimilar is administered by a different method from the originator product, e.g. with a new device, teaching materials should be available to train patients and caregivers to use the different system. It is also important to know the product's shelf life and its susceptibility to degradation if it is stored improperly (for example, if accidentally stored at room temperature instead of being refrigerated).
Quality control to ensure batch-to-batch consistency is paramount with insulin preparations. There should be a guaranteed stock position which will maintain supplies if a newly produced batch fails to meet all the required standards of quality. A sustainable supply chain with reliable transportation conditions should also be established.
Particular attention should be given to any differences in clinical activity, biological activity per unit, relative biological potency and dosage of a biosimilar compared with the originator molecule. The known safety and tolerability profile of the biosimilar, as well as precautions or contraindications for its use, should be comparable with the originator molecule. Because clinical trials which enrol relatively small numbers of patients cannot identify rare side-effects, it is obligatory to monitor safety during the post-approval phase. The use of more than one biosimilar product (for example, a biosimilar insulin and a biosimilar epoetin for the diabetic patient with renal failure) may present an additional layer of complexity regarding safety issues.
Similarly, substituting one insulin for another may require dose adjustment. While the development of antibodies to insulin rarely has major clinical consequences, it may have an impact on efficacy (because higher insulin doses may be necessary) and tolerability (mainly in the form of local injection site reactions). Hence, a biosimilar product should receive thorough antibody tests extending into the post-marketing period.
Summary and Conclusions
Biosimilar products such as epoetin alfa biosimilars are already marketed in the EU, and biosimilar insulins are expected shortly. Patients with diabetes are often candidates to receive both types of products. Therefore, it is imperative for prescribers to be aware of issues presented by biosimilar products, and particularly the special challenges presented by biosimilar insulin. Biosimilars are not interchangeable with the corresponding originator biopharmaceuticals in the same way that non-peptide, small-molecule generic molecules are interchangeable with the original products. Any apparently minor modification in the manufacturing or formulation of a product such as insulin, or in the administration device, has the potential to cause untoward clinical consequences, even if the product appears to be physicochemically equivalent to an accepted reference standard. The consequences are particularly relevant for insulin as the therapeutic window is narrow. For this reason, the EMA has developed robust regulatory requirements before marketing authorisation can be granted for a biosimilar insulin. Prescribers should consider critical issues regarding the manufacture, protein quality and formulation, supply, clinical efficacy, safety and tolerability of biosimilar insulins before substitutin
Sidebar
Key Messages
•Unlike non-peptide small molecule generics, biosimilars are not identical to the originator
•Biosimilar insulins are challenging because insulin has a complex structure and a narrow therapeutic window
•The dosing accuracy of biosimilar insulins depends on the quality of the administration device
•Regarding biosimilars, consider the manufacturer, protein quality, formulation, reliability of supply, clinical efficacy, safety and tolerability
[ CLOSE WINDOW ]
References
1.European Medicines Agency. Press release: Marvel Life Sciences Ltd withdraws its marketing authorisation applications for Insulin Human Rapid Marvel, Insulin Human Long Marvel and Insulin Human 30/70 Mix Marvel. 16 January 2008. EMEA/2435/2008. London: EMA, 2008.
2.Schellekens H. Follow-on biologics: challenges of the 'next generation'. Nephrol Dial Transplant 2005;20(suppl 4):iv31–6.
3.European Medicines Agency. Questions and Answers on biosimilar medicines (similar biological medicinal products). 22 October 2008. Doc. Ref. EMEA/74562/2006 Rev.1. London: EMA, 2008. http://www.emea.europa.eu/pdfs/human/pcwp/7456206en.pdf.
4.Schellekens H, Ryff JC. 'Biogenerics': the off-patent biotech products. Trends Pharmacol Sci 2002;23:119–21.
5.Locatelli F, Roger S. Comparative testing and pharmacovigilance of biosimilars. Nephrol Dial Transplant 2006;21(suppl 5):v13–16.
6.Locatelli F, Del Vecchio L, Pozzoni P. Pure red-cell aplasia 'epidemic': mystery completely revealed? Perit Dial Int 2007;27(suppl 2):S303–07.
7.Casadevall N, Nataf J, Viron B et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002;346:469–75.
8.Schellekens H. Immunologic mechanisms of EPO-associated pure red cell aplasia. Best Pract Res Clin Haematol 2005;18:473–80.
9.Kuhlmann M, Covic A. The protein science of biosimilars. Nephrol Dial Transplant 2006;21(suppl 5):v4–8.
10.R oger SD. Biosimilars: how similar or dissimilar are they? Nephrology 2006;11:341–6.
11.Mellstedt H, Niederwieser D. Ludwig H. The challenge of biosimilars. Ann Oncol 2008;19:411–9.
12.Grammer L. Insulin allergy. Clin Rev Allergy 1986;4:189–200.
13.Fineberg SE, Kaabata TT, Finco-Kent D et al. Immunological responses to exogenous insulin. Endocrine Reviews 2007;28:625–52.
14.Joshi SR, Parikh RM, Das AK. Insulin: history, biochemistry, physiology and pharmacology. J Assoc Physicians India 2007;55(suppl):19–25.
15.Sattley M. The history of diabetes. Diabetes Health 2008. http://www.diabeteshealth.com/read/2008/12/17/715/the-history-of-diabetes/(accessed 10 May 2009)
16.Teuscher A. The history of insulin. In: Insulin: A Voice for Choice. Basel: Karger, 2007;10–13. http://content.karger.com/ProdukteDB/Katalogteile/isbn3_8055/_83/_53/Insulin_02.pdf (accessed 10 May 2009)
17.Neubauer RP, Lin HY, Mathiszik B. Metabolic load of recombinant protein production: inhibition of cellular capacities for glucose uptake and respiration after induction of a heterologous gene in Escherichia coli. Biotechnol Bioeng 2003;83:53–64.
18.Panda AK. Bioprocessing of therapeutic proteins from the inclusion bodies of Escherichia coli. Adv Biochem Eng Biotechnol 2003;85: 43–93.
19.Winter J, Lilie H, Rudolph R. Renaturation of human proinsulin: a study on refolding and conversion to insulin. Anal Biochem 2002; 310:148–55.
20.Singh AM, Panda AK. Solubilization and refolding of bacterial inclusion body proteins. J Bioscience Bioeng 2005;99:303–10.
21.Committee for Medicinal Products for Human Use. Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant human insulin. London: EMA, 2006. http://www.emea.europa.eu/pdfs/human/biosimilar/3277505en.pdf (accessed 13 April 2009).
22.Beals JM, DeFilippis MR, Kovach PM. Insulin. In: Crommelin DJA, Sindelar RD, Meibohm B (eds.). Pharmaceutical Biotechnology: Fundamentals and Applications, 3rd edition. Informa Healthcare: New York, 2008;265–80.
23.European Medicines Agency. Guideline on the suitability of the graduation of delivery devices for liquid dosage forms. Doc Ref EMEA/CHMP/QWP/178621/2004. London: EMA, 2004. http://www.emea.europa.eu/pdfs/human/qwp/17862104en.pdf (accessed 10 May 2009).
24.International Organization for Standardization. Pen-injectors for medical use. Part 1: Pen-injectors. Requirements and test methods (ISO 11608–1:2000). Geneva: ISO, 2000.
25.Brunton S. Initiating insulin therapy in type 2 diabetes: benefits of insulin analogs and insulin pens. Diabetes Technol Ther 2008;10:247–56.
26.Korytkowski M, Niskanen L, Asakura T. FlexPen: addressing issues of confidence and convenience in insulin delivery. Clin Ther 2005; 27(suppl B):S89–100.
27.Korytkowski M, Bell D, Jacobsen C, Suwannasari R. FlexPen Study Team. A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus. Clin Ther 2003; 25:2836–48.
28.Wiecek A, Mikhail A. European regulatory guidelines for biosimilars. Nephrol Dial Transplant 2006;21(suppl 5):v17–20.
29.Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. London: EMA, 2005. http://www.emea.europa.eu/pdfs/human/biosimilar/043704en.pdf (accessed 13 April 2009)
30.Committee for Medicinal Products for Human Use. Guidelines on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. London: EMA, 2006 http://www.emea.europa.eu/pdfs/human/biosimilar/4934805en.pdf (accessed 13 April 2009)
31.Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London: EMA, 2006 http://www.emea.europa.eu/pdfs/human/biosimilar/4283205en.pdf (accessed 13 April 2009)
32.European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment Report for Insulin Human Rapid Marvel. 21 February 2008. Document reference EMEA/CHMP/317778/2007. London: EMA, 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/insulinhumanrapidmarvel/31777807en.pdf (accessed 1 May 2009)
33.European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment Report for Insulin Human Long Marvel. 21 February 2008. Document reference EMEA/CHMP/70349/2008. London: EMA: 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/insulinhumanrapidmarvel/7034908en.pdf (accessed 1 May 2009)
34.European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment Report for Insulin Human 30/70 Mixed Marvel. 21 February 2008. Document reference EMEA/CHMP/70179/2008. London: EMA: 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/insulinhumanrapidmarvel/701790en.pdf (accessed 1 May 2009)
35.Kuhlmann M, Marre M. Lessons learned from biosimilar epoetins and insulins. Br J Diabetes Vasc Dis 2010;10;90–7.
36.Krämer I, Tredree R, Vulto AG. Points to consider in the evaluation of biopharmaceuticals. EJHP Practice 2008;14:73–6.
37.Crommelin D, Bermejo T, Bissig M et al. Pharmaceutical evaluation of biosimilars : important differences from generic low-molecular-weight pharmaceuticals. Eur J Hosp Pharm Sci 2005;11:11–7.
Abbreviations and acronyms
CHMP, Committee for Medicinal Products for Human Use; CMC, chemistry, manufacturing, controls; EMA, European Medicines Agency; EU, European Union; GCSF, granulocyte colony-stimulating factor; HCP, host-cell protein; IGF, insulin-like growth factor; NPH, neutral protamine Hagedorn; PD, pharmacodynamic; PK, pharmacokinetic; PZI, protamine zinc insulin
Acknowledgment
Editorial support for this article was provided by the medical writing agency PHOCUS and by sanofi-aventis groupe. The opinions expressed in the current article are those of the authors. The authors received no honoraria or other form of financial support related to the development of this manuscript.
Declaration of conflict of interest
IK has been a consultant, speaker and member of advisory boards of various (bio)pharmaceutical companies, which had no influence on the content of this article. TS is an employee of Sanofi-aventis Deutschland GmbH.)
British Journal of Diabetes and Vascular Disease © 2010 Sage Publications, Inc.
If the manufacturer claims the original patent is invalid or not infringed, there is a thirty-month litigation period during which the FDA cannot approve the generic.
http://www.fdareview.org/glossary.shtml#anda
Could the claim delay any furtur approval including Teva s apart from the Scientific merits.
we all know what goes on behind the scenes
An old man pedals a bicycle that makes the scenery go by...
We may see some suprise data at AASLD . Just a guess again. Too bad they are not a small biotech but they are primed to be taken over.Nice pipeline trimmed down sales force .
DEW AASLD is in Boston . Are you attending ?
I am 50/50 right now. I orginally was not going but all the potential has me excited. I hate meetings around Halloween
B-I BI 201335 BI 207127 non-nuke TID/BID
Is BI 207127
a hybrid NS3B/NS4B ?
Tia
My guess and its only a guess is that
BMY BMS-650032 BMS-790052 NS5A BID
May turn out to be the creme de la creme .
I'm not so sure Zyprexa is an improvement over Electroconvulsive, one set of problems for another
Of course my response was a complete joke but your response is beyond that.
They are bringing back Maggots and leeches so maybe Electroconvulsive treatment is right around the corner
Then you should have no trouble telling us exactly who is making consequential money selling interferon for HBV
They are probably part of that small group up the road from me thats still holding on to Electroconvulsive therapy VS Zyprexa
Chinese Hamster Ovary
Cerezyme ?
Hasnt Protalix already advanced there ?
The Biosimilars Market Today And Tomorrow
( sorry if its a repost )
The full version of this biosimilars feature can be read in the August issue of our digital magazine: http://www.pharmtech.com/ptedigital0810
Alan Sheppard
Last year, the global market for biological products exceeded $125 billion, accounting for 17% of the total market for pharma/biopharma products; however, its portion of the global market is expected to rise markedly in the next few years. In fact, by 2014, we estimate that the top three products in terms of global sales will be biotech medicines (Avastin, Humira, Enbrel), collectively accounting for $25.4 billion, with today's small molecule brand leaders being relegated to commodity generics. With many of the blockbuster biologics nearing patent expiry in the next 10 years in the US, including Avastin (Genentech/Roche), Enbrel (Amgen) Erbitux (Eli Lilly) and Humira (Abbott), it is easy to understand the appeal that investing in biosimilars holds. However, in spite of this potential, last year biosimilars only generated around $89 million in sales, with Sandoz's omnitrope accounting for the vast portion of those sales (33% market share), hence it is still a largely immature market. On a more positive note, growth in sales between June 2008 and June 2009 increased by a remarkable 200%.
http://www.nxtbook.com/nxtbooks/advanstaruk/pte_201008/#/6/OnePage
i have to get up real early in the morning.Hopefully we can continue tomorrow if you want to continue to discuss
You have a patient group you can not give any of the current SOC treatments and you have a small group of patients that you lose even before you have any chance to treat the HCV. A 5 % cure rate would be a huge step
Right now you have a whole set of patients that there is no treatment that works.Your post transplant patient can not tolerate interferon and Riba.Many of them make it through too where their immune system can be built back up and then they can be treated.Still SVR rates are very low.But their is a subset of the post transplant HCV patients that do not make it.Conceivably an all oral regimen may save a percentage of those patients who were going to die with the current SOC therapy option.
i think BMY may be presenting data on their combo regimen at AASLD
BINGO
He did not come out and say that company but i got that feeling . Great catch
I mean low.Post liver transplant you have 100 % reinfection within hours of the receiving the liver.You have a patient group you can not give any of the current SOC treatments and you have a small group of patients that you lose even before you have any chance to treat the HCV. A 5 % cure rate would be a huge step.Talk to a liver transplant surgeon
the FDA has come a long way in allowing testing of combination regimens in the past year
The problem we have not seen enough partnering to test more combs
"In some instances, a particularly aggressive form of recurrent HCV develops within only a few months post-LTx and this condition has been labelled “fibrosing cholestatic hepatitis” (FCH) "
of course this is not as common but reinfection occurs rapidly and almost at a 100% rate . We know the problem with Interferon and Riba in this compromised group. An all oral regimen would have to show very low SVR rates to get an approval.I think its a brilliant idea considering we have quickly outstripped our liver supply and are tilted toward an epidemic in a few years. LT doctors are desperate.
Nope
benign
I almost fell out of my chair
Your missing an obvious patient group
One other piece of pure babble on the upcoming AASLD.
If you could have polled the top Hepatology HCV researchers 12 months ago on when we would see an all oral regimen.The average time period guessed would have been 5 years away.Now we are seeing fissures in that consensus.One expert recently told me at this upcoming AASLD we may see some shocking data on an all oral regimen.He also stated that some companies are looking at unique approaches to a back door indication for a fast track approval.
Of course i am only going to speak in generalities.This years meeting will be very exciting !