QDIS Blog

After being away for sometime for a variety of reasons including a pinched nerve in my neck, I’m finally back and hoping to post to this blog several times a week, although I doubt I will be able to get back to posting daily due to work and other issues.

I did find the following article I found recently interesting as it talks about differences in Congress regarding biogenerics.

AMNews: Aug. 11, 2008. Disagreements slow progress on biogenerics legislation … American Medical News:

I think the point about the period of exclusivity is a valid point and where I think the the greatest debate will occur. While it may take a while to get compromise I think something will indeed happen on this front in the next year. It may not be a great bill but at least it will be something
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Replidyne is continuing to refine its phase III efforts for the antibiotic faropenem.

Replidyne Defines Preliminary Phase III Development Plan for Faropenem: Financial News - Yahoo!
Finance:

This new antibiotic may be the first to be approved under the FDA’s new community standards for antibiotics.

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There was no love for Advancis from the FDA in this article on Feb 14 when the FDA gave them a refusal to file letter. This is the second one now in the last few weeks.

FDA deny drug application from Advancis - Washington Business Journal: :

What is very interesting to me is that Advancis does not have a press release on this on their website. The last press release they have is dated Jan, 12 2007. This day and age, it is amazing to me that companies don’t react quickly to these sorts of situations. It’s been two weeks since this happened with no word from the company on their website. I understand that time is needed to form a response but something should be immediately announced.

Their Amoxicillin PULSYS once daily dosing is the product concerned and according to the company they were surprised just like Pharmacyclics that I posted about previously at the FDA’s response. The FDA, according to the company, is concerned about how they plan to scale up their manufacturing process to make bulk quantities. Previously, the company had failed some phase III clinical trials which had to be repeated and then had to re-file the NDA in Dec 2006.

I’m wondering if this means the companies are not really listening to the FDA or if the FDA is changing their mind midstream. While this may not seem to be much of difference it could have major implications for other companies getting ready to file NDAs. If the FDA is starting to crack down and not even accept applications, then the industry needs to be much more careful about how they prepare their filings. If on the other hand, these two companies just weren’t really listening and picking up on the nuances from the FDA then it may not have much of an effect on other companies.

I do know from personal experience that you have to be very careful in the questions you ask the FDA. Many times at end of phase x meetings, you submit questions in writing ahead of time and depending on exactly how those questions are worded, you may get different answers. I know of some companies that will only ask yes or no questions and try to word the question so as to get the answer they desire instead of asking questions to really learn what the FDA thinking is on a given set of circumstances. I have always felt this was a mistake. Early on, it is vitally important to ask open ended questions before too much time and money is spent going down a regulatory or development route that may lead to failure at a late stage when it is very costly.

Technorati Tags: Advancis, FDA, amoxicillin pulsys

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Earlier this month, DrugResearcher.com had an article on revamping at major pharmaceutical companies.

Roche revamps R&D for speed:

An import part of the article is in the last paragraph. GlaxoSmithkline reorganized their research into seven Centres of Excellence for Drug Discovery years ago and I don’t know that it has increased their overall productivity. It may gets more drugs into development, but the more important issue of making sure the ones that do go into development have the greatest possible probability of success.

I’ve seen this before and I don’t have much faith in these “reorganizations”. Inevitably, these sorts of moves don’t make major contributions to the bottom line and sometimes actually make matters worse. I personally think that the culture and huge bureaucracies are more to blame for the lack of research results. That isn’t to say re-orgs can’t make thing better, that can be. I just think too many times they don’t pay off.

I’ve also said that just moving the bottlenecks of development from one place to another is not the answer. The bottlenecks need to be removed from the system entirely, rather than just moved from place to place without increasing the overall output.

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Anacor has signed a deal with Schering-Plough for a new topical anti-fungal product called AN2690. It is used to treat onychomycosis, a fungal infection of the nail and nail bed that affects about 10 percent of the U.S. population. Under terms of the deal Anacor will be paid $40 million upfront with an additional $10 million in financing from Schering-Plough. Schering-Plough will be responsible for all development costs with Anacor retaining the right to co-promote the drug in the US. Anacor will also receive double digit royalties if it does make it to the market. AN2690 is in phase II clinical trials.

PharmaLive: Anacor Signs Worldwide Exclusive License Agreement With Schering-Plough for AN2690, a New Topical Anti-Fungal Treatment :

What is interesting is the structure of AN2690 shown below.

Not many drugs have a boron atom in them and so it is very interesting. Anacor claims that this compound inhibits a validated drug target and works in a totally unique and unprecedented way.

One of the main problems with fungus of the nail bed is penetration to get at the infection deep down. Other treatments are oral medications and therefore work systemically. Also, Lamsil as well as Sporanox (itraconazole) capsules have had an FDA public health advisory issued warning physicians about adverse hepatic events and an association with congestive heart failure associated with both of these drugs. Definitely not something you want to risk for a simple thickened fingernail of toenail.

Topicals haven’t had a lot of success in this area so it will be interesting to see how this works. Anacor claims AN2690 penetrates 200 times better than the only other approved product. There is definitely interest in this since the market for onychomycosis is a $1.5 billion dollar market.

Anacor also has piblished some data on this compound.
Microbiological Activity Of AN2690, A New Antifungal Agent (pdf)

Other Resources
ANACOR SIGNS WORLDWIDE EXCLUSIVE LICENSE AGREEMENT WITH SCHERING-PLOUGH FOR AN2690, A NEW TOPICAL ANTI-FUNGAL TREATMENT
Schering-Plough Cites Today’s Anacor Agreement as Latest in Series of Deals
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Technorati Tags: AN2690, Anacor, pharmaceutical deals, anti-fungal, Schering-Plough

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This recent article from Economist.com is a good read about the current state of the pharmaceutical industry from a financial point of view.

Pharmaceuticals | Billion dollar pills | Economist.com

The article talks about many points I’ve made here before and even talks about bringing together scientists in one center and focusing on just a few therapeutic areas. It is an interesting read although think it still falls short of outlining what needs to be changed in the pharmaceutical industry.

One of the premises of the article is that the pharmaceutical industry tries to do it all and does many things in-house. The authors suggest more out-sourcing (although that terms is not used) and to concentrate on just a few strengths. The author uses the term “disaggreagted”. While this may work to some extent, I don’t think it will ever be as prevalent as say the automobile industry. While I do believe there are things the pharmaceutical industry can learn from other industries about how to become more efficient, I think you need to be careful and closely scrutinize the ideas before trying to apply them to pharmaceuticals. All ideas that work in other industry may not be applicable to pharmaceuticals.

One of the major problems from my perspective is still the blockbuster drug mentality. All of the things outlined in the article are still geared towards finding the billion dollar a year drug. This mentality is what has brought on the current situation for big pharma and will continue to be a major issue in the next 4-5 years. By this, I mean anytime the bulk of a company’s revenues are from one or two products, they are in a precarious situation. It would be much better in my view to have three or four $500 million products rather than a single $1 billion. They have basically put all the eggs into one basket. Too many times, projects that have good possibility are not pursued because they don’t meet this arbitrary mark of a billion dollar a year in sales. I would much rather have a company with four or five products generating hundreds of millions of dollars in sales that expire intermittently over many years than one product with a billion dollar a year in sales that expires in a few years.

Here are the top 20 pharmaceuticals companies and the percentage of pharmaceutical revenues generated by their top two selling drugs according to 2005 data. This data is generated from the Top 20 Pharmaceutical Companies article published last year in Contract Pharma.

Pfizer 38% from Lipitor and Norvasc
Sanofi-Aventis 18% from Plavix and Lovenox (increases to 25% if you include Taxotere, its third best selling drug)
GlaxoSmithKline 23% from Advair and Avendia
AstraZeneca 31% from Nexium and Seroquel
Merck 35% from Zocor and Fosamax
Novarits 29% from Diovan and Gleevec
Hoffman-La Roche 31% from Rituxan and Epogin
Bristol-Myers Squibb 40% from Plavix and Pravachol
Wyeth 36% from Effexor and Protonix
Eli Lilly 40% from Zyprexa and Gemzar
Abbott Labs 20% from Humira and Mobic
Boehringer-Ingelheim 25% from Spiriva and Mobic
Takeda Pharmaceuticals 40% from Actos and Prevacid
Scheringer-Plough 24% from Vytorin and Remicade
Astellas Pharma 28% from Prograf and Harnal (increases to 39% if you include Lipitor its third best selling drug)
Daiichi-Sankyo figures not available
Novo Nordisk 66% from insulin and insulin related analogs
Eisai 51% from Aricept and Aciphex
Bayer 27% from Ascensia and Kogenate

As you can see it ranges from a low of 18% for Sanofi-Aventis to a high of 66% for Novo Nordisk. The Novo Nordisk may be an unfair number since they lump insulin products and insulin analogs as their top two drugs and these are really aggreagates. However, the point is that for all the top pharmaceuticals, a large portion of their revenues are generated from only a few products.

Many of these either have patents expiring or have had bad press recently which combined with the decreasing number of potential products will likely lead to a desperate situation for the foreseeable future..

Technorati Tags: pharma pipelines, pharma stats, pharma worldwide markets

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Replidyne is testing its antibiotic Faropenem in phase III clinical trials against Ketek and placebo for treatment of acute exacerbation of chronic bronchitis )AECB). However, due to the joint Advisory Committee meeting of the FDA’s Anti-Infective Drug and Drug Safety and Risk Management committees where concerns about the use of Ketek for this indications. This means they will stop the trial, look into eliminating the Ketek arm and then restart the trial after making changes to the number of patients to be enrolled and possibly considering another comparator.

Faropenem Phase III Clinical Trial Stopped to Consider Exclusion of Ketek Comparator

Replidyn has already received a non-approvable from the FDA back in Oct 2006.

U.S. Food and Drug Administration Issues Non-Approvable Letter for Faropenem

What is somewhat interesting in this respect is that it seems to reflect a change in FDA policy regarding superiority studies in particular with antibiotics and especially for the AECB indication.. In the past, the FDA has not required this for antibiotics and the studies done on Faropenem were non-inferiority designs. Replidyne may be getting caught in the changes where the FDA is now looking into placebo controlled studies for antibiotics. This new study which is being stopped to consider exclusion of Ketek, was planned as a placebo controlled superiority study. However, now the question is do they continue with the comparator Ketek. I think it likely that they will exclude the Ketek arm and likely choose another comparator. This means even more delays.

I do feel for Replidyne and think they have gotten caught up in the changing climate and this is likely not their fault. My concern though is that it may mean even more companies do not get into development of anti-infectives, an area of vital need now in my opinion.

Other Resources
Faropenem - Wikipedia, the free encyclopedia
Replidyne (page on Faropenem Medoxomil)Zoom structure
CID 636379 — PubChem Compound Summary

Technorati Tags: Faropenem, Ketek, Replidyne, telithromycin

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In what most consider a very risky move, GlaxoSmithKline will pit their cervical cancer vaccine Cervarix ,which is in late stage clinical trials, against Merck;s approved cancer vaccine Gardasil.

Glaxo Goes Head-To-Head With Merck - Forbes.com

GlaxoSmithKline is definitely behind in this regard; Merck’s Gardasil is already approved and on its way towards $700 million in sales it first year. GSK on the other hand won’t even submit an NDA until at earliest 2009 and so will be at least three years behind.

Another problem is that the proposed study is only 1,000 patients and some, including myself, wonder if this will even allow you to see if there is a difference. Also GSK is taking a shortcut and making the argument that testing the response generated by the immune system due to the vaccine will be an indicator that the vaccine works better and longer. This has not been proven to be the case and the FDA in general frowns on such approaches. It will definitely be an uphill battle and I see the likely outcome being the FDA asking for longer term data on how well it protects against cervical cancer and precancerous lesions. This would set back GSK by years. It is a risky gambit.

Many consider this risky and in general, the pharmaceutical industry avoids, at all cost, comparing their drug directly against a competitors. The main exception to this is in anticancer drugs where drugs are always tested against a comparator since it is consider unethical to not treat those affected. The choice of comparator, when it is used, is questionable. Many times the drug chosen as competitor is not the best in the field and few experts would suggest this drug as a first choice for there patients.

I often wonder and have actually asked in meetings why not test against the best in class. Many times upper level management touts their drug as a breakthrough in treatment of a disease and over-hype it to the media and the public. However, in private internal meetings, they want to choose a comparator (if used at all) that gives them the best chance of a positive outcome. I say if they have such confidence that they express in public why is it that behind closed doors they do everything they can to tilt the field in their favor. If they have confidence in public, why does that confidence evaporate in private planning meetings?

Technorati Tags: cancer vaccine, GlaxoSmithKline, Merck, cervical cancer, vaccine

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Forbes is reporting that AztraZeneca and Bristol-Myers Squibb are teaming up to develop two new type 2 diabetes treatments saxagliptin and dapagliflozin both initially discovered by BMS.

Bristol-Myers, AstraZeneca in Drug Pact - Forbes.com:

Details are that AstraZeneca will pay BMS $100 million upfront and BMS could earn up to another $650 million in development milestones and then another $300 million in sales milestones. This makes the deal worth potentially over $1 billion dollars!!

It is interesting to look at why this deal may have been done. BMS evidently doesn’t feel they could go it alone on this or they would have. They get AstraZeneca to pick up the bulk of the development costs through 2009 and expenses after that being shared. BMS will make the drug and book sales. Also any future compounds discovered by either company would be included under this partnership.

To me this looks like the first step in a possible future merger. If the drugs are blockbusters then it might make sense in the future for them to merge rather than continue the partnership. Only time will tell. Saxagliptin is in late stage clinical trials whereas dapagliflozin is somewhere in the middle of the process, so it will be several years before we’ll know how this plays out. My best guess; if both drugs are approved and are blockbusters then the companies will likely merger sometime after 2010.

Technorati Tags: AstraZeneca, Bristol-Myers Squibb, dapagliflozin, diabetes treatment, drug development, pharmaceutical deals, saxagliptin

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I always hate to report on drug failures but Telik recently had a major phase III failure for it cancer drug Telcyta and the stock plummeted over 70%.

Telik cancer drug fails trials; stock plummets - Yahoo! News
MercuryNews.com | 12/27/2006 | Telik stock takes a 71% hit

It is unclear why this occurred but the company claims that some patients who were dismissed from the study early may have been part of it. As usual the company is looking at the data to see if anything can be learned and to see if the drug can be possibly salvaged.

One of the things to keep in mind with cancer drugs is that unlike other drug categories, with cancer you have to compare against the standard of care. This means you are comparing your drug against a proven drug for a given indication.

I should also add that it wasn’t just one study; it was three phase III registration trials in ovarian and lung cancer as well as in combination with another drug for ovarian cancer. The fact that all three trials failed to meet its endpoints seems to point to the fact that the drug may not be working and should be discontinued.

One of the problems with small companies is their hesitancy to kill drugs early on. Too many times in my experience they throw good money after bad by trying to keep a project alive when it should have been killed a long time ago. This is especially true if the company only has a single compound in their pipeline. Fortunately, Telik has another drug in its pipeline called Telintra (TLK199) although it is in early stage trials.

It will be interesting to keep an eye on Telintra since this is the second drug to come out of their discovery platform called TRAP (target-related affinity profiling). If a second drug fails, it may point to the fact that this technology isn’t worthwhile.

Other Resources

TELIK REPORTS PRELIMINARY RESULTS ON ASSIST-1, ASSIST-2 AND ASSIST-3 PHASE 3 CLINICAL TRIALS
Yahoo! News Search Results for telik
telik - Google News
Google Blog Search: telik

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