Pharma’s Cutting Edge

A new crop of mega-pharma leaders has been installed recently, so it’s no surprise that they’re making rounds among analysts and reporters, telling anyone who will listen that they’ve seen the errors of their forebears’ ways and are committed to do things differently and better now.  Chief among their messages is that they will tackle the R&D productivity problem.

Look, everyone seems to know that bureaucracy limits pharma R&D productivity and is perhaps the single most important limiting factor.  But we don’t read much about what caused this current bureaucracy.  So let’s do that. 

In 1992, a group of organizational consultants (Boyatzis et al) formerly with McBer (part of Hay Group) published their work conducted between 1986 and 1989 for a major pharma client they refer to as Sinclair, Inc.  Although it’s possible to deduce the identity of “Sinclair”, it’s not important, because all major pharmas use consultants to organize themselves, and all organizational consultants follow the same academic gurus to develop their “best practice” recommendations.  While implementation details differ among companies, the basic organizational structure of major pharma R&D is remarkably similar.

The authors of this study, which to my knowledge is one of the first documented case studies of the project-team/project-champion approach to new drug development (immediately prior pharma structures were functional area-dominated), were clearly at the front edge of an organizational wave sweeping through pharma, as evidenced by their recommendation that project teams evolve beyond simply clinical development structures into vertical organizations that incorporate all strategic elements of drug discovery and development for a given therapeutic area.  Such structures didn’t emerge until circa 2000, some 10 years after this paper was actually written.

The authors imply that the single most important potential (at the time) long-term problem with the matrixed project-team approach to development is its potential encouragement of bureaucratic instutitions.  Stated simply, project champions (i.e. team leaders) and functional area leads eventually get bored and need room to grow their careers.  They become experts at drug development generally and at their respective disciplines specifically, and–justifiably given the costs to the organization of training them to become experts–the organization attempts to retain them by giving them promotions to positions of “greater responsibility” (Have you ever read an executive’s bio that claimed a taking of positions of lesser responsibility??). Read the rest of this entry »

“Always do whatever’s next”  –  George Carlin (RIP)

I popped into the DIA Annual Mtg. for a day this week to chair a session on content reuse in clinical regulatory documents.   Good turnout for the session and, as usual, for the meeting, which continues to be the one industry get-together that clinical-research worker bees are paid to attend.

The exhibitor hall was dominated by full-service CROs touting their capabilities.  Have you noticed that you never hear much from the partial-service CROs?  Boutique CROs were there, but not the partial-service CROs.  The boutiques are just like the partial-service providers, except they offer clients tea while they’re waiting for service to begin.  Okay, enough silliness.

For about a year, up until the end of this April, I was working for what was Fast Track Systems Inc. and what is now a part of Medidata Solutions Worldwide.  Medidata made a smart purchase.  Medidata’s Designer software is the future for structuring information at the head-end of the clinical research value chain.  Structure information while you’re writing a protocol in Word, and then feed all your dependent documents and systems with it, all without losing the original meaning and intent of the protocol authors.  Makes perfect sense, huh?  Medidata also inherited Fast Track’s successful investigator grant and CRO contract benchmarking data/software as part of the deal.

Anyway, I’m now gainfully self-employed.  That is to say I was repositioned out the door following a corporate restructuring.   If you work in pharma, odds are you or someone you know has been through a similar “restructuring”.  Fun…ain’t it? 

I’m available as a consultant, advisor, guru, confidant, or secret friend.  You can look at my consulting website (pharmagrowth.com) to read about me, or just drop me a note [fred at pharmagrowth dot com].  I’m always glad to hear from my readers!

Above: NMR solution structure of exenatide from Ganfyd.org

 taspoglutide advancement announcement

Lead 6 results press release

52-week data from Duration-1 trial

A bit more excitement than usual surrounded this year’s recently completed ADA annual meeting, with a flurry of news surrounding the GLP-1 mimetics and their brethren, the DPP-IV inhibitors.

In my mind, the most interesting bit of news concerned progress on so-called exenatide LAR, a once-weekly formulation for sc injection of Amylin/Lilly exenatide.  According to Amylin’s website, the LAR program is being jointly managed by Amylin/Lilly.  However, Amylin hosted an Amylin-only event at ADA to discuss the development program, leading me to speculate that Lilly’s role in the drug’s development is strictly advisory/financial.  If you know otherwise, do chime in.

Regardless of whose pulling the strings, the program has progressed well into Phase 3clinical development, and Amylin shared the 30- and 52-week results from the first (Duration-1; see above link) of the large Phase 3 studies at the meeting.  I’ve supervised and reviewed lots of clinical trials of diabetes drugs, and I can tell you that the results with exenatide LAR thus far are potentially game-changing.

Sure, there’s a long way to go until registration:  more Phase 3 studies, including head to head with DPP-IV inhibitors, and a bridging program from the research formulation to the commercial form.  Amylin knows this; its management team strikes me as completely realistic and credible regarding the difficult tasks ahead.  I also appreciate the lack of hyperbole and cheerleading we used to get from the Ginger Graham-led team.  There’s no need for these distractions when your drug does the PR for you.

Let’s look at some of the drug characteristics and Phase 3 data that make me bullish about exenatide LAR’s potential impact on type 2 diabetes:

1.9% HbA1c drop from baseline with average BL A1c in low 8’s; an improvement compared with Byetta, although the improvement appears to be confined to those with worse control at baseline.  This is probably due to the better effect on FPG in the high-A1c subgroup.  Presumably high FPG drives the higher A1c, and the LAR is able to suppress overnight FPG better than regular exenatide. 

The A1c drop was extended to 52 weeks in the extension study, which offered LAR to all participants, indicating durability of effect to 1 year.  Many other therapies start to show waning effect on A1c at 1 year.

Both FPG and PPG were suppressed, and the PPG suppression appeared more “physiologic” than with regular exenatide.

Weight loss and cholesterol/SBP reduction were similar to regular exenatide; lipid effect maybe a bit stronger.

Well-tolerated with less nausea than regular exenatide.

Once weekly administration, with 94% of the injections self-administered in the clinical trial (i.e. easy to self-administer after brief education).  Issues regarding formulation consistsency will be worked out before launch.

Compliance likely to be at least as good as Byetta (twice daily exenatide), despite presumably larger gauge needle with higher rate of injection site symptoms (primarily itching), due to the need to inject only once a week.

Once weekly injections will make the drug attractive to somewhat better-controlled patients, for whom injections are rejected as an option now.  How much more attractive awaits real-world experience, but I speculate–an educated guess–that the acceptance will be much greater than either insulin or a once-daily formulation of GLP-1 analog.  Still, I think the role is later in the disease right now, with the DPP-IV drugs dominating the early/better-controlled patient group, along with the other oral meds. 

What I think we’ll see with LAR in the marketplace (whenever that may be; we should know more by the end of this year) is that the average duration of diabetes and average A1c prior to therapy will both drop substantially relative to Byetta within a year of the LAR’s launch.  Eventually, LAR should totally supplant Byetta, and also steal some of the volume share still held by the SUs, the TZD’s, insulins, and some held by the DPP-IVs.  Like I said–game-changing.

Meanwhile, as I teased above Novo is looking like it has a real drug with its once-daily liraglutide, potentially a strong competitor to Byetta.  But remember that liraglutide is an NME; it’s got a scaredy-cat FDA in the US and a diabetes NME-unfriendly EMEA in Europe it must face before selling a thing.  Once it makes its way onto the major markets, exenatide LAR will be breathing down its neck.  Liraglutide may be able to compete for Byetta patients, but I don’t see how once daily therapy can compete with once-weekly, especially when the API in the once-weekly has an enormous amount of patient experience and clinical research behind it.

As for Ipsen/Roche (see above linked press release), they’re pressing forward for now.  They’ve really got their work cut out for them.  A straightforward “me-too” type of development program is unlikely to reap them the ROI they seek.  They’ll need to be creative in Phase 3, and focus on the unmet medical and practical needs that (might) remain after exenatide LAR hits the market. 

Finally an editorial plea, in light of the recent ACCORD and ADVANCE trial results, which suggest that drugs that carry a risk of hypoglycemia are likely not appropriate for strict glycemic control in advanced type 2 diabetes, I urge Lilly and Amylin to provide financial support for a large study of Exenatide LAR with cardiovascular endpoints to be started as soon as feasible.  It is likely our nearest best hope to reduce the risk of CV events (or at least not increase them) in older diabetics, while maintaining glycemia close to normal to prevent microvascular disease.  US government support for such a study is realistic. 

In December 2006, I described my initial impressions of Google Patent Search beta, a free USPTO patent search engine, powered by Google.  As you’ll read, I wasn’t thrilled with this early release.

So, how has Google fared with some time–nearly 17 months–to marinate its patent search engine?

First off, Google hasn’t promoted the service out of beta yet.  I don’t know how Google decides to promote a new tool to production, but I have to think that many thousands of searches have been made with it since beta testing began, and they’ve had plenty of time to work out the kinks.  Beta schmeta…is it good enough to recommend?

Once again, I’ll compare Google Patent Search directly to the USPTO search engine, as Google has not yet added international patents. 

The Google search interface has been improved and provides simple form field searching for patent number, inventor, assignee, classification code (US and international), issue date, and filing date.  Google’s advanced search operators also work, including the “-” for NOT and “OR”.

The USPTO quick search allows search of all these fields plus some two dozen more, and their advanced search interface allows all of these delimiters to be accessed simultaneously, albeit using a complex syntax.  If you’re doing serious patent research, Google’s search interface will simply not provide you with enough search specificity to meet your needs.

For simple searches, the USPTO quick search and Google Patent advanced search interfaces are similar in user-friendliness and utility.  (The basic Google Patent search has very limited utility.)  So, the key differentiators will be result accuracy and result presentation.

Last time I looked at the Google service, it offered results in a list sorted by relevance-according-to-Google.  In my mind, this made the service virtually useless for industry-based searchers.  Google has since added in a date sorting.  I would have preferred having a patent number sorting option, but date at least makes the search worth doing.

As for relevance, I’m still scratching my head with Google.  It seems to return results in some quasi-random way.  For instance, search the exact phrase (in quotes) “Eli Lilly” the field assignee name, using the entire USPTO issued patent database (quick search) or Google Patent Search (advanced search).  The USPTO returns 3,793 hits dating back to 1971.  Google returns only 527 issued patents dated to 1976, and very strangely, only 461 filings of any status (issued plus applications combined–yes this number is lower than issued patnets alone!), and just 46 patent applications (USPTO returns 94 applications).

Clearly, there is something amiss with Google’s Patent Search.  It really does behave as a beta product, despite its protracted time in use.   It has some potential advantages to the USPTO search in theory, claiming, for example, full-content access to all US issued patents, whereas the USPTO offers full-text access only as far back as 1976.  But it remains fatally flawed for all research purposes except cherry-picking individual patents by number, when you are certain the patent number is correct.

GlaxoSmithKline (GSK) to Acquire Sirtris Pharmaceuticals, a World Leader in “Sirtuin” Research and Development for $720M - FierceBiotech

In what must be the highest valuation paid for a Phase 2 drug and a pipeline of follow-ups (all in the same pharmacological category mind you), GSK is paying nearly three-quarters of a billion dollars for Sirtris. 

That’s $180 million for each of Sirtris’ four years of existence.

Okay, so Sirtris has its share of sirtuin-activator patent applications pending (at least 180, according to the company).  But those aren’t issued patents, are they? 

Three-quarters of a billion.  That’s roughly three-quarters of a billion for each of Sirtris’ one issued U.S. patent.

And they’ve got a small-molecule drug that apparently has cleared Phase 2.  But that leaves another development phase and a regulatory review to go before even getting to market by my math.  

Three-quarters of a billion with at least four more years of development time.

History tells me that pioneering small molecules for diabetes that have cleared this development hurdle have roughly a coin’s toss odds of eventually gaining major marketing approval, and a much lower chance of making it to market and becoming blockbusters.

And yet.

Three-quarters of a billion.  Roughly $9 milion per Sirtris employee.

Are you feeling valued yet?