Pharma’s Cutting Edge

With legislation possibly creating a regulatory pathway for follow-on biologics (biosimilars, generic biologics, biogenerics, et al.) in the US as early as 2009 (but more probably later), I figured it’s time to break out the for-no-good-reason top-10 list of major players in this coming market and their first likely drugs approved.  I guarantee that at least one of these top 10 companies might or might not surprise you.  Heed my words, or buy a 2-year old $7600 report on the topic from Datamonitor–your choice.

In no particular order:

1. Novartis (Sandoz/Hexal) – GH, Epoetin alfa
2. Pfizer
3. Teva/Sicor – G-CSF
4. Hospira/Mayne – Epoetin alfa
5. Dr. Reddy’s – Anti-CD20 (Rituxan), G-CSF
6. Matrix Laboratories/Mylan – TBD
7. Biocon – G-CSF, Epoetin alfa, Streptokinase
8. Ranbaxy/Daiichi Sankyo
9. Merck (US) – TBD (Surprised? I was.)
10. Cangene – GH, GM-CSF

Note the presence of several India-based companies.  Some of these, e.g. Biocon, will likely partner with US distributors rather than attenpt to go it alone.  Other Indian firms, like Shantha and Bhata will undoubtedly be manufacturers of FOBs for the US market.  Also, I would look for other major pharmas to announce their intention to be major players in this space.  Smaller US and non-US firms will have signifcant trouble competing heads-on with the major generics and pharmas for bona fide FOBs, given the technical and commercial hurdles facing the category.  However, there will be ample opportunity for companies of all sizes to prosper in the biologics improvement space, a category we will hear much more from in the next decade.

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. 

This is a f/u to the piece I wrote in January describing the preliminary (but widely publicized) results from the ENHANCE study of simvastatin and ezetimibe (Zetia) (combination tablet sold as Vytorin by Schering-Plough and Merck) in patients with familial hypercholesterolemia.  The study looked at the effects of the combination versus simvastatin alone on carotid intima-media thickness.  My previous opinions of the study’s meaning aren’t changed with publication of the final results in the NEJM to coincide with the ACC meeting.  In case you were asleep for the past couple of months, ENHANCE was negative for signs of IMT improvement with the combo. 

Expert opinion of the findings has been decidedly negative and prescriptions for ezetimibe (a $5 billion a year drug, counting both Zetia and Vytorin) have tumbled.  Schering-Plough reported that scripts were 3.2 million in January and 2.8 million in February for both drugs combined (a 12.5% drop), while others have reported that Vytorin scripts have fallen 18%.  Several sell-side analysts believe the latest pronouncements from experts at the ACC will further erode sales of Zetia and Vytorin and have cut their sales forecasts and share-price targets for Merck and Schering-Plough.  Given the overreaction to the results thus far, it’s hard to find fault with their reasoning.

I await results from ongoing studies (particularly IMPROVE-IT) with hard CV outcomes as the primary endpoint in a less highly selected population before changing my own use of Zetia.   If ezetimibe doesn’t work to reduce hard CV outcomes despite robust LDL-C reductions, the findings will be strong evidence supporting pleiotropic benefits of statins and arguing against routine use of ezetimibe.  If ezetimibe does work, the utility of CIMT progression in hypercholesterolemia will be dubious. 

Results from ENHANCE are now available.  I don’t think anyone is terribly surprised, given the delay in reporting the results, that addition of ezitimibe to simvasatin (i.e. Vytorin) did not have a sigificant impact on carotid intimal media thickness compared with simvastatin (Zocor) alone in subjects with heterozygous familial hypercholesterolemia (a disorder of LDL receptors that affects about 1 in 500 people globally). 

See my prior post on the implications of ENHANCE for most current Zetia users.  As I indicated previously, these results will likely have very little impact on prescribing of Vytorin or Zetia, despite pronouncements to the contrary yesterday, primarily from Steve Nissen of the Cleveland Clinic.  Dr. Nissen apparently gave lots of interviews yesterday, saying things like:

This wraps it up…That’s all there is. There just isn’t any evidence that adding ezetimibe to simvastatin produces any advantage.

to the Washington Post.

Of course that isn’t all there is.  One trial with an iffy surrogate endpoint in a highly selected population does not a definitive treatment recommendation make (said Master Yoda).

Since my last post, I was happy to learn about another trial of Vytorin underway, one with a hard outcome.  The IMPROVE-IT trial, sponsored by Merck and Schering-Plough, is a randomized, active-control, double-blind study of subjects with stabilized high-risk acute coronary syndrome. The primary objective in IMPROVE-IT is to evaluate the clinical benefit of Vytorin 10/40mg compared with Simvastatin 40 mg alone, where clinical benefit is the reduction in the risk of the occurrence of a composite endpoint of CV death, major coronary events, and stroke.  Nice.  Now enroll this sucker.

I’m not stopping my Zetia because of ENHANCE, and I’m confident that most other users of Zetia and Vytorin will not either.  Once the ENHANCE dust settles, it’ll be clear that ezitimibe remains our first best hope for atherosclerosis therapy beyond statins, at least until a definitive study demonstrates otherwise.

Disclosures:  I have no financial ties to Merck or Schering-Plough.

Genitope’s Webcast

A week ago Genitope reported the results of a pivotal Phase 3 trial for its only clinical candidate, the idiotype-specific, personalized active immunotherapy for Non-Hodgkin’s Lymphoma, known as MyVax.  I’ve been interested in this budding therapy since around the time the company went public in early 2004, which roughly coincided with the start of the Phase 3 study.  That was back when I was testing my proclivity for biotech equity analysis, so I began following the company.  

I remember being impressed with the long clinical experience with this form of personalized therapy, which dates back some two decades and which was nurtured by no less than Dr. Ronald Levy of Stanford (who you might know as one of the founders of IDEC Pharmaceuticals and a pioneer of immunotherapy for cancer, lymphoma in particular; see this profile).  Based largely on the Phase 2 experience of Dr. Levy and others, which included a convincing number of long-term remissions with MyVax and MyVax-similar idiotype immunotherapy, I recommended investors buy Genitope stock.  I think the stock was just under $10/share then.

My feelings about the stock and the likelihood of a successful Phase 3 study changed dramatically after a second planned interim analysis of efficacy of the MyVax Phase 3 study failed to demonstrate superiority of the therapeutic vaccine over control measured as progression-free survival, but I’m getting ahead of myself.

Backing up to the beginning of the Phase 3 study, its purpose was to test the ability of MyVax to prolong PFS in patients with newly diagnosed NHL who had received one course of chemotherapy  After a 6-month rest, patients with at least a partial response to the course of chemo were randomly assigned to therapy with either MyVax immunizations (recombinant, cancer-specific idiotype protein conjugated to KLH) + GM-CSF or KLH + GM-CSF.  Multiple immunizations were given and PFS, along with a number of biomarkers, was determined.

As mentioned, a second planned interim analysis for efficacy was perfomed in July 2006.  Based on my own accrual and hazard rate assumptions, I had expected that sufficient evidence of efficacy would be seen to allow stopping the trial at that point.  However, the trial was continued.  I suspected then that the study would miss its primary endpoint.  Full planned follow-up was completed earlier this month and, as you’ll see from the market reaction, the study missed its primary endpoint.

What interests me about this story is less the ostensibly failed study and more the way Genitope spun the news into a positive story about MyVax.  “Simply put,” said CEO Dan Denney Jr., “MyVax works.”  Dr. Denney went on to explain that the primary endpoint was missed because the KLH arm did better than expected, with some patients mounting an immune response that caused prolonged PFS.  However, a secondary endpoint that was “highly statistically significant” showed that MyVax prolonged PFS in a subgroup of the subjects who mounted a “positive immune response” to the therapy when compared with those who did not mount such a response to MyVax. Read the rest of this entry »