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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 (AMLN) /Lilly (NYSE:LLY) 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 consistency 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 has 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 (OTCQX:RHHBY) (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.

Source: In GLP-1 Wars, Novo & Others Knock at Amylin’s Door; Find Amylin Moved to Pricier Digs