NewNowNext January 31, 2011

Merck Purchases SmartCells – Wow, an Insulin (Maybe) that Doesn’t Come with Hypoglycemia!

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In late 2010, Merck announced that it had acquired SmartCells, a small Massachusetts-based company that is developing a smart insulin product aptly named SmartInsulin. What’s so smart about SmartInsulin? The compound that Merck is developing is a “glucose-dependent” insulin meaning that once dosed, the fraction of the insulin that is “active” in the body will continually change in response to current blood glucose levels. In theory, this glucose responsiveness will allow patients to control both fasting and postprandial glucose levels and significantly reduce the risks for hypoglycemia. SmartInsulin is still in animal studies, but should enter human trials shortly.  For patients, this means that approval is likely a long way off, probably at least five years away.  That said, an insulin that does not prompt hypoglycemia, no matter how far away is exciting indeed. We are glad to see Merck, one of the world’s largest pharmaceutical companies, make a substantial investment (potentially over $500 million!) in a product that can significantly improve insulin therapy for people with both type 1 and type 2 diabetes. The Merck-SmartCells agreement makes us hopeful that glucose-dependent formulations are feasible long-term, and we are encouraged that other companies, including Novo Nordisk and Biodel, are also working on smart insulin products of their own. We look forward to tracking this field in the years to come and we’ll keep you updated as we hear more. --KC

Dexcom Provides Updates on Upcoming CGM Products

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As we wrote in our NewNowNext column in diaTribe #25, Dexcom is developing several new continuous glucose monitoring (CGM) technologies, including a fourth-generation sensor to replace the current SEVEN PLUS, an integrated pump/CGM in collaboration with Animas, and an integrated pump/CGM with the OmniPod (Insulet). However, in the fall, the FDA requested additional data before approving all these products, causing a delay in their timelines. Now that the companies have (mostly) clarified their next steps, we offer this brief update on their setbacks, their strategies, and ongoing uncertainties.

Dexcom's fourth-generation sensor will be more accurate than the SEVEN PLUS (including 25% better accuracy in the hypoglycemic range), be 50% smaller by volume, have significantly stronger sensor wires, and have a startup time of two hours rather than one hour. Additionally, the sensor will allow for reliable readings sooner after insertion and give the system better chances of lasting a full seven days. Dexcom plans to start clinical trials in the first half of 2011, and the company is hoping to receive FDA approval before the end of the year.

The Animas/Dexcom integrated pump/CGM, which will use the fourth-generation sensor, will be following right behind in the regulatory pathway. The companies plan to start clinical trials for this combination product in mid-2011, as soon as studies for the standalone fourth-generation sensor are finished. Meanwhile, both the fourth-generation sensor and the combination product are already undergoing regulatory review in Europe, where Dexcom and Animas anticipate that they could start selling their integrated devices in the first half of 2011. We're frustrated that both the next-generation Dexcom sensor and the pump/CGM combined product have been delayed in the US.

As for Insulet/Dexcom's combined pump/CGM product, the companies initially submitted a system that pairs Insulet's OmniPod with Dexcom's SEVEN PLUS. In our NewNowNext column in diaTribe #28 we reported on Insulet's announcement that due to the regulatory delays, the system would instead feature the smaller next-generation OmniPod and a CGM sensor to be determined by Dexcom. Since then the companies have reframed the situation. In the coming months, Insulet gets to decide whether the companies will resubmit their original combination product (with the first-generation OmniPod and the SEVEN PLUS) or develop a new version that incorporates the second-generation OmniPod and the fourth-generation Dexcom sensor. The next-generation version would probably not receive FDA clearance until after the middle of 2012, while the original combination product could have a shot at 2011 approval. On the other hand, a combination of the current OmniPod and the SEVEN PLUS might not have much appeal in a few years, after Insulet has released its sleeker pod and Dexcom has launched its smaller, more accurate sensor. We expect to learn more in the coming months, and we'll share updates as we learn them on these companies and others that are working to create the future of continuous glucose monitoring. --JS

Eli Lilly and Boehringer Ingelheim Partner to Develop and Commercialize Several Diabetes Therapies

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Earlier this month, Eli Lilly and the German pharmaceutical Boehringer Ingelheim (BI) announced a major partnership to co-develop and co-commercialize several of their diabetes compounds, including BI’s DPP-4 inhibitor linagliptin, BI’s SGLT-2 inhibitor, and Eli Lilly’s two new basal insulins. None of these drugs are approved yet. As a reminder, DPP-4 inhibitors are oral drugs with few side effects, making them popular treatment options for type 2 patients – when taken alone, they typically prompt modest glucose lowering effects, although taken with metformin has shown greater glucose lowering effects in multiple studies. The currently available DPP-4 inhibitors (Merck’s Januvia, Bristol-Myers Squibb/AstraZeneca’s Onglyza, and – outside the US – Novartis’ Galvus and Takeda’s Nesina) are almost indistinguishable in terms of efficacy, tolerability, and safety. Compared to the currently available options, linagliptin could be a more appropriate choice for people with kidney disease, since it is not primarily cleared by the kidneys as Januvia, Onglyza, Galvus, and Nesina are. Assuming favorable regulatory review, linagliptin should be approved in the US and Europe by the middle of this year.

SGLT-2 inhibitors are a new class of oral drugs that cause blood glucose to be filtered by the kidneys and simply lost in urine. The lead SGLT-2 inhibitors, Bristol-Myers Squibb/AstraZeneca’s dapagliflozin and Johnson & Johnson’s canagliflozin, have increased the frequency in urinary and genital tract infections in clinical trials. However, BI’s SGLT-2 inhibitor has not shown these signs in its own trials so far. With a launch projected for 2014, BI’s SGLT-2 inhibitor will likely come to market after its competitors, but it could ultimately prove to be a more attractive option if it does indeed turn out to be safer. For more information on DPP-4 inhibitors and SGLT-2 inhibitors, please see our Learning Curve in diaTribe #8.

In addition, Eli Lilly expects to initiate phase 3 trials later this year for its two basal insulins in development and submit them both for regulatory review in 2014. Taking these developments and the recent partnership with BI into consideration, Eli Lilly could have the industry’s most comprehensive portfolio of diabetes medications in a few years, allowing the company to explore various combination therapies with ease. --VW

Amylin Submits First GLP-1/Basal Insulin Combination to the FDA

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Although the GLP-1 agonist drug class (like Byetta and Victoza) and basal insulins (like Lantus and Levemir) have been around for some time, only recently have the two drugs been examined as a combination therapy for type 2 diabetes. We know from our advisory team and all the talks we have attended over the past several years that GLP-1/basal insulin combination therapies make a lot of sense for several reasons: 1) GLP-1s reduce food intake (they make you less hungry! – this is often termed “increasing satiety”) and promote weight loss, so they can counteract the weight gain often observed with basal insulin therapy; and 2) GLP-1s and basal insulins work in complementary ways to control glucose levels – basal insulins act over a long interval and at a slow rate to cover background insulin needs while GLP-1 agonists only stimulate insulin secretion when blood glucose levels are high, allowing for improved glycemic control after meals without increasing the risk for hypoglycemia (for more on how GLP-1 agonists work, please see our Learning Curve column in diaTribe issue #1).  As was discussed in diaTribe issue #24’s NewNowNext column, a study examining Byetta in combination with Lantus confirmed much of this thinking, as type 2 patients achieved a greater reduction in A1c and weight loss (instead of weight gain) on both therapies than on Lantus alone. We have also learned from conversations with healthcare providers that--although not approved by the FDA or other regulatory agencies, not promoted by companies, and not covered by many insurance companies--this combination is still quite commonly prescribed today.

As such, following these results, Amylin Pharmaceuticals and Eli Lilly, the maker of Byetta, filed an application with the FDA in late December 2010 asking the agency to approve the use of Byetta as an add-on to basal insulin therapy for type 2 patients. Usually, the FDA takes around 10 months to review such applications, placing possible approval in October 2011. We’re excited by this development because if the combination is approved, Byetta could become an attractive (and reimbursable) option for many who do not want to take “mealtime insulin” to control post-meal glucose levels.

With the success of the Byetta trial above, other companies have also begun investigating additional GLP-1/basal insulin combinations. Novo Nordisk is conducting clinical trials for its GLP-1 agonist Victoza in combination with its long-acting analog insulin Levemir, and plans to begin trials later this year to combine Victoza and Degludec, the company’s ultra-long acting insulin that is now in phase 3 trials. Meanwhile, sanofi-aventis is finalizing plans for trials for its own candidate GLP-1 agonist lixisenatide with Lantus. Unlike for Byetta, the Victoza/Degludec and lixisenatide/Lantus combinations will be dosed using a single pen, reducing the number of injections needed. Both of these combination products, however, will not likely be available before 2013-2014. --BK

Inhaled Insulin Afrezza Denied Approval by FDA

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In a major setback for MannKind Corporation’s inhalable insulin therapy, Afrezza, the FDA is requiring the company to conduct two additional clinical trials of the second-generation inhaler, one in type 1 diabetes and one in type 2 diabetes. Afrezza is an ultra rapid-acting mealtime insulin that is inhaled through a small inhalation device (fits in the palm of a hand). MannKind originally conducted large-scale studies using a first-generation “MedTone” device, but it is now applying for approval of Afrezza with a second-generation inhalation device, dubbed “Dreamboat,” that wasn’t tested in late-stage trials. The FDA’s requests suggest that the agency was not comfortable with the data submitted to show that the devices were equivalent. Interestingly, two ongoing trials of Afrezza in fact closely resemble the studies requested by the FDA. MannKind’s current strategy is to meet with the FDA to determine how the company can best move forward (and if the ongoing studies can be modified to satisfy the agency’s requests). While we had predicted in diaTribe #20 that Afrezza could be in doctors’ offices as early as 2011 if approved, given this recent delay, we now believe that Afrezza could be available in late 2012. We caution that this assumes timely and productive meetings with the FDA as well as positive results from the additional clinical trials. We will be following Afrezza for any updates, and we especially look forward to hearing the outcome of the company’s upcoming meeting with the FDA. --ST