The industry trade and lobbying group Pharmaceutical Research and Manufacturers of America (PhRMA) said in a recent report that its member companies are developing more than 180 new medicines for Type 1[1] and Type 2 diabetes[2] and their comorbities.
But even PhRMA admits that most will never see a pharmacy shelf.
It estimates that for every 5,000 to 10,000 compounds in the pipeline, only one is approved by the U.S. Food and Drug Administration (FDA). Still, despite those odds, in the last six years, eight new classes of diabetes medications have joined doctors’ armamentariums to treat people with diabetes. And some of the most recently approved medications could be game-changers for the marketplace and for people’s lives and pocketbooks.
Possibly the biggest potential game-changer in the diabetes medication marketplace in many years was the December 2015 FDA final approval of Eli Lilly’s Basaglar, the pharmaceutical giant’s first-ever long-lasting basal insulin. But Basaglar is hardly new. In fact, there’s a good chance you’ve used it before under another name: Lantus.
Basaglar is the first FDA approval of what most consumers would regard as a “generic” insulin. But the FDA does not consider Basaglar a generic because generic medications are by definition identical copies of already approved products, and it’s not possible to make identical copies of complex molecules such as insulin. Instead, when making an insulin knock-off, the best that can be achieved is a medication that is highly similar, not identical, to the original. In most countries, this kind of medication is called a biosimilar. But due to the unique semantics of FDA regulations, the biosimilar label is reserved for copycats of medications licensed under the Public Health Service Act, which Lantus is not, leaving Basaglar to be identified as a follow-on biologic, or follow-on for short.
While the difference between follow-on and biosimilar is semantic, the actual difference between a generic and a biosimilar is worth understanding and has an important bearing on regulatory approval. Generics need to show only bioequivalence, with no need for clinical data because the clinical safety and effectiveness of the compound already have been established with the original product’s approval, and the generic is a duplicate product. In short, a generic must only prove it is a good copy. Follow-ons, however, can rely partly on the original product’s safety data, but also must provide data showing that the follow-on is safe and efficacious because it is impossible to create an identical biological product. In the case of Basaglar, the makers submitted data from two clinical trials involving over 1,200 patients — one trial in Type 1s and one trial in Type 2s.
Basaglar received tentative FDA approval in summer 2014, and Lantus’ U.S. patent protection expired in February 2016, but you won’t see Basaglar at a pharmacy near you until the end of this year. That’s because competitor Sanofi alleged infringement of its patents, triggering a rarely exercised provision of the Hatch-Waxman Act (the law governing the approval of generics) that required the FDA to put a 30-month hold on the market entrance of Basaglar. Under the law, filing the suit effectively delayed FDA approval.
The suit revolved around Sanofi’s SoloStar pen, not the insulin itself, and last September, Sanofi and Lilly reached a settlement in which Lilly will pay royalties to Sanofi in exchange for a patent license on the pen. Lilly also agreed to not market Basaglar until December 2016.
In the meantime, Sanofi is marketing its own concentrated version of Lantus, sold under the brand name Toujeo, approved in February 2015. Toujeo in essence is distilled Lantus. Both drugs carry the same scientific designation of insulin glargine (as does Basaglar), but Toujeo is more concentrated, requiring less volume to accomplish the same glucose-lowering effect.
In September, insulin giant and competitor Novo Nordisk received a pair of FDA approvals for a whole new basal insulin molecule called degludec, sold in the U.S. under the trade name Tresiba.
Tresiba is the first of the ultra-long-acting insulins — with a 20-hour half-life and a duration of action up to 42 hours — that allows users to be more flexible in their dosing times. Tresiba was approved in Japan in 2012 and in Europe in 2013. Novo had high hopes for an FDA approval in 2013, and had trained its sales force for a product launch in anticipation. Instead, in February 2013, the FDA rejected Tresiba pending cardiovascular outcomes trials, basically requiring the Danish pharmaceutical giant to prove the new insulin did not increase the risk of heart attack. Almost three years later, with that proof in, Tresiba was approved, along with Ryzodeg 70/30, a mix insulin combining Tresiba with the company’s existing fast-acting Novolog insulin.
But it hasn’t been just insulin that has recently been approved. Two new pills joined the congested marketplace (about 40 different FDA-approved oral medications to treat diabetes currently are available), both from a partnership of Eli Lilly and Boehringer Ingelheim.
Glyxambi has the distinction of being the first polypill to combine a DDP-4 inhibitor (Tradjenta) with a SGLT2 inhibitor (Jardiance) to attack high blood sugars from two angles. While neither drug is new, this is the first time they’ve been combined into a polypill. The DDP-4 component helps maintain the body’s native GLP-1 hormone response, in return limiting postprandial glucose spikes, while the SGLT2 inhibitor changes glucose absorption by the kidneys, allowing excess glucose to be excreted. Shortly after approval of Glyxambi, the FDA revised the labeling of the entire SGLT2 class over concerns of ketoacidosis[3] and serious urinary tract infections.
Lilly/Ingelheim also successfully combined SGLT2 with traditional metformin to create the polypill Synjardy, which received FDA approval in summer 2015 and is the third combo of the two medications approved, joining the previously approved Invokamet from J&J and AstraZenca’s Xigduo.
Recent FDA approvals include two new medications for retinopathy[4], one for foot ulcers and a possible game-changing new class of cholesterol-lowering drugs.
Last summer, within a month of each other, the FDA approved two medications that offer a whole new approach to treating cholesterol called PCSK9 inhibitors. PCSK9 inactivates the LDL transport receptors on the liver that normally suck LDL cholesterol into the liver for processing, so the new class of medicines restores the liver’s ability to remove LDL from the bloodstream, with striking effects. Clinical trials of the first-in-class medication approved, Praluent (alirocumab injection), from Sanofi and Regeneron, showed LDL reductions of 36% to 59%. Biologics like insulin and GLP-1 meds, PCSK9s are injectable medications. Praluent is injected subcutaneously every two weeks.
Within a month after the Praluent approval, the FDA approved a second PSK9 from Amgen called Repatha (evolocumab injection). Both medications, for now, target the most desperately tenacious cholesterol such as familial hypercholesterolemia, and both can cost up to $14,000 per year.
Early in 2015, the FDA granted approval to a pair of medications for treating retinopathy. In February, it approved Genentech/Roche’s Lucentis (ranibizumab injection), granting it an expanded indication for treatment of retinopathy in patients who already have macular edema. The approval was designated as a breakthrough therapy under the agency’s priority review program. Previously, the drug had been approved for macular edema, macular edema secondary to retinal vein occasions, and wet age-related macular edema. Injected by a physician directly into the eye once a month, Lucentis is an anti-vascular endothelial growth factor (VEGF) drug, designed to block the growth factor protein that fuels abnormal blood vessel growth in the eye.
Also under priority review and carrying a breakthrough designation is an expansion of the indication for the use of Regeneron’s Eylea (aflibercept injection), another anti-VEGF medication for the treatment of diabetic retinopathy in patients with diabetic macular edema.
In early January 2016, the FDA granted approval to Inegra Life Sciences to use its Integra Omnigraft Regeneration Matrix for the treatment of diabetic foot ulcers. The product, first approved for the treatment of severe burns in 1996, now is indicated for diabetic ulcers that have not healed in six weeks and do not involve exposure of joint capsule, tendon, or bone.
The product is described by the manufacturer as a “temporary epidermal substitute layer,” in essence, fake skin. It controls fluid loss, serves as a bacterial shield, and allows normal healing to progress. It usually is worn for three weeks.
Recent FDA approvals introduce both cheaper insulin in the form of a biosimilar and lipid-lowering agents with prices that rival the cost of cancer drugs. They also give us brand new ways to lower blood glucose and repair the damage done when glucose control fails. Hundreds more are in the pipeline, of which one or two per year will win marketing approval from the FDA.
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