Global Insight Perspective | |
Significance | Given Januvia's clean safety profile and competitive efficacy versus SFUs and TZDs, the approval was widely anticipated, and it becomes the first drug from the new DPP-IV inhibitor class to reach the market. In many ways, Januvia's approval represents a more critical milestone in diabetes care than the introduction earlier this year of the more "glamorous" first inhalable insulin therapy, Pfizer's (U.S.) Exubera. |
Implications | The approval gives Merck a head-start against Swiss rival Novartis, although it will be a brief lead, as the latter's application for DPP-IV inhibitor Galvus (vildagliptin) will receive action next month. Januvia has set the benchmark for pricing in the class, with once-daily dosing costing US$4.86 per tablet. |
Outlook | Following the approval of another first-in-class drug earlier this month (HDAC inhibitor Zolinza (voronistat)), as well as the ongoing fold-out of cervical cancer vaccine Gardasil (human papillomavirus), Merck is gaining much-needed new revenues streams, which should help to steer the company through a period of less late-stage pipeline activity in 2007. |
DPP-IVs: Here, There and—Soon—Everywhere
U.S. drug giant Merck & Co announced yesterday afternoon that the U.S. FDA has approved Januvia (sitagliptin) as an oral treatment for Type II diabetes. The drug will be used as a monotherapy and as an add-on therapy to either of the two other major oral diabetes drugs, metform or thiazolidineodiones (TZDs). Its starting dose will be 100mg once-daily, designed to control and improve blood sugar (glucose) levels in diabetes patients when diet and exercise is insufficient. Januvia is not indicated for the smaller Type I diabetic population, or for the treatment of diabetic ketoacidosis.
Januvia is the first dipeptidyl peptidase-4 (DPP-IV) inhibitor to be approved in the United States, having previously been cleared in Mexico as its first market. DPP-IV inhibition is currently among the most actively researched areas in the pharmaceutical industry, due to the high unmet clinical need for fewer glucose control-related side-effects among diabetics. DPP-IV inhibitors enhance the natural protein GLP-I, which stimulates the pancreas to produce insulin and limits the liver's production of glucose. Januvia works only when blood sugar is elevated, focusing on lower insulin due to beta-cell dysfunction and uncontrolled production of glucose by the liver, due to alpha-cell and beta-cell dysfunction.
In effect, this means that Januvia and its future DPP-IV rivals work differently from traditional therapies such as sulfonylureas (SFUs), which lose efficacy over time and are associated with dangerously low blood sugar levels (hypoglycaemia). Patients then require insulin shots, and Januvia is expected to reduce the need for such last-resort action. Because Januvia only kicks in when blood sugars are already high, the hypoglycaemia risk is almost entirely removed, disassociating the drug from weight gain (unlike SFUs, TZDs and metformin). It works in a similar way to Eli Lilly's Byetta (exanitide), but is not an injectable therapy, thus enhancing both patient and physician predilection for DPP-IVs.
Cost Analysis
Merck has announced a pricing of US$4.86 per tablet, in line with expectations, with a recommended once-daily starting dose of 100 mg. Thus, for patients who have mild-to-moderate hepatic insufficiency or mild renal insufficiency (where no dosage adjustment is required), the monthly and annual cost will stand at around US$146 and US$1,774 respectively by adding Januvia to the diabetic therapy. Dosing is slightly different for patients with moderate-to-severe renal insufficiency; 50 mg once-daily is recommended for moderate cases, and 25 mg once-daily for severe renal insufficiency. In light of this skewed dosing, and its effects on overall costs, renal function tests will probably be taken before and (periodically) during therapy.
Outlook and Implications
Despite the premium pricing, it is apparent that Januvia's approval and the likely introduction of Galvus later this year, sound the early death-knells for SFUs. It is less clear how the DPP-IVs will affect TZDs, and it appears likely that both Novartis and Merck will target these drugs in their early marketing, taking for granted that they do not need to prove superiority over SFUs. To begin with, the natural uncertainty over how a new class of drugs actually works will probably limit Januvia to second-line prescribing. As confidence grows, it will increasingly become the first-line choice. Both Januvia and Galvus have already set very high standards, which puts added pressure on DPP-IVs in the pipeline—most notably saxagliptin and SYR-322—to prove added benefits.
While Januvia's first-mover advantage over Galvus is minimal at best, it is important to remember that its starting point was quite far behind Galvus. In addition, the advantage of brand recognition as the first DPP-IV will be significant, given that physicians in the United States have already expressed almost universal enthusiasm for the new class, and want to get their hands on a drug as soon as possible. Merck is also far ahead in the development of a metformin combination, which further enhances its competitiveness vis-à-vis Galvus.
Most analysts are projecting sales of around US$1.6-2.0 billion by 2010, but given the relatively strong uptake of Byetta (sales of US$98.6 million in the second quarter of 2006, which is a low-point marker for Januvia's commercial potential), Global Insight is more inclined to stick to the higher area of this range; indeed, this in itself may be conservative. TZDs Actos (pioglitazone; Takeda (Japan)) and Avandia (rosiglitzone (GlaxoSmithKline (U.K.)) achieved sales of ¥244.3 billion (US$2.1 billion; up 26%) and £1.2 billion (US$2.2 billion; up 27%) respectively last year. There is a clear unmet medical need here, as physicians continue to face frustration over the inability to optimally manage blood sugar levels; the majority of Type II diabetes patients are uncontrolled, and Januvia tackles the non-compliance issue through both its ease of administration and lack of safety issues, while not reducing efficacy.
DPP-IV Pipeline | ||
Galvus | Novartis | Filed |
Januvia | Merck & Co | Approved |
SYR-322 | Takeda, Syrrx | Phase III |
MP-513 | Mitsubishi Pharma | Phase II |
saxagliptin | BMS | Phase II |
'823093 | GSK | Phase II |
PHX1149 | Phenomix | Phase II |
TS-021 | Lilly, Taisho | Phase I |
KRP-104 | Kyorin | Phase I |
DPP-IV | Biovitrum, Santhera | Phase I |
DPP-IV | Novo Nordisk | Phase I |
DPP-IV | Probiodrug, Prosidion | Research |
Source: Companies, GI | ||
Both insulin sensitisers (metformin and TZDs) and insulin secretalogues (sulfonylureas and meglitindes) are associated with major side-effects. While metformin remains the gold-standard first-line therapy, this is primarily due to cost and an established efficacy profile; it causes major gastric events, and is contraindicated for renal insufficiency. Januvia can therefore make an immediate first-line impact in this patient population; its add-on potential is clear. TZDs, meanwhile, have generally failed to penetrate the first-line market due to cost, weight gain and heart failure risks. While cheap, the hypoglycaemia problem with SFUs renders them almost entirely replaceable with DPP-IVs. We expect this class to fade away in the United States.
Related Articles:
- Switzerland: 12 October 2006: Novartis Launches Comparative Trial of Galvus and TZD Antidiabetics
- United Kingdom: 18 September 2006: Can Diabetes Prevention Sweeten the Pill for GSK's Avandia?
- United States: 15 September 2006: Merck & Co and Novartis Take DPP-IV Development Rivalry to Europe
- Switzerland: 17 August 2006: Novartis Files for European Approval of Diabetes Drug Galvus
- United States: 14 June 2006: Merck & Co Maps Out the DPP-IV Battleground, Strengthens Outlook for Januvia