Statins

Overview of drug class

Statins are the cornerstone of lipid-lowering therapies. They are nearly universally prescribed to patients with hypercholesterolemia and mixed dyslipidemia, and are widely employed in the primary and secondary prevention of CVD. Statins represent one of the most successful classes of pharmaceutical agents ever made, and this is reflected by Pfizer’s Lipitor (atorvastatin), which remains the best-selling drug of all time, reaching peak sales of $13.7B in 2006 (King, 2013).

Statins are small molecule inhibitors of the enzyme HMG-CoA reductase. This enzyme plays an essential role in cholesterol biosynthesis in the liver by converting HMG-CoA to mevalonate (Figure 20). Through inhibiting this enzyme, statins reduce endogenous cholesterol production, resulting in reduced cholesterol levels in the liver. Moreover, in response, hepatocytes in the liver up-regulate expression of LDLr, leading to increased LDLr on their cell surface and increased absorption of cholesterol from the blood. Together, this results in a net reduction of LDL-C in circulation.

Figure 20 presents the cholesterol synthesis pathway, highlighting the mechanism of action of statins.

Figure 20: Statin Mechanism of Action

Source: GlobalData

The majority of statins are available generically; all of the remaining branded statins are expected to lose exclusivity across the 7MM during the forecast period. Depending on the patient and their LDL-C levels, statins of different intensity are prescribed. High intensity statins have been shown to reduce LDL-C levels by approximately 50% or more, whereas moderate intensity statins reduce LDL-C levels by 30–50%. Table 22 lists the most commonly used statins, along with their dosages and associated intensity.

Table 22: Intensity level of commonly used statins

Statin Dose Intensity

40–80mg High Atorvastatin 10–20mg Moderate

20mg High Rosuvastatin 5–10mg Moderate

Simvastatin 20–40mg Moderate

Pravastatin 40–80mg Moderate

Lovastatin 40mg Moderate

Fluvastatin 40mg Moderate

Pitavastatin 2–4mg Moderate

Source: GlobalData

“Statins remain, until now, the only drugs that show a decrease in cardiovascular morbidity and mortality in the endpoint. They are wonderful drugs. So we have experience for many years with statins. They are actually very safe drugs. I don’t think that the statins would be replaced by the PCSK9 antibodies, they shouldn’t be, because they’re also much cheaper. But we definitely need something more and we don’t have any good drugs on top of that, so that’s where I think the new drugs are coming in.”

5EU Key Opinion Leader

“Well, I think statins would stay there [as standard of care]. I think there is absolutely no doubt that they are very efficacious in lowering cardiovascular disease risk in a wide range of patients where the risk is driven, of course, by the dyslipidemia. That doesn’t mean that statins are solution to each type of cardiovascular disease. But in general, if we talk about atherosclerosis-related processes, then they are basically the starting basis… So any treatment that comes in will be on top of statins.”

5EU Key Opinion Leader

“Given the rising incidences of diabetes in the US, and the aging population, I think the total number of people taking statins in the US will increase.”

US Key Opinion Leader

“Statins remain as the first line except in patients who have severe hypertriglyceridemia. In some of these patients where pancreatitis is a risk, we might start the fibrates first, but eventually, they will be also on statins.”

5EU Key Opinion Leader

Crestor (Rosuvastatin)

Overview

AstraZeneca’s Crestor (rosuvastatin) was approved for use in the EU in November 2002, in the US in August 2003, and in Japan in December 2004 (AstraZeneca, press releases, November 7, 2002; August 13, 2003; December 27, 2004). Crestor is one of the most potent of all of the statins, and as shown in Table 22, this particular statin can be titrated to reduce its potency. The drug is indicated for lipid reduction in patients with hypertriglyceridemia, FH, and for the risk reduction of MI, stroke, and arterial revascularization. It is administered orally, once daily, in 5, 10, 20, or 40mg tablets, with the dosage determined by the severity of the condition.

Crestor was originally approved by the FDA in 2003 to lower cholesterol levels, and the drug’s patent expired on July 8, 2016 in the US, and will expire in 2017 in the EU and Japan (FDA, press release, August 12, 2003). In anticipation of this patent expiry, several drug developers have filed abbreviated new drug applications (ANDAs) seeking approval for their generic versions of Crestor. However, there has been a lot of controversy over the launch of Crestor generics. In 2013, AstraZeneca entered into a settlement agreement with Actavis (previously Watson Laboratories Inc.), permitting the company to market their generic version of Crestor from May 2, 2016 (AstraZeneca, press release, March 25, 2013). This generic version is the only other marketed form of Crestor currently available in the US. To prevent other generics from reaching the market, AstraZeneca filed a Citizen Petition to the FDA seeking exclusivity for Crestor until May 2023. This was in response to the FDA’s recent approval of Crestor for use in patients with HoFH ages 7–17 years on May 27, 2016, granting AstraZeneca orphan drug designation for Crestor, which typically extends exclusivity a further seven years (Karst, 2016). Based on this, AstraZeneca expected market exclusivity of Crestor to be extended until May 2023, which would prevent the steep generic erosion that is typically associated with the launches of cheap generic competing drugs. However, AstraZeneca has garnered even more controversy over Crestor with this potential exclusivity extension, as critics have claimed the company is exploiting the Orphan Drug

Act, since they waited so long to seek approval in this rare indication (Pollack, 2016). Recently though, after suing the FDA, AstraZeneca was denied their exclusivity extension and generic versions of rosuvastatin have since been launched in the US. Crestor will now have to compete with these and other generic statins, particularly atorvastatin, which boasts a low cost and a preponderance of clinical trial data in support of its efficacy and safety. According to the company’s 2015 Annual Report, sales of Crestor have already begun to decline, with a 3% drop observed in 2015, which was put down to competition with generically available statins (AstraZeneca, 2016).

Table 23 presents the product profile of Crestor.

Table 23: Product Profile – Crestor [Rosuvastatin]

Brand Crestor (rosuvastatin) (Molecule)

Launch US – 2003; 5EU – 2002; Japan – 2004 Date

Therapeutic HMG-CoA reductase inhibitor (statin) Class

Alternative Brand Provisacor (EU) Names

AstraZeneca (rosuvastatin was discovered by Shionogi and licensed to AstraZeneca in Developer 1998).

Marketing Shionogi (Japan) Partner

For patients with coronary heart disease risk factors: Crestor is indicated to reduce the risk of MI, stroke, and arterial revascularization in patients without clinically evident coronary heart disease, but with multiple risk factors.For patients with atherosclerosis: Crestor is indicated to slow the progression of atherosclerosis as part of a strategy to lower total-C Primary and LDL-C as an adjunct to diet.For patients with primary hyperlipidemia and mixed Indication dyslipidemia: Crestor is indicated to reduce total cholesterol, LDL-C, ApoB, non-HDL-C, and triglyceride levels, as well as to increase HDL-C.For patients with hyperlipidemia: Crestor is indicated as an adjunct to diet.For patients with primary dysbetalipoproteinemia: Crestor is indicated as an adjunct to diet.For patients with HoFH: Crestor is indicated to reduce LDL- C, total cholesterol, and ApoB.

Formulation Crestor is supplied as 5, 10, 20, and 40mg tablets, taken once daily with or without food. and Dosing

Treatment Cost per day: US – $8.28 ; France – $0.80 ; Germany – $1.68 ; Italy – $0.97 ; Spain – Cost $0.88 ; UK – $1.18 ; Japan – $1.05

Primary Patent or Exclusivity US – 2016; 5EU – 2017; Japan – 2017 Expiry

Source: GlobalData5EU = France, Germany, Italy, Spain, and UK

Efficacy

The METEOR study enrolled 984 patients and examined the ability of Crestor to slow the progression of atherosclerosis by measuring intima-media thickness in the carotid arteries using B-mode ultrasound (Crouse et al., 2007). 984 patients were randomized to receive either 40mg/day of Crestor or placebo. The lipid and lipoprotein-related results of the METEOR study are presented in Table 24. As well as observing significant reductions in LDL-C levels, a net reduction in the intima-media thickness of 0.0014mm/y was also observed in the rosuvastatin group (the placebo group experienced a net increase of 0.0131mm/y).

Table 24 presents the lipid and lipoprotein parameters of rosuvastatin from the METEOR trial.

Table 24: Efficacy of Rosuvastatin – Lipid and Lipoprotein Parameters

Endpoint Rosuvastatin (n = 624) Placebo (n = 252)

Lipid levels – % change from baseline

LDL-C -48.8 (0.7) -0.3 (1.1)

Total cholesterol -33.7 (0.5) 0.3 (0.8)

HDL-C 8.0 (0.6) 2.8 (0.9)

Triglycerides -15.7 (1.4) 10.1 (2.3)

Non-HDL-C -45.1 (0.6) 0 (0.98)

Cholesterol ratios – % change from baseline

Total to HDL-C -37.3 (0.6) -0.3 (0.96)

LDL-C to HDL-C -51.2 (0.8) -0.7 (1.2)

Non-HDL-C to HDL-C -47.6 (0.8) 0 (1.2)

Apolipoprotein levels

B-100 -38.4 (0.8) -1.9 (1.2)

A-I 6.7 (0.5) 3.4 (0.8)

Ratio of ApoB-100 to apolipoprotein A-I -41.5 (0.8) -4.5 (1.3)

Source: GlobalData; Crouse et al., 2007

In the JUPITER Phase III study, 17,802 healthy participants received either 20mg/day Crestor or placebo with the goal of measuring the levels of high-sensitivity C-reactive protein (hsCRP) (an inflammatory marker and predictor of CV events), LDL-C, and a primary endpoint of ACS/CVD-related events (Ridker et al., 2008). The results showed a 37% reduction in hsCRP, a 50% reduction in LDL-C, and reductions in the primary outcome for the Crestor group after two years, at which point the study was terminated. The JUPITER trial was the subject of much criticism, the details of which have been covered thoroughly in literature, but the trial seemed to demonstrate the benefit of statin use for the prevention of CV events in otherwise healthy individuals (Abd et al., 2011; Bajpai et al., 2010).

Safety

Crestor is contraindicated in patients with active liver disease and in women who are pregnant, may become pregnant, or are nursing. Myopathy and rhabdomyolysis are also dose-dependent side effects that are more likely to occur when Crestor is taken concomitantly with cyclosporine and some HIV drugs (Sakamoto and Kimura, 2013).

“There is definitely a problem with compliance and adherence with statins. It happens a lot, especially because this stupid—there’s an insert, a package insert, that focuses so much on muscle side effects [of statins]. So I think that many people develop muscle side effects simply because it’s so intensely described in the packaging.”

5EU Key Opinion Leader

“Some people have more problem with the myopathy than others. I'm talking myopathy as this muscle pain, not rhabdomyolysis—which is of course is no longer an issue, in my opinion. But the myopathy can be disturbing and it’s very difficult to have very objective numbers on that because it's so subjective—if you give somebody a statin and you say that he might have muscle pain, then of course, the next day he has muscle pain.”

5EU Key Opinion Leader

SWOT Analysis

Table 25 presents the SWOT analysis of Crestor (rosuvastatin).

Table 25: Crestor SWOT Analysis, 2015

Crestor is the most potent of the highly-prescribed statins and it is able to elicit the greatest reduction in LDL-C with the lowest dose. As such, it is often used for patients who are refractory to other statins.

Crestor is indicated to help slow the progression of atherosclerosis.

Beneficial pleiotropic effects of statins, such as anti-inflammatory and anti-atherosclerotic Strengths properties, make statins desirable for use in ACS for reasons beyond their LDL-C lowering effects.

Crestor has a relatively easy dosing schedule, requiring only once-daily oral administration.

AstraZeneca is a large company with a well-established line of CVD therapeutics.

Roughly 5–10% of patients are either statinintolerant or have LDL-C levels that do not respond to statin therapy. Weaknesses Statins are most often prescribed indefinitely. Low patient compliance (less than 50%) following the first year of therapy is a well-established trend in statin therapy.

New ACC/AHA clinical guidelines promote a “statins only” approach to LDL-C reduction Opportunities and CVD prevention.

Steadily growing population of individuals with dyslipidemia, obesity, and CVD.

After AstraZeneca was denied an exclusivity extension, several generic versions of rosuvastatin were launched in the US.

Patent expiration of Crestor (US – 2016; EU – 2017; Japan – 2017, China – 2020) will result in steep sales losses to generic rosuvastatin.

Actavis has already started selling its generic version of Crestor in the US. Threats Most other statins are generically available across the 7MM, including atorvastatin and simvastatin.

The launch of the PCSK9 inhibitors, and possible launches of other pipeline LDL-C therapies such as the CETP inhibitors and ETC-1002, threaten the market share of the statins.

Source: GlobalDataCETP = Cholesterylester transfer protein

Forecast

GlobalData projects that AstraZeneca’s Crestor will continue to experience declining sales in the 7MM throughout the forecast period. According to historical figures, Crestor’s sales peaked in 2012, posting approximately $3.2B in the US alone. In 2015, Crestor attained $3.6B in sales for dyslipidemia globally, a figure that is expected to drastically decline to approximately $155M by 2025, reflecting a Compound Annual Growth Rate (CAGR) of -27.0%. The single most important event that will impact Crestor sales within the forecast period will be its loss of patent exclusivity in every major market in this forecast, with expirees due in the US in 2016, and in the EU and Japan in 2017. Although several novel lipid- lowering therapies are set to enter the market during the forecast period, KOLs indicated that statins will remain the mainstay of treatment for patients; however, patients will be actively moved onto generically available options. In general, the use of rosuvastatin is projected to significantly increase against alternate generic statins, simvastatin in particular, but the gain in sales will be allocated to the new generic option of rosuvastatin. GlobalData forecasts generic rosuvastatin will pull in sales of $9.6B by 2025 for dyslipidemia due to an increase in patient share of the now cheaper therapy.

Extracted Date: 24-Jan-2018

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