Gilenya, Aubagio, and Tecfidera in Multiple Sclerosis

Conclusion: Three new oral drugs launched in recent years to treat multiple sclerosis, Gilenya, Aubagio, and Tecfidera, each offer clinical advantages over the beta interferons; Tecfidera has the greatest advantage, followed by Gilenya, and Aubagio has the smallest clinical advantage.  Commercial performance has closely tracked these differences in Clinical Innovation.

Several new drugs have entered the multiple sclerosis market over the past few years. Gilenya (fingolimod) has strong Clinical Innovation at 9.3%, when compared with Rebif (interferon beta-1a). The “Drivers of Improvement” graphic below summarizes the results of that analysis:

• Rebif is modeled as the standard of care (SOC), and it has a total unmet need score of 2.76, as represented by the yellow bar on the left side of the graphic

• Gilenya’s unmet need score is 2.50, the yellow bar on the right side of the graphic

• Gilenya’s Clinical Innovation, or percent reduction in medical need, is 9.3%: Patients treated with Gilenya have substantially less medical need than patients treated with interferon

The graphic also illustrates Gilenya’s advantages and disadvantages compared with the SOC:

• A moderate efficacy advantage (reduction in relapse rates), leading to additional benefits in morbidity

• A modest advantage in safety/side effects

• A substantial advantage in dosing (oral vs. subcutaneous administration)

Gilenya’s overall Clinical Innovation score of 9.3% is at the top of our “good” range – it was launched in Q4 of 2010, and by the end of 2012 it had achieved annual revenues of nearly $1.2 billion.

When Aubagio (teriflunomide) launched in late 2012, it offered 5% Clinical Innovation relative to Rebif, but it was 5% inferior to the already marketed Gilenya . Aubagio’s sales have lagged.

In March of 2013 Tecfidera (dimethyl fumarate) also received FDA approval in multiple sclerosis. It offers substantialClinical Innovation, of 6.3% above Gilenya (15% over Rebif).

The sources of improvement for Tecfidera over  Gilenya are:

• A small efficacy improvement

• Improved tolerability, and

• The improvements in efficacy offer reductions in disease burden

Tecfidera is better than Gilenya, and much better than Rebif. In the fiscal quarter ending June 30, 2013, the Biogen Idec reported sales of $192 million – impressive results for a drug in its first full quarter on the market.

Jardiance: New outcomes data in type 2 diabetes

Conclusion: Jardiance (empagliflozin) gets a Clinical Innovation score of 5.2% in type 2 diabetes patients with comorbid cardiovascular disease (CVD), based on data from the EMPA‑REG OUTCOME trial reported in September 2015. A 5.2% Clinical Innovation score suggests a “Good” ability to compete for patient share — far better than any other new oral agent launched in type 2 diabetes in many years.

To gain insight into the clinical and commercial meaning of new trial data reported for Jardiance in type 2 patients, we analyzed it in our unmet medical need model, which provides a quantitative measure of clinical improvement over the standard of care (SOC). These new data represent a notable improvement in the Clinical Innovation score for Jardiance in the tested population (those with CVD, who constitute 37% of all type 2 diabetics).

The most significant finding from the study is the relative reduction in all-cause mortality — 32% lower than in the control group (SOC plus placebo). That mortality benefit is the primary driver of Jardiance’s overall Clinical Innovation score, as reflected in our “Drivers of Improvement” chart (below). Unmet medical need in diabetics with CVD is relatively high; on our 0–5 scoring system it comes in at 3.16 for the standard of care (sitagliptan plus metformin). Adding Jardiance to this combination (and many other current combination regimens) reduces medical need by a notable 5.2%, to 2.99 (right side of the chart). Green bars show Jardiance’s advantages, red bars its disadvantages.

The efficacy improvement shown in the “Drivers” graphic above reflects the 14% reduction in cardiovascular events that were seen in the Jardiance-treated patients. The disadvantages of the Jardiance combination regimen — the additional side effects, dosing of an additional pill, and higher drug costs — are small in relation to its advantages in mortality, efficacy, and morbidity.

There have been many new drugs launched for type 2 diabetes in recent years, and despite the proliferation of novel mechanisms, all of them have low Clinical Innovation (close to 0%) and are therefore “undifferentiated”. Jardiance (in the CVD subpopulation) is the first to show Clinical Innovation above the 5% level.

We also analyzed Jardiance in the broader type 2 population, assuming relative reductions in mortality and hospitalizations as reflected in the study’s population. Those assumptions yield a Clinical Innovation score of 2% for Jardiance in the broader population.

Using our share prediction algorithm, we project that Jardiance will reach peak U.S. sales of $2.6 billion at its current price and an additional $1.5 to $2 billion outside the U.S. Most of those sales will come from the comorbid CVD population.

Brintellix: Another "me too" in major depression

Conclusion: Brintellix has “negative Clinical Innovation” relative to generic escitalopram, suggesting that Brintellix will struggle in major depressive disorders, and that sales are unlikely to reach the level predicted by the developers.

In September 2013 the FDA approved Brintellix (vortioxetine), a new antidepressant from Lundbeck and Takeda. Marketing authorization from the European Medicines Agency was granted in December 2013. The “Drivers of Improvement” waterfall graphic below summarizes the results of our analysis of Brintellix compared to generic escitalopram (the current standard of care):

• Generic escitalopram’s total unmet medical need score in MDD is 2.01, shown in the yellow bar on the left side of the graphic

• Brintellix’s unmet need score is 2.05

• Brintellix’s Clinical Innovation, or percent reduction in medical need, is negative 2.1%, meaning it is at a net competitive disadvantage relative to generic escitalopram

The graphic shows the magnitude of the advantages and disadvantages of Brintellix compared to the escitalopram:

• The combination of advantages in efficacy and safety/tolerability are modest (summing to 1.6%)

• Those small advantages are overwhelmed by the negative impact of a much higher branded price for Brintellix compared to generic escitalopram, which gives Brintellix a 3.8% disadvantage in direct cost.

For some patients, the clinical differences may be significant, but we think payers will enforce restricted access to Brintellix, owing to its high price and relatively modest clinical benefits.

Fierce Biotech reported on January 6, 2014, that Lundbeck and Takeda estimate peak-year revenue for Brintellix of $2 billion, and Deutsche Bank has estimated peak sales at $1.85 billion. We at Equinox Group think these estimates are too high. By our established metrics, Brintellix is not clinically innovative – we think it will be perceived as a “me-too” product. The Equinox Share Predictor (which reflects the historical relationship between the Clinical Innovation offered by new drugs and the patient shares they achieve) estimates a patient share that would translate into peak revenue of about $1 billion.

The range of uncertainty in predicting patient shares is wide when Clinical Innovation is close to zero as in this instance. Factors such as promotional spend have a greater effect when there is little clinical differentiation. But in 2007 Pristiq launched in MDD with a 0%Clinical Innovations core against branded escitalopram, and it achieved peak year sales of about $650 million, providing further support for the view that Brintellix is unlikely to achieve $2 billion in peak-year sales.

Pradaxa: Stroke prevention in atrial fibrillation

Our analysis shows Pradaxa (dabigatran) to have high Clinical Innovation over warfarin as the previous SOC for preventing stroke in patients with atrial fibrillation (AF). The “Drivers of Improvement” graphic below summarizes the results of our analysis:

• Warfarin’s total unmet need score in AF is 1.23, the yellow bar on the left side of the graphic

• Dabigatran’s unmet need score is 1.04, the yellow bar on the right side of the graphic

• Dabigatran’s Clinical Innovation, or percent reduction in medical need, is 15.9%: Patients treated with dabigatran have substantially lower unmet need than patients treated with warfarin

This graphic also illustrates dabigatran’s advantages and disadvantages compared with the SOC:

• An overwhelming efficacy advantage (fewer patients experiencing stroke/systemic embolism)

• A small advantage in safety/side effects (less monitoring required and fewer drug-drug interactions)

• A slight disadvantage in dosing (BID vs. QD)

Dabigatran’s higher cost diminishes its innovation score, but its net Clinical Innovation of nearly 16% is still high compared with historical norms. As our model predicts, dabigatran has performed well in the AF market since its launch in late 2010.

Following dabigatran’s launch, several other competitors entered the AF market. Rivaroxiban (Xarelto) was approved for this indication about a year after dabigatran, with similar Clinical Innovation relative to warfarin (with somewhat different strengths and weaknesses to those of dabigatran). Rivaroxiban has also competed effectively in this population. In early 2013, apixaban (Eliquis) was also approved, and again it has a similar level of Clinical Innovation compared with warfarin.

All three of these drugs offer substantial improvement over warfarin, and we expect that they will, collectively, dominate this market. However, we do not expect apixaban to achieve as high a patient share, due to its later market entry. For instance, if dabigatran is considered as the new SOC, then apixaban has minimal Clinical Innovation.

Stelara: Exceeding expectations in psoriasis

Conclusion: The magnitude of Stelara’s advantages (especially in safety/tolerability) explain why it vastly exceeded Wall Street’s sales expectations.

When Stelara (ustekinumab) was launched in 2009 for psoriasis, Wall Street analysts forecasted 2013 revenues of $500 million. However, by 2012, sales of the drug exceeded $1 billion. Our Clinical Innovation analysis shows ustekinumab to have a significant safety/tolerability advantage over TNF-alpha inhibitors such as Humira (adalimumab), which was considered to be the standard of care (SOC) for moderate-to-severe psoriasis when ustekinumab was launched.

The “Drivers of Improvement” graphic below illustrates the comparison:

Adalimumab has an unmet need score in moderate-to-severe psoriasis of 1.73, represented by the yellow bar on the left side of the graphic

• Ustekinumab’s unmet need score in this population is 1.61, the yellow bar on the right side

• Ustekinumab’s Clinical Innovation, or percent reduction in medical need, is 6.6%: Patients treated with ustekinumab have lower unmet need than patients treated with adalimumab

Historically, drugs with 5% or greater Clinical Innovation typically achieve strong patient share.

This graphic also illustrates ustekinumab’s advantages and disadvantages compared with the SOC:

• The two drugs have comparable efficacy, with ustekinumab showing a slight advantage over adalimumab

• Based on currently available data, ustekinumab has an improved safety/tolerability profile over adalimumab, with no black box warning and lower rates of infection

• Ustekinumab is administered as an SC injection once every three months, compared to adalimumab’s twice weekly injections; however, the requirement that ustekinumab be administered in the outpatient setting offsets its frequency advantage

• Ustekinumab’s annual drug cost is slightly higher than adalimumab’s

Our analysis shows that ustekinumab offers significant Clinical Innovation over adalimumab, and its commercial performance to date supports this conclusion.

Outlook for IL-17 receptor antagonists

A new class of drugs may soon enter the competitive landscape in moderate-to-severe psoriasis. Amgen, Eli Lilly, and Novartis all have IL-17 receptor antagonists in phaseIIItrials for this indication. Amgen’s product brodalumab has shown the strongest phase II data among the three. Based on these data and assuming price equivalence with ustekinumab, our analysis shows brodalumab to offer a strong 7.3% Clinical Innovation.

While brodalumab and ustekinumab show a similar percentage of patients responding (90% and 91%, respectively achieving at least a 50% PASI improvement at 12 weeks), almost twice as may brodalumab patients as ustekinumab patients (74% vs. 38%) reach at least 90% PASI improvement. Also, significantly more brodalumab patients have a physician’s global assessment (PGA) of disease as “cleared” or “minimal” (83% vs. 65%). Absent long-term data, we conservatively assume that the percentage of patients maintaining cleared or minimal PGA response at two years will be the same as that seen with ustekinumab.

Our analysis shows brodalumab to have a slight safety/tolerability disadvantage compared with ustekinumab; we assume it will have a black box warning due to a rate of severe bacterial infections comparable to adalimumab’s.

Brodalumab dosing is by SC injection every other week, which our framework considers slightly less convenient than an outpatient injection once every three months.

In our view, the Clinical Innovation of brodalumab over ustekinumab is similar to that shown by ustekinumab over adalimumab. If phase III trials of brodalumab replicate the efficacy and safety/tolerability data seen in phase II, we predict that brodalumab will achieve substantial patient share in the moderate-to-severe psoriasis market.

Pristiq: no innovation in major depressive disorder

Conclusion: Pristiq offers no net clinical improvement versus the standard of care — its modest efficacy improvement is offset by its comparable disadvantage in safety/tolerability. This lack of improvement explains its disappointing sales, relative to pre-launch forecasts.

In 2006 senior executives at Wyeth announced that Pristiq (desvenlafaxine) had the potential to exceed $2 billion in peak sales. This forecast included projections for both major depressive disorder (MDD) and vasomotor symptoms (VMS) associated with menopause, an indication for which the drug did not receive approval in the US or EU. In 2012, its fifth year on the market, desvenlafaxine’s global revenue was $630 million, far short of the blockbuster forecast publicized prior to launch. We estimate its patient share in the same year at less than 5% of patients with MDD.

Our Clinical Innovation analysis shows desvenlafaxine to be a “me-too” product, compared with escitalopram (Lexapro) the standard of care (SOC) at the time of launch in 2008.

The “Drivers of Improvement” graphic below illustrates the comparison:

Escitalopram, the yellow bar on the left side of the graphic, and desvenlafaxine, the yellow bar on the right side of the graphic, both have unmet need scores of 2.05

• Desvenlafaxine’s Clinical Innovation, or percent reduction in medical need, is therefore 0%: Patients treated with desvenlafaxine have the same unmet need as patients treated with escitalopram

Small differences exist in the two drugs: desvenlafaxine has slightly higher efficacy, slightly worse side effects, and slightly higher cost. For some individual patients, the differences between these drugs will be significant. In aggregate, however, desvenlafaxine does not offer Clinical Innovation over escitalopram, and its commercial performance supports this conclusion.

Given our analysis of lowClinical Innovation for desvenlafaxine, and upon learning that the primary research was reporting a much more favorable commercial outlook, we would have urged the team to reexamine the framing of the trade-offs between the agent’s efficacy and side effects. A second possible source of error is the conversion of the preference share reported by physicians into the predicted patient share — especially in a market as crowded as the depression market.

Benlysta in SLE: A cautionary tale

Conclusion: Benlysta’s modest efficacy benefit is overwhelmed by its disadvantages in dosing and price, which explains why sales are well below pre-launch expectations.

Shortly before the approval of Benlysta (belimumab), Equinox Group evaluated the Systemic Lupis Ertheymatosus (SLE) market for a client company. Wall Street analysts and industry observers expected substantial commercial success for Benlysta, predicting revenue for the year 2020 from $700 million to $1.7 billion. Part of this enthusiasm was driven by the fact that belimumab is the first new drug approved for SLE in more than 50 years.

Our interviews with KOLs found widely divergent views regarding the appeal of belimumab; half of the interviewed KOLs were enthusiastic about it, and half were not. Our Clinical Innovation analysis at that time (based only on publicly available – and thus incomplete – data about the clinical attributes for belimumab) implied the antibody was not clinically innovative.

The “Drivers of Improvement” graphic below, which is based on complete published clinical results for belimumab, illustrates the comparison:

Plaquenil + azathioprine, representing the current standard of care (SOC), has a total unmet need score in SLE of 2.34, the yellow bar on the left side of the graphic

• Belimumab is used in combination with the current SOC. The combination regimen has an unmet need score of 2.67, the yellow bar on the right side of the graphic

• Adding belimumab to the SOC results in negative Clinical Innovation of 13.9%, compared with plaquenil + azathioprine alone

Our analysis quantifies the advantages and disadvantages of adding belimumab to the SOC:

• Adding belimumab to the SOC results in a moderate improvement in efficacy

• The increase in the safety/side effect burden is relatively modest

• The inconvenience of belimumab’s IV infusion and its very high price overwhelm the modest efficacy gain

The FDA approved belimumab for SLE in March 2011. Wall Street’s billion-dollar expectations have not been met: in 2012 belimumab achieved $106 million in total sales, and for the first half of 2013 one brokerage firm has estimated $105 million. Because the net clinical improvement of belimumab is substantially negative, we think its peak-year sales in this indication are unlikely to exceed $300 million/year.

WHEN PRIMARY RESEARCH AND CLINICAL INNOVATION ANALYSIS POINT IN OPPOSITE DIRECTIONS

We do not know what GSK’s expectations were for belimumab in SLE. If, however, GSK conducted market research that supported the kind of revenue forecasts that outside analysts published at the time of belimumab’s launch, it would not be the first time a drug missed sales expectations set by pre-launch primary research. Given the results of our Clinical Innovation analysis, and upon learning the primary research supported a positive commercial outlook, we would have recommended conducting a careful review of the following aspects of that market research:

• Was the magnitude of the efficacy and safety/side effects trade-off properly captured?

• Was the IV dosing properly framed?

• Was belimumab’s high price accurately reflected in the research with physicians and payers?

• How was preference share converted to patient share?