Hemlibra: A Strong Leader in Hemophilia A

Conclusion: The clear leader for hemophilia A patients with factor VIII (FVIII) inhibitors, Hemlibra (emicizumab, Roche) also brings competitive heft to the larger, more crowded, space of hemophilia A without inhibitors. Combining improved efficacy and convenience, Hemlibra offers significant clinical innovation over the current standard of care (SOC), Advate (Shire).

First approved in November 2017, Hemlibra is well positioned within the hemophilia A market. For patients with inhibitors, it wins in a landslide when compared to bypassing agents such as recombinant activated factor VII (NovoSeven®, Novo Nordisk). Among this small group, Hemlibra substantially reduces cost and administration frequency in addition to improving efficacy.

But how does Hemlibra look in the much larger (and more brand-loyal) population of patients without inhibitors, an indication Hemlibra won in October 2018?

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Compared to Advate, the current SOC among patients without inhibitors, Hemlibra shows meaningful improvements in efficacy, tolerability, and convenience, leading to an 8.7% reduction in unmet medical need, as seen in the waterfall chart. While Advate requires at least three IV bolus administrations a week, Hemlibra can be given as a weekly subcutaneous injection with better outcomes in annualized bleeding rate and in the proportion of patients experiencing zero bleeds per year. 

So far, Hemlibra sales have backed analysts’ high expectations. Hemlibra brought in $224 million in 2018 revenue and looks to claim an even larger market share in hemophilia A patients, both with and without FVIII inhibitors, moving forward.

Our analysis combined clinical trial data from both Hemlibra and Advate prescribing information labels as well as the HAVEN 3 study.



Oral semaglutide: A game changer in type 2 diabetes

Conclusion: Oral semaglutide’s clinical improvement over Januvia (sitagliptin, Merck) is 17 percent – a historically high level of innovation. In type 2 diabetes, nearly every new entrant over the last 20 years has offered an improvement in the low single digits or less. 

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At this writing, oral semaglutide (from Novo Nordisk) is expected to win approval by the end of 2019. Our analysis compares it to Januvia (with metformin in the background).  The waterfall chart shows that oral semaglutide reduces unmet medical need in type2 diabetes by over 17 percent, compared to Januvia. 

Efficacy drives oral semaglutide’s improvement, reflecting superior glycemic control and reduction in CV events. The efficacy advantages ripple through to mortality and morbidity, conferring still more clinical benefit.  Oral semaglutide has a modest disadvantage in safety/tolerability and slightly higher cost relative to Januvia (we assume the oral form will cost the same annually as the subcutaneous Ozempic).  The net benefit is impressive and will be diminished only marginally when generic sitagliptin reaches market.

The clinical data used in this analysis for Januvia comes from its package insert, and for oral semaglutide, most of the information comes from its phase 3 clinical trials: PIONEER 1, PIONEER 2 and PIONEER 3

Tymlos: A new force in the osteoporosis market

Conclusion: In postmenopausal osteoporosis patients at high risk of fracture, Tymlos offers improved efficacy at a much lower price than Forteo. We expect Tymlos to slowly but significantly cut into Forteo’s share.

Tymlos to Overtake Forteo in PTH-treated Market Segment

Direct competitors, Tymlos (abaloparatide, Radius) and Forteo (teriparatide, Lilly) are both anabolic agents, delivered subcutaneously, and indicated for postmenopausal women at high risk of fracture.* In a study comparing both agents to placebo (ACTIVE trial), Tymlos outperformed Forteo on almost every endpoint, including percent reduction in patients with vertebral and non-vertebral fractures and increased bone mineral density at various bone sites. At less than half the price of Forteo (WAC = $17,000 versus $40,000 /yr), Tymlos is well-positioned to cut deeply into Forteo’s market share. Since osteoporosis patients are unlikely to switch medications, we expect Tymlos will rely on capturing newly diagnosed patients. So far, Tymlos has been successful in this approach: Radius claims that Tymlos captured 40% of new anabolic patient starts in December 2018. The impact Tymlos will have on Forteo’s market share is already emerging. After years of constant growth, Forteo’s revenue decreased steadily throughout 2018.

Evolution of the Osteoporosis Market

The osteoporosis market continues to become stratified into lines of therapy. Payers will likely require all newly diagnosed patients (except those with very high fracture risk) to try a generic bisphosphonate first. Next, a patient will likely be directed towards Prolia (denosumab, Amgen) due to its moderate efficacy, better convenience, and lower cost compared with the anabolic agents (Prolia costs $2,400 per year and is administered subcutaneously every 6 months). Patients failing Prolia would then try Tymlos or Forteo.

 

On the Horizon

Amgen and UCB’s drug Evenity (romosozumab) will soon win approval and will directly compete with Tymlos and Forteo in the high-risk population. Evenity looks inferior to Tymlos in our model because its advantages in side effects and convenience don’t make up for its poorer efficacy. However, with its efficacy on par with Forteo and with better convenience, Evenity should further erode Forteo’s patient share and challenge Tymlos if priced similarly.

*Advanced age, frailty, glucocorticoid use, very low T scores, and increased fall risk are indicators of higher fracture risk in osteoporosis patients.

Xeljanz: Is ulcerative colitis finally the place for JAKs to shine?

When the first JAK (janus kinase) inhibitor, Xeljanz (tofacitinib, Pfizer), was approved for rheumatoid arthritis (RA) in 2012, many thought it would quickly eat up a large piece of the market.  Sales since then, however, have been disappointing.  Some believe this has to do with its initial failure to get approved in Europe, while others believe that there were lingering safety issues that were not recognized in the label. Regardless, sales have continued to climb.

Six months ago, Xeljanz hit the ulcerative colitis (UC) scene –the first JAK to do so. Compared to the current standard of care, Entyvio (vedolizumab, Takeda), Xeljanz shows significant improvement in ­­­both efficacy and convenience, demonstrating that having an oral route of administration could be a game-changer in the world of ulcerative colitis.

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Now that Xeljanz has an EMA approval in RA (as of March 2017) and more long-term safety data has been released, we expect it to quickly eat up a corner of the UC market. With four other JAKs in late development, this class could pose a serious threat to anyone else hoping to compete in ulcerative colitis. 

Imbruvica: Closing the window of opportunity in CLL

Conclusion: Imbruvica (ibrutinib) delivers profound improvements in efficacy and outcomes in first-line chronic lymphocytic leukemia (CLL); as a result it virtually eliminates the opportunity for developmental agents to offer significant Clinical Innovation in this indication.

The key data supporting the March 2016 label expansion granted to Imbruvica (ibrutinib) for the first-line treatment of chronic lymphocytic leukemia (CLL) are dramatic: 98% progression-free survival at 18 months and 90% survival at 24 months (RESONATE-2 trial). Regardless of the standard of care to which we compare Imbruvica, it represents dramatic innovation, changing a feared malignancy into a mostly manageable chronic disease, much as Gleevec (imatinib) did in chronic myelogenous leukemia (CML) more than a decade ago. The waterfall chart compares Imbruvica to chlorambucil, reflecting RESONATE-2 data.

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The implications for companies developing drugs targeted at CLL are profound:

  • It will be virtually impossible to deliver significant Clinical Innovation beyond what Imbruvica appears to offer; the only remaining significant unmet need targets are safety/tolerability and cost (see schema figure below).

  • It will become difficult to recruit first-line patients for clinical trials when as attractive a treatment option as Imbruvica is available, and the trial duration needed to show equivalence to Imbruvica begins to look onerous in relation to the opportunity.

  • At the same time, relapsed/refractory CLL becomes a much less attractive commercial target. By pushing out progression from first line for years, Imbruvica will radically reduce the number of treatable patients available at second and third lines during the next 5-10 years.

  • With CLL joining CML, hepatitis C viral infection, and multiple myeloma as serious diseases that can now be more or less cured with drugs, price will become a more important factor in product selection. Agents no better clinically than Imbruvica in CLL or Harvoni in HCV will need to accept lower prices, whether directly or through contracting, to capture much market share.

Since Imbruvica has reduced unmet medical need so dramatically, companies with competing drugs targeting CLL in Phase II or earlier must rethink their development strategies, redirecting resources to other cancer targets.

This figure shows the domains of medical need in first line CLL. The gold bars reflect how well ibrutinib satisfies need in each domain. The grey area above the gold bar shows the extent of opportunity for improvement for developmental agents. We derive ibrutinib’s values by transforming clinical data to dimensionless index scores between 0 (no need―e.g., perfect efficacy) and 5 (no satisfaction of need―e.g., no efficacy). The transformation functions are consistent across indications, and domain analyses are built up from detailed sub-analyses.    The interpretation for ibrutinib in CLL is that little opportunity remains for improving efficacy, convenience, mortality, or morbidity. The only remaining opportunity for meaningful improvement is in safety/tolerability. The high level of need in the cost domain is driven by high drug cost (which is warranted, given the magnitude of clinical benefit).

This figure shows the domains of medical need in first line CLL. The gold bars reflect how well ibrutinib satisfies need in each domain. The grey area above the gold bar shows the extent of opportunity for improvement for developmental agents. We derive ibrutinib’s values by transforming clinical data to dimensionless index scores between 0 (no need―e.g., perfect efficacy) and 5 (no satisfaction of need―e.g., no efficacy). The transformation functions are consistent across indications, and domain analyses are built up from detailed sub-analyses.

The interpretation for ibrutinib in CLL is that little opportunity remains for improving efficacy, convenience, mortality, or morbidity. The only remaining opportunity for meaningful improvement is in safety/tolerability. The high level of need in the cost domain is driven by high drug cost (which is warranted, given the magnitude of clinical benefit).

Keytruda: Exceptional early results in a small colorectal cancer population

Conclusion: Keytruda (pembrolizumab) is highly efficacious in a subset of colorectal cancer patients that are heavily pretreated, have metastatic disease, and have mismatch repair deficiency. Despite a very high price for a course of therapy, the clinical results overwhelmingly favor pembrolizumab’s use over best supportive care in this subpopulation.

Results were recently published of Keytruda (pembrolizumab) in metastatic colorectal cancer patients who had been treated with a median of four prior therapies. In such a sick and heavily pretreated patient population, it would not be expected that any therapy would make a significant difference, and for most colorectal cancer patients that is the case. However, for a low single-digit percentage of them who are mismatch repair-deficient, pembrolizumab is highly effective. Limited Phase II data show a clinically significant overall response rate, along with exceptionally promising trends in progression-free survival and overall survival. Despite a steep $350,000 pre-discount price for a 20-week course of therapy, the percent reduction in unmet medical need is a highly innovative 35%.

We project that Keytruda will extend median overall survival by 1 to 2 years as opposed to the handful of months to be expected with best supportive care. Survival data in the mismatch repair-proficient population were not nearly as impressive, with clinical performance probably not sufficient to offset the price. We expect pembrolizumab will achieve a label in mismatch repair-deficient colorectal cancer, and will become the standard of care. Furthermore, we expect pembrolizumab will eventually be used in earlier lines of therapy, and testing for mismatch repair deficiency will become far more common.

Blincyto: High price for an undifferentiated drug

Conclusion: Amgen’s Blincyto (blinatumomab) shows minimal efficacy and tolerability gains over older multi-drug induction regimens, yet it is priced at around $200,000 for a full course of treatment. If the company succeeds in expanding the drug’s label, it is likely to face pressure to lower the price significantly unless it can show considerably more clinical improvement in those expanded patient populations.

In December 2014, the FDA approved Blincyto (blinatumomab) for 2nd line treatment of a rare form of acute lymphoblastic leukemia (ALL). The addressable patient population is so small that Blincyto usually wouldn’t have drawn much attention, but it has been in the headlines due to its steep price. The drug is priced in line with other ultra-orphan drugs. But Blincyto doesn’t deliver the step-change in efficacy that other six-figure drugs have brought to the table. Before Blincyto’s approval, induction was carried out using various multi-drug regimens. Some are better than others, but none had become a universal therapeutic choice.

Blincyto does have an efficacy advantage over all of the multi-drug regimens, but it is incremental in most cases. Blincyto also has a slight side effect advantage, and it is likely more convenient for the infusion centers to dose (patients might not notice much of a difference). For all these advantages, Blincyto’s improvement in Clinical Innovation, or percent reduction in unmet medical need, is more than offset by its huge price, which is roughly an order of magnitude more than that of the multi-drug regimens. Blincyto is currently being trialed in larger ALL patient populations, as well as the largest subset of non-Hodgkin’s lymphoma patients. We expect there will be much more pressure on the drug price if Blincyto is able to gain a label in a larger patient population.

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

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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).

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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.

PD-1 Inhibitors: Strong starts in three indications

PD-1 inhibitors are the newest class of immunotherapy drugs approved for cancer.  They have a unique mechanism of action and debuted in the market for melanoma amid great promise.  Like Avastin (bevacizumab) before them, PD-1 inhibitors have labels in multiple cancers and are in late-stage trials in many more.  The data for Keytruda (pembrolizumab) and Opdivo (nivolumab) in both melanoma and non-small cell lung cancer (NSCLC) clearly demonstrate that PD-1 inhibitors represent a major advance in cancer therapy.    Equinox Group will monitor this area and update our analyses as more clinical data becomes available. Below we focus on Opdivo in several tumor types.

Opdivo in non-small cell lung cancer (NSCLC):

Opdivo has a label for previously treated advanced squamous NSCLC where the standard of care (SOC) has been docetaxel.  Opdivo has superior efficacy compared to docetaxel in all measures: median overall survival, median progression-free survival, overall response rate, as well as a better side effect profile.  Docetaxel’s generic pricing is approximately $3,000 for a 2nd line NSCLC course of therapy, whereas Opdivo has a branded price of approximately $46,000 for a course of therapy in the same indication. Based on historical comparison, Equinox Group concludes that Opdivo’s clinical performance in this population is worth the price premium.  Opdivo will replace docetaxel as the SOC, and should achieve good patient share in NSCLC.

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Opdivo in malignant melanoma:

Opdivo was approved as both a monotherapy in later-line melanoma and in combination with Yervoy (ipilimumab) in 1st line melanoma.  In the 1st line setting, the Opdivo + Yervoy combination has a strong 14.6% Clinical Innovation score (or percent reduction in unmet medical need), over the combination of Mekinist (trametinib) + Tafinlar (dabrafenib); it offers better efficacy, side effects, mortality, and morbidity.  While the Opdivo + Yervoy combination has a disadvantage in dosing and higher drug costs, the superior efficacy of the antibodies is decisive.  We therefore expect the Yervoy + Opdivo combination to become the new SOC.  Complete data on a Zelboraf (vemurafenib) and cobimetanib combination in 1st line melanoma will be reported soon.  When that data becomes publicly available we will update this analysis and post our findings here.

Opdivo in 2nd line renal cell carcinoma (RCC):

Opdivo has not yet been approved in 2nd line RCC, but we anticipate its approval based on its superior efficacy over the current SOC.  Opdivo also has a better side effect profile than Afinitor (everolimus), with its only disadvantages being a less convenient dosing regimen and a slightly higher price.  Upon launch, we predict that Opdivo will become the new SOC, and will achieve strong patient share in this population, given its 8.0% Clinical Innovation score.

Avastin: One molecule in multiple cancers

Overview: Avastin (bevacizumab) was the first anti-angiogenesis oncology drug. When it launched in 2004, it was thought that Avastin had virtually limitless potential to be highly effective in a wide range of cancers.  More than a decade later, we know that Avastin competed well in some indications, but not others.  The level of Clinical Innovation Avastin offers in each of these populations correlates well with the level of commercial success the agent has achieved respectively across indications.

Note: Bubble size reflects size of the patient population

Note: Bubble size reflects size of the patient population

The graphic above compares Avastin in multiple oncology indications for three criteria – level of Clinical Innovation, size of the patient population, and level of unmet medical need.  The X axis shows the level of Clinical Innovation Avastin offers in each population; indications right of 0% have positive Clinical Innovation, and those on the left of 0% have negative Clinical Innovation. For instance, Avastin has strong Clinical Innovation (9.2%) in 1st line colorectal cancer. At the other extreme, in 1st line pancreatic cancer, its Clinical Innovation is negative; Avastin never received a label in this population.

 

The size of the bubble reflects the size of that patient population, and the Y axis reflects the level of medical need (most of these cancer indications have relatively high medical need). Mechanisms with potential in multiple patient segments, such as PD-1 inhibitors, can be assessed in similar ways, given hypotheses for the clinical characteristics of the drug in each of the target populations.  This is useful information to inform the prioritization of indications for development. Below we provide more detail comparing Avastin in two of its labeled indications.

Avastin in colorectal cancer:

In 2004, Avastin was approved in 1st line colorectal cancer as an add-on to the standard of care (SOC) FOLFOX6.

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There is a strong efficacy advantage in combining Avastin with FOLFOX6 in this population. The improvement in median overall survival (mOS) results in mortality gains; these benefits more than offset the increased cost of adding Avastin to the regimen.  The Avastin combination regimen has Clinical Innovation of 9.2% which is good and should therefore become the SOC, which is exactly what occurred.  

 

Avastin in non-small cell lung cancer (NSCLC):

Avastin was approved in 1st line NSCLC in 2006, based on a trial in which it was added to a paclitaxel + carboplatin regimen.  However, our analytical framework shows that the paclitaxel+ carboplatin regimen is inferior to a cisplatin + gemcitabine regiment, and therefore this latter regimen should be considered the SOC.  When we analyze the trial data of gemcitabine + cisplatin with and without Avastin, the Clinical Innovation for the Avastin combination is only 0.4% (“undifferentiated” by our rule of thumb); the efficacy gains are insufficient to offset the increased side effects and drug costs associated with adding Avastin to the gemcitabine combination regimen.  This finding explains why Avastin has had low market penetration in this population. 

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