Monjuvi: Newest Blockbuster in Relapsed/Refractory DLBCL

Conclusion: Monjuvi achieves an impressive clinical benefit for its substantial efficacy improvements over Polivy (polatuzumab vedotin) + bendamustine + rituximab for adults with R/R DLBCL who have failed one or more prior lines of treatment, but favorable market access may be linked to the availability of generic lenalidomide, which remains a question

Monjuvi (tafasitamab-cxix, MorphoSys and Incyte) was approved in August 2020 in combination with Revlimid (lenalidomide) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. Though the populations enrolled in the Monjuvi and Polivy trials were similar, having received between one to three or more prior lines of therapy, Monjuvi was approved with a differentiated second-line label for R/R DLBCL, while Polivy was approved for third-line.

Monjuvi + lenalidomide boasts a significant increase in progression-free survival compared to Polivy + bendamustine + rituximab (12.1 vs.7.5 months), as well as a notable improvement in overall response rate (55% vs. 42%). While survival data is not yet mature, even the most conservative modeled estimate (22.8 vs. 12.4 months) sees Monjuvi offering significant clinical benefit for R/R DLBCL patients eligible for a second or later line of treatment.

The waterfall chart below shows that Monjuvi offers a significant improvement in efficacy, which produces further benefits in mortality and morbidity, delivering a strong clinical benefit score of 19%.

While offering substantial clinical benefit, this regimen is expensive, exceeding $360,000 annually, assuming Revlimid’s branded price (WAC).  

Analysts expect Monjuvi to be a blockbuster, projecting $1 billion sales at peak. We believe Monjuvi’s commercial success hinges on the availability of cost-effective generic lenalidomide (expected to be rolled out in 2022 on a limited volume basis), in the absence of which payer pushback is a near certainty.

Comparing Opportunity Across Subpopulations: Rozlytrek as a Case Study

Medical need and the opportunity to reduce it can vary widely across patient segments within a tumor type.  Analyzing those differences can help development teams gain meaningful insights into the range of commercial opportunities across segments.   

Roche’s targeted cancer drug Rozlytrek was approved in August 2019 for metastatic non-small-cell lung cancer (NSCLC) patients whose tumors are ROS1-positive. ROS1 rearrangements present in just 1-2% of NSCLC patients, and a little over one third of these patients develop brain metastases. By analyzing the published clinical data in Equinox Group’s modeling framework, we conclude that:

1. The level of medical need in patients with brain metastases is considerably higher than it is in the writ-large ROS1-positive population, and more importantly

2. Rozlytrek’s clinical improvement in ROS1-positive patients with brain metastases is substantial, while among the writ-large population the improvement is modest

Comparing the Level of Medical Need in Two Populations

The chart below compares unmet medical need (as measured in Equinox’s model) for the two populations when treated with Xalkori, which was the standard of care for ROS1-positive patients before the approval of Rozlytrek. Patients with brain metastases have 24% higher medical need than the writ-large population.  As the chart shows, higher need in the brain metastases population is driven by inferior efficacy and worse mortality outcomes.

Comparing Rozlytrek’s Clinical Improvement over Xalkori in Each Population

When we model Rozlytrek against Xalkori in the writ-large ROS1-positive population, we find little difference in efficacy between the two agents. Rozlytrek’s overall clinical innovation (mostly attributable to safety/tolerability) is only 1.3% in this broader group; historically, drugs with less than 5% clinical innovation are seen as undifferentiated.

However, when we restrict the analysis to patients who have brain metastases, Xalkori is less effective and Rozlytrek achieves an impressive clinical innovation score of 12.8% (drugs with clinical innovation above 10% usually dominate their branded segments).  The far greater overall improvement in patients with brain metastases is attributable primarily to over 3 months greater mPFS (we assume mOS changes are proportional, as those data were not mature at publication).

Rozlytrek’s efficacy in cancer that has spread to the brain is an important advantage over Xalkori that is clearly illustrated only when we model the appropriate subset of ROS1-positive NSCLC patients. And while both the writ-large and brain metastases population analyses provide useful information on their own, examining them side-by-side sheds further light on the sources of advantage for the asset in this tumor.

Pfizer Combo Gains an Edge in BRAF+ Melanoma

Conclusion: The Braftovi + Mektovi regimen has bolstered the role of BRAF + MEK inhibitor combinations in BRAF-mutated melanoma.

The Braftovi + Mektovi combination (Pfizer via Array BioPharma) gained approval in 2018 for patients with unresectable or metastatic melanoma with a BRAF mutation. It is the most recent combination of a BRAF and MEK inhibitor to be approved for this indication, following Novartis’s Tafinlar/Mekinist combination and Genentech’s Zelboraf/Cotellic.

The new combination offers moderate clinical benefit over the previous BRAF/MEK inhibitor combinations, showing an incremental benefit in PFS, but a strong survival benefit that underlies the improved mortality score in the Equinox unmet need framework. Although the new combination faces two well-established competitors and was relatively late to the party, its moderate level of clinical innovation (drugs with improvements of 5 – 10% typically compete reasonably well) suggests that it will capture a meaningful share of this market.

The Braftovi + Mektovi also combination appears to be priced appropriately, relative to the incremental clinical benefit it confers over Zelboraf + Cotellic.  The figure below shows that, compared to our exemplar set of oncology drugs that have achieved good market access, it is in the cloud, suggesting the incremental price and benefit are in good balance; early sales reports confirm that the combination is achieving good access.

New Treatments on the Horizon

The pipeline for new melanoma treatments is robust, with many new combinations for both BRAF mutated and wild-type patients, including triplet regimens targeted to BRAF patients.  Whether those triplets offer sufficient clinical benefit to justify their incremental costs remains to be seen.

Current major melanoma players (BMS, Merck, Novartis, and Roche) and other companies are investigating novel agents and combinations targeted to melanoma sub-populations. Analyzing those new agents and combinations through our lens can help development teams anticipate the commercial outlook of their programs under a range of plausible clinical outcomes.

Trikafta: A Major Step Forward for Cystic Fibrosis Patients

Cystic fibrosis (CF) affects more than 30,000 patients in the US. Recent treatments for CF focus on modulating the CFTR gene, with Vertex Pharmaceuticals’ Kalydeco (ivacaftor), Orkambi (lumacaftor/ivacaftor), and Symdeko (tezacaftor/ivacaftor) as the only approved therapies that provide more than symptomatic relief. Those agents, however, either are indicated for small segments of the CF population or offer modest clinical improvements as measured in Equinox Group’s model. 

Enter Vertex’s newest treatment, Trikafta (elexacaftor/tezacaftor/ivacaftor), approved in October 2019, which expands the number of CF patients who can benefit from CFTR modulators and offers significant improvement in clinical outcomes.  Trikafta has a broad label for all CF patients aged 12 years and older with at least one F508del mutation (approximately 85% of CF patients in the US carry a copy of the F508del mutation). Trikafta’s approval allows Vertex to treat both the underserved heterozygous F508del population and the homozygous F508del population, where both Orkambi and Symdeko are options.

Trikafta offers very high clinical innovation in patients with the heterozygous F508del mutation, delivering a 15% improvement over Pulmozyme (dornase alfa, Genentech) — with clear gains in efficacy, mortality, and morbidity:

For these heterozygous patients, Equinox’s Rare Disease Normative Price Calculator finds Trikafta to be reasonably priced at annual US WAC of $311,500, given its level of clinical benefit.

Equinox Group’s research and predictive model for pricing agents targeted to rare diseases has found that three factors drive pricing potential:

• Size of the patient population

• Level of disease seriousness (mortality and morbidity), and

• Clinical improvement as measured in the Equinox unmet need model

Trikafta’s published data in the homozygous population is not sufficient to allow Equinox to accurately characterize the clinical benefit for those patients, so we cannot comment on the appropriateness of its price in that population. 

In Q1 of 2020, Trikafta achieved $900 million in sales.  That substantial and rapid commercial success is attributable both to a much larger target population than Vertex’s older CF treatments and to its very high clinical innovation in the heterozygous F508del group. 

A Reliable Predictor of NICE Recommendation

The United Kingdom’s National Institute for Health and Care Excellence (NICE) began publishing recommendations on cancer drugs in 2000. Nearly three-quarters of these recommendations are positive: either recommended, optimized or recommended for use in the Cancer Drugs Fund (CDF).

We looked at the 31 instances of drugs/indications that Equinox had assessed and that received or could have received NICE appraisals (in two instances, companies declined to seek appraisal). As the table below shows, we find a strong correspondence between Equinox’s evaluation of innovation for an agent in an indication and the result of the NICE appraisal, whether positive (recommended, optimized or recommended for use in the CDF) or negative (not recommended or no appraisal).

Note: “Innovative” means 5% or higher on Equinox Group’s Clinical Innovation metric

As with NICE’s evaluation of cost-effectiveness, Equinox employs a robust method to calculate the magnitude of value delivered, which depends on the clinical benefit a drug offers as well as the seriousness of the disease that it treats. In the figure below, the value delivered for the same 31 instances of drug/indications is color-coded based on NICE recommendation status.

Overall, we see that Equinox’s measures of clinical innovation and of value delivered are compelling predictors of the recommendations NICE will ultimately make.

Brukinsa: Shooting behind the duck in R/R mantle cell lymphoma

Conclusion: Brukinsa will have a hard time differentiating itself as the third BTK inhibitor to reach market in relapsed/refractory mantle cell lymphoma (R/R MCL).

Brukinsa, developed by the Chinese biotech Beigene, is the most recent BTK inhibitor to earn an indication in R/R MCL. Approved in November of 2019, Brukinsa follows Imbruvica and Calquence to market, with those two enjoying a 6- and 2-year head start, respectively.

As shown in the clinical characteristics table above, Brukinsa has a marginally better response rate, but an inferior mPFS when compared to up-and-coming Calquence. Equinox’s Unmet Need framework allows us to numerically compare the net clinical advantage/disadvantages these agents offer in this indication.

The figure below illustrates the level of remaining unmet medical need in R/R MCL with each therapeutic option. As shown, Imbruvica was a truly transformative medicine when it was approved in 2013— 22.6% better than Velcade (historically, 10% or more represents strong differentiation).  Calquence offered a further 8% improvement over Imbruvica as measured in our framework (between 5% and 10% is considered medium improvement).  Brukinsa, however, is 6.1% worse than Calquence.  Keep in mind when viewing the graphic below that lower values represent improvement.

We expect Brukinsa to struggle to differentiate itself from the other two BTK inhibitors that beat it to market in this indication, and we believe its weak initial revenue figures are an early indicator of the trying path to success that lies ahead.

Lynparza: Expanding into Prostate Cancer

Conclusion: Lynparza shows significant clinical benefit in its newest indication, second-line HRR-mutated metastatic castration-resistant prostate cancer.  Even when competing against generically priced Zytiga, Lynparza’s efficacy advantages support its current price.

On April 24th, Lynparza (olaparib, AstraZeneca/Merck) announced positive data in second-line homologous recombination repair gene mutated (HRRm) metastatic castration-resistant prostate cancer (mCRPC). Assuming approval, this is the PARP inhibitor’s sixth indication, joining BRCA-mutated pancreatic, ovarian, and breast cancer.

An FDA approval is expected to follow the data published from the PROfound study, a prospective, multicenter, randomized, open-label, Phase III trial testing Lynparza versus enzalutamide or abiraterone in HRRm patients. The trial was broken out into two cohorts, BRCA- and ATM- mutated patients, and other HRR mutations. Lynparza showed significant clinical efficacy over the control arm in both groups, more than doubling progression-free survival (7.8 vs. 3.6 months in HRRm writ-large).  These improvements come to a high-need population—patients with HRR-mutated prostate cancer are on average younger and have more aggressive disease than non-mutated patients.

The waterfall chart below illustrates how Lynparza compares to Zytiga/Xtandi across the different domains of unmet need in HRRm writ-large. Looking at the chart, it’s clear that Lynparza’s efficacy and reduction of mortality offset its higher cost; in the HRRm population the overall improvement as measured by our Clinical Innovation score of 9.1% suggests a well differentiated agent (at the high end of our medium range). In BRCA/ATM mutated patients, Lynparza performs even better, with an overall improvement of 16.6%, which qualifies as high Clinical Innovation.

We can plot Lynparza’s clinical benefit over Zytiga/Xtandi against its increase in price. Doing so, we see that in both HRRm writ-large (top) and BRCA/ATM mutated (bottom) mCRPC Lynparza falls neatly into the “cloud,” a set of exemplars that have achieved good market access. This is good news for AstraZeneca and Merck— with generic Zytiga now widely available, Lynparza needed to show significant benefit to battle a drug with generic pricing, and it does just that.

Given Lynparza’s significant reduction in overall unmet need in second-line HRRm mCRPC, we expect it to be approved and adopted quickly.

Finding the Right Price for a Drug across Multiple Indications; Learnings from Keytruda

Previously, Equinox has described a hypothetical exercise in which a development team attempts to find an optimal price for an agent that is in development in multiple indications.

Here we repeat this exercise with a real-world example, Keytruda.

Keytruda has been approved for a variety of indications.

These indications differ in the size of the addressable patient population (bubble size), the level of unmet need (y axis) and, most importantly, the degree to which Keytruda delivers benefit to patients (x axis).

Finding the right price-per-vial across diverse indications is challenging. Equinox’s analytical tools allow product teams to quantify the value delivered in each population. When we plot the incremental clinical benefit delivered against incremental cost for successful agents, we see the following “cloud” relationship:

Each point represents a new agent in a specific patient population.

Equinox predicts that emerging agents that map within this cloud will receive favorable reimbursement, but agents that land below the cloud risk significant push-back from payers in those indications. Points above the cloud represent indications where the agent is under-priced.

Compared to these exemplars, Keytruda’s various indications map as follows:

Keytruda’s price appears appropriate for Gastric, Head and Neck, and Lung Cancer. As a consequence, it offers poor value for money in RCC and Endometrial, and leaves money on the table in HCC and Melanoma. Overall, the price point appears optimized.

Equinox’s analytical tools allow product teams to assess the trade-offs inherent in arriving at a price for any agent in development for multiple indications.

Enhertu: A New Leader in Later-Line Breast Cancer

Conclusion: Enhertu achieves an impressive clinical innovation score for its substantial efficacy improvements over the current SOC (trastuzumab + capecitabine) for adults with HER2+ metastatic breast cancer who have failed multiple prior therapies.

Enhertu (trastuzumab deruxtecan, Daiichi-Sankyo and AstraZeneca) was approved in December 2019 for HER2+ unresectable or metastatic breast cancer patients who have received multiple prior anti-HER2 treatments. It boasts a significant increase in progression-free survival compared to the current standard of care (SOC), trastuzumab + capecitabine (16.4 vs. 5.6 months), as well as a notable improvement in overall response rate (60.9% vs. 22.8%). While survival data is not yet mature, even the most conservative of estimates sees Enhertu winning the day for HER2+ patients eligible for a third or later line of treatment.

The waterfall chart below shows that Enhertu’s improvements in efficacy far outweigh its higher cost and slightly worse side effect profile when compared to the current SOC. The jump in efficacy, as well as its trickle-down effect on mortality and morbidity, deliver a strong clinical innovation score of 26%.

We expect Enhertu to dominate treatment in this setting within two years. Analysts’ estimates of peak sales around $2.5 billion are reasonable.

PARP Inhibitors: Promise in New Maintenance Indications

Conclusion: PARP inhibitors Zejula and Lynparza both show significant clinical benefit in new maintenance populations in ovarian and pancreatic cancers, respectively. Fortunately for both assets, their clinical benefit in the new indications supports their current prices.

PARP inhibitors are advancing into more indications after their initial approvals in later-line ovarian and breast cancer.  While the cancers that the PARP inhibitors are pursuing differ significantly in unmet need, our analyses suggest that both Zejula and Lynparza are unlikely to encounter market access friction in their latest indications.

Results were recently published for Zejula (niraparib, GlaxoSmithKline) in the maintenance setting for newly diagnosed stage III and IV ovarian cancer patients who respond to platinum-based chemotherapy. Zejula is still awaiting approval in this indication, but there are no maintenance options for most of these patients, leaving a wide window of opportunity. Lynparza (olaparib, AstraZeneca/Merck) is the only PARP inhibitor currently playing in first-line ovarian maintenance, and only for the 15% of patients who have a BRCA mutation. Should Zejula receive its sought-after label expansion, its new maintenance data includes results for both BRCA-positives and “all comers”. Zejula is already approved in both ovarian cancer patients with refractory disease who have homologous recombination deficiencies (HRDs) and in second-line maintenance.

Fortunately for GSK, adding Zejula as maintenance therapy for first-line ovarian cancer patients (regardless of BRCA mutation) offers a tremendous clinical benefit of 39% in our framework, largely driven by improvements in both efficacy and mortality. The benefit is even greater in HRD patients, in whom Zejula provides a 56% clinical benefit.

Like Zejula, AstraZeneca/Merck’s PARP inhibitor, Lynparza, recently sought out and received approval as maintenance therapy in pancreatic cancer patients with a BRCA mutation. This is Lynparza’s fifth approval and the first approved therapy for maintenance following first-line therapy in pancreatic cancer. While BRCA-mutated pancreatic cancer has a smaller overall population than Lynparza’s other indications (ovarian and breast cancer), the low level of competition makes for an attractive opportunity, especially among BRCA-mutated patients.

Lynparza offers a significant clinical benefit of 16.6% as maintenance in BRCA-mutated pancreatic cancer. While it didn’t show a significant survival benefit, Lynparza nearly doubled time to progression from 3.8 months to 7.4 months in a recent phase 3 trial.

Using our Cost vs. Benefit tool, we can plot both Zejula and Lynparza in their respective indications within a historical data set of new oncology drugs that achieved favorable market access. Incremental cost (inverted) is plotted along the y-axis and clinical benefit along the x-axis, showing a clear relationship between clinical benefit in successful therapies and cost.  We believe that drugs that fall within the resulting cloud are priced appropriately given their clinical benefit.

While Zejula and Lynparza are priced slightly higher than other agents offering similar levels of clinical benefit, they are within range of historical analogs.  We consider them appropriately priced in these indications and expect them to receive favorable market access.

U.S. WAC prices are $372/day for Zejula and $472/day for Lynparza.

While our analysis predicts strong market access for Zejula, the competition for this indication is likely to be fierce. Avastin/Lynparza dual therapy and veliparib monotherapy have both recently released positive results in maintenance clinical trials. Though capturing the market will be no easy feat for GSK, Equinox Group believes Zejula is well positioned to become the market leader. This is largely due to the fact that the PRIMA trial (Zejula maintenance vs placebo) included patients who responded to any chemotherapy regimen, while the trials for Avastin/Lynparza and veliparib maintenance only included patients who received induction with, respectively, Avastin-containing and veliparib-containing regimens, limiting the potential patient populations they can tap into.

Contrastingly, Lynparza faces only one potential competitor, Rubraca (rucaparib, Clovis Oncology). Given the low level of competition and the clinical benefit that Lynparza offers compared to its price, we believe that Lynparza will also achieve considerable market share.

Our analysis incorporated data from the PRIMA, VELIA, PAOLA-1 and POLO trials, as well as prescribing information for Zejula and Lynparza.