Xolair for food allergies: effective therapy at a high price

Food allergies affect 5-10% of the American population. Their prevalence continues to increase, with significant quality-of-life impairments for patients and their families[1]. It is a unique indication in that patients are not chronically ill, but acute illness can occur within minutes even with proper precautions. Death is extremely rare[2].  For decades, the space has seen little in the way of treatment, with the cornerstone of management being strict allergen avoidance. Oral immunotherapy is an option to desensitize patients to their allergens, but it is burdensome and carries risk of allergic reactions and high discontinuation rates[3]. Xolair (omalizumab, anti-IgE antibody, Genentech/Novartis) offers high clinical benefit, safely increasing the amount of allergen that patients can tolerate without experiencing symptoms of severe allergic reactions that can occur through accidental exposure.

Xolair is incredibly efficacious in this indication, with modest safety/tolerability and convenience drawbacks. Even though it comes with a black box warning for anaphylaxis, safety is a minor concern in practice- it boasts a mild side effect profile and its safety is well established, as it has been on the market for more than 20 years in other indications.

Xolair also confers benefit in common comorbid allergic conditions, such as rhinitis, asthma, and eczema. Xolair comes as a metered-dose autoinjector or prefilled syringe that can be administered at home approximately every other week or every four weeks, depending on baseline IgE levels and body weight, and must be administered indefinitely for continued benefit. Typically, drugs with clinical innovation of 5% or more go on to achieve reasonably strong patient share. Xolair in this indication has very high clinical benefits, but at a steep price of around $100,000 a year. We anticipate strong interest from patients and physicians, but strong push-back from payers.

Xolair will likely become a candidate for biosimilar development when it goes off patent within the next few years, which will likely mitigate the high price and expand access in this poorly served indication. 

[1] https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/20220126.htm

[2] Umasunthar et al. 2013

[3] Mori et al. 2021

Monoclonal antibodies for Alzheimer’s disease: questionable clinical benefit at a high price

With novel treatments for Alzheimer’s disease dominating the headlines, the most recent being donanemab with the FDA requesting an independent advisory committee to review its safety and efficacy[1], questions remain about their clinical benefit. As the number of patients with Alzheimer’s disease in the US is projected to grow in the coming years, so does the need for a paradigm-changing treatment. However, our model finds that the new monoclonal antibodies offer little clinical innovation over the old standard of care, donepezil. Leaving aside price, their disadvantages in safety/tolerability and dosing outweigh their modest efficacy gains.  

Despite remaining on the market, unlike its ill-fated predecessor Aduhelm, Leqembi shows negative clinical innovation over donepezil of -10.0% in our framework. This is little better than Aduhelm, which shows -11.0% clinical innovation vs. donepezil. As shown above, much of the negative clinical innovation is driven by convenience. Leqembi is given as a one-hour IV infusion every two weeks, compared with donepezil’s once-a-day pill. While Leqembi offers an efficacy benefit measured by standard measures of cognitive decline in AD, this pales in comparison to the inconvenience of the regimen, combined with high cost, high prevalence of potentially serious side effects and a black box warning for amyloid-related imaging abnormalities (ARIA). Questions also remain about how clinically meaningful the improved efficacy is: it is unclear how much patients and their families can appreciate a slowing in cognitive decline of about 6 months for the fraction of patients that experience it.[2]

Even though little separates Leqembi from Aduhelm in our framework, Leqembi has managed to achieve modest sales – around $10.1 million in 2023, still well below the original Eisai projections of $28 million for the year.[3] This is despite the fact that the Institute for Clinical and Economic Review (ICER) deemed its current annual WAC price of around $26,000 to offer low long-term value for money, suggesting a more appropriate price is around $10,000 annually.[4]

In spite of these equivocal results, in-class Eli Lilly drug donanemab was originally expected to be approved this year, with some analysts projecting blockbuster sales of more than $1 billion by 2025.[5] However, our model suggests donanemab will offer slightly lower clinical innovation than Leqembi or Aduhelm, owing to a poorer safety/adverse event profile and higher rates of ARIA.

Leqembi is currently trialing in subcutaneous form, as is donanemab.  More convenient dosing would improve the outlook for these agents, but they will still face the headwinds of modest efficacy and significant safety concerns, as well as burdensome monitoring/imaging requirements. With all these considerations, it is difficult to believe that Eisai will hit its revenue target of $8.8 billion by 2032.[6]

[1] Edited to note 3/8/24 New York Times article

[2] https://memory.ucsf.edu/lecanemab

[3] https://www.biopharmadive.com/news/eisai-leqembi-alzheimers-target-revenue-earnings/706668/, https://www.pharmalive.com/eisai-sees-dramatic-increase-in-leqembi-uptake-following-full-fda-approval/, https://www.reuters.com/business/healthcare-pharmaceuticals/eisai-expects-alzheimers-drug-rake-revenue-665-mln-by-march-2023-11-07/

[4] https://icer.org/wp-content/uploads/2023/04/ICER_Alzheimers-Disease_Final-Report_For-Publication_04172023.pdf

[5] https://www.investors.com/news/technology/eli-lilly-stock-why-version-alzheimers-treatment-could-become-a-blockbuster-in-2025/

[6] https://www.fiercepharma.com/pharma/eisai-dials-sales-ambitions-alzheimers-med-leqembi-amid-launch-growing-pains

Evrysdi: A Potential Game-Changer for SMA Type 1 Patients

Spinraza was the first effective treatment option for Spinal Muscular Atrophy (SMA) Type 1.  Zolgensma and Evrysdi are reshaping the market because of their superior efficacy.

SMA Type 1 is a rare, debilitating genetic disorder, affecting about 1 in 10,000 live births, with symptoms beginning before six months of age. Historically, infants born with this disorder could not sit without support.  Most were expected to live two years or less.

The FDA approval of Spinraza (nusinersen, Biogen) in 2016 finally offered hope to families. The ENDEAR trial of Spinraza had such positive results that it was terminated early to give all participants access to Spinraza in an open-label extension (SHINE). Since then, Zolgensma (onasemnogene abeparvovec, Novartis, approved 2019) and Evrysdi (risdiplam, Roche, approved 2020) have emerged as alternative treatment options.

Like Spinraza, Evrysdi is a chronic treatment. However, it offers several benefits over Spinraza. In infantile-onset, symptomatic SMA Type 1 patients less than two years old, Evrysdi has noticeably higher efficacy (event-free survival and motor milestone response). These gains reduce mortality and morbidity. Evrysdi is a daily oral therapy, more convenient than Spinraza’s intrathecal bolus route.

Evrysdi is dosed by kg/bodyweight, with an annual price cap not to exceed that of treating a 44 lb child, complicating any simple cost comparison. However, even at its maximum price, the annual cost of Evrysdi is less than that of maintenance Spinraza.

In the Equinox model, Evrysdi offers 15.1% clinical innovation versus Spinraza. Historically, drugs that have scored >10% clinical innovation have become market dominators, and so far, annual sales of Evrysdi have trended in this direction.

One way that Spinraza has an edge over Evrysdi is its quantity of supporting data, since Evrysdi has not been around as long to establish a track record.

Zolgensma is another promising treatment option for SMA type 1. Unlike Spinraza and Evrysdi, Zolgensma is a single-dose gene therapy. At approximately $2.25 million 2023 USD (WAC, Micromedex), its price tag has been criticized in the past. However, Novartis offers different payment plans, including outcome-based and over-time payment plans, both up to 5 years.

Spinraza and Evrysdi (at maximum dose) overtake that $2.25 million mark after about 5 and 6 years of treatment, respectively. However, this calculation ignores other direct costs (such as hospitalization) and the potential for additional therapies if the initial treatment is insufficient. This added cost is worth considering since recent data shows that 7.5 years after dosing, almost one-third of Zolgensma-treated patients had received follow-up treatment. Unlike Spinraza and Evrysdi, a patient cannot simply switch off of Zolgensma if it does not perform as expected. Discounts, negotiations, and payer willingness to sponsor an expensive one-time therapy like Zolgensma also complicate the picture.

In summary, in a head-to-head comparison against Spinraza, Evrysdi is the clear winner. This sets it up to become a future standard-of-care as data continue to accumulate. Zolgensma is also innovative over Spinraza. However, it will likely continue to face challenges as payers continue to negotiate the best way to finance an expensive one-time treatment where a cost-effective outcome cannot always be guaranteed.

CAR-T Outlook

Chimeric antigen receptor T-cell (CAR-T) therapies promise to transform treatment of many cancers but have been slow to gain wide use. We argue that the CAR-Ts’ high costs ought to be thought of in light of the many years of life they can add over standard therapy. Even amortizing CAR-T costs over two years puts them in a similar cost-benefit zone as many other highly innovative cancer therapies. Pay-for-performance schemes, such as some being used for CAR-Ts in Europe to reduce payer risk, offer another path to more acceptable costs.

Marketed CAR-Ts are indicated only for hematological malignancies, but there are many developmental programs targeting solid tumors. Moreover, efforts are under way to extend the technology beyond the current autologous approach to include allogeneic solutions, which could ease the cost and complexity of treating with CAR-T therapies. 

In this post we analyze the commercial outlook for CAR-Ts, given their unique characteristics, especially:

• dramatic clinical improvement (near-cures in approximately 40% of treated patients) and

• very high prices (typically north of $400,000 to treat a single patient)

We have analyzed several CAR-T therapies through the lens of our Disease Target Assessment (DTA) framework, which provides (1) an objective and comparable basis for quantifying the magnitude of clinical improvement offered by a therapy, and (2) a measure of clinical benefit compared to price – is the benefit/cost ratio similar to other new oncology drugs that have achieved good market access?

Yescarta

Yescarta (axicabtagene ciloleucel) won its first FDA approval in 2017 and can be considered a moderate commercial success. Its clinical innovation, notably its efficacy, puts it in what has historically been breakthrough territory by our measures. In third-line-plus diffuse large B cell lymphoma (3L+ DLBCL), Yescarta boosted median overall survival to 25.8 months from 6.3 months for Rituxan regimens, with similar improvements in progression-free survival and response rates. Importantly, five-year survival with Yescarta was 42.6%--reflecting a fat tail to the survival curve.

Entering these results and other clinical information in our framework puts Yescarta’s clinical innovation over the Rituxan regimen as 21.5%.  This figure is well above the 10% threshold that we observe for new drugs that achieve dominant patient share. Yescarta clearly delivers substantial clinical improvement, on par with other commercially successful new drugs. Yescarta shows nearly identical clinical innovation in the newer 2L+ DLBCL population, suggesting strong share potential in that patient group. 

Benefit vs. Cost

To address the question of how a drug’s price affects its outlook, our techniques measure the ratio of “Clinical Benefit” vs. cost; through empirical observation we have shown there is a clear benefit/cost relationship among oncology drugs that have achieved favorable market access (see figure below). Priced upwards of $400K, Yescarta is much more expensive than Rituxan regimens in DLBCL, which average ~$20K annually. CAR-Ts incur substantial ancillary costs for apheresis, bridging therapy, conditioning therapy, infusion and post-infusion, along with hospitalization, ICU stays, and ER visits. Patients with life-threatening adverse events such as high-grade cytokine release syndrome (CRS) incur higher than average costs. All told, the total direct costs of CAR-T therapy can reach ~$650K in DLBCL. In contrast to more conventional drug therapies, all of that cost is incurred up-front. 

Because costs are front-loaded while the benefits are durable, we believe these costs should be amortized. We consider a two-year horizon reasonable (i.e., cutting first-year costs in half). Using that assumption, Yescarta’s benefit to cost ratio in 3L+ DLBCL is in line with other novel oncology therapies that have achieved good market access. This is also true for Yescarta in the 2L+ DLBCL population).

Other Approved CAR-Ts

BMS’s Breyanzi has similar clinical characteristics to Yescarta’s in both 3L+ and 2L+ DLBCL, and although launched several years after Yescarta, it is seeing reasonably good uptake. Still more recent is Janssen’s Carvykti in 5L+ multiple myeloma; this agent has even more impressive clinical innovation (40%), and also offers a good clinical benefit to price ratio. Given those results, we think Carvykti will be successful as it gains approvals in earlier lines of therapy.

Barriers to Use

Factors aside from clinical benefit and price also affect CAR-T share. CAR-Ts are only available at authorized treatment centers (ATCs). While there are over 110 ATCs in the United States, their uneven geographical distribution poses challenges. The elapsed time between sampling a patient’s T-cells and reinfusing treated cells limits CAR-T use to patients who have enough time to benefit from it. Ancillary costs are high and may face uncertain reimbursement.

Key Questions Affecting the Outlook for a New CAR-T Program

Equinox conducted this analysis to investigate the extent to which our analytical tools can help development teams anticipate the commercial potential for CAR-T (and other regenerative medicine therapies) programs. Our preliminary conclusion is that the same metrics we have applied for years to more traditional oncology therapies seem to provide similar insight even in the special case of cell therapies. Evidence so far confirms that the level of clinical improvement and its relationship to price remain important factors.

Prospects for ulotaront in schizophrenia

Conclusion: Though ulotaront offers an improved safety/tolerability profile over the generic antipsychotic risperidone for patients with schizophrenia, its likely price would consign it to later-line use if approved.

Antipsychotics such as risperidone, olanzapine, and quetiapine provide efficacy for patients with schizophrenia, but come with substantial safety/tolerability baggage. However, Ulotaront (Sunovion), an antipsychotic in phase 3 clinical trials, may reduce unmet need by providing efficacy comparable to current therapies with fewer tolerability issues.

We modeled risperidone as the standard of care, as it gave the lowest unmet need score in our framework. Efficacy values on the Positive and Negative Syndrome Scale (PANSS) in our analysis are from short-term trials, but efficacy may differ in long-term settings and uncontrolled patient populations.

While ulotaront did not reduce PANSS scores as much as risperidone did, it had a lower discontinuation rate, giving it a slight edge over risperidone in efficacy. Ulotaront appears to provide acceptable efficacy with improved tolerability over the commonly used atypical antipsychotics.

However, we expect ulotaront’s cost will limit its share. We projected its annual wholesale acquisition cost (WAC) at about $17,000, equal to that of Lybalvi (olanzapine/samidorphan, Alkermes), a schizophrenia drug with a similar therapeutic profile that entered the US market in late 2021. Generic risperidone’s yearly cost is about $130. The assumed price diminishes ulotaront’s clinical innovation by -6.9%. The result is overall minimal clinical innovation of 1.8%. History shows that new drugs need to hit 5% clinical innovation to have good commercial prospects.

If we compare ulotaront with Lybalvi, ulotaront has 2.7% clinical innovation over Lybalvi, based on a slightly better side effect profile and marginally better efficacy.

We predict that ulotaront will occupy a niche similar to Lybalvi’s. Both drugs have efficacy like the second-generation antipsychotics, a high price penalty, and notably improved safety and tolerability. Generics will remain the top first-line choice owing to price. However, even with low clinical innovation compared to risperidone, we expect ulotaront and Lybalvi will be important for patients who fail or cannot tolerate generic antipsychotics.

Lybalvi’s team is already thinking about competing against generics, expecting that the frequent drug-switching (usually driven by adverse events) seen in schizophrenia will get their drug tested in many patients. Sunovion will likely adopt a similar strategy with ulotaront.

Download PDF of references used for model

Enhertu shows high clinical innovation in second-line metastatic breast cancer

Conclusion: Enhertu achieves impressive clinical innovation versus Kadcyla, the current SOC, in second-line HER2+ metastatic breast cancer, and in the newly defined HER2-low metastatic breast cancer population at second or later lines of therapy versus chemo.

Enhertu (trastuzumab deruxtecan, AstraZeneca) was approved[1] in December 2019 for HER2+ unresectable or metastatic breast cancer patients who have received multiple prior anti-HER2 treatments. In May 2022 the FDA approved Enhertu in second line HER2+ breast cancer, based on results from the DESTINY-Breast03[2] trial, which show impressive efficacy in the second-line setting in HER2+ unresectable or metastatic breast cancer.

In these patients, Enhertu boasts a significant increase in progression-free survival compared to the current standard of care (SOC), trastuzumab emtansine (Kadcyla) (25.1 vs. 9.6 months), and a notable improvement in overall response rate (79.7% vs. 43.6%). Coupled with a hazard ratio for death of 0.55, Enhertu appears poised to take over from Kadcyla in second-line HER2+ metastatic breast cancer.

The waterfall chart above shows that Enhertu’s improvements in efficacy far outweigh its slightly worse side effect profile when compared to Kadcyla. The jump in efficacy, as well as its trickle-down effect on mortality and morbidity, deliver a strong clinical innovation score of 25.9%.  Drugs with clinical innovation above 10% usually dominate their segments; Enhertu’s improvement in this population is similar to Tagrisso’s advantage in second-line EGFR+ NSCLC.

We expect Enhertu to dominate treatment in this setting within two years.

Moreover, the FDA recently granted Enhertu Breakthrough Therapy Designation in patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who received a prior systemic therapy in the metastatic setting or developed disease recurrence within six months of completing adjuvant chemotherapy. HR+ patients should additionally have received or be ineligible for endocrine therapy.

The DESTINY-Breast04[3] trial studied Enhertu versus investigator’s choice chemotherapy (e.g., eribulin) in 2L+ HER2-low metastatic breast cancer. Enhertu offers a significant increase in progression-free survival (9.9 vs. 5.1 months) and median overall survival (23.4 vs. 16.8 months) compared to chemo, and a dramatic improvement in overall response rate (52.3% vs. 16.3%). This trial could portend a paradigm shift in breast cancer classification, targeting the entirety of HER2 expression.

The waterfall chart below shows that Enhertu’s improvements in efficacy in HER2-low patients, and resultant impact on mortality and morbidity, offer strong clinical innovation of 14% compared to chemotherapy.

Enhertu is a transformative advance for HER2-low metastatic breast cancer patients, and should dominate the space in the near future.

[1] https://www.daiichisankyo.com/media/press_release/detail/index_3159.html

[2] Cortes et al. 2022

[3] Modi et al. 2022

Weighing Efficacy vs. Tolerability: Lenvima + Keytruda in Advanced ccRCC

Conclusion: Despite its toxicity, the overwhelming efficacy advantage of the Keytruda + Lenvima regimen in first-line (1L) treatment of advanced clear cell renal cell carcinoma (ccRCC) puts it in a position to lead the market in this indication. Tolerability concerns will limit its share.

Winning an FDA approval in August 2021, the combination of Lenvima (lenvatinib, Merck + Eisai) and Keytruda (pembrolizumab, Merck) is the most recently approved TKI/IO therapy with an NCCN category 1 recommendation for 1L treatment of advanced ccRCC. This is the third TKI/IO combination to secure an FDA approval and category 1 recommendation, with Inlyta (axitinib, Pfizer) + Keytruda being approved in April 2019, and Cabometyx (cabozantinib, Exelixis) + Opdivo (nivolumab, BMS) approved in January 2021. The approvals and category 1 recommendations of these regimens span all risk groups. These regimens have since bumped sunitinib (Sutent by Pfizer, which went generic in August 2021) from a category 1 recommendation to a category 2A recommendation. Our comparison of the category 1 TKI/IO regimens in this indication shows that although the Lenvima + Keytruda regimen may be more toxic than the others, this disadvantage is modest relative to its major improvement in efficacy. Our analysis is based on phase 3 clinical trial data (CLEAR, CheckMate 9ER, and KEYNOTE-426).

Historically, new regimens with clinical innovation over 10% achieve strong patient share. Lenvima + Keytruda shows 13.4% clinical innovation over Inlyta + Keytruda, driven by improved efficacy.

Lenvima + Keytruda should excel commercially in patients who are able to tolerate it. Dose reductions and interruptions will help manage the toxicity of this regimen and expand its usage to patients who may not able to tolerate it otherwise.

For the clinical benefit that Lenvima + Keytruda provides relative to Inlyta + Keytruda, its higher price is reasonable. Because of this, it falls within the “cloud” of drugs that have historically achieved good market access, and we predict that Lenvima + Keytruda will perform well commercially.

As a side note, Cabometyx + Opdivo is likely to capture share in this indication as a more tolerable alternative to Lenvima + Keytruda, with its efficacy improvement driving its 7.1% clinical innovation over Inlyta + Keytruda.

Rybrevant and Exkivity: two highly innovative new therapies to treat EGFR Exon 20 Insertion positive mNSCLC

Conclusion: Two highly innovative new therapies, Rybrevant and Exkivity, were approved by the FDA within four months of each other. We think that Janssen’s Rybrevant is likely to come out on top in this competition.

EGFR- positive NSCLC has several targeted options for treatment such as Tagrisso (osimertinib) and Tarceva (erlotinib). However, EGFR exon 20 insertion positive mNSCLC, for which existing EGFR TKIs are ineffective, is still treated with chemotherapy.  These patients have a poor prognosis and this mutation affects approximately 2% of those diagnosed with NSCLC.

Janssen’s bispecific antibody therapy, Rybrevant (amivantamab- vmjw), was launched May 2021 and Takeda’s oral tyrosine-kinase inhibitor, Exkivity (mobocertinib), was launched September 2021. Both agents are approved for EGFR Exon 20 insertion patients who have progressed on or after platinum-based chemotherapy. We reviewed data from the phase I/II approval trials for these two agents, CHRYSALIS (Rybrevant) and EXCLAIM (Exkivity). These drugs were granted accelerated approval by the FDA based on ORR and response duration.

Both Rybrevant and Exkivity show significant Clinical Innovation over the previous standard of care, docetaxel, with 19.0% and 17.4% improvement respectively. New agents with Clinical Innovation over 10% historically achieve strong patient shares. These drugs have similar efficacy (mOS, mPFS and response rates) and WAC prices. However, they differ notably in safety/tolerability, with Rybrevant having a significant advantage over Exkivity.   Rates of serious diarrhea are high in patients who took Exkivity, and it has two black box warnings for cardiovascular safety - QTc prolongation and torsades de pointes (an abnormal heart rhythm that can lead to sudden cardiac death). Rybrevant is administered as an IV infusion every two weeks, while Exkivity is taken orally once a day.

Rybrevant was approved four months ahead of Exkivity, and is vying for more approvals in all-comers (i.e., beyond the Exon 20 mutation) in 1L EGFR+ mNSCLC vs. Tagrisso with a phase III trial in progress, in addition to phase III trials in 2L EGFR+ mNSCLC. It also has phase II trials in other cancers, including esophageal and gastric.

Exkivity appears to be further behind in earlier phase trials, including a phase I/II trial in solid tumors harboring EGFR or HER2 mutations and phase I studies in renal and hepatic impairment. The Janssen strategy is to compete in the broader EGFR+ NSCLC population, whereas Takeda pursues opportunities in other malignancies and therapeutic areas. 

Prioritizing Indications: An Analytical Framework

Developing drugs with potential across multiple populations requires setting priorities. Equinox helps development teams quantify opportunity and risk by indication, to better inform prioritization decisions.

Clinical Improvement, Population Size, and Medical Need: A New Drug in 8 Indications

This graph shows how important commercial factors compare across candidate indications for a new drug: the sizes of the target populations, the level of unmet medical need in each population, and the improvement the drug would offer over the standard of care (SOC), which drives patient share.

This improvement will vary by indication. We use a rigorous technique to quantify that improvement, which we call “Clinical Innovation”. Validating using real world market performance, we have observed that these general rules hold up remarkably well:

• Drugs with 10% or greater Clinical Innovation typically dominate their segments

• Drugs with 5 to 10% Clinical Innovation achieve good patient shares

• But new drugs with less than 5% Clinical Innovation typically struggle; they impose high risk on the developer

Moreover, we have quantified how Clinical Innovation correlates with a new drug’s market access, pricing potential, and patient share.  We use those correlations to predict commercial outcomes for a drug in each of its target patient segments, providing development teams with a strategic perspective to compare opportunity and risk by indication.

In this example, the agent is highly innovative in 2L CRC (a large population), as well as in 2L TNBC and 1L ALK+ NSCLC.  It also is moderately innovative in 1L and 2L melanoma, and 2L pancreatic cancer.  In 2L prostate cancer, however, the agent’s Clinical Innovation is well below the 5% threshold, suggesting the agent will not be competitive in this population.  In 3L melanoma, it offers modest improvement, but this indication will be required to get to the more lucrative 1L and 2L melanoma populations.

Calculating patient share as a function of Clinical Innovation, we can estimate the revenue outlook for the asset in each target population. Development teams use this output (and others from our process) to inform decisions about development strategy.

Trodelvy: A New Option for Later Lines TNBC

Conclusion: Trodelvy offers moderate clinical innovation in relapsed/refractory triple-negative breast cancer (R/R TNBC), suggesting it will be prescribed to a large share of patients in this population.  We compare the results with other recent launches in breast cancers.   

In April 2020, the FDA granted accelerated approval to Trodelvy (sacituzumab govitecan-hziy, Gilead) in patients with metastatic TNBC who have failed two prior lines of therapy. Now, a year later, the FDA has granted full approval to Trodelvy for women with TNBC who have had received two or more systemic therapies, at least one for metastatic disease. Our analysis is based on phase III clinical data (NCT02574455).

TNBC makes up 15-20% of metastatic breast cancer incidence and remains an area of high unmet need. Patients at later lines have historically had few options—all of which offered short time to progression and poor survival rates.

Trodelvy boasts a significant increase in both median progression-free survival (mPFS) and median overall survival (mOS) when compared to physician’s choice chemotherapy. In the phase III ASCENT trial, Trodelvy patients without brain metastasis had an average PFS of 5.6 months, compared to 1.7 months for chemotherapy; mOS almost doubled, going from 6.7 months to 12.1. Trodelvy’s efficacy in patients with brain metastasis was only marginally less impressive. When modeled in Equinox’s framework, these results yield a Clinical Innovation score for Trodelvy of 9.3%, which is moderately differentiated (defined as 5-10% improvement), based on a large set of historical examples.

To put into context Trodelvy’s commercial outlook in R/R TNBC, we can compare it with other breast cancer therapies launched in recent years, regarding:

• Sizes of the populations (bubble size)

• Level of medical need (Y-axis)

• Clinical improvement over the previous standard of care (Equinox Group’s “Clinical Innovation” metric, on the X-axis)

Green bubbles represent drugs with a clinical innovation score greater than 10% (highly innovative drugs)

Yellow bubbles represent drugs with a clinical innovation score of 5-10% (moderately innovative drugs)

Orange bubbles represent drugs with a clinical innovation score of less than 5% (low innovation drugs)

The level of unmet medical need in R/R TNBC treated with chemotherapy is extraordinarily high at 4.22 on Equinox Group’s 0-5 unmet need scoring system.  Need is driven by the excess risk of mortality: 50 times higher than in an age-matched population. 

Our analysis suggests Trodelvy will achieve good patient share in this small population.  Its Clinical Innovation is only slightly lower than that achieved by Perjeta (in combination with trastuzumab + docetaxel) in 1st line HER2+ metastatic breast cancer – a regimen that dominates treatment in its population.

Enhertu in 3rd line HER2+ mBC addresses the second highest level of medical need among the indications here; it offers strong clinical innovation of 26%, suggesting it has strong patient share potential.

Trodelvy’s modest revenue of $72 million in Q1 2021 reflects its initial launches in small patient populations.  In contrast, Ibrance is targeted to a much larger, lower-need population, offers high clinical innovation (15.7%) and has achieved a substantial patient share and sales ($5.4 billion in 2020).  Kisqali’s more modest sales of $687 million in 2020 are explained by its lack of meaningful improvement vs. Ibrance and a launch that was two years later.

Trodelvy is in development in larger populations, including early lines of TNBC, HR+/HER 2- metastatic breast cancer and metastatic non-small-cell lung cancer. Its commercial outlook in those indications, including patient share and pricing potential, will depend on the level of Clinical Innovation it delivers.