Rigel’s Veppanu scores its first nod in HER2-, ER+, ESR1-mutant locally-advanced or metastatic breast cancer, making it the first PROTAC approved
Veppanu (Rigel Pharmaceuticals) was approved by the FDA on May 1, 2026 and targets ESR1-mutations, which often arise following treatment with aromatase inhibitors, a staple in the 1L breast cancer paradigm. Its approval is based on the Phase III VERITAC-2 trial, run by Pfizer and its co-developer Arvinas, who licensed Veppanu to Rigel Pharmaceuticals in a $405 million milestone-based deal that officially closed on June 11, 2026. [1, 2]
Protein degraders are among the most exciting drug classes, with dozens of ongoing clinical development programs in a slew of indications from prostate and breast cancers all the way to Alzheimer’s and Parkinson’s Disease. Rather than merely blocking the active site or downstream signaling of an oncogenic protein like traditional small molecule inhibitors (SMIs), protein degraders cause their destruction. These drugs are effective at overcoming resistance mutations, but offer inferior pharmacokinetics when compared to SMIs.
The first monovalent protein degrader to be introduced in breast cancer was Faslodex (AstraZeneca), which was later followed by other selective estrogen receptor degraders (SERDs). While effective, these drugs bind to the estrogen receptor and are stoichiometric in nature, meaning each drug molecule indirectly leads to the destruction of exactly one estrogen receptor. PROTACS, or “bivalent protein degraders,” on the other hand, are catalytic in nature with each molecule directly causing the destruction of multiple estrogen receptors. This fast-acting and potent approach is expected to transform a variety of landscapes in the coming years.
Despite its mechanistic novelty, Veppanu has its work cut out for it as the PROTAC’s approval comes three years behind that of next-gen SERD Orserdu (Stemline Therapeutics) and one year behind Inluriyo (Eli Lilly and Company). Each next-gen agent displayed strong Clinical Innovation over the first-generation SERD, Faslodex in their respective trials (Figure 1A,B).
Veppanu likewise showcased a dominant performance over Faslodex, with a 0.57 hazard ratio for progression-free survival (p-value = 0.0001), establishing itself as a viable option in the space (Figure 1C). [3]
Figure 1: Drivers of Clinical Innovation for Each Protein Degrader, Each Compared with Its Respective Control Arm
However, when compared head-to-head with Inluriyo, there is little differentiation to speak of aside from slight efficacy gains, which are moderately clawed back due to cost. The result is a Clinical Innovation score of 1.6%, well below the traditional differentiation benchmark of 5%. Unless Veppanu is able to post a better-than-expected median overall survival when the endpoint matures, it will likely only split the branded market with Inluriyo and Orserdu (Figure 2).
Figure 2: Drivers of Clinical Innovation, Veppanu vs. Inluriyo
Notwithstanding, this approval not only marks the beginning of an exciting development in pharmaceuticals, but also brings another treatment option to a historically underserved population.
[1] Pfizer. A Phase 3, Randomized, Open-Label, Multicenter Trial of ARV-471 (PF-07850327) vs Fulvestrant in Participants With Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer Whose Disease Progressed After Prior Endocrine Based Treatment for Advanced Disease (VERITAC-2). ClinicalTrials.gov identifier: NCT05654623. Updated March 18, 2026. Accessed August 18, 2026. https://clinicaltrials.gov/study/NCT05654623
[2] Rigel enters exclusive global licensing agreement for VEPPANU (vepdegestrant), an oral PROTAC, for the treatment of 2L+ ER+/HER2-, ESR1m advanced or metastatic breast cancer. News release. Rigel Pharmaceuticals, Inc.; May 12, 2026. Accessed August 18, 2026. https://www.rigel.com/news-media/press-releases/detail/437/rigel-enters-exclusive-global-licensing-agreement-for
[3] FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. US Food and Drug Administration. May 1, 2026. Accessed August 18, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast
Lipfendra Brings PCSK9i Efficacy with Oral Convenience
Last week, Merck’s PCSK9 inhibitor, Lipfendra (enlicitide), was approved (1) for lowering LDL-C as an adjunct to diet and exercise in adults with hypercholesterolemia. PCSK9 inhibitors are powerful drugs that offer an add-on or monotherapy option for patients who have not reached their LDL-C goals on statins alone or who cannot tolerate statins.
Trials of other drugs, including Repatha (evolocumab, Amgen), have demonstrated that lowering LDL-C with statins or PCSK9 inhibitors can lower risk of major adverse cardiovascular events (MACE) in adults at increased risk for MACE (primary prevention) or who have already had a MACE (secondary prevention).
Lipfendra’s effect on cardiovascular outcomes is still being evaluated in the CORALreef Outcomes trial (2). Using existing data and reasonable assumptions about what future outcomes data may look like, the Equinox model can estimate how Lipfendra may measure up in primary and secondary prevention.
Drivers chart depicting what Equinox believes Lipfendra may look like in the future compared to Repatha for primary prevention of MACE in high-risk patients.
Lipfendra’s main driver of improvement is convenience, as it is the first approved oral PCSK9 inhibitor in a market of injectables. In Repatha’s Phase 3 MACE prevention trials (3, 4) and Lipfendra’s Phase 3 hypercholesterolemia trial (5), these drugs appeared to have a similar net-of-placebo effect on LDL-C reduction and both were well-tolerated. Based on these data, Equinox believes if Lipfendra were to be approved for primary and secondary prevention, it would be based on data demonstrating a similar tolerability and relative risk reduction in MACE as seen with Repatha.
Drivers chart depicting what Equinox believes Lipfendra may look like in the future compared to Repatha for secondary prevention of MACE
Currently, Lipfendra has a substantially lower annual WAC than Repatha, resulting in overall innovation scores of 7.3% and 5.5% in primary and secondary prevention, respectively. We expect that the arrival of biosimilar Repatha will degrade this advantage somewhat, but Lipfendra would remain differentiated and commercially successful in both populations (at 6.1% and 5.0%).
Cogent’s bezuclastinib reduces risk of disease progression or death by 50% in 2L metastatic GIST when combined with standard of care
Following a primary readout of the phase 3 PEAK trial at ASCO in late May, Cogent Biosciences seems poised to receive its first FDA approval with highly-innovative bezuclastinib in 2L GIST (following 1L failure on imatinib) with a PDUFA goal date of November 30, 2026.
Imatinib, which has been off-patent since 2020, remains the standard of care (SOC) in 1L GIST and has brought 5 year survival for advanced GIST patients to 56%. [1] However, once patients reach second line, they are left with treatment options that leave plenty of room for improvement. Unlike the currently approved tyrosine kinase inhibitors (TKIs), bezuclastinib is a highly selective inhibitor of mutant KIT, an oncogene acting as the driver in over 75% of gastrointestinal stromal tumor (GIST) cases. [2] This selectivity, when combined with a multi-kinase inhibitor such as sunitinib, offers improved coverage of post-imatinib resistance mutations.
In the phase 3 PEAK trial, combining bezuclastinib with the 2L SOC sunitinib resulted in a 50% reduction in the risk of disease progression or death, with the median progression-free survival increasing from 9.2 months on sunitinib alone to 16.5 months on the combination regimen. Adding bezuclastinib also delivered a 20 percentage point-improvement in overall response rate. [3]
Although overall survival data are not yet mature, the progression-free survival data are strongly suggestive of an improvement in OS. Using our historical oncology database which explores the relationship between mOS and mPFS across tumor types, Equinox Group estimates the base case mOS to be 45.0 months with the upside case being 51.4 months. These represent a 22% and 32% improvement over sunitinib monotherapy, respectively.
If we assume that Cogent will price bezuclastinib similarly to Sanofi’s KIT TKI Ayvakit (approved in 2020), we can see that despite the substantial cost increase when compared with generic sunitinib, bezuclastinib offers strong Clinical Innovation scores of 6.4% and 9.4% in the base and upside cases.
Figure 1: Drivers of Clinical Innovation - Base Case
Figure 2: Drivers of Clinical Innovation - Upside Case
These percentages represent the reduction in unmet medical need that a drug offers when compared to the standard of care. Historically, a Clinical Innovation score >5% predicts that a drug will be commercially successful, with scores >10% being characteristic of a market dominator. Under this framework, it is clear that bezuclastinib is commercially promising and a noteworthy advancement in the GIST paradigm.
This readout comes at an advantageous time for Cogent. Its closest competitor, Qinlock (ripretinib, Deciphera Pharmaceuticals), which previously failed to differentiate itself against sunitinib in the second-line population, won't deliver its own phase 3 results until the primary readout of the INSIGHT trial in December 2027. [4] Importantly, this trial is exclusively looking at a subset of patients harboring co-occurring KIT exon 11 + 17 and/or 18 mutations, a strategy informed by a retrospective analysis of the previous phase 3 INTRIGUE trial’s failure. [5] Qinlock's fourth-line approval and established manufacturing, along with physician familiarity suggest it could scale quickly in this second line subset if the INSIGHT trial succeeds. Cogent's task is therefore to capitalize on its one to two year lead and entrench bezuclastinib + sunitinib as the broad second-line standard of care before Qinlock enters the space.
[1] BRF14 data demonstrate long-term efficacy of imatinib in advanced GIST. OncLive. August 22, 2025. Accessed July 6, 2026. https://www.onclive.com/view/brf14-data-demonstrate-long-term-efficacy-of-imatinib-in-advanced-gist.
[2] Helbing A, Menon G. Gastrointestinal Stromal Tumors. [Updated 2025 Sep 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554541/
[3] Andrew J. Wagner et al. Primary results of the phase 3 peak study of bezuclastinib + sunitinib vs sunitinib monotherapy in advanced gastrointestinal stromal tumors (GIST). J Clin Oncol 44, 11500-11500(2026).DOI:10.1200/JCO.2026.44.16_suppl.11500
[4] National Library of Medicine (US). ClinicalTrials.gov. Published February 17, 2023. Updated December 2025. Accessed July 6, 2026. https://clinicaltrials.gov/study/NCT05734105
[5] Heinrich MC et al. Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial. Nat Med. 2024 Feb;30(2):498-506. doi: 10.1038/s41591-023-02734-5. Epub 2024 Jan 5. PMID: 38182785; PMCID: PMC10878977.
TROP2 ADCs: A Major Innovation for 1L TNBC
Gilead’s Trodelvy has made a name for itself in breast cancer, but recently Daiichi Sankyo AstraZeneca’s competing TROP2 ADC, Datroway, has beaten Trodelvy to market in 1L TNBC, a patient segment with traditionally no treatment options aside from chemotherapy alone. Approved one month apart from each other, Datroway has the stronger data, but Trodelvy has a broader label and physician experience on its side.
Approval Histories
In April 2020, Immunomedics’ novel TROP2 ADC, Trodelvy (sacituzumab govitecan-hziy), was granted accelerated approval for the treatment of relapsed or refractory triple-negative breast cancer (R/R TNBC), making it the first ADC approved by the FDA for this indication. Gilead went on to acquire Immunomedics and Trodelvy six months after its initial approval. Trodelvy was granted full approval in R/R TNBC in April 2021 and accelerated approval in pre-treated HR+/HER2- metastatic breast cancer in February 2023. Along the way, Gilead picked up and subsequently voluntarily withdrew an accelerated approval for the ADC in metastatic urothelial cancer.
No new TROP2 ADC had been approved since Trodelvy until January 2025, when Daiichi Sankyo and AstraZeneca’s Datroway (datopotamab deruxtecan-dlnk) was approved in pre-treated HR+/HER2- metastatic breast cancer, almost two years after Trodelvy’s approval in this indication. Datroway’s next approval came in June 2025 for pre-treated EGFR-mutated non-small cell lung cancer (NSCLC), an accelerated approval based on response rates from a pooled subgroup analysis of a broader population, beating Trodelvy to launch in lung cancer.
Clinical Data Summary
Now, within just one month of each other, the two TROP2 ADCs have each gained approval in previously-untreated TNBC, a patient population which to date has had chemotherapy as their only option in immunotherapy (IO)-ineligible patients. Datroway was first to be approved in 1L TNBC ineligible for IO, boasting an impressive 43% reduction in disease progression or death (PFS HR 0.57, p<0.0001) and 21% reduction in mortality, statistically significant at the 5% threshold (OS HR 0.79, p 0.0290) [1]. Trodelvy, just one month later, received approval regardless of a patient’s PD-L1 status, a broader population than that of Datroway. Trodelvy’s overall survival data are immature across both of its 1L TNBC populations, but its PFS benefits are still significant. In the PD-L1-negative/IO-ineligible segment, Trodelvy reduced the risk of disease progression or death by 38% (PFS HR 0.62, p<0.001)[2] compared to Datroway’s 43% reduction. For patients with a PD-L1 combined positive score (CPS) ≥ 10, Trodelvy + Merck’s Keytruda (pembrolizumab) boast a PFS HR = 0.65 (p<0.001) when compared to Keytruda + chemotherapy [3].
Equinox Group’s Analysis
Compared to their respective control arms in the IO-ineligible population, Datroway looks highly innovative using Equinox Group’s Disease Target Assessment (DTA) framework, reducing medical need by 10.6%; historically, improvements ≥10% become leaders in their market segments.
Clinical Innovation is displayed graphically in the below waterfall chart, where the unmet need score of the comparator regimen (chemotherapy) is represented on the left and the entrant (Datroway) on the right. Unmet need is scored on a 0-5 scale, with lower scores representing less unmet medical need. The individual green and red bars total to a regimen’s Clinical Innovation score.
Figure 1: Drivers of Clinical Innovation – Datroway in 1L TNBC ineligible for IO
In comparison, Trodelvy’s weaker PFS benefit and immature (and insignificant at this time) OS data produce a less favorable gain, with a net Clinical Innovation score of -0.7%, essentially looking equivalent to chemotherapy.
Figure 2: Drivers of Clinical Innovation – Trodelvy in 1L TNBC ineligible for IO
Compared against each other, Datroway’s Clinical Innovation score is 6.7%, significantly differentiated against Trodelvy.
Figure 3: Drivers of Clinical Innovation – Datroway vs. Trodelvy in 1L TNBC ineligible for IO
Trodelvy’s story is rosier in the PD-L1-positive cohort, delivering a 7.2% reduction in unmet medical need when combined with Keytruda, compared to chemotherapy plus Keytruda—a competitive Clinical Innovation score.
Figure 4: Drivers of Clinical Innovation – Trodelvy in 1L TNBC, PD-L1-positive
Share Prediction
With the innovation scores above and low levels of existing competition, Equinox Group predicts that Datroway could achieve a 56% peak share in the IO-ineligible population and that Trodelvy could achieve a 60% peak share in the PD-L1-positive cohort.
Datroway is currently in clinical development for the treatment of PD-L1-positive 1L TNBC, in combination with AstraZeneca’s in-house PD-L1 inhibitor, Imfinzi (atezolizumab), which to date has no approvals in breast cancer (this trial, TROPION-Breast05 is expected to read out by mid-2027). Both Datroway and Trodelvy are trialing in pre-metastatic TNBC, as well, with Datroway’s trial expecting to read out mid- 2027 and Trodelvy’s by the end of 2028.
What remains for this field is the promise of yet another TROP2 ADC, Merck’s sacituzumab tirumotecan (sac-TMT). In its phase 2 OptiTROP-Breast05 trial, Sac-TMT demonstrated improved response rates over its in-class competitors across the PD-L1 spectrum.
[1] Dent et al. 2026 (TROPION-Breast02)
TP53, the most altered gene in oncology
With the evolution of RAS inhibition, ambitions are high and drug developers are looking for the next big target. TP53 is a noble contender, as it is the most altered gene across solid tumors with no approved targeted therapies and little progress made thus far. The RAS pathway spent four decades on the same “undruggable” list as TP53. Now, KRAS G12C inhibitors have been on the market for five years and pan-RAS and allele-specific agents are in development that, together, could address ~90% of pancreatic cancers, representing a major paradigm shift.
Below are cancers with the top 10 percent prevalences of TP53 alteration.
Lifyorli Approved in Platinum-Resistant Ovarian Cancer Thanks to a 35% Reduction in Mortality
Lifyorli (relacorilant, Corcept Therapeutics) received its first approval on March 25th based on the results from the phase 3 ROSELLA trial, which looked at the Corcept agent as an add-on to nab-paclitaxel in platinum-resistant ovarian cancer (PROC) patients who have received prior bevacizumab. [1] These patients have limited treatment options and a mortality rate in the first year of platinum-resistant disease that is 16 times higher than that of their age-matched peers. Recent FDA approvals have emerged in subsets of PROC patients with actionable biomarkers, but little options remain for patients without them. As a result, these patients will typically receive non-platinum chemotherapy, such as paclitaxel, pegylated liposomal doxorubicin, or topotecan. [1]
When added onto nab-paclitaxel, Lifyorli offered over 4 additional months of survival compared with nab-paclitaxel alone. (16.0 vs 11.9, HR = 0.65) [1] This substantial benefit helps to meaningfully address the most substantial unmet need of this disease. However, the regimen did not offer the same magnitude of improvement in progression-free survival and overall response, only scoring one additional month of PFS (6.5 vs 5.5) and not achieving a statistically significant difference in the secondary endpoint of overall response rate (36.9% ORR vs 30.1%, p=0.17). [2] Together, these attributes make up an interesting efficacy profile, as an OS improvement more than 4x the PFS improvement of a given regimen is highly uncommon.
When taking into account the modest drawback of increased side effects, Lifyorli achieves a solid 5.8% clinical innovation when compared to nab-paclitaxel. While this is not a blockbuster score, it is no doubt a meaningful efficacy improvement that will make this drug competitive.
Figure 1: Drivers of Clinical Benefit
Oveporexton Could be a Game-changer for Narcolepsy Type 1
Narcolepsy is a rare neurological disorder that affects an estimated 200,000 Americans [1], and about half of those people have narcolepsy type 1 (NT1) [2]. While both NT1 and NT2 cause sleep attacks and excessive daytime sleepiness, NT1 also causes cataplexy: episodes of sudden muscle weakness often triggered by intense emotions. Not only does NT1 severely impact quality of life, but it can also be dangerous when cataplexy episodes or sleep attacks occur during activities such as driving or operating machinery [3].
In February 2026, the FDA accepted the NDA for oveporexton, Takeda’s investigational agent, and granted it Priority Review. Instead of simply managing symptoms, oveporexton is a potentially first-in-class OX2R-selective agonist that targets the orexin deficiency that causes NT1 [4].
Oveporexton yields an exceptional clinical innovation score of 20.4% over standard-of-care Xywav when it is priced at a modest premium. Based on currently available data, we view oveporexton as a more efficacious and convenient option, and, if launched at this price point, expect it will take a commanding lead of the NT1 market.
The Problem with Primary Market Research
Pharmaceutical companies spend millions on primary market research (PMR) every year — and often walk away with the wrong answer. PMR plays a genuine role in the R&D process: interviews with physicians provide insight into treatment paradigms, patient types and “journeys,” and reasonable expectations for the future of a disease. Equinox Group routinely conducts such interviews to inform our modeling efforts. This type of research has been a staple in the industry for decades, making it something people at all levels of organizations understand and can use to extract actionable insights. So, what’s the problem?
Too often, PMR is asked to be something it is not: a replacement for rigorous techniques that can quantify the advantage of a particular drug over another and communicate how that advantage actually translates to patient share potential. Below, we examine the specific instances where PMR comes up short and explain the approaches we take at Equinox Group to overcome these deficiencies.
1. Primary market research is not dynamic
Given that PMR consists of semi-quantitative interviews, much of the content of these interviews is only applicable so long as important details such as the treatment paradigm, current clinical data, and competitive pipeline remain unchanged. For example, if new post-approval data that come out show a drug to be a much greater improvement over the standard of care than previously thought, such as in the case of Kisqali in HER2-, HR+ 1st line breast cancer, any PMR done involving the current treatment paradigm and efficacy in this population prior to the new data being read out would immediately become outdated and of little use to development teams. So, if a company wants new insights into the potential of their drug in the market, they have no choice but to commit more time and money to additional PMR.
At Equinox Group, we handle this problem by creating dynamic, data-driven models that can instantly deliver new outputs with a few clicks of a button. Any clinical data, launch date, competitor, or price of an agent can be updated in our models as soon as that new information is available, resulting in a new patient share prediction for your agent.
Consider the Kisqali example. At launch, Kisqali showed a mere 0.5% improvement over Ibrance — barely enough to move the needle — and initial sales reflected that.
Figure 1: Kisqali at launch
However, years later Ibrance was found to have disappointing survival data, proving it to have been far less efficacious than previously thought. A slight improvement in efficacy for Kisqali was also shown over this period. As a result, Kisqali actually proved to be far superior to Ibrance and that was reflected in the patient share that it ended up receiving.
Figure 2: Kisqali update
In our model, this shift was captured instantaneously by updating a handful of numbers — a process that took seconds, not months at no additional cost.
2. Primary market research is not unbiased empirical data
As noted above, PMR is effective in obtaining insights from physicians regarding a variety of topics. However, these insights remain opinions — capable of being influenced by personal biases — and do not reach the level of objectivity of empirical clinical evidence. This is especially true in longer interviews, where respondents become fatigued and the quality of their answers deteriorates. Framing effects compound this problem: the way an interview is structured can meaningfully shift the responses given. While exercises such as conjoint analysis can yield a rough estimate of how one additional month of mPFS or a cleaner side effect profile affects commercial success, this method is not optimal.
As a core principle, the qualitative should only be used to predict the qualitative, while the quantitative should predict the quantitative. Results from PMR can suggest whether a drug will obtain “significant” share and dominate the market, but they cannot reliably pinpoint what that share would be.
By looking at historical drug launches and quantifying the effect of the clinical innovation of a drug on its patient share potential, we have a way of discovering the impact of these factors on commercial outcomes strictly based on peer-reviewed clinical data without the need for any guesswork or opinion.
3. Preference share ≠ patient share
While the outcomes of conjoint analyses are not without their uses, at times they are misinterpreted. Perhaps the most important of these outcomes is preference share – an estimate of the percent of physician’s that would choose a given TPP among the profiles of all relevant drugs in the market. Assuming that the interviews are conducted in a way that minimizes bias, the insights gained regarding the relative strengths of TPPs are actually of great value. However, they cannot be used as a proxy for patient share. This is in large part due to the fact that these interviews are incapable of capturing the intricate market dynamics that contribute to a drug’s share. Furthermore, the TPPs that are being assessed lack the necessary detail and often do not consider important factors such as order of entry or price. Therefore, just because we can obtain an estimate for what percent of prescribers favor TPP A over TPP B, it does not necessarily mean that we can know what share either of these agents will obtain. It is also important to note that the subjects of these interviews are, at times, not a nationally representative sample of prescribers.
We avoid these issues by deriving our patient share projections from a consistent, analytical framework that weights clinical innovation (which includes price), order of entry, and competitive environment according to the results of our extensive work with historical drug launches.
4. Primary market research is expensive and labor intensive
Finally, PMR projects often take months and impose large costs upon biopharmaceutical companies. As mentioned above, these costs may compound as new information makes additional research necessary.
In comparison, Equinox Group’s models can be completed in as little as 6 weeks and include two years of after-sales service from the project start date. Because our models are driven by published clinical data rather than primary fieldwork, they can be updated in real time by the client as new information becomes available — without incurring additional research costs every time the market shifts.
If you’d like to see more about this framework, we’d be glad to walk you through a live example. Feel free to schedule a meeting.
Since 1995, Equinox Group has provided analytics to support R&D decisions at biopharmaceutical firms, assessing the potential of drugs from discovery to launch, and anywhere in between. Equinox Group specializes in predicting the commercial performance of drug programs in all stages of research and development, delivering quantitative insights regarding:
Disease Area Strategy
Business Development Decisions
Market Access
Patient Share Forecasting
Epidemiology and Patient Flow
Gene Therapies for Sickle Cell Disease: Expensive but Worth It
Sickle cell disease affects roughly 100,000 Americans and is more common among African American and non-Hispanic Black people [1]. About 20,000 suffer from recurrent vaso-occlusive crises (VOCs), making them ideal candidates for the novel gene therapies Casgevy (exagamglogene autotemcel, Vertex) and Lyfgenia (lovotibeglogene autotemcel, bluebird bio, rebranded as Genetix Biotherapeutics) [2]. Priced at $2.2 million and $3.1 million, respectively, these drugs are highly innovative and – we conclude – worth the high price tags if payers can figure out how to foot the bill.
Approved in December 2023, Casgevy is a CRISPR/CAS9-based therapy, the first of its kind. Its administration procedure is similar to that of a stem cell transplant and it is incredibly efficacious, with 93% of patients in the clinical trial remaining VOC-free 12 months after treatment [3]. Casgevy also boasts an approval in transfusion-dependent beta-thalassemia, a rare blood disorder that affects only 1,300-1,500 people in the US [4]. Lyfgenia is similarly efficacious and works via a lentiviral vector to insert a functional copy of the beta globin gene to increase the production of normal hemoglobin.
Both therapies demonstrate high clinical innovation when compared to the standard of care, hydroxyrurea, with a direct cost amortized over three years. Amortization is based off clinical data demonstrating that patients who achieve VOC-free status over 12 months remain VOC-free for approximately 3 years [5, 6]. This assessment may change as more long-term data becomes available. With the life expectancy of sickle cell disease patients being far shorter than for those without the disease, these therapies have the potential to substantially close that gap, with a University of Washington study finding a benefit of approximately 17 years of increased life expectancy from the gene therapies [7]. Our model captures a dramatic 85% reduction in mortality to align with this. These therapies are even more impressive when considering the high unmet need of sickle cell disease, in addition to the societal and indirect cost savings they may bring.
However, the issue of paying for these high-priced therapies looms large. An analysis conducted by the Institute for Clinical and Economic Review (ICER) in 2023 concluded that they are cost-effective at a price range of $1.5-$2 million [8]. At $2.2 million, Casgevy is pushing that limit, and at $3.1 million, Lyfgenia is well out of the range. With these steep price tags, it will be a challenge for payers to figure out how to pay for them, especially considering that a large percentage of the patient population is underserved and on Medicaid [9]. Currently, CMS has proposed an outcomes-based pricing scheme (CGT access model) that individual states can opt into. Only patients enrolled in Medicaid could benefit from the model, which began in early 2025.
This model has the potential to reduce the cost for states to bear, as CMS is the central negotiator for all states and will be providing federal funding for the treatment. States can choose which gene therapies to cover [10]. Based on our analysis, we believe that covering Casgevy is more reasonable than Lyfgenia, but having more options could be beneficial for patients, even with Lyfgenia’s black box warning for hematologic malignancy that demands long-term monitoring indefinitely [11]. Manufacturers will be encouraged to provide rebates and reimburse accordingly in cases where clinical performance falls short. The initiative will also be collecting data over eleven years, with an outcomes-based agreement term of one to six performance years, which will provide further insight into navigating these expensive gene therapies [12]. The model does not include private insurance plans for those not enrolled in Medicaid. Patients on private insurance plans may face additional requirements for treatment, such as meeting a specific threshold of number of VOCs per year, and a baseline level of decent health.
Gene therapies have limits; they are not foolproof cures. Not all cells can uptake the edits, there may be off-target gene editing effects, they are not effective for every patient, and immune system responses may limit efficacy and compromise health [13]. The treatment journey is also time-consuming, with the Casgevy website stating that it can take up to one year [14]. Since long-term data are not currently available, we must learn as we go, but it is clear that Casgevy and Lyfgenia are an important milestone in the cell and gene therapy space.
Keytruda Grabs its 42nd Approval in PD-L1+ PROC
Keytruda (pembrolizumab, Merck) received its 42nd approval from the FDA this Tuesday, February 10th based on the results from the phase 3 KEYNOTE-B96 trial, which looked at the blockbuster PD-1 inhibitor as an add-on to paclitaxel with or without bevacizumab in PD-L1+ platinum-resistant ovarian cancer (PROC). [1] This subset of ovarian cancer patients has developed resistance to standard platinum-based regimens. As a result, they receive non-platinum chemotherapy, such as paclitaxel, pegylated liposomal doxorubicin, or topotecan.
When compared to paclitaxel +/- bevacizumab, the Keytruda regimen showed improvements in survival, progression, and response while maintaining a comparable safety and convenience profile. Importantly, the mortality benefit is what stole the show: an impressive 30% increase in mOS over paclitaxel +/- bevacizumab (19.2 months vs. 14.0 months). [2]
Taking into account the cost impact of adding on Keytruda, the Clinical Innovation is clawed back slightly to a respectable 5.0% overall (Figure 1). Although Keytruda has seen higher levels of innovation elsewhere, such as its many NSCLC indications, a score of 5% typically suggests market differentiation and shows promise for Keytruda's use in this space.
This Clinical Innovation exhibited by Keytruda will increase in the coming years, as Keytruda is scheduled to lose exclusivity in 2028, which will slightly ease the cost burden.
[1] U.S. Food and Drug Administration. FDA approves pembrolizumab with paclitaxel for platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. February 10, 2026. Accessed February 12, 2026.
[2] Cortese T. Pembrolizumab combo significantly improves PFS/OS in recurrent PROC. CancerNetwork. October 18, 2025. Accessed February 12, 2026.