My name's Kevin Meli, from the biotech team here, and it's our pleasure today to have Dean Schorno, CFO of Rigel Pharmaceuticals. Dean, take it away.
Great. Thank you, Kevin. Thank you, RBC, for having us at your conference this year and for all of you for your interest in Rigel. Really excited to tell this story today. I'll be making some forward-looking statements, so I'd encourage you to look at our rigel.com site. You'll find our SEC filings. You'll also find our complete corporate deck. I'm gonna move through the business fairly quickly today. You can also find a link to our conference call last week, where we announced the in-license of VEPPANU. Really important big news for the business. Also remind you as I talk through today that this transaction's still subject to HSR clearance.
As we get started, Rigel's transformational growth strategy, there's really four pillars to our strategy, and it's been a key to the success of our business and the future growth of our business. We've got growing the commercial business. We've got expanding our portfolio through in-licensing and business development, advancing our development pipeline, and maintaining financial discipline. This all works together, so it's hand in hand to lead us to what we think will be transformational growth in the future. Important news just this last week in the top two. In-licensing, we in-licensed VEPPANU, vepdegestrant, which I'll describe to you all, which we think will have meaningful contribution to growing our commercial business. As we look at the transformational growth strategy over time, in 2020 we were a one-product company.
We had a limited development pipeline, and we were, you know, in a negative cash position. Accelerate through 2025, we're a three-product company. We have a really important R289 program in lower-risk MDS I'll describe, opportunities to expand that beyond lower-risk MDS, we've been profitable since Q3 of 2024. Really important milestones. As we look into the future, we're very excited about the 2030s and beyond of growing four commercial products when we add VEPPANU, the potential for additional in-license opportunities, as well as transformational opportunities with R289 in lower-risk MDS and other potential indications. As you look at the impact of this strategy, we've had 32%-35% compound annual growth rate over the last five years.
You see this large increase in revenues into the future. That'll be driven by, you know, continued growth in our existing commercial platform, the VEPPANU addition, as well as these the potential IRAK 1/4 program opportunities. Touching on growing our commercial business, our existing products, TAVALISSE, GAVRETO, and REZLIDHIA. TAVALISSE indicated in adult chronic ITP, GAVRETO in RET fusion-positive non-small cell lung cancer and thyroid cancer, a solid tumor, REZLIDHIA in relapse refractory IDH1 positive AML. A great suite of products, we'll be adding to that with the VEPPANU transaction. From a commercial performance perspective, year-over-year growth from $43 million up to $55 million. TAVALISSE at 31%, GAVRETO at 7%, and REZLIDHIA at 31% year-over-year growth.
We're continuing to see that base business perform, and meaningful revenue numbers to support the other objectives that we'll talk about today. From an ex-U.S. perspective, we've also got a great group of partners for TAVALISSE, where product is available through Grifols in Europe, in Japan, with Kissei and Medison in Canada and Israel. Our partners, Knight, we have approvals in both Brazil and Mexico and looking to make product available there. We've expanded our relationships for REZLIDHIA, with both Kissei and Dr. Reddy's, and they're working on making those products available in various geographies. An important part of our business, generating, you know, meaningful revenues and something that we can continue to expand upon.
Touching on in-licensing and business development, really the second pillar, what we've been trying to do, and we started, our first in-license was in 2022. What we're looking for are differentiated assets in hematology and oncology. We're looking for late-stage programs, you know, programs that, you know, up to and including approved products, and synergistic to our in-house capabilities. We have 40 field sales representatives calling on community doctors. We have about eight, we call them IBMs, institutional business managers, who are calling on the academic centers. We're looking for products that are synergistic with this footprint we have. Back in 2022, we in-licensed REZLIDHIA the global rights. We followed that up in 2024 with GAVRETO and the acquisition of the U.S. rights in GAVRETO.
Just last week we announced the licensing agreement for the global rights to VEPPANU. It's FDA approved for second and third line, ER+/ HER2 -, ESR1 mutated metastatic breast cancer. Big market opportunity for Rigel and extremely excited about the opportunity. Really shows that, you know, our path towards this transformational strategy and our execution towards that strategy. A brief overview of the VEPPANU transaction. Extremely excited about the opportunity, and here's some of the reasons why we're so excited. It's the first and only FDA-approved PROTAC. It's a new class of targeted treatment for these patients. It's a differentiated mechanism. Novel and unique mechanism of action, important new therapy.
Our success in launching TAVALISSE and then REZLIDHIA and then and moving GAVRETO forward, we'll certainly leverage that and we're very excited to have VEPPANU in our product portfolio. This could become our largest revenue producer, even larger than TAVALISSE. It's an important add to our business. The economics of the transaction, a brief overview. Upon closing, again, this is subject to HSR, Arvinas and Pfizer will receive $70 million in an upfront. They'll receive $15 million in the near term for certain transition activities, and then up to $320 million of additional milestones consisting of $60 million of regulatory, $260 million of commercial milestones. The royalty structure is a tiered royalty in the mid-teens to mid-20s.
Pfizer and Arvinas remain responsible for the clinical trials. There's a variety of ongoing clinical trials. Rigel will contribute up to $40 million over the next four years in support of those studies. Great economics for our business and it fits nicely into our structure. From a mechanism of action and differentiation perspective, again, first and only FDA-approved PROTAC, and the proteolysis targeting chimera is different from the SERDs, and I'll describe this on the next slide. The mechanism of targeting, tagging, and degrading the ER, the target protein, is unique.
And one of the unique features is that once the PROTAC has done this target tag degrade process, it gets released to go on and, and do that process, you know, again and again. It's a, it's a differentiated mechanism and a new mechanism for this for these, for these patients. As we look at the PROTAC degraders versus the SERDs, it's, it's differentiated. The SERDs bind to the estrogen receptor, they destabilize it, and they make it prone to degradation, and that's in contrast to the PROTACs that target the estrogen receptor, they mark it for selective destruction, and then that PROTAC is released and it can continue to, you know, target more, more ER. A SERD is a one-to-one relationship and the PROTAC is a one-to-many relationship. Addressing the significant unmet medical needs.
Metastatic breast cancer, there's 170,000 people, mostly women, in the U.S. who have metastatic breast cancer. The ER+/ HER2- population's about 70% of those patients. The standard of care is endocrine therapy, plus a CDK4/6 inhibitor, and about up to 50% of these patients due to that endocrine therapy exposure will develop an ESR1 mutation. That creates an addressable population of about 20,000 patients in the second and third line. Meaningful group of patients with, you know, continued medical need that we think, you know, this PROTAC will nicely meet. This is another representation of that, the market I just described, the 170,000 patients going down to 20,000 patients.
We think that this is a billion-dollar plus market and could be growing with incremental testing, particularly in the community setting. As we look at the market dynamics, and you see in the blue bars here, you've got second line on the left, you've got third line on the right, you're seeing that there's rapid adoption of the oral SERDs. In the 60%+ you see the adoption's higher in the academic center than the community center. When you look at the third line, you're seeing about 30% adoption of the oral SERDs, which means you're seeing chemotherapy and other treatment, you know, that it's still being utilized.
We think there's great opportunity for VEPPANU, and we think that the sales force that I described is uniquely positioned to address this population and we think we can make a meaningful impact in this market. This product has a potential to become market-leading treatment for the ER+/ HER2-, ESR1-mutated, metastatic breast cancer for a variety of reasons. Proven efficacy, demonstrated tolerability in real world, applicability. From an efficacy perspective, the progression-free survival in the VERITAC-2 study was a 2.4-fold increase over fulvestrant, which was 2.1 months, going up to five months.
From a demonstrated tolerability perspective, it's important to note that the incidence of and the severity of GI-related events was low, and that's a differentiating feature from some of the other treatments in this area. There were also very low rates of discontinuation at 3% and dose reduction at 2%. Dr. Hamilton, who was on our call last week, and I encourage you to listen to the call, who is the lead investigator on the VERITAC-2 study, really commented that these differentiating features are important to physicians and patients. Again, encourage you to listen to that call.
From a real-world applicability, the population that's been studied for VEPPANU is very representative of the real-world setting, which is both endocrine therapy. Patients had received both endocrine therapy as well as 100% of them had received the CDK4/6 inhibitors. Our readiness for having product available and launching is strong. We expect to kinda leverage all of our capabilities that we have from our TAVALISSE launch through REZLIDHIA through GAVRETO to make VEPPANU available in the August-September timeframe. We look to have product available, we look to launch, you know, in that, in that same timeframe. On the left side, we've got great expertise in the manufacturing and supply, and we can make the product available.
On the right side, our commercial and medical affairs teams are excited, ready, and experienced across the teams I've described, including our MSLs. There's broad experience in oncology. Important that we'll be able to leverage those folks in a significant way. Then from a patient access and distribution network, we've got a, you know, a trusted group of distribution partners and a team that can really, you know, make this available to patients in a meaningful way. Moving on to our development pipeline, the third pillar. Two key areas. On the right side, REZLIDHIA, the IDH1 inhibitor, olutasidenib.
We've got a variety of strategic collaborations where we're studying olutasidenib in with MD Anderson, there's five studies in both monotherapy and combination therapy across a variety of disease states from AML, MDS, CCUS, CMML, and MPN. We have a study ongoing in high-grade glioma with the CONNECT organization, and we're working with MyeloMATCH to establish a combination therapy AML and MDS study. So continued data in with respect to olutasidenib. There's also incremental work we're doing in, you know, the post-ven setting and seeing the results, which is important in that indication.
From an R289 perspective, I'll describe in a little bit of detail our phase I-B study, which is ongoing, and we've got opportunities, you know, as we move, you know, past lower-risk MDS with this asset into other opportunities. Brief overview of the landscape of lower-risk MDS, the population we're studying. In the first-line, a typical first-line treatment is an ESA followed by, you know, post-ESA or ESA and eligible patients will get luspatercept or imetelstat typically. These are therapies that work 38%-40% of the time. Following that, you know, hypomethylating agents are available. They work 18%-20% of the time.
As we think about this population, and these are large markets, these are billion-dollar type of markets, there's certainly, you know, area for improvement with 38%, 40%. There's 60% of patients who aren't responding in these later stage, these later lines. Huge opportunity for Rigel, and that's the population we're studying. What's the value proposition? Why are we excited about the opportunity? Large unmet medical need. You know, 12,200 patients who've been previously treated. There is a novel mechanism of action. The mechanism of action of R289 is really targeting the dysregulated inflammatory signaling that's happening in the bone marrow.
We have a clinical proof of concept that we did where we had an LPS-induced cytokine release challenge, and we saw marked reduction in those cytokines with the introduction of R289. We have Fast Track designation, Orphan Drug designation, and I'll describe the promising, you know, safety and efficacy that we've seen that was reported at ASH last December. Briefly on the study, we've completed the dose escalation phase of the study. Typically six patients in each of those dose, you know, escalation phases. We're in the process of enrolling, and it's going well. The dose expansion phase where we'll look to up to 20 incremental patients in the 500 mg QD and BID.
Once we select the dose, we'll then in this dark blue box, we'll look to do an open-label exploratory cohort in frontline post-ESA, treatment-naive, lower risk MDS. This is ongoing and excited to share the data later in the year on this. Brief overview of the data that was again presented at ASH last year, and I encourage you to look at our corporate site where you'll see the complete set of slides. What you see here is this was an elderly, heavily pretreated population with a high baseline transfusion burden. What we saw was R289 was generally well-tolerated. Importantly, there was a low incidence of Grade 3/4 cytopenias and infections, and this is important to those patients.
Six of 18 evaluable transfusion-dependent patients receiving 500 mg once a day or above achieved red blood cell transfusion independence of over eight weeks. That's the key measure that is studied. Really great results for this again, this elderly, heavily pre-treated population. We'll look to see, you know, the results of that dose expansion phase again later this year. Median duration 5.5 months and median time to onset 1.9 months. Very encouraging for us at this point.
From a development next steps, what's ahead of us, and this is in the near term now, is we'll complete the enrollment of dose expansion phase, select the recommended phase II dose for future studies, and we'll do that in the back half of this year. We'll share the updated top-line data by the end of the year, and we'll open that exploratory cohort I described. With this data set I'm describing, we'll initiate conversations with the FDA on a registrational path for low risk MDS. Incrementally we're considering other opportunities for the asset, and we look forward to describing that in the future to all of you. From a financial discipline perspective, you're seeing, I've described the year-over-year revenue growth.
You're seeing that revenue growth. We do see in Q1, we do see a and we've seen this over the years, you know, a sequential reduction in our net revenues, followed by, you know, increases in that sequential revenue. You're seeing $55.55 million of net product sales and about $4 million of contract revenues from the businesses I've described. From a financial statement perspective, again, we've been profitable since Q3 of 2024. Have $147 million of cash in the bank as of March 31st. Our financial outlook that we put out on May 5th with our earnings call is $275 million-$290 million and will remain profitable.
That guidance is certainly before the VEPPANU transaction that we announced last week. To wrap things up, the four pillars growing our commercial business, we've got the $58.8 million of Q1 revenues. We'll expect to see, you know, VEPPANU revenue contribution later this year. Excited about the announcement of the VEPPANU in-license and really showing kind of our third successful in-license business development effort. Very excited about that. Advancing the pipeline I've described for R289, we're very close to seeing incremental data. And again, incremental data in up to 20 incremental patients, which we believe will be meaningful.
From a financial discipline perspective, we'll look to, you know, upon closing, really leverage the entirety of the organization, the commercial, the medical affairs, you know, our patient access programs, as well as just our overall structure to bring VEPPANU in, and we expect, as we've seen with the other products we've brought in, to see great synergy and leverage in our business. With that, thank you again for your interest in Rigel. We're always available for questions, so please reach out to us if we can ever be of any help. Thank you again.