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Barry Greene

Thanks, Ashley, and thank you, everyone, for joining us this afternoon. 2024 was an important year for Sage, underscored by the early commercial success of ZURZUVAE, the first and only oral treatment approved for adults with postpartum depression or PPD. We enter 2025 with a plan to build on ZURZUVAE's commercial momentum, a recalibrated R&D approach, and a commitment to financial discipline as we focus on enhancing growth for our shareholders.
As we outlined at the JPMorgan conference in January, we're focused on executing against the three core priorities in 2025, which are intended to deliver short-, medium-, and long-term value creation for shareholders and serve unmet needs of patients and families. Our foremost priority is to continue efforts to establish ZURZUVAE as a standard of care for PPD.
The first year of launch exceeded expectations, and we plan to invest in 2025 to fuel top-line revenue growth. In 2024, we were pleased to see more than 6,600 shipments of ZURZUVAE to women with PPD, which we believe reflects the growing demand for a fast-acting treatment for PPD and physician adoption across HCPs who treat PPD.
There are two important dynamics we're starting to see as the launch progresses: a promotionally responsive market and a system-wide paradigm shift. Specifically, we're seeing signs of ZURZUVAE changing practice patterns among OB-GYNs and elevating a national dialogue around maternal mental health. These dynamics have the potential to accelerate growth and further drive urgency among HCPs in treating PPD.
We believe these early successes validate our commercial strategy and provide greater evidence that ZURZUVAE is the key to unlocking blockbuster potential in PPD. Importantly, that means helping many women suffering from this urgent medical condition.
In addition to building on the commercial momentum of ZURZUVAE, we're prioritizing our pipeline to focus on neuropsych and neurodevelopmental disorders. We believe a recalibrated R&D approach can create value over the long term. Laura will provide additional details on SAGE-319 and SAGE-324, as well as our NMDA receptor NAM platform.
Lastly, we're committed to maintaining the strength of our financial position. With the commercial momentum of ZURZUVAE PPD, our R&D approach, and expected cash runway to mid-2027, we believe we are well positioned to focus on our goal of creating value for our shareholders.
Now before I turn the call over to Chris, I want to briefly acknowledge Biogen's unsolicited non-binding proposal to acquire Sage, as well as our Board's decision to initiate a strategic alternative process. As we stated in our press release last month, the Sage Board concluded that the proposal significantly undervalues Sage and is not in the best interests of shareholders. The Board also decided to initiate a strategic review to evaluate a broad range of opportunities to maximize value for shareholders.
As a reminder, we've not set a timetable for the review process, nor is there any assurance that the review process will result in any transaction or other strategic outcome. With this in mind, we will not be talking about this further on this call. I do appreciate your understanding.
And with that, we'll move forward, and I'll now turn the call over to Chris. Chris?

Chris Benecchi

Thanks, Barry. As mentioned, we've made tremendous progress in the first full year of ZURZUVAE's launch in PPD, and I'm excited to discuss our recent achievements and ongoing initiatives. Afterwards, I'll review our results for the fourth quarter and full year 2024.
Starting with the launch of ZURZUVAE, we are pleased to see consistent demand growth quarter over quarter with nearly 2,500 prescriptions shipped to women with PPD in Q4. This represents a 21% increase from the third quarter of 2024, even with far fewer days in the field engaging with customers due to the holiday season.
Across the full year of 2024, more than 6,600 prescriptions of ZURZUVAE were shipped to women with PPD. We believe that we have continued to see strong demand growth in patient shipments because HCPs are becoming confident in the value proposition of ZURZUVAE and what it potentially delivers.
In the fourth quarter, ZURZUVAE was prescribed across a breadth of HCPs who treat PPD, including OB-GYNs, psychiatrists, and PCPs. Almost 80% of those prescriptions came from OB-GYNs, who are the foundational focus of our launch strategy since they see women throughout their peripartum journey, the most critical time to screen, diagnose, and treat.
While OB-GYNs are at the forefront, we believe that over time we will continue to see utilization of ZURZUVAE increase among all HCPs who treat women with this condition. More than 70% of ZURZUVAE patients are receiving ZURZUVAE as their first new treatment for PPD.
Further, we saw strong trends among prescribers in 2024, with about 60% of targeted HCPs writing repeat prescriptions after prescribing ZURZUVAE. We also see that once an OB-GYN has prescribed ZURZUVAE, there is a significant increase in the number of women with PPD they treat based on prescriptions for all medications.
Our messages are resonating. ZURZUVAE has a greater than 90% aided brand awareness among OB-GYNs and psychiatrists. Before I turn to our plans for 2025, I'll provide an update on coverage.
As of today, greater than 95% of commercial and Medicaid lives are covered or have a path to coverage, with the majority having no step edits or complex prior authorizations. This remarkable level of coverage one year into launch reflects payer recognition of the value proposition of ZURZUVAE, which enables broad and equitable access for all women with PPD.
To support the continued scaling of ZURZUVAE, we plan to move forward with a robust investment plan which includes a joint sales force expansion to cover a wider reach of healthcare providers, investment in media opportunities intended to further amplify the message that PPD is an urgent medical condition, and greater visibility via social media designed to increase awareness and educational efforts. We are also planning to expand ZURZUVAE DTC, including the potential for targeted branded TV media later this year. Today's technology allows us to meet women with PPD in their most trusted channels, empowering them to speak to their physician about their PPD symptoms and appropriate treatment options.
In terms of personal promotion, we are already seeing an early impact from the sales force expansion. In the territories where we expanded our sales force in the fourth quarter, we saw a 33% growth rate in patient shipments. We believe these efforts are important as we are seeing PPD to be a promotionally responsive market with significant growth potential.
We have made remarkable progress in 2024 and are continuing to think big about the commercialization of ZURZUVAE as a treatment for women with PPD. We look forward to sharing additional updates in the coming quarters.
Now turning to our financial results for the fourth quarter and full year of 2024. As a reminder, our full financial results for these periods are detailed in our press release issued this afternoon.
We reported collaboration revenue from the sales of ZURZUVAE of $11.4 million in the fourth quarter, a 4% increase compared to the third quarter of 2024 and $36.1 million for the full year. As a reminder, our reported collaboration revenue is 50% of the net revenues Biogen reports for ZURZUVAE.
It is important to note that while revenue may fluctuate based on inventory dynamics, we continue to see strong quarter over quarter demand growth in patient shipments and expect this growth to continue. R&D expenses were $37 million, and SG&A expenses were $54 million in the fourth quarter of 2024.
Additionally, there were one-time restructuring expenses of $22.5 million in the fourth quarter of 2024. While ZURZUVAE joint commercialization investment will increase in 2025, we anticipate overall operating expenses will substantially decrease in 2025 relative to 2024. This reflects reductions in R&D and G&A from our pipeline prioritization and the cost savings from the October 2024 reorganization. The first full-quarter of savings are expected to be realized in Q1 of 2025. Our net loss for the fourth quarter of 2024 was $95.8 million.
Based upon our current operating plan, we anticipate that our existing cash, cash equivalents, and marketable securities of $504 million as of December 31, 2024, together with the anticipated funding from ongoing collaborations and estimated revenues and excluding any potential milestone payments we may receive under our collaboration agreements will support our operations to mid-2027.
Now with that, I'll turn the call over to Laura. Laura?

Laura Gault

Thanks, Chris. As Barry mentioned earlier, we remain focused on developing medicines for neuropsychiatry and neurodevelopmental disorders, where there is a strong scientific rationale and opportunities to address meaningful unmet needs.
I'll begin with SAGE-319. Our wholly owned, extrasynaptic-preferring, GABAA receptor, positive allosteric modulator or PAM, which is designed to have novel pharmacology and a differentiated profile from other GABAA PAMs in our portfolio. SAGE-319 is currently being investigated as a potential treatment for behavioral symptoms associated with certain neurodevelopmental disorders, including autism spectrum disorder, Tourette's syndrome, and other rare neurological disorders. These disorders place a high burden on patients, families, and the healthcare system.
We are currently conducting a Phase 1 multiple ascending dose, or MAD, study to help us better understand the safety, tolerability, and target engagement of SAGE-319 across a range of doses. We expect to share data from the Phase 1 MAD study by late 2025 and anticipate that the upcoming results from this study could enable potential studies in the patient population in early 2026.
Further, we have two orally administered NMDA receptor negative allosteric modulators, or NAMs, in pre-clinical development: SAGE-817 and SAGE-039. Our intention with these drug candidates is to provide a drug with similar or better efficacy than NMDA receptor blockers like ketamine but with a potentially improved safety and tolerability profile. In addition, we continue to explore potential partnerships and out-licensing opportunities for some clinical and pre-clinical stage compounds.
Lastly, as we have previously noted, we are also exploring SAGE-324 for potential indications, including seizures and developmental and epileptic encephalopathies or DEEs. We expect to provide an update on next steps, if any, in mid-2025. To be clear, we are not spending to further develop SAGE-324 now, but rather we are evaluating SAGE-324 as part of an overall portfolio decision.
With that, I will turn it over to Ashley to help facilitate the Q&A portion of today's conference call.

Ashley Kaplowitz

Thanks Laura. As a reminder, we will not be answering questions related to our Board's decision to reject Bijan's unsolicited acquisition proposal or to initiate a review of strategic alternatives and ask that questions be focused on our Q4 and full-year 2024 results.
Please limit yourself to one question. If you have additional questions, feel free to return to the queue. Now, I'll turn the call over to the operator to handle Q&A. Operator?

Question and Answer Session

Operator

Thank you. (Operator Instructions)
Ritu Baral, TD Cowen.

Ritu Baral

Hi, guys. Thanks for taking the question. Barry, I wanted to ask about Biogen buy-in to the expansion of the marketing opportunity or the marketing effort. You mentioned that the sales force expansion is underway. It's in certain geographies.
Can you elaborate on that? Specifically, has Biogen matched the personnel expansion that Sage has implemented or sort of the number and depth of the programs that Sage has put into place?

Barry Greene

Thanks for the question, Ritu. I appreciate it. So based upon the performance we saw in 2024 and as Chris mentioned on the call, the success we saw in our sales force expansion, we entered 2025 with an aligned integrated commercialization plan. That includes not just the increase of sales force to a new level but also appropriate investment behind all the other aspects of our commercialization effort, namely medical affairs, disease state awareness, DTC, including continued progress on the coverage side, which is outstanding, but we want to continue to make better. So we're highly aligned and excited for a very successful 2025 helping as many moms as we can this year.

Ritu Baral

Could we get a little more color on what the expanded efforts are?

Barry Greene

Let me ask Chris if he could provide some color.

Chris Benecchi

Yeah. So beyond the point about sales force expansion, social media and a social media influencer campaign through TikTok and Instagram as well as Facebook are an important part of the social media effort designed to reach not only those that are living with PPD but also HCPs who are treating many of these women with PPD. As Barry noted, connected TV and DTC is an important part of how we think about another way to reach those that are living with PPD that are out in the community, as well as peer-to-peer education, digital efforts more broadly.
And I would round that out by saying that we have seen an interesting dynamic that we talked about in our prepared remarks, where this is not only about the work that we do to make sure that physicians and women with PPD are aware of ZURZUVAE, disease state awareness also plays an important role here in the importance of screening and diagnosis and all of this. So again, that's a key component to our initiatives in 2025 as we think about reaching as many women with PPD as possible.

Operator

Salveen Richter, Goldman Sachs.

Shrunatra Mishra

Hi, thank you for taking my question. This is Shrunatra on for Salveen. Could you please elaborate on the inventory dynamics for the quarter, noting the slight disconnect between the prescription growth and the sales growth? And also, could you speak to the proportion of free drugs being provided in 4Q?

Barry Greene

Yeah, Shrunatra. So we're, as I just talked about, really happy with what we're seeing across the board in terms of 2024 performance, and that is we're seeing an OB-GYN step-up to own the disease, ACOG guidelines being in line. We're seeing a promotional responsive market, and we're seeing accelerants in terms of system-wide change. Media continues to cover ZURZUVAE and PPD at extraordinary high level.
So all the dynamics that set up ZURZUVAE entering blockbuster potential are there. We also were happy that we saw over 20% growth in demand quarter on quarter, and I'll ask Chris to talk about sort of the inventory dynamic. But just to be clear, by demand, demand is when especially pharma after a script has entered ships that prescription to moms. That's the true measure of future revenue, because that's the leading indicator.
But Chris, you want to talk about kind of inventory demand in the supply chain?

Chris Benecchi

Revenue is measured when product moves from our alliance partner into the channel at the wholesaler level. Now when it comes to inventory management, there's inventory that sits at the specialty pharmacies and inventory that sits at the wholesalers, and what we saw over the fourth quarter is that based on channel dynamics, inventory can fluctuate through both what we've seen at specialty pharmacies as well as wholesalers. So as Barry noted, when it comes to truly measuring performance, really looking at demand quarter over quarter is the most important metric that we can look at as we go forward.
Now with respect to the question about free drug, we said that broad and equitable access is paramount for this launch, and we've really worked to ensure that broad and equitable access. Free drug plays a role. Free drug helps those that are not insured or underinsured have access to ZURZUVAE, moms with PPD who need this. And what we saw over the course of the fourth quarter is a reduction in the percentage of free drugs from what we saw in Q3,.
And we would anticipate that based on additional coverage that we would see with respect to commercial and Medicaid plans, that that percentage would decrease over time. Again, very encouraging when it comes back to ensuring that all women with BPD have access to this very important medication.

Operator

Anupam Rama, JPMorgan.

Anupam Rama

Hey, guys. Thanks so much for taking the question. Just thinking a little bit more acutely about the first quarter, given historical sort of quarterly seasonality in one Q in the industry due to payer dynamics, how are you thinking about this relative to how we should be thinking about ZURZUVAE potential headwinds in the first quarter? Thanks so much.

Barry Greene

Yeah. Anupam, thanks for the question. I'll start and see if Chris wants to add color. So we anticipate a continued quarter-on-quarter growth, including the first quarter. And keep in mind that our reimbursement is commercial and Medicaid reimbursement. So we don't see a classic kind of Medicare donor hole first-quarter issue. We should see continued growth on all dimensions in the first quarter.
Chris, anything to add?

Chris Benecchi

What I would add is that we know this is a promotionally responsive market from what we saw over the course of the first full year. And what we saw when we increased the sales force during the fourth quarter of 2024, there were fewer selling days during the month of December, and it's part of November as well due to the holiday season. We don't anticipate that kind of disruption based on holidays during the first quarter. So we're excited about what we have in front of us with respect to our ability to continue the success of ZURZUVAE in Q1.

Operator

Vikram Purohit, Morgan Stanley.

Morgan Gryga

Hi. Thanks for taking our question. I wanted to dig a little bit deeper on the sales force expansion -- and also this is Morgan on the phone for Vikram.
So for this recent sales force expansion, how significant of a sales bump are you anticipating over time and how quickly does the addition of reps to the field result in incrementally higher revenues? And then additionally, how many reps were added through the last round of expansion and how large is the field force currently sitting? Thank you.

Barry Greene

Yeah, Morgan. Thanks for stepping in for Vikram. So I can give you some color on what you're asking, but we're not giving guidance or specifics. So as Chris noted, we increased our sales force in the fourth quarter. So we had them in place for the entire fourth quarter. And in those territories we expanded, we saw 33% increase. So we can't give go-forward guidance, but that's what we saw in the fourth quarter.
We're very confident that the combined sales force extension will continue to be accelerant to our launch, and we'll see quarter-to-quarter demand and revenue growth going forward.

Operator

David Amsellem, Piper Sandler.

Hi, yes, this is Alex on for David. I have one question for you. On the back of the corporate restructure last quarter and the extended cash runway, do you think you're at all constrained in terms of how much commercial support you can put behind ZURZUVAE, particularly relative to the support that Biogen provides for the assets? Thank you.

Barry Greene

Yeah. I don't think we're constrained at all. And as we've talked about from the beginning of ZURZUVAE launch, we thought really big about the opportunity with PPD. Again, we believe that ZURZUVAE has blockbuster potential. Epidemiologically, there's about 0.5 million women a year that have symptoms of PPD, less than half of those are diagnosed, and even less are treated. So the opportunity here is significant.
We're thinking big about the opportunity. We continue to focus and scale with success. We've scaled with success based upon 2024 volts into 2025. And we can continue to do so, where we believe that the dollar spent will result in immediate improvement in demand and revenue. So we don't feel we're constrained at all.

Operator

Paul Matteis, Stifel.

Paul Matteis

Hey. Thanks for taking my question. On the pipeline, Barry, can you just talk a little bit more about how you selected these indications? And I guess, taking a step back, neurodevelopmental disorders is an extremely challenging area for drug development, and you probably picked one of the hardest. DEEs, those are the toughest to treat epilepsies. Why are these the best uses for capital for Sage going forward over other alternatives? Thanks.

Barry Greene

Paul, I'll start, and I'll ask Laura to jump in. So as we've talked about, we took a hard look at really the last decade of development of Sage and decided to focus on neurodevelopment, neuropsych with molecules that have pharmacologic properties that expresses the learnings we have, and I'll let Laura talk about those a little bit more. So we think we've got the right molecules going forward and the right kind of match to the pharmacology of these diseases. But Laura, do you want to talk more about that?

Laura Gault

Yeah. Sure. As we thought about the pharmacology of the molecules in our pipeline, we realized that they would be a good fit for disorders like neurodevelopmental disorders or NDDs and for the DEEs. For the DEEs, in particular, we have a lot of pre-clinical data looking at GABAA PAMs and animal models of seizure disorder, and we've seen efficacy across a number of GABAA PAMs including SAGE-324.
We also know that another GABAA PAM, Ganaxolone, has demonstrated efficacy in one of the DEEs. So there's a strong evidence base there that suggests that we could be successful in moving SAGE-324 for an indication like that.
With regard to the neurodevelopmental disorders, one of the reasons that drug development in this space has been so challenging is that people are trying to treat the core symptoms of the disorder like autism. They're trying to treat the communication difficulties.
The approach that we're taking is different. We're really looking to address the behavioral symptoms associated with these disorders, and we believe based on the biology of GABAA PAMs and how they work that we are likely to have improvements in anxiety and sleep in sensory hypersensitivity and in irritability. And so, we believe strongly that moving SAGE-319 forward for an NDD such as autism is warranted based on the data that we have.

Barry Greene

Yeah, I'd add that -- and we'll share more in the quarters to come, but we're also taking a capital allocation approach where we can get answers relatively quickly versus the way that Sage has developed for the last decade. And Paul, you and I talked about this in January, the NMDA NAMs are an incredibly well-validated target relative to the PAMs. We took a big swing and didn't see the results we wanted.

Paul Matteis

Right. And Barry, when do you think you could get POC for each of these?

Barry Greene

We'll share more in the future. So for SAGE-319, we'll have results from our multiple ascending dose later this year; we said late this year. What that will tell us is, do we have an efficacy profile that looks good but differentiated from the balance PAMs, and more importantly or as importantly, do we see a broader therapeutic index, in other words, less CNS effects? So we'll have that at the end of the year.

Operator

Tazeen Ahmad, Bank of America.

Tazeen Ahmad

Hi, thanks for taking my question. Sorry if you already addressed it in your prepared remarks, but can you just talk a little bit about the dynamics of inventory? What have they been, and how should we be thinking about incorporating that into our estimates for 2025? Thanks.

Barry Greene

Yeah, Tazeem, we did. But let me start. I'll hand it over to Chris. So we believe the most important metric to look at is shipments. That's the true measure of demand. That is when ZURZUVAE exits the specialty pharma and gets into the hands of moms specifically directly to their home. And the fact that we saw over 20% growth quarter to quarter with far less days educating healthcare providers in the field is a very strong sign. The revenue is more a function of inventory management.
Chris, do you want to highlight where that supply chain (multiple speakers) ?

Chris Benecchi

Yeah. I mean inventory is managed, as Barry noted, at the specialty pharmacy level and at the wholesaler level, and I think what we see is that at both of those points, you have organizations trying to manage inventory based on what's happened in the past and their expectation for the future. And there's variability in how they think about assessing channel dynamics in order to make those decisions.
So as you noted, there's fluctuations in how they see inventory, and it's most important instead of looking at inventory and the implications that it has on revenue to really focus in on demand, which is the truest way of assessing the demand for this product, the interest in this product on behalf of physicians and the women that they're trying to treat.

Barry Greene

Right. And we said this before but just for clarity, revenue is a shipment to the wholesaler, and that's when revenue is recorded. It's then pulled through the specialty pharm and then again shipped to mom's house. So that whole supply chain, the inventory dynamic fluctuates there.

Operator

Ami Fadia, Needham.

Ami Fadia

Hi, good evening. Thanks for taking my question. Just with regards to the additional investments that you highlighted, whether it's through DTC and some of the other sort of media and education efforts, can you try and quantify by how much you're increasing that? And with regards to the sales force expansion, is there additional expansion anticipated later this year? And at this point, in terms of investments from Sage and Biogen, is it sort of about equal or if you could sort of share any details on Biogen's role in that, that'll be helpful. Thank you.

Barry Greene

Thanks, Nadia. I'll start and I'll ask Chris to come in. And again, we can give more color than detailed specifics, because we're not giving guidance. What I said is based on the success of 2024, we've entered 2025 with an aligned commercialization plan, which is a 50-50 COCO plan. So for every $1 spent, we're each spending $0.50. We're both expanding sales force, and we're both expanding efforts across all the other dimensions that I highlighted.
Chris, any other color to add?

Chris Benecchi

What I would add is the sales force expansion and the investment in non-personal promotion, we're amidst that. So we're investing in the sales force expansion now and investing in, as I mentioned earlier, things like social media and the influencer campaign and getting ready to kick off DTC, particularly through channels like connected TV, where we can be very precise around our ability to reach certain populations that are actually suffering with PPD using DTC as well as disease state awareness to really not only highlight the importance of medication like ZURZUVAE but the importance of screening and diagnosis and when you have symptoms presenting those symptoms to your clinician, whether it's an OB-GYN, a psychiatrist, or a PCP. So all of those things are coming together right now, and we believe will have impact as we continue to roll those out.

Operator

Brian Abrahams, RBC Capital Markets.

Hi, this is Kevin on for Brian. Thanks for taking our questions. Can you maybe talk a little bit about whether there's certain characteristics for OB-GYNs that currently are not prescribing ZURZUVAE? Does it mostly come down to awareness, or is there some other factor at play, maybe geographical location? Thank you very much.

Barry Greene

Yeah, Kevin. Let me ask Chris to comment on that.

Chris Benecchi

Yeah. So I think as Barry noted, 80% or nearly 80% of our prescribers are OB-GYNs, who are on the forefront of care. These are the clinicians who see women throughout their peripartum journey and who have the best lens on what it is that they need when they express the signs and symptoms of PPD.
What we see is that when we have an opportunity to engage in OB-GYN with the safety and the efficacy profile of ZURZUVAE, and they have the opportunity to try the medication that they respond very positively to that experience with more than 60% of those OB-GYNs becoming multiple prescribers of the medication. So what I think it comes down to is just our ability to really increase our reach and to increase our frequency in order to deliver what is very compelling messaging from a product that is performing in the real world setting much like it did in ROBIN and SKYLARK, our Phase 3 pivotal clinical studies. So very excited about the opportunity, as I noted, about increasing the size of the sales force and the investment in non-personal ultimately, to get to the broader audience of clinicians that we can reach.

Barry Greene

Yeah, Kevin, once an OB-GYN office has been educated and uses ZURZUVAE, we're seeing a significant amount of rewriting and a significant amount of more -- over 300% actually more PPD in that practice area. So we're excited as 2025 unfolds and we see the sales force expansion having an impact.

Operator

Laura Chico, Wedbush Securities.

Hello. This is Dylan on for Laura Chico. Thanks very much for taking our question. Just one on PPD. Do you anticipate any near-term revisions to treatment guidelines in the PPD setting from perhaps ACOG or AAP? I'm wondering how this might accelerator impacts commercial uptake.

Barry Greene

Yeah, Dylan, I'll start. ACOG, we've got phenomenal guidelines. Before ZURZUVAE was approved, there was ACOG guidelines that instructed OB-GYNs and their office to screen, diagnose, and treat with pretty easy-to-use tools that don't require special training. And ZURZUVAE is the drug to specifically mentioned in guidelines.
So I've launched a lot of drugs in my day. It doesn't get any better than having your drug mentioning guidelines before you launch. And ACOG's been a great partner.
In terms of other congresses, we continue to work with others to update guidelines. The fact that ACOG did it so quickly is really helpful, because as we've already talked about, our prime audience here because they're at the beginning of the patient journey are OB-GYNs.

Chris Benecchi

Yeah. Barry, what I would add, I think, as you noted, the ACOG guidelines were in place in and around the time of our approval and launch. There were a number of tailwinds, the ACOG guidelines being one of those tailwinds, the media behind it, the paired ecosystem and how they really have enabled broad and equitable access to this medication. So a lot of things really supporting this launch out of the gate that really augment what we've been able to take advantage of with the ACOG guidelines.

Operator

Douglas Tsao, H.C. Wainwright.

Douglas Tsao

Hi, good afternoon. Thanks for taking the question. Just curious, you've obviously had a lot of success getting the OB-GYNs to prescribe. Are you surprised that you haven't had more penetration with psychs? Thank you.

Barry Greene

Yeah. Doug, thanks for the question. So we're actually -- we're not surprised by the dynamic we're seeing at all. As we talked about, strategically, in any drug launch, you want to focus on the front-end of the patient journey. In this case, that front-end is OB-GYNs, and we're seeing tremendous penetration there and tremendous uptake in OB-GYNs.
As we said, once an OB-GYN is educated about ZURZUVAE and uses ZURZUVAE, we're seeing significantly more rewriting and coverage of this disease in their practice. So that's what we want to see.
Now, as Chris highlighted, of course, there are other healthcare providers that we want educated on PPD and ZURZUVAE, psychs, primary care because not every OB-GYN picks up every mom and not every woman develops symptoms in the course of being seen by their OB-GYN. It could happen two or three months after giving birth. So we are seeing the kind of dynamic exactly as we expected, and as we continue to expand use, OB-GYNs will remain the front-end of coverage here and care.

Douglas Tsao

Okay, great. And just as a follow-up, the question I've gotten from investors in terms of 319 and the SAD and MAD data that you'll have this year, I'm just curious, I think it'd be helpful to provide some additional perspective on beyond just the exposure, but what types of information you'll get from that study that will give people confidence that you have an active drug. I mean, obviously, you won't have clinical data in terms of patients, but just in terms of what you'll see that should give people increased confidence that this will ultimately have success in the clinic. Thank you.

Barry Greene

Yeah, good point, Doug. Laura, why don't you talk about the EEG signal we'll have and then the safety database, which is both of which will be very helpful instructing the path forward?

Laura Gault

So as we mentioned, we're conducting a Phase 1 program, and it includes a SAD study and a MAD study, very conventional. The primary endpoints, of course, are safety and tolerability. But we know from pre-clinical data using extrasynaptic preferring molecules that there's a different EEG signature that you can see in animals, and that different EEG signature represents a different type of engagement of brain circuitry. We are able to look in the clinic using EEG to look for that same signature. And so when we come to the end of these studies, we'll be able to say whether that differential signal that reflects different activation of brain circuitry that we see pre-clinically also happens in patients.

Operator

Uy Ear, Mizuho.

Uy Ear

Hey, guys. Thanks for taking our question. Just breaking away a bit from the other questions. Just wondering what -- maybe could you help us understand a little bit what's going on with the agreement with your collaborator in Japan, Shionogi? Are you expecting any milestones or anything to that effect? I think they are expecting -- or there could be a decision on their MDD application sometime in September. Thanks.

Barry Greene

Yeah. Absolutely. Thanks for going there. So I'll come and then Chris can talk about milestones. So what our Japanese friends have shared is that they expect a decision on MDD from the Japanese FDA later this year. And it's an MDD indication, which in Japan also includes women that have given birth. So it's folded under there as well.
Chris, do you want to talk about the milestones?

Chris Benecchi

Yeah, sure, Barry. If approved, we're entitled to receive regulatory and commercial milestones from Shionogi. Regulatory milestones amount to a total of approximately $55 million, of which a portion would be achieved upon MDD approval. Now there are additional commercially related milestones, including upon first commercial sale. Currently, no milestones have been assumed in our cash runway expectations into 2027.

Barry Greene

Yeah. So if they're successful in getting approval, and we get the milestones and royalties, that's upside to our cash runway.

Uy Ear

Could you maybe just speak a little bit about the potential opportunity in Japan? For what reasons (multiple speakers)

Barry Greene

I think what I can say the way Japan works, and you need to talk to them about it is if they get the KOLs behind them, they should have a pretty interesting commercial uptake. But we have to talk to them directly about what their expectations are.

Operator

Joel Beatty, Baird.

Joel Beatty

Hi. Thanks for taking the question. Could you give a sense of how sensitive the market is to marketing to physicians versus raising awareness among inpatients? And are scripts tending to come for patients who are already aware of ZURZUVAE and asking about it or more about patients who may not have heard of it before?

Barry Greene

Yeah, Joel, I'll ask Chris to come in.

Chris Benecchi

So as I've already said, this is a promotionally responsive market. We see that whether it is the sales force or it is non-personal promotion and the various different tactics that we talked about that really there is an impact of those. In terms of, is it coming from physician behavior or is it coming from directly engaging with patients either through DTP or DTC, the sense that we have is it's coming from really a balance of both of those things, that this is a market in which, as Barry noted, we have an activated group of healthcare professionals, OB-GYNs, who are really willing recipients of this message and then are subsequently not only treating but screening and diagnosing at a higher level.
We also know that this is a market where patients are activated with the information that we provide. And they're engaging their healthcare professionals in informed discussions that enable those clinicians to provide them with perspective on not only the importance of treating PPD but using a medication like ZURZUVAE. So we believe that what we're doing right now is not only launching ZURZUVAE, but we're building an opportunity, expanding opportunity through increased screening and diagnosis through education and disease state awareness.

Operator

Sumant Kulkarni, Canaccord.

Sumant Kulkarni

Good afternoon. Thanks for taking our question. Given what we know about the size of the PPD market in terms of patient and prescriber numbers, do you believe this collaboration is required to get commercialization right on ZURZUVAE? And how would you characterize the sales force's level of focus with all the stuff that's going on in the background?

Barry Greene

Yeah. So the collaboration exists, so that's how we're operating. And I can tell you that on a day-to-day basis, the sales force and both commercialization teams are laser focused in helping as many moms in 2025 as possible. There are no distractions.

Operator

Joon Lee, Truist Securities.

Joon Lee

Thanks for taking our questions. What proportion of the patients who get ZURZUVAE are getting it as their first-line therapy? And for those who are diagnosed with PPD but getting some form of pharmacotherapy other than ZURZUVAE, what are some of the challenges there? Is this an issue of access or something else like perception as a novel drug with relatively less safety data? Thank you.

Barry Greene

Yeah, Joon, thanks. Chris, you want to start, and then I'll loop back to fill in some of the other color.

Chris Benecchi

Yeah. So what we've said is that with respect to all of the work that we've done with not only payers but also with physicians, we want to ensure broad and equitable access. And in doing so, this has enabled physicians to use this medication, ZURZUVAE, as a first-line treatment.
What we've communicated in our prepared remarks is now that more than 70% of those that are receiving the medication through the targeted HCPs that we're calling on, they're able to get this medication as a first-line medication, which is really incredible when you think about it, to have that degree of first-line use right out of the gate. So to me, I think that's something really to reflect on not only the work that we've done with physicians but also with payers.
Now in terms of other patients who may not be getting this in the first line, there are patients who come through who have a prior history on other antidepressants because perhaps they've been diagnosed with the condition by a clinician in the past. So those that aren't getting it in the first-line position aren't getting it, because they're being excluded from getting it. They typically come forward on another medication, and that's the rationale for it.

Barry Greene

As you said, Joon, in any novel drug launch, you have to overcome historical bias. Someone was used to using something one way. They've got to understand ZURZUVAE and how to use it.
We're certainly seeing, as we highlighted, tremendous insurance coverage and very little, if any, out-of-pocket expenses. So it really is about historical bias more than anything else to continue to move to front-line. And just to emphasize, as Chris said, for those that we're targeting me, we've educated, we've engaged, we're seeing significant front-line use for ZURZUVAE.

Operator

Marc Goodman, Leerink Partners.

Basma Radwan

Hi, this is Basma on for Marc. Thank you for taking our question. Can you provide some color on the gross and net in the quarter, given that there was higher -- greater demand, but the revenue kind of seemed to be flattish, if you compare the fourth quarter to the third quarter?
And also, we have another question about, can you tell us now after one year from the launch if any of the treated patients needed to receive more than one treatment course? If so, can you provide some color on the proportion of these patients and whether there has been any pay of pushback. Thank you.

Barry Greene

Yeah. Let me take that kind of in reverse order. So what we've seen and what we're hearing reported back is that the performance of ZURZUVAE in the real world is good or better than we saw in our clinical trials. So it's a rapid and durable response. We're not picking up much of any kind of re-treatment at all. We're seeing that the 14-day course works rapidly and is helping moms, and that response is maintained.
In terms of the dynamic, we've talked about this a couple of times. The over 20% demand growth is encouraging in the fourth quarter. The revenue growth is really a matter of sort of channel management inventory, not really a matter of gross to net. And again, we're excited by -- thank you -- we're excited by the start to 2025 and where the launch is going.

Operator

Thank you. That will conclude the Q&A portion of today's call. With that, I will turn it back over to Mr. Green for closing remarks.

Barry Greene

Thanks, Taryn, and thanks, everyone, for joining us on this afternoon to review our results from the fourth quarter and full year 2024. As we look ahead to the ongoing commercialization of ZURZUVAE and PPD and advancements in our focus pipeline, I'm confident we're making important progress for patients. We move forward with investments intended to power ongoing commercial success and create value for shareholders. Thanks, everyone. Have a great evening.

Operator

This concludes today's call. Thank you, again, for your participation. You may now disconnect and have a great day.