Hello, and thank you for standing by. My name is Regina, and I will be your conference operator today. At this time, I would like to welcome everyone to the Innate Pharma's third quarter 2024 business update and financial results conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during this time, simply press star, then the number one on your telephone keypad. To withdraw your question, press star one again. I would now like to turn the conference over to Henry Wheeler, Vice President, Investor Relations. Please go ahead.
Thank you. Good morning, good afternoon, and welcome, everyone. This morning, Innate issued a press release for our Q3 2024 business update and financial results. We look forward to highlighting the progress made during the year to date, as well as addressing future goals and milestones. The press release and today's presentation are both available on the IR section of our website. On slide two, before we start, I would like to remind you that we'll be making forward-looking statements regarding the financial outlook in addition to regulatory and product plan development. These statements are subject to risk and uncertainties that may cause actual results to differ from those forecasted. Slide three. On today's call, we are very pleased to be joined by Jonathan Dickinson, our new Chief Executive Officer. Jonathan is a seasoned healthcare professional and joins from Incyte.
He has a strong background in oncology, and previous roles include ARIAD, BMS, Roche, and Novartis. On the next slide, to cover today's agenda, after an introduction from Jonathan, Sonia Quaratino, our Chief Medical Officer, will cover updates on lacutamab, IPH6501, and IPH4502. We will then hand to Yannis Morel, Chief Operating Officer, who will then discuss our ANKET platform, ADC, SITC, and monalizumab updates. Arvind Sood, EVP U.S. Operations, will wrap and close, and we'll also have Frédéric Lombard, our CFO, on the line for questions. Jonathan, I now hand the call over to you.
Thank you, Henry. Good morning and good afternoon to everybody on the call. I'm very excited to join Innate Pharma, a company which is at the forefront of cutting-edge science in oncology. The innovative work being done at Innate is truly inspiring and world-class, and I'm looking forward to using my extensive oncology experience to shape the Innate portfolio to maximize the future commercial potential and drive the next chapter of Innate's exciting journey. I look forward to meeting with as many of you as possible in the coming weeks. Turning to slide six, I would like to remind you of our strategy. As a company with proprietary assets in early clinical stages and partnered assets in early to later stages, our strategy involves leveraging our world-class expertise to develop first and best-in-class antibody-based therapies for cancer.
Our current business model centers around the three priorities highlighted in slide six, where we look to drive value from our proprietary R&D efforts through our well-established late-stage partnerships. Our ambition is to take our proprietary assets further along the clinical development pathway and thereby transform cancer care through a strong pipeline of novel differentiated antibodies. The first of these priorities is our lead proprietary asset, lacutamab, where we look to create near-term value. lacutamab is in development for T-cell lymphoma with the top-line phase II CTCL data already presented. Based on this data, we have had recent interactions with FDA. Sonia will cover this feedback later in today's presentation, and we're now assessing the best path forward to maximize the potential of lacutamab, including a potential partnership.
Second, we continue to fuel our pipeline and create longer-term value by leveraging our antibody engineering capabilities to develop innovative molecules with a primary focus on our multi-specific NK cell engager proprietary platform called ANKET. We're pleased to see continued progress with Sanofi presenting various updates for the lead ANKET program, IPH6101/SAR579. We're pleased to see our lead proprietary ANKET, IPH6501, continue to progress in phase I. As we develop antibody targets for our ANKET platform, we recognize that some of these targets may be better suited to an ADC approach. We will illustrate further details of our ADC pipeline today, where our lead asset, IPH4502, has now received IND clearance from FDA and will start phase I trials by Q1 next year. Finally, we're building strong and sustainable foundations for our business by developing value-creating partnerships across industry and academia.
Monalizumab, which is partnered with AZ, is a good example of these partnerships, and the product as part of this collaboration is advancing well in phase III trials in lung cancer. Turning to slide seven, this shows a summary of our pipeline, which highlights how we continue to translate our science into a robust portfolio of proprietary and partnered assets. When the IPH4502 phase I study starts by Q1 next year, we will have eight clinical assets. The slide also illustrates how we are executing against our strategy with our lead proprietary assets, lacutamab, ANKET, and emerging ADCs, and which is supported by partner products from late to early stage with AstraZeneca and Sanofi. We anticipate a series of potential clinical data readouts and catalysts in the short to midterm as we leverage our R&D engine and scientific know-how to create a sustainable business.
Moving to slide eight, which highlights our Q4 conference activity at SITC and ASH. At the SITC meeting last week, we presented further clinical data on our next generation CD20 targeting ANKET, IPH6501, as well as preclinical data on our Nectin-4 targeting ADC, IPH4502, which will be covered by Yannis later in today's presentation. At ASH, we're pleased to see that lacutamab data was accepted for an oral presentation highlighting follow-up on the TELLOMAK trial in relapsed recurrent cutaneous T-cell lymphoma, as well as a poster on translational analysis. I would like to now pass the call over to Sonia, who will review the progress made with our clinical portfolio. Sonia.
Thank you, Jonathan. I will now cover the key proprietary clinical programs in the next slide: lacutamab, IPH6501, our CD20 targeting NK engager, and now also IPH4502, the Nectin-4 ADC that is fast approaching the clinic. Can you move to the next slide, please? Thank you. On this slide, I will briefly recapitulate where we are with lacutamab before moving to the feedback from our recent interaction with the FDA. We have already presented the primary result of the TELLOMAK trial, a phase II single-arm study that includes both Sézary and Mycosis Fungoides patients. The data in Sézary syndrome were presented at ASH last year, and the results in Mycosis Fungoides at ASCO this year. Also, this year, we will have a relevant presence at ASH with an oral presentation on the health-related quality of life in Sézary and translational results from TELLOMAK.
The TELLOMAK study is continuing, and we collect more follow-up data from these patients. Similarly, in peripheral T-cell lymphoma, we continue to enroll patients in the KILT trial, a randomized phase II where lacutamab is administered in combination with gemcitabine and oxaliplatin versus gemcitabine and oxaliplatin alone. We believe that this combination may offer additional benefit to patients with PTCL. As a reminder, lacutamab is a monoclonal antibody that targets KIR3DL2 and was shown to deplete the cells that express the receptor, which is expressed in more than 90% of Sézary syndrome patients and approximately in 50% of patients with Mycosis Fungoides or PTCL. The FDA granted an orphan drug designation for lacutamab for the treatment of CTCL and fast track designation for the treatment of adult patients with refractory relapsed Sézary syndrome who have received at least two prior lines of systemic therapies.
We submitted the results from the TELLOMAK trial and the proposed regulatory pathway to market approval, including the possibility for an accelerated approval for Sézary syndrome, to the FDA and received encouraging feedback. And the company will continue to align with the FDA around the necessary confirmatory phase III trial. We are currently evaluating the next step for the program, including potential licensing with a partner to deliver the confirmatory phase III trial in CTCL. Now, where do we stand in terms of business case? On this slide, the data generated from the TELLOMAK trial confirm clinical benefit not only in SS but also in Mycosis Fungoides , regardless of the expression of the target KIR3DL2, highlighting an opportunity for the CTCL space without a companion diagnostic.
Therefore, the number of CTCL patients that could potentially benefit from lacutamab expands from 1,500 to 3,500 in the two-plus line of therapy and to 5,000 patients should we move to an earlier line setting. With the strong Sézary syndrome and Mycosis Fungoides data we presented at ASH last year and ASCO this year, there is increased confidence in the potential of lacutamab. And our aim is to ensure that lacutamab gets to patients who need it as quickly as possible and to maximize the value via an accelerated approval.
On slide 13, we now switch gear to our most advanced proprietary ANKET asset, IPH6501, a tetraspecific antibody-based NK cell engager therapeutic, or ANKET in short, which is a first-in-class NK engager that engages the tumor via a tumor-associated antigen, in this case, CD20, and the NK cells via two activating receptors, NKP46 and CD16, as well as the interleukin-2 receptor via an IL-2 variant or IL-2V. The IL-2 variant is the characteristic of this second-generation tetraspecific ANKET aimed to induce activation and proliferation of endogenous NK cells in the tumor microenvironment. We were pleased to announce earlier this year that IPH6501 entered the clinic and the first in human has started with the first patient being dosed in March. The trial is currently recruiting patients with relapsed refractory B-cell non-Hodgkin lymphoma.
We presented preclinical data at ASCO meeting this year, showing that IPH6501 effectively and preferentially stimulated NK cell proliferation from PBMC of NHL patients and depleted autologous CD20 positive B cells from healthy donors with greater efficacy than a CD20 T-cell engager and inducing lower level of pro-inflammatory cytokines, which is often a limiting use of T-cell engagers. The current phase I/2 study has been presented as trial in progress at ASCO this year and the European Hematology Association Congress, and more recently at the SITC annual meeting, which Yannis will cover shortly. In the next slide, I'll give you an overview of timeline for IPH6501. Throughout the year, we plan, and next year, we plan to complete the dose escalation and look forward for initial safety data, PK, and pharmacodynamic readouts, as well as preliminary efficacy signals.
Throughout 2025 and beyond, we will open the dose optimization part of the study to select the optimal dose for subsequent studies and then open expansion cohorts in non-Hodgkin lymphoma subtypes. On slide 15, I will summarize the next step of our lead ADC, IPH4502, following the IND clearance at the end of September. We are actively working to progress towards phase I, and we are looking forward to generating preliminary phase I safety data in 2025 and then establishing anti-tumor activity in tumor types with both low and high expression of Nectin-4. IPH4502 is a Topo I ADC targeting Nectin-4, and the preclinical characterization was presented at AACR and SITC this year, highlighting the key differentiation features of this product.
And based on this data, we feel that we have a novel and differentiated ADC to target Nectin-4 in a broad panel of tumor indications beyond blood cancer by overcoming the challenges associated with Nectin-4 MMAE-based ADCs, including enfortumab vedotin . I will now turn it over to Yannis to cover the earlier pipeline of ANKET and ADCs, as well as partnered asset, monalizumab .
Thank you, Sonia. I will now highlight the two classes of exciting next-generation antibody therapeutics on which we are focusing all our research activities: the NK cell engagers, ANKET, and the ADCs. On slide 17, I draw your attention to our portfolio of ANKET. ANKET is our proprietary first-in-class NK cell engager platform. It is a multispecific plug-and-play technology aiming at engaging NK cells towards tumor cells by triggering the most stable activating receptor expressed from NK cells called NKP46. The interesting feature of this platform is that by swapping the tumor binding portion of the ANKET molecule, it can produce multiple drug candidates addressing a variety of targets in oncology. But it can also potentially harness NK cells to eliminate pathogenic cells in other diseases, like in autoimmune disease.
Earlier this year, Sanofi progressed the most advanced ANKET, SAR579 to phase II, on the back of initial efficacy data showing single-agent activity with durable complete responses in relapsed refractory AML patients, and started also a new phase I/II trial in frontline AML in combination with venetoclax and azacitidine. As mentioned by Sonia, our lead proprietary ANKET, IPH 65, is now in the clinic. It is a second-generation molecule which incorporates a variant of IL-2 to induce expansion of patients' own NK cells. The first patient was dosed in March, and we recently presented new supporting preclinical data at the SITC conference. I will now cover the key updates we presented at SITC for both IPH 65 ANKET program and the Nectin-4 ADC IPH 45. The IPH 65 poster presented at the conference summarized the rationale to target the various subtypes of relapsed or refractory BNHL patients.
First of all, on the left, you can see what we think is the key advantage for ANKET over existing CD20 targeting antibodies like rituximab. Whereas CD16, the receptor for the Fc portion of antibodies to mediate ADCC, is strongly downmodulated on NK cells in the leaf node of patients, NKP46 expression is maintained, providing a stable anchor for the ANKET. By assessing the function of NK cells for multiple patients, we have shown also that IPH6501 was able to induce efficient killing by diseased NK cells across BNHL subtypes, including diffuse large B-cell lymphoma, follicular lymphoma, or mantle cell lymphoma. Finally, we made the interesting observation that post-CAR T patients had an increased NK T-cell ratio and, as shown here on the right, an increased NKP46 expression level, further supporting the rationale to evaluate IPH65 in these patients.
On the next slide, the IPH4502 poster summarized the key differentiating features of our drug candidates. As shown earlier in the year at AACR, IPH4502 is a novel DAR8 exatecan-based Nectin-4 ADC that had the ability to target Nectin-4 low-expressing tumors where Padcev does not work. In the SITC poster, we further demonstrated that IPH4502 has also the ability to target tumors having a heterogeneous expression of the Nectin-4. Indeed, by mixing at a one-to-one ratio Nectin-4 expressing cell line with the same cell line CRISPRed out for Nectin-4 in order to mimic a heterogeneous tumor showing only 50% of positivity, IPH4502 induced complete tumor regression of the mix. This effect is completely Nectin-4 dependent and is not related to a non-toxic effect since IPH4502 had no effect in the Nectin-4 non-expressor model.
We also generated a PDX model of Padcev-acquired resistance. We obtained it by making five injections of Padcev, resulting in a PDX model that is eventually relapsing under Padcev but is completely sensitive to IPH4502, highlighting the ability of IPH4502 to address patients pre-exposed to Padcev. These two posters are available on our website. On slide 20, I would like to remind you of monalizumab, the anti-NKG2A that we have licensed to AstraZeneca for oncology. On this slide, you can see an overview of the late-stage development of monalizumab in lung cancer. Based on the phase II COAST data, AstraZeneca started in May 2022 the phase III trial called PACIFIC-9, evaluating the addition of either monalizumab or oleclumab to durvalumab in unresectable stage three non-small cell lung cancer patients who have not progressed after concurrent chemoradiation therapy.
We were encouraged that over the summer, the independent data monitoring committee recommended the continuation of the phase III PACIFIC-9 trial based on the pre-planned analysis. Together with the COAST and the new COAST data, the new COAST-2 data presented at the World Conference on Lung Cancer in September provided a third proof point in a controlled phase II study that monalizumab provides additional anti-tumor activity on top of durvalumab in early lung. I will now hand over to Arvind.
Thank you, Yannis. Good morning, good afternoon, everybody, so we have several upcoming R&D catalysts that can be meaningful to our long-term growth. I would draw your attention particularly, this I believe is slide 23. I would draw your attention particularly to the ones that are bolded on this slide. Near term, we are looking forward to the next steps for lacutamab now that we have the positive FDA feedback. Programs coming out of our ANKET platform continue to advance as IPH6101 targeting CD123 in hematologic malignancies and partnered with Sanofi progressed to phase II earlier this year. Our proprietary tetraspecific ANKET that goes by IPH6501 is now in clinical development, and our ADC targeting Nectin-4 has cleared IND and is due to start phase I soon. I would like to conclude our prepared comments with a few thoughts outlined on slide 24.
We have a differentiated pipeline with several first-in-class opportunities. Excuse me, we now have seven products in clinical development with three that are proprietary and four that are partnered. Our cash position of around EUR 96.4 million through the end of September will enable us to fund operations through the end of 2025. So with that, I would like to open the call for Q&A. Regina, perhaps you can review the process for asking questions for our listeners.
At this time, I'd like to remind everyone in order to ask a question, simply press star followed by the number one on your telephone keypad. Our first question will come from the line of Liisa Bayko with Evercore ISI. Please go ahead.
Hi, this is Jamie Nguyen for Lisa. Thanks for taking our questions. So I'm just wondering, could you please provide some color on lacutamab data to be presented at ASH? Especially, what does the translational data entail? Also, it would be nice if you could give some color regarding the regulatory path for lacutamab. Is FDA supportive of filing with current data in Sézary syndrome for accelerated approval? Or is the, and then is the filing predicated on financial partnership? Thank you.
Thank you for the question. Sonia, could you take that one, please?
Absolutely. Just unmuted. Regarding the data that are going to be presented at ASH, I'm afraid I cannot add any color. There are some embargoes that need to be respected, and so I'm afraid you have to wait until December for that. I can provide a bit more perhaps color on the FDA interaction that we had. We have received this encouraging initial feedback, and the FDA endorsed our proposed regulatory pathway in general lines. The FDA acknowledged that the currently available data from the phase I and the phase II TELLOMAK studies may be sufficient to support a BLA submission paving the path for an accelerated approval for Sézary syndrome, and the company will then align with the FDA around the confirmatory phase III trial to support such, let's say, accelerated approval. We are working towards this to make it happen.
Got it. If I may follow up really quick, could you provide some color on timing for the next step? Or when should we expect to hear about details for, or alignment with FDA for the phase III confirmatory trial? Thank you.
Around the timing for the FDA will also depend on our, let's say, business case in the sense that, as you know, we are also looking for partners that can potentially carry out such a phase III trial. We will pave the way by producing a regulatory strategy, which eventually may also need to be discussed with the potential partner.
Got it. Thank you.
Our next question comes from the line of Daina Graybosch with Leerink Partners. Please go ahead.
Hi, thanks for the question. I think I understand from the previous one. I'll just follow up on that. You really need to find a partner to do a confirmation study, and that will gate reviewing that with FDA and having a more concrete path to accelerated filing. Can you confirm that and then talk to us about what you're doing to find that partner and how those conversations have been going?
Sonia, do you want to take the first part of that question, and then we'll come back to Yannis and myself?
Certainly. As I just briefly mentioned, we are working towards this confirmatory phase III study for the CTCL indication in more general terms, and of course, this would be nice to be, let's say, aligned with a potential partner before going for another, let's say, type C meeting with the FDA to discuss, let's say, the go-live of such a study, and we are looking for partners or many other, let's say, options to make this happen.
Thank you, Sonia. So I mean, I can add something to what Sonia has just said. So I guess we're keeping our options open at this stage. We are very actively seeking a partner, but we're also exploring other ways that we might be able to take forward a lacutamab phase III study that would meet the FDA requirements here. So I think it's difficult to say any more on that. We're in discussions at this point in time, and I think when we have some information that we can provide, we will share that moving forward.
Can you provide maybe your guiding principles for why you would go with a partner versus these other ways so we can better understand that process?
Yannis, do you want to take a stab at that one?
Yeah, hi, Daina. So like Jonathan said, we are entertaining several options in parallel. I would say classical partnering is one option. And what will guide us is the way to maximize the return for Innate. So we really want to. We think that here we have potentially a drug that is really active in CTCL, and we really want to execute swiftly the registration part of the development. And anything that will maximize the return for the company and the shareholder will be prioritized.
Our next question will come from the line of Rajan Sharma with Goldman Sachs. Please go ahead.
Hi. Thank you for taking my question. Sorry, just another one on lacutamab and partnering strategy. I was just wondering, do you kind of have an internal deadline or sort of line in the sand in mind for finding a partner and executing on a potential deal there versus will there be some point in time when you decide that that's not going to happen and you'll start to take this forward alone? And then maybe related to that is just one on cash. So your runway is to the end of 2025, so you're sort of into the last 12 months. I guess, is that something that you're comfortable with, and what are the options to extend the runway here? And then I've got a follow-up on Nectin-4, which I'll come back to.
Thanks, Rajan. Maybe Yannis, you can take the first part, and then we can go to Frédéric for the cash runway.
Yeah. Hi, Rajan. Yeah, obviously, it will be busy during the next few months. Obviously, the FDA feedback was an important milestone to actually resume discussion with several partners, but also for the other type of option we are looking at. So it's clearly something that will come during the next several months, hopefully.
Okay. Thank you, guys. Frédéric?
Yeah. On the cash runway, just one thing first is that when we communicate on this cash runway, there are no options that are not fully guaranteed. So we are comfortable with the cash runway that we are publishing first. And second, we are, as usual, constantly monitoring financing needs, including dilutive and non-dilutive options that we are currently working on. And we will provide an update when needed and when finalized.
Any other question on the Nectin-4, Rajan?
Yeah. So just on that one, and obviously clear on the slides that you see the potential for the asset in kind of Padcev or EV refractory patients. But just thinking about kind of differentiation beyond that, do you think there's an opportunity to differentiate on tolerability or safety, and are there any key adverse events, for example, that you might call out as a differentiation?
So Yannis, do you want to take that one?
Yeah. We think that there are several lines of differentiation, like what we have shown here at CTCL, that IPH4502 is working in preclinical models that are resistant to Padcev either through primary resistance or acquired resistance, like I just showed today. We have also, and it's in the poster that you can find on the website, shown that it can target Nectin-4 low expressor tumor model, and we are now accumulating data in other tumor types like breast cancer. And this is really a differentiating factor compared to Padcev, which is really working well in bladder where the expression of Nectin-4 is high and homogeneous. In terms of tolerability, as we are using exatecan, we do not expect the same kind of toxicity as with MMAE.
Yeah, that's basically the different possibilities that make the potential business case for this Nectin-4 exatecan IPH4502 broader than Padcev because there are, and it's also in our poster, there are many, many solid tumors that do express Nectin-4, if not at the same level of bladder, but that could be within the reach of 45, but not Padcev.
As a reminder to ask a question, simply press star one on your telephone keypad.
I'll take a question received online from Eric Le Berrigaud at Stifel. On lacutamab, is the understanding correct from your initial interactions with the FDA that the agency would not be against a filing with the drug for Sézary syndrome and maybe even CTCL, with potential in the second case to get a conditional approval based on a confirmatory phase III trial? If this understanding is correct, is it what a partner was waiting for to move on and sign up for a collaboration with you on the asset, or is it more the PTCL data dependent? So I'll stop there. Sonia, probably a question for you.
Henry, I'm not sure I understood the first part of the question. Would you mind to repeat that?
Is the understanding correct from the initial interactions with the FDA that the agency would not be against a filing with the drug for Sézary syndrome and maybe even CTCL with the potential in the second case to get a conditional approval based on a confirmatory phase III trial?
Correct. Right. Yes. Sorry. It was the negative that escaped my understanding before. Yes. Basically, the data in Sézary where we would be looking for the accelerated approval because, of course, accelerated approval can only be given to indication with a high unmet medical need, and Sézary would qualify for such an indication, would be given based on the phase II and phase I data. But of course, any accelerated approval can only be obtained when the confirmatory trial is up and running, and depending on the recruitment rate must be quite advanced on that. And this approval is completely independent from the PTCL, which is a very different indication in that respect.
Yannis, do you want to take the?
Yeah. And with the question on the partnership, I would not say that the FDA feedback was awaited to sign a deal, but it was more an important milestone to progress discussions. And that's where we are today.
And then the second part of Eric's question, what would you consider as the most likely next step for lacutamab? A formal filing with the FDA or a partnership with a third party? And what are the reasonable timelines for this to happen? Maybe Sonia?
Okay. The most likely timelines is really to go ahead and prepare a phase III that can be then taken up by a partner or eventually finding either option to fund the study and make it in a different ways.
Okay. Thank you. Another offline question from Jingming at Evercore ISI. Could you please remind us why Sanofi decided to return IPH67 and ANKET? Is it due to activity signals, safety, or other reasons, e.g., strategic prioritization? Yannis?
Yeah. Hi, Jingming. Sanofi did not provide any specific reason for the termination. I just remind you that IPH67 was a very early-stage research program, so not even at the candidate selection. It was even years away from candidate selection. So there is no specific technical or scientific reason behind that decision. It's really up to Sanofi to comment on that. And I also remind you that the rest of the agreement is untouched. We are having the CD123 and the BCMA in phase II and phase I and having the B7H3 on ANKET program progressing well in the preclinical development.
Operator, next question, please.
We'll take our next question from the line of Arthur He with HCW. Please go ahead.
Hi, good morning. This is Arthur He for HC W . Thanks for taking my question. So I have two questions on the ANKET. So one is for IPH6501, your own IPH6501. Sorry. You said you are currently already in the clinical trial. So could you give us some guidance on the timing for the data update from your own program?
Sonia, can you take that one, please?
Of course. I think you are referring to IPH6501, which is the second-generation ANKET in the B-cell non-Hodgkin lymphoma. We opened the phase I, the dose escalation that goes according to the usual times of a dose escalation with DLT windows, etc. And we believe that we will complete the dose escalation by 2025 and then open a dose optimization. And so we will have by 2025 data around safety, pharmacokinetics, pharmacodynamics, and early clinical antitumor efficacy, even though the number of patients tested in each dose level are very limited, classic of any dose escalation. But this is what we expect by, let's say, 2025 and in 2026, let's say, more clinical efficacy data, of course.
Thanks, Sonia. And so another question is just want to follow up on the IPH67. Are you able to disclose which target these assets are targeted for, or it's still kind of the status quo?
I can answer that one. That's a target that we're not currently disclosing at this point in time.
Okay. No problem. Thanks. Thanks for taking the question.
Again, for any questions, simply press star one on your telephone keypad. That's star one for any questions. We have no further questions at this time. Ladies and gentlemen, that will conclude today's meeting. Thank you all for joining. You may now disconnect. We're all clear.
Great. Thank you, Regina.
Thank you.
Great. Thank you, Regina.