Alaunos Therapeutics Inc (TCRT) 2019 Q1 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to the Ziopharm Oncology First Quarter 2019 Results Call.

(Operator Instructions) I would now like to turn the conference over to your host, Mr. Chris Taylor, Vice President, Investor Relations, Corporate Communications.

Sir, you may begin.

Thank you, Bridget, good afternoon.

Welcome to the Ziopharm Oncology conference call and webcast to review results for the first quarter of 2019.

This afternoon, we filed our 10-Q and issued our Q1 news release, both of which are available in the Investors Section of our website, ziopharm.com.

During the course of this call, the company will make forward-looking statements, including statements regarding the potential therapeutic candidates in our development pipeline, regulatory status, financial information and business trends.

Forward-looking statements are subject to numerous risks and uncertainties as described in our 10-Q and within other filings that we may make with the SEC.

Participating on the call today are Dr. Laurence Cooper, CEO of Ziopharm; and Dr. David Mauney, our company President.

Each will provide commentary, and we'll open the call for Q&A.

Now I'd like to turn the call over to Dr. Mauney.

Good afternoon, David.

Yes, thanks, Chris, and welcome aboard here at Ziopharm.

And thank you for everyone -- thank you, everyone, for joining us today on the call.

We are pleased to speak with you this afternoon to provide an overview of results for the first quarter of 2019, to provide you an update on our core programs and to highlight value-creating milestones we expect for this year.

We extend a special welcome to those of you who have taken a new look at Ziopharm over the last few months.

We benefit now from an increasingly strong and supportive base of shareholders, and we are pleased to see evidence of new support this year.

We also welcome 2 new analysts on this call, each of them initiated coverage of Ziopharm in recent weeks.

We began 2019 with significant corporate momentum.

In addition to a reinforced corporate structure and balance sheet, we are now well positioned to achieve multiple-critical and value-driving milestones this year, including being in the clinic with all of our filler programs, namely TCR-T, CAR-T and Controlled IL-12.

We are pleased to report that all of the important clinical milestones articulated on our year-end call are on track, and today, we reaffirmed our timelines for attaining those events.

With these milestones essentially upon us, the table is set for what we believe will be very a strong balance of the year.

To accomplish our goals, we have established strong partnerships with those, we think, are the most recognized leaders in our field.

For our solid tumor TCR program, our external clinical lead is Dr. Steven Rosenberg, Chief of the Surgery Branch and Head of the Tumor Immunology Section at the NCI.

We spent increasing amounts of time at the NCI over the past quarter, and together, we agreed to extend our CRADA in February.

Also in February, Ziopharm appeared in the Federal Register of the United States Government, contemplating a perspective and exclusive license from the NCI for additional patents and inventions.

The joint decision to extend the CRADA and the pursuit of expanded licenses shows our commitment to this program and also reflects the commitment we see from Dr. Rosenberg and our shared vision for scalable, nonviral approaches to delivering TCR-T cell therapies.

We remain the only nonviral means for gene transfer for clinical grade TCRs being used by Dr. Rosenberg's group, and both parties feel our platform could be a key to targeting solid tumors of all types.

These efforts at the NCI could enable truly personalized autologous therapies, which almost certainly will require multiple targets per patient, something we think is not commercially viable with viral-based manufacturing.

Thus, with the full support and full agreement with the team at the NCI, we are pleased to reiterate that we expect Sleeping Beauty TCR-T cell therapy to be in the clinic in mid-2019.

We also maintain a long-standing relationship with the MD Anderson Cancer Center.

Our Sleeping Beauty platform represents a paradigm shift where Ziopharm plans to solve ongoing commercialization hurdles with CAR-T therapies by manufacturing CAR-T faster and at a fraction of the expense compared to viral vectors.

This has the potential to dramatically expand patient access and reduce cost.

The enthusiasm within MD Anderson for our Sleeping Beauty technology, which has now expanded across multiple clinical groups, is palpable.

We are currently exploring ways to deepen our relationship within MD Anderson, efforts that would provide us an opportunity to expand our preclinical, clinical and GMP initiatives there.

Last summer, the FDA mandated that we achieve viability rates greater than 70% for our CD19-specific CAR-T cells.

I'm happy to report that we have made considerable progress on this front, and we expect to respond to the FDA and meet our stated goal of being in the clinic at MD Anderson in the second half of this year.

I'm proud of our entire team and the collaborative efforts underway to achieve this clinical milestone.

To further develop our Controlled IL-12 platform, we partnered with Regeneron late last year, and I am pleased to report that our respective teams have worked tremendously well together, such that we are on time and on track to open our Phase II trial for Recurrent GBM that combines our IL-12 with Regeneron's PD-1 inhibitor, Libtayo, this quarter.

This, in addition to the acceleration and enrollment we have seen in our other IL-12 trials, gives us increasing confidence that control of IL-12 is shaping up to be the drug platform we envisioned all along.

Finally, we are very excited about the progress we are making with Eden BioCell, our joint venture in Greater China.

This effort oversees will essentially mirror the same CD19 CAR-T Sleeping Beauty program that is underway at MD Anderson.

This joint venture is structured as 50-50 ownership with our partner TriArm Therapeutics, to commit it up to $35 million to this program.

We have been incredibly impressed by the intensity of the team's effort out of the gate and look forward to updating you on our progress and timelines.

We remain committed to these partnerships and also to potential, additional, external opportunities and collaborations that we believe will add to our core portfolio and build value to the business of Ziopharm going forward.

Now for some internal updates.

Over the past several months, we have strengthened our management team and Board of Directors.

We have recently made several key additions to our Boston headquarters as well to our Houston R&D and manufacturing teams, and are actively working with leading search firms to identify and recruit 2 critical hires for the C-suite as well for our final 2 open Board seats.

As we announced last week, Jim Cannon, who joined the Ziopharm Board in 2004, will not stand for reelection.

I wanted to take this moment to sincerely thank Jim for the contributions made during his tenure, as well his generosity and time and effort, especially over this last critical year, as we reshape the company.

For both open Board seats, we have identified strong potential candidates, seasoned leaders who would bring valuable and complementary skills to our Board.

With 4 new members last year, 2 more on the horizon and a new chair, we will have completely reshaped our board in less than a year, efforts that had been paying dividends to us as a management team since day 1.

We believe that in building out our team at Ziopharm, we are now clearly on the right path to deliver best on the potential of our technology for the months and years to come.

Finally, an update on our financial status.

This afternoon, we issued a press release detailing our financial results for the quarter.

As of March 31, 2019, we had cash and cash equivalents of $51.5 million.

This is the primary funding source for our Controlled IL-12 platform, the work with the NCI, as well our G&A, which is primarily based in Boston.

We reiterate today that we have sufficient cash to support these activities into the second quarter of 2020.

There's an additional $26.4 million at MD Anderson that has been prepaid to cover our clinical and preclinical development work there.

These resources cover all of our existing CD19 work planned at MD Anderson well into 2020 as well as other important initiatives we are exploring now in partnership with them.

Of course, securing our balance sheet to support our visions is a priority as well.

We are now very confident in our ability to sufficiently capitalize the company going forward and will be creative and opportunistic in these efforts, updating the market as appropriate.

Before I turn the call over to Laurence, let me wrap up with a few final thoughts.

While it is only been 8 weeks since our last call, there is tangible progress being made at Ziopharm.

Progress that we believe will have very positive impact to the development of Ziopharm as a business and more importantly, to the impact of changing the lives of patients.

It is quite clear that we are executing better than ever and rapidly expanding our team and deepening many relationships.

We are pleased to welcome new analysts and investors and are equally pleased to see that our story is beginning to resonate with Wall Street.

As we look ahead at the balance of 2019, we have multiple milestones to look forward to.

With the strength in management team and a Board of Directors and all 3 clinical pillars enrolling this year, 2019 is poised to be a very significant year for Ziopharm.

And now I would like to hand the call over to Laurence.

Thank you, David.

And thanks to everyone for joining us today.

Let me also thank Director Jim Cannon for his service to Ziopharm.

He has provided terrific help and support to me and the company, and we wish him the best.

Ziopharm aims to be a leading developer of immunotherapies to target cancers by harnessing the power of our 2 platforms: Sleeping Beauty and Controlled IL-12.

I will provide an update on both, beginning with the Sleeping Beauty platform.

One of the hottest areas in immunotherapy is centered on the use of T-cell receptors or TCRs to target neoantigens for the treatment of solid tumors, the leading cause of cancer deaths in the United States.

We believe the enthusiasm associated with TCRs today mirrors where CAR-T was several years ago, and we plan to be a leader in the category.

So a key question: what sets us apart from others?

There's 4 things.

First, Ziopharm is focusing on the use of TCRs to target solid tumors, as we believe chimeric antigen receptors or CARs will have limited commercial appeal.

The evidence is that unless the T-cell therapy addresses antigens that are expressed within all of a patient's cancer cells, then that patient will progress or relapse due to the overgrowth of tumor cells that failed to express the targets.

Second, Ziopharm has developed a solution to enable the cost-effective production of T cells, expressing neoantigens-specific TCRs.

This is based on the use of DNA plasmids from the Sleeping Beauty system.

The simplicity and elegance of this nonviral gene transfer technology sets us apart from the complexity and cost of genetically modifying T cells with virus.

Third, Ziopharm recognizes that there is currently no off-the-shelf cellular solution to generating T cells that express TCRs.

This is because the TCR repertoire needed to address solid tumors needs to match the number of targeted neoantigens and in addition, has to match the HLA background of the recipients.

If you can't easily swap in and out TCRs targeting a multitude of neoantigens, then you will not be able to fully tackle the tumor, which will lead to incomplete responses.

Further, if you can't readily swap in and out TCRs representing the HLA background of patients, then you'll have difficulty enrolling patients.

In other words, there is no CD19 equivalent target for TCRs, in which one receptor can be used over and over, justifying the time and expense to manufacture virus and off-the-shelf T cells.

Our solution, the Sleeping Beauty system, can be scaled to express multiple TCRs.

DNA plasmids enable the desired TCRs to be readily swapped in and out.

Of note, to help safeguard against relapse, we anticipate in fusing populations of T cells in the patients that have more than one introduced TCR, which further highlights the need for a clinical solution based on DNA plasmids.

And fourth, Ziopharm has the most clinically advanced, nonviral, clinical gene transfer technology.

Our Sleeping Beauty system has been evaluated in more than 40 patients to date.

We have multiyear survivors and contract the presence of CAR-modified T cells for years in some of these recipients.

Importantly, we have derisked the Sleeping Beauty System in the CAR-T space, enabling us to soon evaluate this technology for TCR-T.

This contrast, with alternative transpose on technologies and other nonviral gene transfer approaches, that it just getting going.

And we believe have an uncertain path ahead of them.

In summary, we are working with the right team at the NCI, we are targeting the right targets, neoantigens and with the right tool, the Sleeping Beauty system, to genetically modify patient-derived T cells.

At the plenary session of this year's AACR annual meeting, Dr. Rosenberg from the NCI highlighted that the advantage of cell therapy in fighting solid tumors will be to administer large numbers of T cells that express TCRs for neoantigens.

To date, he and his team, in multiple publications, have shown that the Sleeping Beauty system can express TCRs, targeting more than one neoantigen.

They have shown that these modified T cells can then be grown to numbers needed and as the produced T cells meet anticipated release criteria.

We reiterate our plans to initiate a Phase I clinical trial midyear, in collaboration with the NCI team, to treat patients who have a variety of solid tumors using the Sleeping Beauty platform to genetically modify T cells to target patient-specific neoantigens.

David and I, with our respective teams, were recently together at the NCI, and the enthusiasm to start this trial is obvious.

Turning now to our second program, also built on the Sleeping Beauty platform, is our work on rapid personalized manufacture of CD19-specific CAR-T, which we are now advancing in the United States and in Greater China.

The approach is also centered on DNA plasmids from the Sleeping Beauty system, which allows us to genetically modify resting T cells without the need to propagate T cells in a bioreactor.

When a CAR is coupled with our proprietary membrane-bound IL-15, we will likely be able to administer small numbers of T cells by comparison to other approaches as our cells would have an embedded cytokine go signal, which is designed to provide a survival advantage for our modified T cells.

We also believe that the same go signal may work even in the absence of lymphodepleting chemotherapy, which would infer yet another competitive advantage to our CAR-T program relative to others, especially off-the-shelf therapeutics.

Thus, the cost efficiency and the speed of production, coupled with the potential to avoid lymphodepletion, will provide an advantage for our approach in the production of CD19-specific CAR-T.

We recognized last year that there were opportunity to expand on our clinical efforts without CD19-specific CAR outside the United States, and we're very pleased to announce the formation of our joint venture, Eden BioCell, in December.

Our partners at TriArm are ideal for this joint venture as they, in Greater China, have strong relationships with front-line physicians and officials at leading hospitals and regulatory bodies.

A commitment to conduct high-quality trials and state-of-the-art facilities with good manufacturing practices.

The team at TriArm has considerable experience in drug development, including scientific research, clinical and regulatory areas as well as significant laboratory and manufacturing know-how regarding T-cell therapy.

Thus, TriArm will manage all clinical development to execute trials in greater China for Eden BioCell.

Our teams will be working to map out the best clinical strategy for Sleeping Beauty-generated CAR-T therapies in Greater China, and we look forward to sharing our progress with you.

Turning to the Controlled IL-12 program.

IL-12 is one of the most potent immune stimulators that, if correctly administered, can safely lead to profound antitumor effects.

We believe that our switch technology provides the precision to safely harness IL-12, which will enable us to turn it into a potent drug.

In our clinical studies, we had demonstrated that IL-12 recruits and sustains a significant and long-term inter-tumor T-cell response and enough regulation of immune checkpoint such as PD-1.

We recently announced that FDA granted fast-track designation for our Controlled IL-12 program for the treatment of recurrent glioblastoma multiforme in adults.

The fast-track program is designed to facilitate the expedited developments and review of drugs to serious, life-threatening conditions and demonstrate the potential to address unmet medical needs.

In our monotherapy studies, we rapidly completed enrollment and treated a total of 36 patients in a substudy to expand a Phase I trial during the first quarter.

All 36 patients were enrolled in less than 6 months and the enrollment exceeded our planned total of 25 patients.

We attribute this to the compelling emerging data on overall survival, particularly in patients who received 20 milligrams of veledimex and low-dose steroids.

As a reminder, we showed data at SNO last November where the median overall survival for that subset of 6 patients reached 17.8 months, which we believe is quite remarkable compared to historical controls of 6 to 9 months.

We now have more than 50 patients in cohort receiving 20 milligrams of veledimex, with the expansion substudy completed.

And we expect approximately half of them will have been treated with low-dose steroids.

Some of these data will be available at ASCO this year in a poster presentation.

We also have 2 combination trials of controlled IL-12 with PD-1 inhibitors in our Phase I dose-escalating trial in combination with Opdivo, which began dosing in June of 2018.

We have commenced the third quarter now, combining the PD-1 inhibitor with IL-12 and expect to complete enrollment later this quarter.

Some of these data will be available at ASCO this year in an oral presentation.

These data will continue to mature as more patients are enrolled and as the time and follow-up lengthens.

Building on this initial Phase I combination study, we are on track to open in the second quarter of 2019 a Phase II trial to evaluate Controlled IL-12 in combination with Regeneron's PD-1 antibody Libtayo for patients with recurrent GBM.

Compared to the Phase I dose escalating trial with multiple cohorts for Opdivo, we expect that the enrollment for this Phase II checkpoint combination trial will be rapid, so we are eager to get started.

In summary, for these first few months of 2019, we have worked to build on the momentum of our significant transformation of late last year.

We remain steadfastly focused on our near-term goals and another transformation -- transformative year for Ziopharm.

And to summarize, our key milestones this year include: commencing through NCI a Phase I trial for TCR-T cell therapy midyear; initiating a Phase I trial in the second half of 2019 at MD Anderson and providing data to FDA to lift the clinical hold status; working through Eden BioCell's to advance the Sleeping Beauty platform in Greater China; presenting information from 2 approved abstracts at ASCO next month; and finally, initiating a Phase II combination trial with Regeneron's Libtayo this quarter.

And with that, we will turn the call to the operator for your questions.

(Operator Instructions) Our first question comes from the line of Ren Benjamin with Raymond James.

Can you hear me okay?

Yes.

Sorry about that.

Congratulations on the progress.

Maybe just to start off with the third generation CAR-T, Laurence, can you just remind us kind of where we are in the process of getting this -- getting the trial started?

And whether you have now been able to consistently sort of generate product above the viability threshold that's required by the FDA?

Yes.

Thanks, Ren, and good to hear from you.

So the key concern from the FDA really was not associated with the Sleeping Beauty system, so in other words, didn't penetrate the core nonviral approach.

It really went to the idea that when you rapidly produce T cells, and we're talking doing this in 2 days or less from gene transfer, those cells, essentially, are coming out of the electroporator and being delivered to the patient as a bulk product, if you would.

So there's a mixture of cells that have gone through that physical process of viable and nonviable.

The FDA guided us last year in June that, that essentially ratio had to be 70% in favor of viable cells.

So what we've done, basically, since that time is develop a process to achieve that goal, in other words, achieve the critical threshold of 7-0, 70% viability.

So by reiterating today that we are on track to open this trial in the second half of this year, I'm giving good guidance, I think, to The Street that the process engineers, who are based in Houston, and we're very grateful to them, really have made significant progress in this area.

And I'm really delighted by what I've been seeing behind the scenes, if you would.

Got it.

And just maybe as a follow-up and switching gears to the IL-12 program.

The ASCO data, you have a poster, you have an oral presentation.

Can you give us just any color as to how many patients in each of those presentations?

How much follow-up should we be looking for?

And what are the key endpoints that we should be focused on?

Sure.

So thank you.

So there's 2 presentations: a poster and an oral.

The poster is going to really focus on the monotherapy and be able to start addressing the expansion cohort.

Now as you'll recall, that expansion study has very rapidly accrued.

In fact, we've actually completed the accrual.

And so the data is locked in, but essentially, the stopwatch is going.

And the reason I highlight that is that we hold ourselves to a high standard around the quality of data and that data is, do the patient survive, do patients who have basically a lethal diagnosis of recurrent GBM, will they survive longer than historical controls, that 6 to 9 months benchmark.

So for that, essentially -- to achieve that, we have to follow those patients out for the bulk of this year.

So the -- I think, the way that I would guide you and investors for that presentation is this will be an interim update.

And I think it will be important for the investor community, but it's a story, really, this will unfold and continue to unfold this year.

The oral presentation, obviously, got a lot of interest from the society, and the reason [this] is, is because we're the company that, for the -- really the first time is solving the problem of why PD-1 inhibitors, such as Opdivo or Libtayo, why they have had such a difficult track record in the treatment of GBM within use of monotherapy.

And the reason is because the most GBMs are immunologically sterile.

There just aren't T cells in there to essentially disinhibit or to engage with your PD-1 asset.

Ziopharm has the answer, and we've published these data with you in the community, showing that IL-12 can change that immunologic desert into one where it's now flush with T cells, and those T cells will reside in that tumor for a long time.

This has, I think, a lot of opportunity and a lot of upside and the abstract and the oral presentation will address that type of technology.

So again, I think it's a really outstanding opportunity for the investors and for the scientific community to learn about how IL-12, really, for the first time, can be partnered with PD-1 in patients with brain tumor.

Our next question comes from Eric Joseph with JPMorgan.

I just wanted to follow-up to start maybe on -- well, on Ren's question regarding the NCI program.

I'm just trying to get better visibility on the path to start of the clinical trial, and you -- just given the TCR program also being based on the Sleeping Beauty technology, the assay -- the IND sort of outstanding for the CD19 hematology program.

Sort of -- is -- are you -- do you -- I guess you'd be thinking about sort of a formal IND having been filed or in place for the CRADA program?

Or they potentially exempt?

Yes.

Sure.

So no, the NCI follows the same type of procedures as any academic or any company.

In other words, they would have approval through the FDA for this, essentially, first-in-human gene therapy trial.

Okay.

Got it.

Got it.

And just on the hematology program with the CD19 Sleeping Beauty CAR.

The -- just wondering sort of what the gating steps are.

I know you guys are on track to providing key feedback in the second half of the year, but just what -- any kind of clarity you can offer in terms of the remaining hurdles that can be overcome?

I guess particularly given that a competitor [was] using a similar technology platform is currently in clinic.

To what extent is your means of modifying the T-cell, not necessarily the CAR itself but modifying the T-cell potentially differentiated from other platform approaches that (inaudible) through the approach?

Yes, I mean, I can't comment on others and what their program is.

But you're talking to the team that invented the very rapid manufacturing of CAR-T.

We understand not only what it is to essentially genetically modify these T cells in 2 days or less but also essentially what the path is to get that trial open and accruing patients.

So we are -- developed the solution to that.

That solution is on track.

It really is associated with the viability question.

That's the primary thrust where we're working.

And solutions that we've developed are elegant, they're our own, and from the data I've seen, they're reproducible.

So we're buoyant about our chances now and I think at this trial, not only off clinical hold but enrolling patients this year.

Our next question comes from the line of RK from H.C. Wainwright.

Regarding the combination study with Regeneron's drug, Libtayo, do you need to wait for the newer study to mature a little bit more before finalizing the protocols so that you can come up with a steady -- with better data from the initial combination study?

And also, what sort of tumors are we looking at with the Libtayo molecule?

Sure.

So, in terms of the package, if you would, about being able to move forward here, the Phase II study is actually really benefited from our work with Opdivo.

This is a risk that Ziopharm took, really, last year, starting a combination in June of 2018.

And I -- And it may not have been apparent to The Street, but the reason why that risk is paying off is that we have essentially understood how IL-12 now can be combined with the PD-1 asset.

We've gone through a number, and I just announced this is -- we've just enrolled into the third dosing cohort here.

So that gives you a clear signal that we've been successful in essentially marrying IL-12 and the PD-1 asset and doing so, in a very careful way, such that we can achieve what we think are the correct doses.

That data has been essentially transmitted to our partner at Regeneron and allowed us now to essentially get to a Phase II trial, which -- the signals are that, that will also be essentially enrolling patients this quarter.

In terms of the types of tumor, this really remains focused on recurrent GBM.

Most patients with a diagnosis of GBM, it's something like 8 out of 10, 9 out of 10 of those patients will recur, and when they recur, they die 6 to 9 months despite everything that's currently commercially available.

So those are the patients that our heart goes out to, those are the patients that are interested in the trial, and I would just add that we have a waiting list for our therapies.

Patients and providers see IL-12 and see the combination with PD-1 as really life changing, and we want to be able to essentially execute on that enthusiasm.

And our next question comes from the line of I-Eh Jen with Laidlaw & Company.

Probably just a follow-up on the IL-2 part as well a little more.

The first one is that there was a paper published about 2 years ago regarding why the PD-1 -- the study failed in the GBM and there's -- some hypothesis has been suggested.

Do you feel that the combination now you have with IL-12 potentially could sort of overcome some of those potential hurdles, as been mentioned in the publications?

Yes.

Thanks, I-Eh.

And thanks also for really being involved now in our story.

So the reasons for PD-1 failure, as I understand that, primarily is driven by the fact that in the GBM and especially in the recurrent setting, is immunologically isolated.

You can't get T cells in there.

So even though the PD-1 asset can essentially activate those T cells by disinhibiting the PD-1, PD-L1 access.

If you don't have T cells nested into and in with the tumor, then those T cells essentially can't get to the problem.

They're circulating, if you would, and they're not intratumoral.

So we are very buoyant on the idea that by IL-12 being intratumorally administered, will totally change the landscape of the tumor microenvironment, essentially using buzzwords, turning a cold tumor hot, getting an immune signal and then getting T cells in there that essentially can be -- essentially activated with this PD-1 inhibitor.

The data around monotherapy of PD-1, you [cite] -- I probably saw the paper from a couple of years ago, I've also been recently updated in a series of monographs and in the Nature Medicine periodical.

And those papers clearly guide around what I'm talking about.

In other words, the immunological signature is critical, if you would, to understanding how well PD-1 will work, and IL-12 essentially takes that immunological signature from a negative to what we think is going to be a positive.

Okay.

Great.

That's very helpful.

Maybe just follow up a little bit on that.

For the collaboration -- for the combo study with the Regeneron's PD-L1, just curious, what dose you might be starting will be repeating what you have, whether before, or you are going to jump on maybe 1 or 2 dose starting with the higher dose?

Yes.

That is an excellent question.

So here, we're building up our data with Opdivo.

So we have a dosing strategy that really is appropriate for a Phase II trial.

I mean, we're not going to be doing a dose-finding study.

We are pretty confident that we know what the sweet spot is for IL-12, and we are pretty confident, based on really the approval of cemiplimab or Libtayo, that we know the dose for that asset.

We know that we essentially can put those together because of all the dose-finding studies we've done where we had to incrementally creep up to where we think the -- sort of the inflection point is.

So as we get ready to enroll, it will be a Phase II study which would -- should enroll rapidly because [we're] essentially pressure testing what we think is the correct dosing.

Our next question comes from the line of Thomas Flaten with Lake Street Capital.

Great.

Just a follow-up on the question about the IND at NCI.

I heard you confirmed that they would be subject to the same rules, but could you confirm that the IND's actually been submitted to FDA?

Or is that still outstanding?

Yes.

Thanks, Thomas, and also thanks for being involved in our story.

So our guidance here is that we're going to be open, essentially, mid-2019.

As we were mentioning on the last -- really call just a few weeks ago, our intent here is to get away from the sort of day-to-day rhythm about regulatory processes.

That, in the past, has essentially not updated the Street nor served Ziopharm well.

But to give you, essentially, confidence about what's going on here, when we're talking to the NCI, and when we are essentially working in partnership with them, they're giving us full confidence that they're on track to enroll patients mid-2019.

And that should give you a good signal about the status of the regulatory process.

Yes.

No, that's great.

And then just a quick housekeeping follow-up.

On R&D spend, there was a bit of an uptick from the fourth quarter, even though compared to first quarter last year, it was down.

Is the first quarter R&D spend a good number for us to use going forward?

Or should we be thinking about a different level of spend for the last 3 quarters of the year?

Sure, sure.

And we can work with you offline a little bit if you need to hear some additional color there.

I think the way to think about that is that when we really went out on our own, we separated from what had been our primary partner Intrexon, they were taking care of a lot of the R&D for us.

That was part of the agreement.

As we now are independent, that R&D budget has to reflect, essentially, that we're in R&D shop as well as prosecuting our commercial assets.

So I think that's part of the story, and I think, for the investors, the good news is that we are now fully in control of our assets.

We are prosecuting our ideas, essentially, to the full extent that we can now because we are on our own, and I can see that, together with my team, a clear opportunity for Ziopharm to essentially make inroads on a variety of ideas and cancer opportunities.

And we're going to go full force on those.

So yes, there may be a sort of a small uptick, but that essentially is, I think, welcome news for the investors.

And we do have a follow-up from Ren Benjamin with Raymond James.

Just -- are you there?

Can you hear me okay?

Yes.

Thanks, Ren.

Yes.

So great.

Just the Eden -- the joint ventures, can you just provide -- I know you mentioned it, can you provide some color as to where we are?

When do you think we might be able to get into the clinic in China?

Just sort of what your thoughts are?

You now had several months.

And then maybe just as a follow-up to that, there are several companies that are developing nonviral systems as you guys are aware of.

But it seems like they're taking a different approach, which is to partner the technology, and there seems to be a lot of interest.

Can you talk a little bit about maybe why you feel or maybe others feel that Sleeping Beauty is really the best nonviral option that's out there?

Or are they roughly the same, and it's really just a race of who gets there first?

Sure.

So first, the Eden BioCell, I actually just got back from China.

And while I can't tell you all of the insight scoop here, I can certainly share the overview that it's dramatic progress, really from an accelerator going from 0, they're now going 100.

People are hired, infrastructure's in place, GMP's being essentially built out, and it looks fantastic.

I mean you would be proud of this operation if it was based here in Boston, it would essentially rival any other company.

Those -- that essentially -- infrastructure essentially then is being married to really a set of clinicians, regulatory people and additional sort of -- if you would, sort of external infrastructure to be able to access greater China.

And that really is remarkable in just a few short months.

And they have now, essentially, the people, the money and our help to be able to now go after this rapid manufacturing of the CD19 asset.

So in terms of the -- when they're going to be treating patients, I can't go much further than say that it's all lining up beautifully, that it's the right people, the right time, and stay tuned because it's a rocket ride.

The next part of your conversation is really around nonviral gene transfer.

So it actually brings a smile to my face because a lot of time, the questions were "Hey, Lawrence, how come you not doing virus?

What's special about Sleeping Beauty kind of thing because why are you doing nonviral when the world is doing viral?" And I just sort of see a -- smile a little bit to myself because the questions now are coming, "Okay.

We see that nonviral is the solution." And so we have been talking about nonviral ever since I got here, and actually, obviously, when I was at MD Anderson, working to get the first human trials done.

So that is a long history now of being able to work in the nonviral space and fully understand how Sleeping Beauty, how a nonviral system essentially can be used.

And I think what you see is that we're not just trying to replace lentivirus or retrovirus, we're not just trying to replace or have a different transposon compared to, say, a piggyback, we're going after solutions, and that's the critical message.

The solution that we're providing in the TCR space is that the Sleeping Beauty system because we've treated so many patients in the CAR-T, has a direct line of sight now for TCRT.

I'm not worried about whether Sleeping Beauty works anymore or not, we know it works.

The question now is, can it now execute in the TCR space?

So we derisk the program to get its essential question: can TCRs against neoantigens put a patient in remission?

Similarly, we're providing the solutions around, essentially, the cost and the complexity of viral-based gene transfer in the CARs.

Again, we're not just trying to replace lentivirus, what we're trying to do is provide, essentially, The Street and the community with a solution for those big problems, the cost and complexity, and that, of course, is where we combine the Sleeping Beauty with, essentially, CARs and the IL-15.

So we have an inside track, we're first movers here in the TCRT space, and we're first movers in getting, essentially, the manufacturing time for 2 days for CD19, which is a commercially approved product.

And I'm not showing any additional questions.

Okay.

So thank you, operator.

And thank you all on the phone.

Have a great day.

Ladies and gentlemen, this does conclude the program.

You may now disconnect.