Medicenna Therapeutics Corp (MDNA) 2022 Q1 法說會逐字稿

Hello, and welcome to Medicenna Therapeutics fiscal first quarter earnings call. (Operator Instructions) Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to Dan Ferry of LifeSci Advisors. Please go ahead.

Thank you, operator, and thank you all for participating in today's conference call. This morning, Medicenna issued a press release providing financial results and corporate updates for the quarter ended June 30, 2021. If you have not yet seen the press release, it is available on the Investors page of Medicenna's website.

Before we begin, I would like to remind you that certain statements and information shared during this call constitute forward-looking information within the meaning of applicable securities laws and relates to the future operations of the company and other statements that are not historical facts, including statements related to the clinical potential in development of the MDNA11, MDNA55 and BiSKITs programs; the potential of Superkine platform, partnering activities, cash runway, and the presentation of additional data.

All statements other than statements of historical fact included in this conference call including the future plans and objectives of the company are forward-looking statements that are subject to risks and uncertainties. There can be no assurance that such statements will prove to be accurate and actual results and future events could differ materially from those anticipated in such statements. Important factors that could cause actual results to differ materially from the company's expectations include the risks detailed in the recently filed annual information form, management's discussion and analysis in Form 40-F of the company and in other filings made by the company with the applicable securities regulators from time to time in Canada and the United States.

Listeners are cautioned that assumptions used in the preparation of any forward-looking information may prove to be incorrect. Events or circumstances may cause actual results to differ materially from those predicted as a result of numerous known and unknown risks, uncertainties and other factors, many of which are beyond the control of the company. You are cautioned not to place undue reliance on any forward-looking information. Such information, although considered reasonable by management, may prove to be incorrect and actual results may differ materially from those anticipated.

Forward-looking statements contained in this conference call are expressly qualified by this cautionary statement. Except as required by law, we do not intend and do not assume any obligation to update or revise publicly any of the included forward-looking statements only as expressly required by Canadian and the United States Securities law. Now I will turn the call over to Dr. Fahar Merchant, President and Chief Executive Officer of Medicenna Therapeutics. Fahar?

Thanks, Dan, and thanks to all listening for joining us on the call today to discuss our Fiscal Q1 2022 Corporate Update. In addition to that, I'm joined by Dr. Mann Muhsin, our Chief Medical Officer; and Liz Williams, our Chief Financial Officer. The last several months have been an important period of execution during which we achieved key clinical, scientific, and corporate milestones. These milestones have left us poised for sustained success with a steady cadence of catalysts expected over the coming months.

On today's call, we will briefly review some of these recent accomplishments, discuss our plans and expectations for the upcoming Phase I/II ABILITY Study of our selective long-acting IL-2 super-agonist MDNA11 and lay out the clinical, scientific, and corporate objectives we will be working towards as we continue through the remainder of fiscal year 2022 and beyond.

So let's start with some recent accomplishments beginning with our MDNA11 program. Last quarter, we completed the submission of our clinical trial application to a human research ethics committee in Australia in order to commence our Phase I/II ABILITY Study. Mann is going to speak at length about the clinical trial in a few moments, but what I would like to emphasize now is that we remain on track to start enrollment in the study in Australia during calendar Q3 and we will be expanding additional sites in the U.S., Canada and U.K. thereafter. We expect the remaining regulatory submissions and approvals for these different jurisdictions to be complete before the end of the calendar year.

I will now turn your attention briefly to MDNA55, our IL-4-guided toxin targeting recurrent glioblastoma or rGBM, the most common and uniformly fatal form of brain cancer. We are very pleased to have data from our Phase IIb trial published in a prestigious peer-reviewed journal Clinical Cancer Research last quarter, which provided important external validation for our program. These data were discussed at length during our last earnings call in May.

So in the interest of time, I will now just emphasize the paper's main finding, which was that the early determination of progression free survival using modified renal criteria appears to be a strong surrogate for overall survival in recurrent GBM. Together with previously presented modified renal-based response rates and overall survival data from the study, we believe this finding bodes well for the conduct of the planned Phase III MDNA55 trial where mRANO based PFS could potentially be a reliable early surrogate for overall survival.

Looking forward to our MDNA55 program, we remain in active discussions in pursuit of a partnership to facilitate its further development and commercialization. While the details of these conversations need to remain confidential at this point, we look forward to providing a more thorough update on these activities when appropriate.

In the interim, we at Medicenna continue to advance the required regulatory activities associated with MDNA55 GMP manufacturing and future commercial supply for potential market launch. Submission of the Phase III protocol to the regulators and selection of a contract manufacturing organization for long-term commercial supply of MDNA55 will be finalized jointly with our future development partner with the expectation that the Phase III registration trial can be initiated in 2022.

On the discovery and preclinical front, we recently announced a peer-reviewed publication in Frontiers in Immunology featuring data on MDNA109, which is our IL-2 Superkine platform, which is the precursor of MDNA11. The paper, which was independently authored by researchers at the University of Helsinki and other institutions, evaluated oncolytic adenoviruses that were either unarmed, armed to code for MDNA109 or armed with wildtype IL-2 in a hamster pancreatic cancer model.

To provide some brief background, oncolytic adenoviruses lead to selective infection and lysis of cancer cells and can effectively deliver therapeutic levels of cytokines into tumor lesions and also promote antitumor immune response. Data presented in the paper showed that compared to treatment with IL-2 armed virus, treatment with MDNA109 armed virus led to superior tumor growth inhibition with a clear tendency towards achieving complete tumor regression.

Mechanistic analysis showed that this was due to MDNA109's superior ability to reprogram the tumor microenvironment as MDNA109 virus induced efficient T cell receptor signaling, it activated cytotoxic anti-cancer immune cells and inhibited tumor protecting myeloid cells in the tumor microenvironment. Additionally, MDNA109 virus demonstrated the ability to induce a potent antitumor immune memory response to protect previously treated hamsters against rechallenge with pancreatic cancer cells.

Collectively, these results externally validate the versatility of the MDNA109 platform and its potential to overcome limitations associated with less active versions of IL-2 such as native IL-2, particularly in immunologically cold tumors such as pancreatic cancer where a great unmet need exists today. Going forward, we plan to continue leveraging the versatility offered by our Superkine platform in our discovery and preclinical programs as we seek to develop next-generation Superkine-based therapies such as our BiSKITs platform.

In addition to forming the basis of MDNA11, our IL-2 Superkine platform, MDNA109, is also a core component of our BiSKITs program. As a reminder, BiSKITs are highly versatile and targeted by functional molecules that comprise of a Superkine fused to a second anticancer therapeutic agent such as a checkpoint inhibitor or a second Superkine. The BiSKITs platform enables us to design bespoke immunotherapeutic agents that incorporate 2 synergistic mechanisms required to treat more aggressive and recalcitrant tumors where our simultaneous 2-pronged approach may be necessary to improve safety and efficacy.

During the fiscal first quarter, we presented at the AACR Annual Meeting, data on our MDNA19, MDNA413 BiSKIT. These data, which were discussed in detail during our last earnings call in May, demonstrated MDNA19 and MD413's potent immune modulating effects and it's potential to overcome immunotherapy resistance mechanisms and treat immunologically cold tumors.

They also showed how the biscuits platform can efficiently combine the enhanced immune signaling properties of multiple Superkines, in this case, an IL-2 super-agonist and an IL-4 IL-13 super-antagonist into a single bifunctional long-acting therapeutic. Looking forward, we remain very excited about the potential of the BiSKITs platform and expect to declare a lead BiSKIT candidate by the end of the calendar year.

Lastly, before I hand the call off, I'd like to highlight 2 corporate milestones we achieved last quarter. These were the appointments of Dr. Mann Muhsin and Dr. Kevin Moulder as CMO and CSO, respectively. You were introduced to Mann and Kevin on our last earnings call and since then, each has continued to integrate seamlessly into our management team. I look forward to our continued work together and I am that we were able to attract candidates of their caliber to the company. And with that, I'll hand the call off to Mann to provide some more details on our MDNA11 program. Mann, please go ahead.

Thank you, Fahar, and good morning everyone. I'm happy to have the opportunity to speak with you all today about Phase I/II ABILITY Study of MDNA11, which is our novel selective and long-acting IL-2 super-agonist. As Fahar mentioned, we remain on track to start enrolment in the study in Australia in calendar Q3 and we'll then be expanding the trial to sites in U.S., Canada and U.K. thereafter, in line with our previously stated guidance.

Now one thing I want to emphasize is that we feel reassured in this guidance even in light of Australian government's recent COVID-related restrictions. Conversations with our clinical sites, trial investigators, and Australian domiciled-CRO have confirmed that the treatment of oncology patients is considered an essential service and therefore exempt from COVID restrictions, including travel between different regions.

Further, during our conversation with these parties, we were ensured that prior government-mandated lockdowns in Australia had minimal impact on enrollment in Phase I oncology trials, which adds to our level of confidence. We will, of course, remain in constant contact with our CRO, trial sites, and investigators as the study progresses and we'll keep the market updated if any material changes occur to our stated timelines.

Now with regards to the design of the ABILITY Study. It will be a Phase I/II [BASK] study that will evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of various doses of intravenously administered MDNA11 every 2 weeks in patients with advanced solid tumors. It will begin with an MDNA11 monotherapy dose escalation phase, which will be followed by a dose expansion with both an MDNA11 monotherapy arm as well as a combination arm designed to evaluate MDNA with a checkpoint inhibitor.

The dose escalation phase will permit alternative dosing schedules and also include options for intra-patient dose escalation, which will allow us to gain a wealth of information to inform the expansion phases of the study. Patients that will be enrolled in the ABILITY Study may have any one of 10 different solid tumor types, including advanced renal cell carcinoma and metastatic melanoma. These 2 tumor types are of particular interest as they are known to respond to recombinant human IL-2 also [aldesleukin], but to date have not shown comparable responses to the new long-acting variants of Proleukin currently in the clinic. We, therefore, believe that by evaluating MDNA11 in these tumor types will present an opportunity to demonstrate MDNA11's best-in-class potential.

Now what clearly differentiates MDNA11 from Proleukin and other agents in the IL-2 landscape is that it has been engineered so that binding to IL-2 receptor alpha is abolished whereas binding to IL-2 receptor beta is substantially enhanced. This is crucial as stimulation of IL-2 receptor alpha leads to preferential activation of tumor protecting TRx cells that can suppress systemic antitumor immune response and causes extreme toxicity whereas stimulation of IL-2 receptor beta is key for activation of cancer killing immune cells that are the target vectors of IL-2 therapies.

MDNA11's beta-only IL-2 receptor selectivity gives the molecule the potential to outperform other agents in the IL-2 landscape, which rely entirely on the not alpha approach. What I mean by this is that rather than having reduced IL-2 receptor alpha binding and enhanced IL-2 receptor beta binding compared to Proleukin, as in the case of MDNA 11, these competing IL-2 variants were designed to simply reduce IL-2 receptor alpha binding. This was done via PEGylation.

Now while PEGylation does reduce IL-2 receptor alpha binding and improve half-life, it also considerably interferes with and reduces IL-2 receptor beta binding when compared to Proleukin. We believe this is the reason as to why not alpha PEGylated variants have produced sub-optimal clinical data to date compared to Proleukin as these molecules are likely not sufficiently activating cancer killing immune cells due to their sub-optimal IL-2 receptor beta binding affinities.

Now in addition to believing that MDNA11 will outperform competing not alpha IL-2 variants, we also believe that it has the potential to overcome the shortcomings of Proleukin. As I mentioned a few moments ago, Proleukin stimulates IL-2 receptor alpha. This leads to activation of TRx, which inhibits the antitumor immune response and is associated with unfavorable prognosis in [CAS]. It also causes extreme toxicity, which necessitates dosing of Proleukin in the ICU. Finally, Proleukin must be dosed every 8 hours for 9 days due to its poor pharmacokinetic properties.

We believe that MDNA11's beta-only selectivity will allow it to overcome the toxicity concerns associated with Proleukin and its high affinity to beta receptor will also lead to improved efficacy. Additionally, using human albumin as part of the MDNA11 confirms improved pharmacokinetic properties on the molecule. This should enable much more convenient closing schedules, potentially dosing every 2 or 3 weeks. We also expect that it will lead to improved tumor accumulation, which in turn would further enhance the molecule's efficacy.

Our belief that MDNA11 has the potential to be a best-in-class therapy is supported by a robust preclinical data set. Looking forward, we are eager to bolster this support with the clinical data updates we expect to report from the ABILITY Study in the coming months. The first update from the trial, which is expected later this calendar year, will include preliminary safety, PK, PD and biomarker data from the dose escalation cohorts of the study. From their prospective pharmacokinetics, we aim to see preferential MDNA accumulation in the tumor and albumin mediated half-life extension that would facilitate dosing every 2 or 3 weeks, consistent with an extended PD effect following 2 weeks dosing in the non-human primate studies.

With regard to PD and biomarker data, we will be taking paired biopsies from patients before and during treatment and assessing the changes in the tumor microenvironment. We'll also be looking at the peripheral biomarkers and immune cell markers to see size of anticancer immune cell activation, a lack of activation of TRx and pro-inflammatory and sensitive tumor microenvironment, which would confirm that MDNA11 is making the tumor microenvironment more immunogenic, which in turn would bode well for subsequent data readouts.

Now speaking of subsequent data readouts, preliminary efficacy updates from the ABILITY Study are expected throughout calendar year 2022 as monotherapy and combination efficacy data from the study are reported and mature throughout 2022. We hope to see objective response rates that meet or exceed those generated with agents in the same drug class long with improved durability of response and a more favorable safety profile. When coupled with a more convenient dosing regimen, it would clearly position MDNA11 as the best-in-class agent and bode well for its continued clinical development and collaboration opportunities for a variety of indications and combinations. With that, I'd now like to hand the call off to our CFO, Liz Williams, to discuss our recent financial results. Liz?

Thanks, Mann, and good morning, everyone. Before I begin, I would like to note that all references are in Canadian dollars, unless otherwise noted. I'm pleased to report that Medicenna maintained its strong cash position over the last quarter as we had cash, cash equivalents and marketable securities of $35.9 million as of the quarter close. During and subsequent to the quarter-end, Medicenna received a total of USD1.4 million for the reimbursement of past expenses through our non-dilutive grant from the Cancer Prevention and Research Institute of Texas, further strengthening our cash position. We believe this cash will be sufficient to fund our operations through to the end of calendar 2022, including through preliminary updates on biomarker PK/PD, safety and efficacy data from our Phase I/II ABILITY Study of MDNA11.

Net loss for the quarter ended June 30, 2021, was $6.4 million or $0.12 per share compared to a loss of $2.4 million or $0.05 per share for the quarter ended June 30, 2020. The increase in net loss for the quarter ended June 30, 2021 compared with the quarter ended June 30, 2020 was primarily a result of increased research and development expenditures related to the MDNA11 program as well as costs associated with the NASDAQ listing, in particular, directors and officers insurance premiums in the current period.

Research and development expenses of $4.3 million were incurred during the quarter ended June 30, 2021 compared with $1.8 million incurred in the quarter ended June 30, 2020. The increase in R&D expenses in the current year quarter is primarily attributable to higher CMC costs associated with the GLP and GMP manufacturing of MDNA11 for the ABILITY Study, increased pre-clinical expenses associated with GLP compliant MDNA 11 IND enabling studies as well as discovery work on our BiSKITs platform, increased clinical costs due to activities in preparation of the initiation of the ABILITY Study, and higher salary and benefit cost associated with increased headcount necessary to support increased activities. These increases in expense in the quarter were partially offset by the reimbursement of expenses from the CPRIT grant.

General and administrative expenses of $1.9 million were incurred during the quarter ended June 30, 2021 compared with $0.7 million during the quarter ended June 30, 2020. The increase in expenditures year-over-year is primarily attributable to increased directors and officers liability insurance premiums due to our NASDAQ listing. For further details on our financials, please refer to our financial statements and management's discussion and analysis, which will be available on both SEDAR and EDGAR, respectively. With that, I'll now hand the call back over to Fahar.

Thanks, Liz. Before we can move on to the Q&A, I'd like to take a moment to recognize the talent and dedication displayed by the Medicenna team as well as our partners and investigators over the past months. Thanks to their efforts, our MDNA11 ABILITY Study and other programs have continued to advance as planned despite the ever-evolving circumstances around the pandemic. This has left us poised to achieve a steady cadence of value creating milestones, in line with our previously stated guidance. Looking forward, we expect the continued advancement of these programs to drive our sustained growth and most importantly, address the unmet needs of the patients.

With that, we will now open the lines for questions. Operator?

(Operator Instructions) Our first question is from Matt Biegler with Oppenheimer.

Congrats on the recent progress. Fahar, looking ahead to year-end, just wondering if you could elaborate on what types of translational data you think are most relevant as we look for early signs of efficacy. Assuming it's things like Ki67 induction and potential for regulatory T cells but just wondering if there are others we should be interested in. And also, I may have missed this, but can you just remind us if you're hoping to get any biopsy data from this trial?

Yes. Thanks, Matt. Good to have you join the call today. Certainly, what I will do is both of the questions, I'll pass them along to Mann who'll be better able to provide you with the details on both of those questions. Mann?

Thank you, Fahar and thanks for the question. So the study will be looking into an area of immunophenotypes and biomarkers in the peripheral blood. So there are certain biomarkers that are known to be associated with T cell activation, exhaustion, recruitment and tumor infiltration.

So the study will examine, for example, CD8 to Treg ratio as well as change from baseline and level of increase as well as the increase in the expression, upregulation of biomarkers in favor of clinical benefit driven by immune cell activation such as Ki67, which you indicated in the question, ICOS, CD25, PD-1, [spore] CTLA-4 and many, many others. Furthermore, we will anticipate some favorable trends in increases in the surrogate efficacy markers.

We will expect also albumin mediated half-life extension, preferential biodistribution in the tumor and Th1 bias in the tumor microenvironment as measured by increased T cell priming, trafficking, and filtration TILs. In paired biopsies as well as markers such as CD3, CD4, CD8b, FOXP3, GNLY and natural killer cells marker and we'll assess major cell lineages, T cell subtypes, CXCR3, CCR6 and CCR7 and exhaustion markers, classically PD-1 and LAG-3 and finally, we will study gene expression patterns in the NanoString IO 360 panel, which is commonly used in IO agents.

So based on the pre-clinical data, the half-life MDNA11 seemed to be longer than comparable novel agents in the drug class alone for dosing every 2 or 3 weeks and that is what the ABILITY Study will evaluate and those markers should map well with this half-life extension. Furthermore, the pharmacodynamic markers associated with the MDNA11 treatment seem to substantially outlast the pharmacokinetic trends.

The half-life flexibility is significant because it will enable our agent MDNA11 to be combined with all checkpoint inhibitors whether the backbone treatment has a cycle of 2 weeks or 3 weeks or even for 4 weeks, we will be considering that given the pharmacodynamic marker that's substantially outlast the pharmacokinetic markers. I hope I answered your question to the level of detail that you would like and feel free to follow-up if you have any follow-up questions.

I mean that seems consistent with the pre-clinical data, which is cool. Fahar, I wanted to ask a follow-up just relating to the IL-2 field more broadly. As you know, it's getting pretty crowded with several entrants, also testing new approaches like [conditional] activation, targeted IL-2 -- just maybe if you could just speak to why you believe an optimized version of Proleukin, which is effectively what MDNA11 is, why that's the best approach to take.

Thanks, Matt. Clearly, yes, you're right. There's lots of different approaches being pursued with respect to the IL-2 space and we are aware of those, but generally, I would say, first and foremost, I would like to make it very clear that although we sort of classify our program very much like an optimized version of Proleukin, in fact, our molecule is far from it.

So that although you might look at the other candidates that are in the clinic very much as optimized versions of Proleukin, MDNA109 actually is dramatically different from Proleukin in the sense that not only does it have the extension of half-life, which is common with all other interleukins that are in the clinic at the moment, but I think the important differentiation here is clearly that not only do we reduce binding to CD25 and therefore, have reduced alpha dependency, our molecule has been engineered so that it has substantially better affinity for beta or CD122.

And this is where the big difference is between the work that's being currently in the clinic versus the work we are doing and therefore, I believe we have that unique differentiation and the desire for selective binding to CD122 and therefore, preferentially stimulating naive CD8 T cells, NK cells as well as effector T cells is crucial with the approach that we are pursuing. Now yes, there are other approaches for localization, for instance, using ways of tumor based activation using conditionally activated IL-2.

Again, remember those IL-2s tend to be similar to Proleukin and there is a whole bunch of dependency of those particular tumor types because, remember, activation of those tumors or at the tumor site itself will be dependent on what kind of tumor it is, whether it is producing the required protease to activate the IL-2 et cetera. So there will be quite a lot of variability from tumor type to tumor type, patient to patient and we can never expect that the dosing regimen et cetera that is established will work in multiple tumor types or not because there's so much other dependencies as well.

So yes, there are potential ways of localization, but what we have achieved with MDNA11 is that by virtue of us fusing our molecule to albumin, there is considerable amount of data to also support the fact that molecules like MDNA11 that have an albumin domain tend to passively accumulate in the tumor itself as well as we know from data that they accumulate in tumor draining lymph nodes.

Both of those accumulations of our IL-2 are crucial because they provide, we believe, a much better safety profile, but also localized stimulation of the immune cells in addition to that you might see from a peripheral perspective. So I think we are achieving both goals with our MDNA11 program in terms of localization by virtue of the albumin, but also the selectivity towards CD122. So that's I guess the key differentiator. And I'll ask Mann if he has got anything else to add?

Thank you, Fahar. Yes, I think I want to emphasize on the albumin component of our compound and if we just learn from history, there is no tumor as desmoplastic as pancreatic cancer and the very only drug approved in this tumor type is ABRAXANE, which a nab-paclitaxel, it's a nanoparticle albumin bond paclitaxel, which is able to accumulate and penetrate through tumor as desmoplastic as pancreatic cancer.

So I believe albumin is a key component of the drug on top of the mutations and affinity to CD122 and it's limited, if any, Treg activation, I think albumin will enable us to grow the tumor types with huge unmet needs, (inaudible) immunogenicity spectrum but are not that -- not be that responsive to IOs and that will give MDNA11 positive attributes that make it superior and best-in-class compared to competing agents in the IL-2 development landscape.

Our next question is from David Martin with Bloom Burton.

So my question is a competitive one as well. One of your competitors instead of your approach of increasing CD122 and decreasing CD25 binding has reduced binding to CD132. I'm wondering if you can talk about biologically what you'd expect out of your approach versus the reduced CD132 binding. And in particular, they seem to think that the activation of the naive T cells and the NK cells might be the underlying cause of the toxicity of the vascular leak syndrome? And can you talk about what you've seen so far as far as VLS?

Right. So answering your last question with respect to VLS. So far, all the doses that we have tested in non-human primates going as high as 600 micrograms per kilogram, we haven't seen either clinically or histologically any signs of vascular leak syndrome so far. So that's very encouraging and it sort of consistently supports the hypothesis that the binding it to beta is not the culprit here in terms of vascular leak.

In fact, the same author of the work that you mentioned regarding the competitor has published in Nature the work with MDNA109 where you had clearly a higher affinity to CD122 and that publication demonstrated lack of vascular leak or lung edema in that paper and clearly showing that having high affinity to CD25 was the cause of vascular leak. So in a sense, we feel quite encouraged with those data and consistent with other approaches and other data that have been published to date, the CD25 is likely the more critical culprit in the vascular leak scenario.

So with respect to reduced binding through Gamma C, clearly, what you sort of end up doing is that you will reduce the signaling and therefore, proliferation of this actual cells mainly the effector T cells to fight the cancer and on top of that, you prevent signaling and proliferation of naive CD8 T cells and also the same with NK cells. And I must say that we believe that activation of NK cells is important in tumor control and I will sort of pass that along to Mann, who has obviously a much better understanding of the role of NK cells and naive CD8 T cells and why the approach that we are taking is the correct one. Mann?

Yes, thank you, Fahar. Yes, so NK cells are very important, critical components of the immune surveillance in human immune system and the human immune surveillance mechanism is key and it's evolved to protect against tumorigenesis. So the importance of the NK expansion and modulating the tumor microenvironment and to achieving some therapeutic effect in certain agents [and newer models] and it's clearly shown that it does that.

It does that immune surveillance. It modulates the tumor microenvironment without eliciting toxicity and this has been established in tumor models and in publications as well and as Fahar indicated, last but not least, our GLP studies, the data we have seen so far from the MDNA11 show clearly those findings and it's well aligned with the existing knowledge today, publications and animal models that stimulation of CD122 will not result in that toxicity that is prohibitive of dosing in humans and as we all know, this is the basis of many IL-2 agents in the development landscape today. And thanks for the question.

Our next question is from Naureen Quibria with Maxim Group.

So I guess the first one is, I'd like to just sort of drill down on -- can you hear me?

Yes.

Okay. I'd like to drill down on what Matt asked earlier with regards to the biomarker data that will be presented or will be reported at year-end. So Mann, you kind of rattled off quite a few biomarkers. Are there any specific ones that will give you greater confidence in the drug's profile? And are there any benchmarks related to those specific biomarkers that we should focus on?

Thanks for the question. Yes. So we do have -- the list I provided is the short list. We have an extensive list of biomarkers. Some of them are classical for the IL-2 pathways and some of them are novel that we believe we will see some substantial effect of movements or ratio like the example I gave about CD8 to Treg and at this point in time, it's hard to predict which one of them exactly moves to what level to make it significant.

As you know, those markers could be variable from one patient to another. As a matter of fact, some of those markers, as you know, can be even variable within the same patient as they progress from one treatment to the next. So it's hard to disclose specifically what markers will move at what level at this point in time but as indicated earlier, we will be absolutely providing you guys with continuous update as we close more patients and progress through the course of the study.

Got it. That's helpful. And Fahar, with respect to the same ABILITY Study, obviously, you're planning to expand. You've mentioned beyond Australia to other jurisdictions, North America, U.K., Canada. I guess perhaps I missed it, will you be planning on to go -- have those other sites come online at about the same time or is there a specific sequence in the regions that you plan to have the study come online?

Right. Yes, good question. The key thing for us is that before the end of this year, we should have submitted and secured approval from each of these 3 jurisdictions, namely U.S., Canada and U.K. to start enrolling in this global Phase I/II clinical trial. So the sequence is not -- it's basically going to be whichever comes through first and we'll proceed along that basis and therefore, unlikely that we have full control over that.

Of course, that would be based on each of the territory's process of reviewing, namely ethics review and regulatory review and we will be submitting though, most of these different applications at more or less the same time frame. So nothing special in terms of which territory should come online first.

Our next question is from RK from H.C. Wainwright.

A lot of my questions have been answered. In terms of the BiSKITs program, what's the next thing that we should expect?

Yes, so with BiSKITs, as you know, we did present some data at the AACR meeting in early first half of this year. It was really focused very much along the 2 fusion partners, namely MDNA413, which is the IL-4, IL-13 antagonist fused to our IL-2 super-agonist. So that program was the data that we shared with. The company is continuing to screen a number of different versions of BiSKITs that consist of different Superkines, but also different fusion partners and those activities are continuing with respect to optimization of the specific linkers that we use, the specific cytokine or Superkine that we use and also the orientation of these Superkines.

So that work is currently well underway. We are hoping to identify a lead candidate that is an optimized candidate before the end of this year so that we can then start IND-enabling studies in 2022. So that is our plan and the identification of a lead candidate has not been finalized yet. It will be done at the end of this year.

And then on the ABILITY Study itself, would patients from Europe and U.S. be included or do you need to do some additional work to get the regulatory filings started both at the FDA and the EMA?

Yes. Sorry, yes, we are looking to U.S., Canada and U.K., and those 3 territories, the filings will be identical with respect to all the work that has been done to date for the Australian submission. So in that sense, we do not expect to have any additional work required for these different filings. So the data that we have so far will be sufficient and of course, if you have additional data from the Australian patients as they are enrolled, those will certainly be supplemented, if necessary, but otherwise, no, the package would be more or less identical other than the required geographical changes in how you sort of submit the document, but the content will be identical.

(Operator Instructions) Our next question is from David Bautz with Zacks Small-Cap Research.

So most of my questions have been answered, but Liz, a question about spending. How do you think we should -- how should we think about R&D spending in the upcoming quarters compared to the current quarter?

Yes, so our projected burn by quarter for the next sort of 18 months is about CAD5 million to CAD6 million per quarter. It will fluctuate up and down. This quarter, we did have some significant costs associated with GMP manufacturing and we do expect that, that's split over the current quarter as well as our fiscal Q2, so ending September 30. And then in the second half of the year, it will be a bit lower, but of course, the CMC costs will be replaced by clinical costs. Yes, that's our projection. So about sort of CAD3 million to CAD4 million per quarter in terms of R&D expenses going forward.

And our next question is from Kumar Raja with Brookline Capital Markets.

With regard to the CTA review, where do we stand? What are your expectations there? Like do you have any update there from the agencies? And also, are you able to screen patients while the CTA is being reviewed?

Right, good question. So yes, the application is under review. We are on target to enroll patients this quarter. So things are progressing well and we will notify the markets as soon as we've enrolled our first patient. With respect to the second question regarding -- I'll sort of pass it on to Mann.

Thank you, Fahar. Yes, so we are in direct communication with our investigators in Australia. Now technically for the screening and pre-screening activities, as you know, they won't happen without a patient signing the informed consent, which requires the full submission to be accepted, approved and so forth, but we have, as Fahar indicated, we have every reason to believe and full evidence that we will continue as our timelines and projections and as our guidance to dose the first patient in the study by the end of calendar Q3 and we'll provide updates as soon as we are able to.

Okay. With regard to U.K. and U.S., you mentioned that you'll be moving forward with the application as and when possible, but in terms of the clinical trials in these 2 restrictions, how are you thinking about leveraging data from Australia?

So clearly, with Australia, we would -- as I mentioned earlier, the study design is essentially the same design across the globe. The data, as we obtain this data will be, therefore, used to supplement. So we would be required to provide any additional evidence to the regulators if we have them at that time. So that would be the normal course of business and therefore, we'll sort of follow the same regulatory guidelines with respect to any new data that is generated.

And that will certainly help with respect to dosing and therefore, we can continue with the dose escalation along the same basis once we have data from the earlier cohorts that should translate into proceeding with the higher dose cohorts in those other territories as well.

We have reached the end of our question-and-answer session. I would like to turn the conference back over to Fahar for closing comments.

Thank you, operator. Thanks again to everyone for joining us on the call and also our loyal shareholders. We look forward to the continued advancement of our pipeline and we'll keep everyone updated along the way. Thank you again. Take care and bye-bye.

Thank you. This does conclude today's conference. You may disconnect your lines at this time and thank you for your participation.