MacroGenics, Inc. H.C. Wainwright 28th Annual Global Investment Conference

I'll jump right in. I'll be making some forward-looking statements during today's presentation, so please refer to our SEC filings for additional disclosure on the various risks that we face. As was just highlighted, I've now stepped into the CEO role about a year ago, and it's been a really exciting year for the company. It's been a transformative year for the company, and I'd say it's been underscored by a renewed sense of urgency and focus across all aspects of the business, a commitment to a simpler organization structure, which was also highlighted by some of the decisions we made earlier in the year to divest our embedded CDMO operation to Bora Pharmaceuticals. That deal closed at the end of Q2, brought in $120 million. We're able to also right-size the operation to about now 140 employees. Previously, we were well into the 300 number.

We're definitely a leaner, meaner organization, very much committed to delivering value for our shareholders and for also delivering transformative medicines for the patients that we serve. You can see on the slide we have a broad base committed to next-generation antibody therapeutics with three core platforms. Much of that is leveraging homegrown technology, including our DART and TRIDENT platforms that enable multi-specific targeting. We also have a keen interest in ADCs, where we're leveraging best-of-breed technology that we've licensed through third parties that have proprietary drug linker chemistries, four clinical stage programs, and soon to be five with another ADC that will be entering the clinic imminently. What's also important to highlight is we're not just a technology boutique.

We have had a history of really being able to navigate drug development and take things all the way with three assets from our early-stage portfolio that are now on the market and being sold. For all three of the assets listed here, we maintain some residual economic interest in those programs. Over this last year, we've been phenomenally productive with BD in partnering. We've brought in over $300 million into the company, so we have a very strong financial footing with cash runway through the end of 2028. The pro forma cash balance that we highlighted on our last earnings call is about $327 million.

That gives effect to also the Bora Pharmaceuticals consideration for the sale of the manufacturing facility, some milestone that we received from Sanofi related to the TZIELD asset, as well as a partnership milestone that was paid by Gilead, which is a really important corporate collaborator for the company. You can see on our pipeline slide eight separate assets that are listed here. Many of them we retain global rights, including all of our ADC portfolio listed as MGC026, MGC028, and MGC030. Two of those ADCs are first-in-class programs. That includes the ADAM9 program, which is called MGC028, and a third program, which is still an undisclosed target, where IND was filed actually a quarter ahead of schedule. It was cleared, and we're now going to be dosing patients very soon.

We have our dual checkpoint molecule, lorigerlimab, and then the T-cell engager portfolio, where Gilead has been a really strong partner here. First project was partnered in late 2022. About a year later, they came back. They wanted to expand with a second molecule, which is a TRIDENT-based construct, so that enables trivalent targeting for solid tumor applications. Last November, we added a third molecule into the mix here, so three active programs. What we also just highlighted recently in our earnings press release was a new molecule called MGD032. This is a next-gen T-cell engager that we think potentially addresses some of the challenges of conventional CD3-based targeting approaches, both better safety as well as potential extended durability, which is something we're very excited about, and that molecule is moving into IND-enabling studies. It is directed against an undisclosed target.

Just quickly, a little bit on some of these future assets. MGC026, this is a program we'll be presenting a clinical update at ESMO in late October. This is a program we're very excited about. Also, I think the broader industry has shown renewed interest in this target and has really started to appreciate the potential of B7H3 targeting ADCs, which now have shown broad clinical validation in almost 15 different solid tumors. Small cell lung cancer is the one that has obviously garnered the most attention, but we think there's still a lot of room here to really build the franchise with our program. We have highlighted to date that we have an encouraging safety profile, including no ILD, which we attribute to some of the design features of our molecule.

It is an Fc silenced design, which we think abrogates some of the nonspecific uptake of alveolar macrophages that potentially has driven some of the ILD liability for other groups. Head and neck cancer, we've now recently highlighted as an emerging lead indication, which we think is an area of high unmet need and very well matched with the profile of our molecule. I mentioned that B7H3 is a very attractive target. Part of the appeal here is its multimodal kind of mechanisms. The fact that B7H3 is expressed in the epithelial tumor, it's also expressed in the tumor-associated stromal component and the tumor vasculature.

We've also seen evidence that it's expressed in the myeloid-derived suppressor cell populations, which means if you can take out those cells, you may also potentially further improve the activity when combined with other complementary mechanisms like immune checkpoints, and we'll show you some data there, which we're really excited about. There are a number of other competitors in this space. We highlight on this slide four other programs that are very well-resourced. Daiichi Sankyo and Merck, they actually have a PDUFA date in October for their small cell lung cancer efforts. Hansoh Pharmaceutical Group, GSK, MediLink Therapeutics, Roche, and DualityBio and BioNTech all working with Topo 1-based approaches. Each of these molecules has unique features. We highlight a few of the distinguishing factors. One is we are the only group here that has a site-specific conjugation approach, which enables a much more uniform DAR 4 species. We have a silenced Fc domain.

Within the Topo 1 class, not all Topo 1s are the same. Exatecan has shown in some preclinical work that has higher potency relative to deruxtecan, which is the operative payload with the Daiichi construct, about 2 to 5-fold higher potency, actually better bystander killing effects, and less susceptibility to multi-drug resistance. So very good payload, very good linker. We also are very excited about the actual antibody construct that we have, which is a very efficient internalizer. We have completed the dose escalation of this study, which is on this slide. That happened late last year. We initiated expansion cohorts in these tumor-specific populations. Head and neck cancer is the one that's furthest along.

We did successfully clear the first stage of this Simon two-stage design that was based on meeting a predefined ORR threshold and continue enrollment in a cohort for endometrial, melanoma, soft tissue sarcoma. Head and neck cancer, again, this is a space that a lot of attention in the last year or two, a lot of that's been driven by the successes of some of the EGFR bispecifics. You see here in terms of current standard of care, pembro plus or minus platinum-based chemo is the regimen of choice for frontline. Second line, there really is no clear preferred standard of care regimen. If you look at the efficacy of these second-line populations, it's pretty limited. Mid-teen response rates, in some cases depending on the subsets, it's even single-digit response rates. Beyond that, things are really purely relying on investigational therapies.

I mentioned earlier that ADX-B7H3, given that it has an immune modulatory component as well as the potential to drive a cytotoxic that primes for antigen presentation and then sensitizes to immunotherapy. The notion of a combination regimen makes a lot of sense, especially for an indication like head and neck, where I mentioned pembro is well entrenched. This is some preclinical data that highlights the really nice complementarity of these two mechanisms. On the left panel, you see a mirroring surrogate molecule for PD-1, and on the right-hand side, you see actually the additional benefit of dual blockade of both PD-1 and CTLA-4. MGC028, that is our next ADC pro first-in-class molecule targeting ADAM9, ADAM disintegrin and metalloprotease 9. That is the target that plays a role in tumor genesis and cancer progression.

Very excited about the profile of this molecule. We completed all the IND enabling activities, including a GLP tox, which showed a 60 mg per kg HNSTD. The dose escalation is ongoing across a number of tumor types. You can see based on the IHC data, this target has very nice expression profile across a range of both GI cancers, lung, breast cancer, as well as others, and very potent killing in some of these animal model systems. MGC030, I mentioned that IND has been submitted and cleared, and we're doing a phase I startup as we speak. This is a Topo 1-based molecule, although the tumors that we're addressing for this program are ones that are currently, I'd say, underserved by other competing ADC approaches, which makes this a really exciting molecule.

For competitive reasons, we decided not to disclose this molecule given that we are a first-in-class program with a Topo 1-based approach. lorigerlimab, this is our dual molecule. You can see based on the cartoon schematic that it's a tetravalent structure. You have two binding domains for PD-1, two binding domains for CTLA-4. We think that actually enables some differentiation from some of the bivalent approaches like volrustomig. That's the 1-by-1 structure that's under development by AstraZeneca. We've had a lot of development experience with this molecule. I'd say a lot of lessons learned as well in terms of both target populations that we want to go after, as well as dosing and dose optimization. We have seen some early data in clear cell gyn cancer, which we're excited about, a 25% response rate.

That's a population that's typically more susceptible to immunotherapy and actually quite refractory to conventional platinum-based chemo approaches. The early experience with this molecule was predominantly at a 6 mg per kg dose every 3 weeks. We've decided to explore a lower dose of 3 mgs. That was based on some PK and PD modeling, which we believe we have complete receptor occupancy of PD-1 even at doses as low as 1 mg. We show good evidence of ICOS upregulation at these lower doses, and that's a marker for CTLA-4 blockade. Quite frankly, in the phase I, we had very strong activity with multiple resist responders at that 3 mg dose. That's what we're currently testing in our ongoing study. We have done some benchmarking work against volrustomig. That's the 1-by-1 structure. Given that it has only monovalent engagement of PD-1, it really is not able to recapitulate the efficient PD-1 blockade of a typical PD-1 antibody, whereas our agent can.