Spruce Biosciences, Inc. Common Stock H.C. Wainwright 28th Annual Global Investment Conference

Thank you so much, and thank you so much to H.C. Wainwright for having me here. It will be a real pleasure to walk you through our story, to talk to you about Spruce. I will be making some forward-looking statements throughout my presentations and refer you to our SEC filings, our 10-K and other filings for reference as I go along. Spruce Bio is a global neuroendocrine biopharma company. We have a couple assets in our current pipeline, frankly, driven by diseases that are rare or ultra-rare, for which there is a very meaningful market need, intend to be best in class, ideally first in class. Currently working, our flagship product is tralesinidase alfa, enzyme replacement therapy is a drug that we acquired about towards the end of 2024.

It is an enzyme replacement therapy, and it is used to treat a disease called Sanfilippo syndrome type B or MPS IIIB, for which there is no available therapy. Kids suffer from this devastating, terrible disease, super debilitating, that affects not just the kid, but also the caregiver. When we looked at the acid, we realized that the effect size of the enzyme replacement on the surrogate biomarker then deemed to be a difficult path forward for FDA. Later on, over time, the FDA kind of laxed the criteria, ended up accepting heparan sulfate as a viable surrogate endpoint for approvals in the space of neuronopathic MPSs, and that, in many ways, changed the whole story. But we durably normalize or nearly normalize heparan sulfate in nearly all patients.

As I said earlier, the FDA aligned not just with us, but with other companies doing work in neuronopathic MPSs like Ultragenyx, Denali Therapeutics, BioMarin, JCR Pharmaceuticals, on the viability of heparan sulfate as an RLSE, reasonably likely surrogate endpoint of clinical benefit. We've worked since we acquired the asset in demonstrating meaningful clinical benefit throughout the clinical data set that was generated prior to the acquisition of a product. We've done, I think, a really good job at defining what is the clinical benefit that extends beyond cognition. There are a number of endpoints that measure how patients feel and function, which are very critical for FDA approvals, as you know.

Unfortunately, the prior sponsor discontinued the studies, the studies that were actually tracking patients, but we were fortunate to inherit a data set that's 5 to 6 years long in duration, which allows us to make meaningful assessments on efficacy and safety. If a drug gets approved, we will qualify for priority review voucher. Luckily, the FDA renewed the PRV regulation last year, extending it for another 5 years, and have the potential, obviously, to be first to market and IP exclusivity to 2038. This type of orphan drugs tend not to be too much challenged by biosimilars. They're very difficult to make in general. Our drug, in particular, has a very unique construct where the enzyme is actually teamed up through an amino acid linker with a truncated IGF2 molecule that enables the compound to get into cells.

This was kind of the genius from BioMarin, designing a drug that not only just gets to the CSF through the delivery mechanism, bypassing blood-brain barrier, but also penetrating neurons. Often, drugs or ERTs rely on mannose-6-phosphate, which is a residue that lives in the surface of the drug and penetrates the cells. This one has a very unique structure that will make biosimilars or entry of biosimilars much more difficult. In addition to this BLA-ready program, we also have a pre-IND stage monoclonal antibody that leverages our prior experience in CAH, on congenital adrenal hyperplasia. It acts high up in the HPA axis, is a CRH ligand monoclonal that has the potential to have very long half-life and overcome probably the biggest challenge in CAH, which is patients not feeling that they have a disease.

They tend not to be very compliant with treatment and therefore end up not being very controlled with hyperandrogenism and symptoms of hyperandrogenism in females and male patients alike. I will not be speaking about our monoclonal antibody. We're not allocating any cash to its development at the moment, but frankly, seeking to be able to find ways of developing it. Most of our efforts, if not all, are dedicated on TA-ERT. In this slide, you can see the natural history of patients with this bad neurodegenerative disease. Kids fall off very rapidly, the standard kind of perpendicular developmental line. Usually at the ages of 2 and a half, 3 years of age, they start missing developmental milestones. That's when parents start seeking care. They realize that something is going on with their kids.

They end up bouncing from physician to physician, not for too long, because their facies and phenotype are very descriptive of a mucopolysaccharidosis. They have these broad eyebrows and large forehead and micrognathia, so their lower jaws are a little smaller. More importantly, they initially become very hyperactive. They do not sleep at night, which is a major key feature, keeping their parents awake and disrupting the whole family. Then they start missing learning milestones, and they start regressing. Their memory goes away. Their speech loss, the little few words that they had gained, they lose, and that is when they typically get diagnosed, around age 4, which is actually the average age of enrollment in our pivotal trial. They continue to regress, and by age 12, they are usually intubated.

They have a PEG tube, and they usually die in their mid-teenage years with what people refer to as pediatric Alzheimer's. It is a very bad disease, and we think that our drug, if we treat kids early, can probably revert them back to normal or near normal. I will tell you a couple stories momentarily. MPS IIIB is a genetic disease, is a recessive disease. Both parents need to carry the recessive gene, passed to 50% of their children. The enzyme is dysfunctional. There is usually a frameshift mutation that results in an inability to secrete a normal enzyme and degrade heparan sulfate. Heparan sulfate is, think of it as a large sugar. That sugar gets chomped by different enzymes along the way, and if there is a missing enzyme, then that sugar accumulates and builds up.

It is the accumulation of heparan sulfate that results in lysosomal dysfunction, which ultimately leads to neuroinflammation and neurodegeneration. With the advent of enzyme, which you see at the bottom part of this cartoon, the lysosomes are normally functioning, and the neurons regain normal function. The disease starts intrautero. There is some research going on by McKenzie, cannot recall her last name, at UCSF, that does research of children intrautero. There have been a lot of research going on with replacing enzyme intrautero, which we are not doing, obviously. Our clinical development program is comprised of a natural history piece at the very top of this swim lane, these top two boxes. Frankly, very unique. Most companies do not do natural history studies these days. They rely on historical reference. BioMarin originated these 902 and 901 trials. 901 was a feeder study into the treatment trial, 201.

They watched patients for 48 weeks, and then they enrolled them in 201. 201 was a treatment trial, and 201 has a couple of extension studies, 202 and 401. 401 did not really last very long. The prior sponsor discontinued the program because they did not have cash. Let me tell you a little bit about that piece of history. They in-licensed the product from BioMarin in 2019, when the CEO of BioMarin decided to pivot the pipeline into larger indications like achondroplasia and hemophilia A. This drug, along with another two, got out-licensed to Allievex, who tried to push the approval of a compound by FDA and get funded. FDA was very reluctant, as I said earlier, to get these drugs through, up until February of 2024 when they convened a Reagan-Udall Foundation forum where industry, academia, patient groups, and the FDA itself attended.

They deliberated the viability and value of accepting heparan sulfate as a viable surrogate, and there was unanimous consensus. So at that point, the FDA opened up the floodgates, if I may, allowed for companies to actually meet with the FDA, issue good meeting minutes acknowledging the usefulness of a surrogate as a RLSE. But it was too late for Allievex. They ended up discontinuing all of their clinical programs, inclusive of 401. So 401 only enrolled 5 patients. Tried to revamp, get funding, it was too late. They already laid off all the employees, closed all the programs. So that's when we luckily pick up the program. All of what you see on this slide was already done, with the exception of a 301 study, which we have designed. It was agreed upon by Allievex and the FDA.

We decided not to, frankly, rock the boat too much, and accepted what the FDA had aligned with Allievex in the context of a confirmatory trial for the approval of product. And we've met again with the FDA, and obviously have submitted to the FDA a clinical operations study plan. Timelines are on the 301 confirmatory trial, and aligned with the FDA, along with other things, on how much of the 301 study they need to see ongoing prior to the approval of product. We are currently being reviewed under, or will be reviewed under, accelerated approval. At least that's how we are basing our application. The FDA has the prerogative to approve us fully, if they so choose to. But it is based on the biomarker of HS NRE, non-residual ENTs, under accelerated approval, followed by a confirmatory trial for full approval.