BlossomHill Therapeutics, Inc. Common Stock H.C. Wainwright 28th Annual Global Investment Conference

Welcome to our next fireside chat. I am Robert Burns, the managing director at 1865 Tech Analytics. I am joined today by J. Jean Cui, the CEO of the newly formed BlossomHill, which just IPO'd. Jing, thank you for joining us today.

Thank you for having us here.

No problem. I guess let's start from the 10,000 foot view. Considering that you just IPO'd in August, maybe for those who may be unfamiliar with the BlossomHill story, tell us a little bit about the company, and its pipeline.

Thank you. I am J. Jean Cui, and the scientific founder and also president and CEO of BlossomHill Therapeutics. BlossomHill Therapeutics was founded in June 2020, just in the middle of the COVID-19 pandemic. Stay at home and have, kind of a real extra time and to really think about the science and because every company founded really need to have the directions and what exactly what we should do and what is our capability be able to solve high unmet medical needs, especially the needs the innovation of the chemistry. By training, I am the chemist and this is why, kind of, we really want to fund the clinic and medical need, needs the chemistry innovation.

With the strong support of the leading investors, we have built a very strong leadership team and advanced the two macrocyclic molecules into clinic, and also one in the IND-enabling studies. As a chemist, as a founder, we have built up all of our pipelines from the ground up, from identify unmet medical needs. Here is the summary, the BlossomHill way to deliver our candidates and identify unmet medical needs for patients. This is definitely, we want to really identify something might be stuck, quite difficult in the field. Then using the analyzing what is the issue there, and how we can solve the issues from which angle.

The different part, we have to do the structure-based design. However, different from structure-based design, here, we really focus on the protein dynamics because in the disease state the protein probably stay in a different confirmation at which state is better to overcome. The first line of therapy requirement probably is different compared to resistant setting there. Then, lead optimization to identify the clinic candidates there. This is our pipeline, and we have only EGFR inhibitor, and this is a macrocyclic molecule. We will talk more about this molecule. It has the broad inhibition against the classical EGFR mutation, atypical mutation, and also most important, be able to tackle all of these resistant mutations and currently in the late expansion stage.

We hope to have the end of the phase I meeting in Q4 2026. The CLK inhibitor is a target and a broad resistant mechanism associated cancer treatment. We know the cancer treatment, the ultimate goal is to shrink the tumor, and then shrink the tumor will generate common resistant mechanism and escape for the survival, and also most important, DNA damage repair pathway. CLK is modulated the serine/arginine-rich splicing protein, and then leading to the modulate, and the end result is a modulated DNA repair pathway and also survival balance there. This project currently in the dose escalation in both monotherapy and also in combination with venetoclax. Then our pan-KRAS inhibitor has the novel chemical design leading to very distinctly different profile with a pseudo-irreversible characteristic.

This molecule in the late IND-enabling studies, and we plan for IND submission in the first half, first quarter 2027.

Thanks, Jing. Similar to what we saw with your prior company, Turning Point Therapeutics, there seems to be a recurring theme here when we look at the approach you took when designing BlossomHill's drug candidates. In particular, two of the three of your assets are macrocyclic-based structures. Maybe, help investors who might not be as scientifically inclined understand the rationale between this and the advantages that macrocyclic-based inhibitors actually possess over non-macrocyclic-based ones.

Yeah, great question. That is kind of my first design for macrocyclic and from lorlatinib and later and repotrectinib. Macrocyclic design is a common tool for medicinal chemists to solve the issues. Quite often by the end, macrocyclic will deliver super cell, super potency and good drug-like properties and also, kind of the good safety profile. The bottom line, macrocyclic is rigidify the confirmation to have the precise interaction with the protein there. Not all of the target are suitable for the macrocyclic design, such as KRAS and Switch-II pocket inhibitor may not good for the macrocyclic. However, when we work on the kinase, and especially for resistant patient population, this is really the tool we have to use.

When we are talking about the resistant and the kinase already and the pathway is highly activated and develop resistant as a later generation, the need to overcome the resistant, that is number one requirement. Also the molecule needs to be also super better potency against the primary mutation. We know that different sub-clones of primary and mutation still co-existed, either cis or trans, with the resistant mutation. Therefore, the molecule need to be significant better than previous generation, be able to overcome all of this resistance. Also, to aware other mutations. That is why, for the kinase and next generation, when we design the molecule target ATP center, need to achieve the super potency, the macrocyclic is the best tool to use. As you can see, I designed both lorlatinib, repotrectinib as the macrocyclic.

You can see, the small cycle, the macrocyclic there. Be able to achieve both the super cell potency against the primary mutation and also most important is resistant mutation and good PK properties enables the molecule to overcome resistance in the later line. Also when it used to the front line and make the treatment outcome significantly, like lorlatinib used into the front line. It has improved the PFS from original crizotinib less than one year to over seven years. This is what we target to. Then, during the pandemic, I was think about EGFR. EGFR and the C797S. Already third generation EGFR inhibitor has been approved, and Tagrisso is the third generation covalent irreversible molecule. This one here it shows Tagrisso's structure there.

The osimertinib, the chemical structure is not really the true binding for the EGFR protein there. Without the covalent binding part, I highlight there is a blue color to form the covalent binding there. Without the covalent, that will be submicromolar activity there. To overcome the C797S, the molecule design have to be a non-covalent molecule, and also need to capture the true and binding the protein characteristic of the EGFR. We designed a novel macrocyclic structure, and after this structure I could design, as you compare the first generation and the third generation, this structure not share any of the commonality with them. After this optimization, we are able to achieve the super cell potent subnanomolar against the classic ATCC mutation, the brown color, that is a compound-resistant mutation. As you can see, it is equipotent against them.

This is very important when we use it in the later then there. The molecule is also tenfold more potent compared to covalent molecule osimertinib there. This is also the only molecule be able to achieve this broader activity against both primary and resistant mutation, and have a greater selectivity window over the wild type EGFR.