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Item 1. Business

2025-03-28 compared with 2024-03-13 · 342 added, 343 removed, 478 unchanged (59% of the section changed)

We are a biopharmaceutical company focused on developing and commercializing precision therapies for cancers with alterations in the mTOR pathway, a key regulator of cell growth and cancer progression.

Our lead drug product, FYARRO ® (sirolimus protein-bound particles for injectable suspension (albumin-bound);

nab -sirolimus), combines two established technologies - nanoparticle albumin-bound ( nab ) technology and the anti-cancer agent, sirolimus.

Nab -sirolimus is a potent inhibitor of the mTOR biological pathway with demonstrated anti-cancer activity in our lead indication, advanced malignant perivascular epithelioid cell tumor (“PEComa”), a rare cancer.

We believe our approach to utilizing the novel combination of technologies has the potential to produce transformational therapies for patients with cancers beyond PEComa that have known mTOR pathway activation and/or cancers in which other mTOR inhibitors have not been fully exploited due to problems of pharmacology, effective drug delivery, safety, or effective targeting to the disease site.

We exclusively license FYARRO, previously called ABI-009, nab -sirolimus, from Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, which is a wholly owned subsidiary of Bristol-Myers Squibb Company (“BMS”).

Throughout this document we refer to FYARRO ( nab -sirolimus, sirolimus protein-bound particles for injectable suspension (albumin-bound)) as FYARRO in the context of commercialization for the treatment of advanced malignant PEComa, investigational use, our clinical trials, regulatory matters such as orphan drug designation and our license agreement with BMS and collaboration agreement with Mirati Therapeutics, Inc.

("Mirati"), all further discussed below and throughout this document.

On November 22, 2021, the U.S.

Food and Drug Administration (the “FDA”) approved FYARRO sirolimus protein-bound particles for injectable suspension (albumin-bound) for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa.

On February 22, 2022, we launched FYARRO in the United States for treatment of advanced malignant PEComa and recognized net product sales of $24.4 million and $15.2 million for the years ended December 31, 2023 and 2022, respectively.

In addition to advanced malignant PEComa, based on exploratory data from the completed Phase 2 registrational study, Advanced Malignant PEComa Trial (“AMPECT”) and data for FYARRO in other solid tumors with TSC1 and TSC2 inactivating alterations , we initiated a registration-directed tumor-agnostic Phase 2 study (“PRECISION1”) of FYARRO in patients with Tuberous Sclerosis Complex 1 (“ TSC1 ”) and Tuberous Sclerosis Complex 2 (“ TSC2 ”) alterations.

The PRECISION1 trial was opened for enrollment in the United States during the first quarter of 2022, with dosing of our first patient in March 2022.

On December 14, 2023, we announced results from an interim analysis on the first third of participants in the PRECISION1 trial (discussed below).

As of December 2023, 80 patients were enrolled in the PRECISION1 trial and we expect the trial to be fully enrolled by May 2024 and completed by the end of 2024 with results anticipated in early 2025.

Our objective is to develop and commercialize innovative drugs that address the serious unmet medical needs of cancer patients that are driven by alterations in the mTOR pathway.

The principal components of our strategy include:

• Expand the market opportunity for FYARRO by pursuing development of a tumor-agnostic indication in cancer patients with alterations in the TSC1 or TSC2 genes.

Tuberous Sclerosis Complex acts upstream of mTOR in the pathway to inhibit mTOR activity and negatively regulate cell growth.

In cancer, Tuberous Sclerosis Complex genes, TSC1 and TSC2 are tumor suppressors that when activated by gene alterations can contribute to cancer progression.

We estimate that TSC1 and TSC2 inactivating alterations occur at a rate of approximately 2% across cancers, or approximately 16,000 new cases each year, with no approved therapies for TSC1 or TSC2 inactivating alterations.

Based on exploratory data in patients with TSC1 or TSC2 alterations from the completed AMPECT, we initiated a registration-directed tumor-agnostic study called PRECISION1 in patients with malignant solid tumors driven by TSC1 or TSC2 alterations.

• Expand the application of FYARRO as a monotherapy and combination therapy with other agents.

We believe there is a significant opportunity to utilize FYARRO in other cancers, particularly in combination with other anti-cancer therapies where there is potential additive benefit of mTOR inhibition.

These additional indications may be important drivers of commercial value, and we believe that strategic partnerships, particularly in combination therapies, may be an effective means of developing and commercializing these

opportunities.

While we are primarily focused on cancer, the mTOR pathway is also relevant in other indications and we may opportunistically study these indications to broaden the application of FYARRO or satisfy unmet medical needs.

We are currently enrolling patients in (i) a Phase 2 open-label, multi-institutional study to evaluate the efficacy and safety of the combination of FYARRO with letrozole for the treatment of advanced or recurrent endometrioid-type endometrial cancer ("EEC") and (ii) a Phase 2 multicenter, open-label, single-arm trial to evaluate adult patients with functional or non-functional, well-differentiated, locally advanced unresectable or metastatic neuroendocrine tumors ("NETs") of the GI tract, lung, or pancreas who have received ≤2 prior lines of therapy excluding somatostatin analogs (SSTa).

In addition, in October 2022, we entered into a collaboration and supply agreement with Mirati to evaluate the combination of Mirati’s adagrasib, a KRAS G12C selective inhibitor, and FYARRO in KRAS G12C mutant non-small cell lung cancer ("NSCLC") and other solid tumors.

• Continue to commercialize FYARRO in advanced malignant PEComa .

For FYARRO, we initially targeted advanced malignant PEComa, an ultra-rare sarcoma with no approved therapies other than FYARRO.

In May 2021, we completed the filing of a rolling new drug application ("NDA") submission with the FDA for FYARRO for the treatment of advanced malignant PEComa based on the positive results from AMPECT, our pivotal Phase 2 study in this patient population, which met its primary endpoint.

The FDA accepted the NDA in July 2021 and we were granted approval for commercial sale of FYARRO on November 22, 2021.

We built a cross functional commercial team and infrastructure and launched FYARRO for advanced malignant PEComa in the United States in the first quarter of 2022.

• Establish capabilities and/or partnerships outside the United States to effectively commercialize and maximize the value of FYARRO.

We have built capabilities in the United States to commercialize FYARRO.

Outside the United States, we intend to selectively evaluate strategic partnerships with partners whose development and commercial capabilities complement our own.

We are an oncology therapeutics company applying advanced technologies to established tumor biology that are intended to efficiently deliver improved cancer treatments.

We have deep experience in chemistry, formulation, and drug delivery, as well as research, clinical, and commercial pharmaceutical development, resulting in successfully taking product candidates from the clinic to approval, launch, and commercialization.

We recently entered into an intellectual property license agreement (the “WuXi License Agreement”) with WuXi Biologics (Shanghai FX) Co., Ltd.

(“WuXi Biologics”) for the development and global commercialization of a portfolio of three next generation antibody drug conjugates (“ADCs”) targeting clinically validated, broadly overexpressed tumor antigens in high potential cancer indications with significant unmet need.

These ADCs are constructed utilizing an advanced linker-payload platform called CPT113 that has been shown to provide increased stability in blood circulation and deliver targeted release of a Topoisomerase I (“TOPO1”) inhibitor payload into cancer cells.

These in-licensed assets originated through the collaborative efforts of WuXi Biologics, a leading global contract research, development and manufacturing organization (“CRDMO”), and Hangzhou DAC Biotechnology (“Hangzhou DAC”), a global leader in ADC innovation, where Hangzhou DAC’s CPT113 linker-payload has been conjugated to novel antibodies developed by WuXi Biologics against three tumor targets:

Protein Tyrosine Kinase 7 (“PTK7”), Mucin 16 (“MUC16”) and Seizure-related Protein 6 (“SEZ6”).

The antibody targeting MUC16 targets the membrane-bound form of MUC16 (mMUC16).

The antibody targeting SEZ6 is a biparatopic SEZ6 ("biSEZ6") antibody targeting two different epitopes on SEZ6.

We believe the resulting ADCs will be able to target cancers expressing these respective tumor markers precisely and deliver the potent, cytotoxic TOPO1 inhibitor at the site of cancer.

Each of these ADCs have demonstrated tumor cell binding, tumor cell line cytotoxicity, and in vivo antitumor activity in preclinical models of cancer.

We refer to these in-licensed ADC assets as the "ADC Therapies" herein.

We anticipate submitting three investigational new drug (“IND”) applications with the U.S.

Food and Drug Administration (“FDA”) in the coming 12 to 24 months, starting with HWK-007 for the treatment of solid tumors, including non-small cell lung cancer (“NSCLC”) and ovarian cancer, in the second half of 2025;

HWK-016 for the treatment of cancers of female origin by the end of 2025;

and HWK-206 for the treatment of cancers of neuroendocrine origin in mid-2026.

With these three assets, we have the ability to pursue multiple cancer indications with high potential in large addressable patient populations, including and beyond those indications currently expected to be targeted in the upcoming Phase 1 trials.

Our track record of strong execution of novel drug formulation, research, clinical development, and commercialization in oncology, combined with our deep understanding of ADCs positions us to unlock the high potential of this differentiated ADC portfolio.

Our management team has extensive experience in the discovery, development, and commercialization of cancer therapeutics, including in senior roles at leading oncology companies.

We are supported by our board of directors and specialized scientific advisors, who contribute their deep understanding of drug discovery and development, as well as expertise in building public companies and business development.

We believe that our team is well positioned to execute on our strategy to develop and commercialize FYARRO and future pipeline assets to ultimately bring significant benefit to cancer patients worldwide.

Importance of the mTOR Pathway in Cancer

mTOR is a serine–threonine kinase that is the key component of two multi-subunit complexes with non-overlapping downstream targets:

mTOR Complex 1 (“mTORC1”) and mTOR Complex 2 (“mTORC2”).

mTORC1 plays a vital role in the regulation of cell growth and division by controlling the balance between anabolic and catabolic cellular processes and facilitates the progression of cell-cycle from G1 to S phase.

Due to its key role in anabolic processes needed for cell division, the majority of cancer cells have activation of mTORC1 through one mechanism or another.

Thus, the effective inhibition of mTORC1 in cancer cells may inhibit their proliferation.

Activation of mTORC1 may occur downstream of the PI3K/AKT or Ras/MEK/ERK pathways, or through inactivating alterations in negative regulators of the mTORC1 pathway, including TSC1 or TSC2 .

Downstream signaling nodes of mTORC1, specifically S6K and 4EBP1, are key drivers of mTORC1 activity.

Decreased phosphorylation of S6K leads to decreased activity, while decreased phosphorylation of 4EBP1 leads to increased activity.

Sirolimus (also known as rapamycin) is an allosteric inhibitor of mTOR, which binds to the 12-kDa FK506-binding protein 12 ("FKBP12"), and the complex directly and strongly inhibits mTORC1.

Figure 1 – mTOR Pathway

Currently approved mTOR inhibitors are limited in their applicability due to poor and variable absorption of the oral drugs (sirolimus and everolimus) or variable conversion from prodrug to active drug (temsirolimus) and premedication requirements (temsirolimus).

These drugs have a narrow therapeutic index and a reduction from the labelled dose can result in decreased efficacy.

Preclinical study comparisons with FYARRO showed significantly higher tumor uptake, greater downstream mTOR target suppression and increased suppression of tumor growth for FYARRO compared to the oral mTOR inhibitors.

A literature comparison of the clinical pharmacokinetic profiles of the drugs shows that FYARRO has a longer half-life, higher peak blood concentration and greater total exposure than the other approved mTOR inhibitors.

FYARRO is administered in cycles that are given weekly for two weeks followed by a week off and does not require therapeutic monitoring to ensure adequate blood levels.

Nanoparticle Albumin-Bound (nab) Technology

The nanoparticle albumin-bound, or nab , technology was created and developed by Neil Desai, our founder and Executive Chairman, and former colleagues while at Abraxis Bioscience, LLC.

This technology takes advantage of the protein albumin, a natural carrier of water insoluble molecules (e.g., various nutrients, vitamins and hormones) found in humans.

Due to various active and passive transport processes in the body, albumin can accumulate preferentially in different tissues including tumors, areas of inflammation, or areas of tissue remodeling, i.e., at sites of disease.

The nab technology takes advantage of these transport properties of albumin and its affinity of binding to certain drug molecules to increase the efficiency with which these molecules may be brought to these sites of disease.

The first clinical and commercial validation of this technology is BMS's Abraxane ® , which is approved in the United States and worldwide for the treatment of breast cancer, non-small cell lung cancer and pancreatic cancer.

Abraxane has generated greater than $1.0 billion of sales in the United States every year since 2018 until its loss of market exclusivity in 2022.

We are applying the nab technology to the molecule sirolimus, a potent inhibitor of the mTOR pathway that is hindered in large part by a poor pharmacologic profile (e.g., poor and variable absorption with incomplete target suppression).

The relevance of albumin transport in cancer has been extensively studied and albumin is known to accumulate in tumor tissues due to the leaky capillary system within the tumor, defective lymphatic drainage of tumors, and active caveolae-mediated transport across tumor blood vessel endothelium.

In addition, albumin can be taken up by proliferating tumor cells via endocytosis and macropinocytosis, then catabolized by lysosomal degradation to support de novo protein synthesis, energy, and tumor growth.

Ultimately, nab technology allows FYARRO to take advantage of albumin transport pathways to accumulate at high levels in tumors and deliver sirolimus directly to cancer cells where it can effectively inhibit mTOR.

The accumulation of albumin in tumors can be easily visualized by using evans blue dye which has a high affinity for

Intravenous injection of albumin-evans blue complex in animals bearing tumors resulted in rapid accumulation of the complex within the tumors which could be easily visualized a few hours after injection.

Similarly, a fluorescent labelled albumin when injected into human glioblastoma patients 24-48 hours before surgery resulted in excellent visualization of the tumors during surgery under fluorescent light and allowed the complete resection of the tumor margins in the majority of the patients treated.

Figure 2 – Albumin Accumulation

FYARRO ® ( sirolimus protein-bound particles for injectable suspension (albumin-bound))

FYARRO is a form of sirolimus bound to albumin.

Sirolimus is a potent inhibitor of the mTOR biological pathway and inhibits downstream signaling from mTOR, the activation of which can promote tumor growth.

FYARRO is composed of nanoparticles of sirolimus bound to human albumin with an average size less than 100 nanometers.

An artist’s impression of these nanoparticles is shown below.

Figure 3 – Nanoparticle artist impression

The orally available mTOR inhibitors have poor and variable absorption, often require therapeutic drug monitoring, and have incomplete target suppression.

The combination of sirolimus with human albumin in FYARRO achieves higher area under the curve (AUC), Cmax and longer half-life in humans at its clinical dose when compared with published clinical data for other mTOR inhibitors, demonstrating FYARRO’s differentiated clinical pharmacologic and pharmacokinetic profile.

Figure 4 – FYARRO PK Profile

These differences in pharmacology can result in advantageous differences in the clinical behavior of FYARRO when compared to the other mTOR inhibitors.

This is effectively illustrated in comparative experiments in animals bearing bladder cancer tumors or liver cancer tumors.

Data from these tumor-bearing animal models showed many-fold higher tumor drug levels for FYARRO at equal dose to the other mTOR inhibitors which was correlated with a greater degree of mTOR target suppression as indicated by inhibition of phosphorylation of S6 and 4EBP1 (downstream signaling nodes of mTORC1 that are known to play a role in downstream activity of mTOR as well as resistance to mTOR suppression), and a correspondingly higher suppression of tumor growth.

We believe that other mTOR inhibitors on the market or active in clinical development do not have the required favorable pharmacological profile to fully exploit the benefits of mTOR inhibition.

We believe that FYARRO’s differentiated pharmacologic profile, high tumor accumulation, and ability to effectively inhibit important targets in the mTOR pathway make it a well-positioned drug to address resistance and suboptimal efficacy of existing mTOR inhibitors.

We are studying FYARRO in cancers with known mTOR pathway activation, including indications targeting specific genomic alterations that activate the mTOR pathway, such as our trial to evaluate adult patients with functional or non-functional, well-differentiated, locally advanced unresectable or metastatic NETs of the GI tract, lung, or pancreas who have received ≤2 prior lines of therapy excluding somatostatin (SSTa).

We have additional ongoing studies evaluating FYARRO in combination with other targeted agents, such as our study to evaluate the efficacy and safety of the combination of FYARRO with letrozole for the treatment of advanced or recurrent EEC and our current collaboration with Mirati to evaluate the combination of Mirati’s adagrasib, a KRAS G12C selective inhibitor, and FYARRO in KRAS G12C mutant non-small cell lung cancer (NSCLC) and other solid tumors.

Our ongoing studies are summarized in the figure below.

Figure 5 – Pipeline

FYARRO - Commercial

Advanced Malignant PEComa.

PEComas are mesenchymal neoplasms, composed of histologically and immunohistochemically distinctive cells, perivascular epithelioid cells (“PEC”s).

Most PEComas are clinically benign and do not metastasize, but malignant PEComas can demonstrate local invasion and aggressive metastatic spread.

PEComas show a wide anatomical distribution, but most often arise in the retroperitoneum, abdominopelvic region, uterus and gastrointestinal tract, and have a 4:1 female predominance.

Malignant PEComas are classified as one of the ultra-rare soft-tissue sarcomas with an estimated annual incidence of roughly 100-300 patients per year in the United States, although formal epidemiology studies have yet to be conducted.

FYARRO is the first FDA approved treatment specifically for malignant PEComa.

The disease is often treated with the cytotoxic chemotherapy regimens used in soft tissue sarcomas, which have shown only modest benefit for malignant PEComa.

PEComas commonly show evidence of mTORC1 activation due at least in part to loss-of-function mutations in or deletions of the TSC1 or TSC2 genes.

In a retrospective analysis, patients with malignant PEComa treated with available mTOR inhibitors (mTORi, sirolimus, everolimus, and temsirolimus) benefited from treatment suggesting that mTORC1 inhibition may be a promising therapeutic approach for malignant PEComa.

As a result, available mTOR inhibitors may also be used to treat malignant PEComa.

In May 2021, we completed the filing of a rolling NDA for FYARRO to the FDA for approval to treat patients with advanced malignant PEComa.

The NDA was based on results from AMPECT, our Phase 2 registration-directed study in advanced malignant PEComa, which met its primary endpoint.

In advanced malignant PEComa, other than FYARRO, there are no existing FDA approved therapies or drugs that have been studied in prospective clinical trials.

Following FDA approval, the National Comprehensive Cancer Network (“NCCN”) Sarcoma panel included FYARRO as the only preferred regimen for treatment of malignant PEComa.

We are supported by our board of directors and specialized scientific advisors, who contribute their deep understanding of drug discovery and development.

Furthermore, our investor base includes top life science investors.

We believe that our team is well positioned to execute our strategy to develop and, if approved, commercialize the ADC Therapies and future pipeline assets to ultimately bring broad benefit to cancer patients worldwide.

Legacy FYARRO Business .

Historically, our lead drug product was FYARRO ® (sirolimus protein-bound particles for injectable suspension (albumin-bound);

nab-sirolimus), which combines two established technologies:

nanoparticle albumin-bound (nab) technology and the anti-cancer agent, sirolimus.

Nab-sirolimus is a potent inhibitor of the mTOR biological pathway with demonstrated anti-cancer activity in advanced malignant perivascular epithelioid cell tumor (“PEComa”), a rare cancer.

We exclusively licensed FYARRO, previously called ABI-009, nab-sirolimus, from Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, which is a wholly owned subsidiary of Bristol-Myers Squibb Company (“BMS”) and we refer to the development, production and commercial sale of FYARRO herein as the “FYARRO Business”.

On February 22, 2022, we launched FYARRO in the United States for treatment of advanced malignant PEComa and recognized net product sales of $26.0 million and $24.4 million for the years ended December 31, 2024 and 2023, respectively.

FYARRO - Ongoing Clinical Development

FYARRO in TSC1 and TSC2 inactivating alterations (PRECISION1 Clinical Trial)

PRECISION1 is a registration-directed tumor-agnostic Phase 2 study of FYARRO in patients with TSC1 and TSC2 inactivating alterations that is based on evidence of activity seen in patients with TSC1 and TSC2 inactivating alterations from the completed AMPECT trial (presented at the Connective Tissue Oncology Society (CTOS) Annual Meeting in

2020) and our expanded access program (presented at the ASCO Annual Meeting in 2021).

We have completed a Type B meeting with the FDA in which we discussed the trial design with the FDA.

The PRECISION1 trial opened for enrollment in the United States during the first quarter of 2022 and the first patient was dosed in March 2022.

The TSC1 and TSC2 genes encode for proteins that form a tumor suppressor complex that down regulates mTORC1 activity.

Inactivating alterations in the TSC1 or TSC2 genes can result in activation of mTORC1.

TSC1 or TSC2 alterations have been reported across a broad range of cancer types.

Real-world next-generation sequencing analysis of nearly 440,000 patients with advanced cancer showed that TSC1 or TSC2 known or likely pathogenic alterations occurred in approximately 2% of all solid tumors (see chart titled “ TSC1 and TSC2 Inactivating Alterations Represent Significant Opportunity Across Common Cancer Types” below).

While there are no therapies approved specifically for TSC1 or TSC2 alterations, numerous case reports show durable responses to mTOR inhibition in patients with these alterations.

Figure 6 - TSC1 and TSC2 Prevalence

On December 14, 2023, we reported results from a planned interim analysis on the first third of participants in the PRECISION1 trial.

The interim analysis included data from the first third of trial participants (n=40) with a minimum of

4.5 months of follow-up, including investigator-assessed response and safety analyzed separately in each of the TSC1 and TSC2 arms.

Nine different tumor types were enrolled in the TSC1 arm and 13 tumor types were enrolled in the TSC2 arm.

Table 1 - PRECISION1 Interim Analysis Tumor Types

With respect to the efficacy of nab -sirolimus in patients with tumors harboring pathogenic inactivating alteration in TSC1 , of the 22 patients enrolled, 19 patients received ≥ 1 post baseline scan and were evaluable for efficacy.

Observations included:

• a 26% Overall Response Rate (ORR) including 5 partial responses (PR) with 4 confirmed responses and 1 unconfirmed response (uPR).

The patient with uPR remains on treatment and is awaiting a confirmatory scan;

• 9 patients had stable disease (SD), 3 of which were greater than or equal to six months in duration, resulting in a clinical benefit rate of 42% (5 PR + 3 SD ≥ 6 months);

• patients were heavily pre-treated with median of 3 prior lines of therapy;

• median time to response was 1.4 months and all responses were ongoing at time of data cutoff;

• responses were seen across four different epithelial carcinomas;

• 60% of responders experienced > 50% tumor reduction.

With respect to the efficacy of nab -sirolimus in patients with tumors harboring pathogenic inactivating alteration in TSC2 , of the 18 patients enrolled, all 18 patients received ≥ 1 post baseline scan and were evaluable for efficacy.

Observations included:

• An 11% ORR including 2 PRs with 1 confirmed and 1 uPR;

• 12 patients had SD, 3 of which were greater than or equal to six months resulting in a clinical benefit rate of 28% (2 PR + 3 SD ≥ 6 mos);

• Patients were heavily pre-treated with median of 3.5 prior lines of therapy;

50% had ≥ 5 prior lines of therapy;

• Responses were seen in one epithelial carcinoma and one sarcoma.

No new safety signals were observed, and no grade four treatment-related events or deaths occurred.

One patient discontinued the study due to grade two pneumonitis that completely resolved after discontinuation of therapy.

Across both arms, the safety profile was consistent with the nab -sirolimus label and the mTOR inhibitor drug class.

As of December 2023, 80 patients were enrolled in the PRECISION1 trial, supporting the two-thirds interim analysis that we expect in the third quarter of 2024.

The ORR analysis in two-thirds interim analysis cohort will be based on

independent radiological review with a minimum of six months of follow-up for all patients.

We expect the trial to be fully enrolled by May 2024 and completed by the end of 2024, with results anticipated in early 2025.

FYARRO in endometrial cancer

In August 2023, we announced the expansion of our FYARRO clinical pipeline through the further investigation of mTOR pathway inhibition by studying FYARRO in endometrioid endometrial cancer (EEC).

We are currently enrolling patients in a Phase 2 open-label, multi-institutional study to evaluate the efficacy and safety of the combination of FYARRO with letrozole for the treatment of advanced or recurrent EEC.

Endometrial cancer is the most common cancer of the female reproductive organs, with an estimated 10,000 cases of EEC diagnosed annually in the United States.

The mTOR pathway is known to be activated in many cases of endometrial cancer;

approximately 93% of EEC patients have mutations in the PI3k/AKT/mTOR pathway.

In previous clinical trials, mTOR inhibitor everolimus in combination with letrozole (an anti-estrogen agent) has demonstrated efficacy in the EEC population.

FYARRO in neuroendocrine tumors

In August 2023, we also announced the study of FYARRO in neuroendocrine tumors (NETs).

We are currently enrolling a Phase 2 multicenter, open-label, single-arm trial to evaluate FYARRO in adult patients with functional or non-functional, well-differentiated, locally advanced unresectable or metastatic NETs of the GI tract, lung, or pancreas who have received ≤2 prior lines of therapy, excluding somatostatin analogs (SSTa).

NETs develop from neuroendocrine cells found in various organs throughout the body, including the pancreas, gastrointestinal tract, and lung, with approximately 3,500 cases diagnosed annually in the United States.

While NETs are slow growing, they may result in a variety of severe symptoms, including pain, organ dysfunction, and in the case of functional (hormone secreting) NETs, intractable diarrhea, refractory gastric ulcers, or uncontrolled glucose levels that may respond poorly to treatment.

While everolimus is approved for NETs based on a progression free survival benefit over placebo, we believe, based in part on everolimus's preclinical studies results, that there is an opportunity for nab -sirolimus to provide enhanced therapeutic benefit.

FYARRO in combination with KRAS G12C inhibitors for KRAS G12C -mutated cancer xenografts

In 2022, we conducted preclinical studies to investigate the antitumor activity of mTOR inhibitors, FYARRO or everolimus, in combination with KRAS G12C inhibitors, sotorasib or adagrasib, in KRAS G12C-mutated cancer xenografts.

KRAS is frequently mutated in non-small cell lung cancer (NSCLC) and other tumor types, with the KRAS G12C present in approximately 9% of NSCLC patients.

The mTOR pathway is often activated in patients with the KRAS mutation and contributes to adaptive resistance to KRAS inhibitors.

We conducted these studies to determine the utility of a combination of the mTOR inhibitor nab- sirolimus and KRAS inhibitors, which could have synergistic potential in the treatment of KRAS mutated cancers.

Results of these studies showed that combining FYARRO with either of the KRAS G12C inhibitors significantly improved response against KRAS G12C mutant lung cancer and bladder cancer tumors in vivo and FYARRO also showed significantly greater potency in the combination compared to everolimus.

FYARRO - Historical Clinical Development

Advanced Malignant PEComa Trial (AMPECT)

AMPECT was the first prospective clinical trial in advanced malignant PEComa.

Patients with metastatic or inoperable locally advanced disease were treated with FYARRO at 100 mg/m2 administered as an IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle.

The primary endpoint for the study was ORR evaluated by independent radiology review.

Secondary efficacy endpoints included duration of response (“DOR”), progression free survival (“PFS”) and overall survival (“OS”).

The sample size estimation assumed an observed ORR of 30% for a sample size of 30 patients, which would exclude values less than 14.7% for the lower bound of the 95% confidence interval.

This registrational trial met its primary endpoint demonstrating the efficacy of nab- sirolimus in this rare disease for which there was no FDA approved treatment, with an independently assessed ORR of 39% (95% CI:

Disease control (defined as complete or partial response (“CR” or “PR”) + stable disease ≥12 weeks) was achieved in 71% of patients.

FYARRO ( nab- sirolimus) was subsequently approved by the FDA for the treatment of advanced malignant PEComa on November 22, 2021.

Sixty-seven percent (8 of 12) of responses were seen at the first scan after baseline at week six (median time to response 1.4 months, 95% CI:

1.3 to 2.8 months).

At the time of the primary analysis (predefined as when all patients had an opportunity to be treated for 6 months), the median for the key secondary endpoint of DOR was not yet reached, with 9 of 12 responders still on treatment (DOR range 4.2+, 27.7+ months).

At 1.5-years of follow-up after the primary analysis date

(i.e., 2-years after the last patient-initiated treatment), 7 of 12 responders were still receiving treatment and the median DOR was still not reached, with 50% of patients exceeding 2.5 years (DOR range 5.6, 47.2+ months).

Figure 9 shows the target tumor responses (waterfall plot).

One patient with a primary renal PEComa metastatic to the lungs and lymph nodes had a PR for 10 months that converted to a CR.

Responses were independent of the primary site and were observed in tumors originating in the uterus (3), kidney (3), retroperitoneum (2), pelvis (2), liver (1), and small bowel (1).

Notably, 43% (3/7) of patients with uterine PEComa had a partial response.

Responses were also observed in 3/4 patients who had previously received chemotherapy.

Figure 7 – Waterfall plot of Maximum Reduction in Target Lesions, Two-year Follow-up (Wagner et al., JCO 2021)

*A patient with unconfirmed PR is considered having SD as best response (trial required confirmation of responses per RECIST v1.1).

Additionally, a patient with a complete response of target tumor reduction had a PR as best response because of unresolved nontarget lesions at the 2-year data cutoff (Wagner et al, JCO 2021);

however, this patient later achieved a confirmed complete response (FYARRO Prescribing Information).

Treatment-related adverse events (“TRAE”) were consistent with those reported for other mTOR inhibitors.

The most common hematologic events were anemia and thrombocytopenia, and the most common nonhematologic events were mucositis, rash and fatigue.

The details are provided in Table 1 below.

There were no grade 4 or 5 TRAEs.

Noninfectious pneumonitis occurred in 6/34 (18%) patients and all were low grade (G1/G2).

Patient discontinuation due to adverse events occurred on 3/34 (9%) patients (one grade 2 anemia and one grade 1 cystitis).

Dose reductions occurred in 12/34 (35%) patients;

11 patients had a one dose reduction from 100 mg/m2 to 75 mg/m2 and 2 patients had two dose reductions to 56 mg/m2.

Table 2 – Treatment-related adverse events

TRAE Any Grade ≥ 25%, No.

Patients with any TRAEs

Hematologic TRAEs

16 (47) 4 (12)

Thrombocytopenia a

On December 19, 2024, we entered into a Stock Purchase Agreement (the “Divestiture Agreement”) with KAKEN INVESTMENTS INC., a Delaware corporation (“KAKEN”), KAKEN PHARMACEUTICAL CO., LTD (“Guarantor”), and Aadi Subsidiary, Inc., a Delaware corporation and our former wholly owned subsidiary and the operating company for the FYARRO Business (“Aadi Subsidiary”).

Under the Divestiture Agreement, KAKEN acquired 100% of the outstanding shares of capital stock of Aadi Subsidiary from us at the closing of the transaction for a cash payment of $102.4 million

(following applicable purchase price adjustments under the Divestiture Agreement) (the "FYARRO Divestiture").

The divestiture transaction closed on March 25, 2025 and, as a result, we no longer operate the FYARRO Business.

Our vision is to make bold choices in applying technology to efficiently deliver improved oncology therapies for people living with difficult-to-treat cancers.

The principal components of our strategy include:

• We leverage “next wave” ADC architecture.

Recently, next wave ADCs have been associated with double-digit improvement in objective response rates (“ORR”) over first generation ADCs against the same target across a variety of solid tumors, including ovarian, breast cancer, and lung cancers.

Next wave ADC architectures are typified by improved linker-antibody stability, optimized pharmacokinetics and improved inhibitor payloads, such as using TOPO1 inhibitor in lieu of monomethyl auristatin E (“MMAE”).

• We preferentially pursue clinically validated targets and identify opportunities for differentiation.

Rather than expend resources on target discovery, we leverage our team’s deep experience in oncology and biologics, review existing oncology target literature, and engage with key opinion leaders to identify promising tumor antibodies, antibody conjugates, and antigens.

We focus on tumor targets of product candidates previously tested in clinical trials by other biopharmaceutical companies and where the trials results were made available, the rationale for discontinuation of such product candidates were well-known and where we have identified opportunities for differentiation.

We also prioritize those targets that we believe have both strong precedent data and potential broader applicability, including expansion beyond the indications in which they were initially tested.

• We innovate antibody design to improve ADC performance .

We strive to develop ADCs that couple next wave ADC architecture with cutting-edge antibody strategies to further improve antibody performance, including, but not limited to, high affinity, biparatopic, Fc modifications that increase ADC potency or safety.

• We focus our development strategies to demonstrate differentiation of our assets compared to first generation ADCs to maximize our asset’s competitive profile.

Our development strategy leverages precedent data from first generation ADCs to benchmark potential improvements to guide further expansion in both precedent and non-precedent indications.

We also plan to pursue combination strategies early in our programs to reach more patients and take full advantage of Project Frontrunner, the FDA’s effort to shift cancer therapeutics development in earlier lines of therapy.

• We utilize an efficient virtual model with outsourced clinical development and manufacturing .

We plan to utilize an outsourced model for research, development and manufacturing operations.

Initially, we intend to continue to benefit from the continuity of partnership with WuXi Biologics and Hangzhou DAC for near-term IND-enabling studies and ADC manufacturing.

We will expand our CRDMO network as appropriate as our portfolio advances further in clinical trials.

• We look to continue to build our portfolio through strategic partnerships.

We plan to continue to use our management and board expertise, as well as our extensive network, to maximize and grow our portfolio through additional strategic partnerships and transactions.

Our Portfolio

We were deliberate in identifying promising tumor targets that are broadly expressed across multiple cancer types, and plan to focus our initial development efforts on high potential indications where first generation ADCs against these targets have already shown proof of concept in Phase 1 clinical trials.

The three tumor targets we selected – PTK7, MUC16 and SEZ6 – are each validated by a first-generation ADC that demonstrated promising efficacy in key indications, but were discontinued, largely due to safety and limited therapeutic index.

Importantly, we prioritized the ability to be in the clinic quickly, and we expect to file INDs in the next 12 to 24 months, starting with our PTK7-directed asset in the second half of 2025, followed closely by the MUC16-directed asset by the end of 2025, and the SEZ6-directed asset in mid-2026.

• HWK-007 presents a differentiated opportunity to be among the first next wave ADCs in clinical development for high PTK7 expressing cancers, including NSCLC, ovarian cancer, and several other major indications.

• HWK-016 is potentially the first ADC that targets membrane-bound portion of MUC16, a glycoprotein often overexpressed in cancers of female origin, such as ovarian cancer, endometrial cancer, cervical cancer, or breast cancer.

• HWK-206 is designed to bind to two epitopes on SEZ6, which is often overexpressed in cancers of neuroendocrine origin.

We believe this biparatopic approach can potentially improve internalization and drive increased effectiveness of the ADC.

We believe that improving ADC architecture can increase treatment efficacy in solid tumors.

Each of the ADC Therapies utilizes the advanced CPT113 linker-payload technology from Hangzhou DAC, which consists of a highly stable yet cleavable linker that delivers a TOPO1 inhibitor payload, and high affinity antibodies designed using the industry-leading antibody capability of Wuxi Biologics.

The portfolio leverages an advanced ADC platform technology and are engineered for minimal off-target toxicity, greater stability and higher therapeutic index.

We believe these assets can potentially overcome the limitations that hindered the first generation ADC therapies against these targets to deliver improved results for patients.

Under the WuXi License Agreement, we have worldwide development and commercialization rights to all of our product candidates.

We intend to develop each of our programs as a monotherapy and also in combination with other therapies.

Industry Background

Antibody-Drug Conjugates

An antibody-drug conjugate (“ADC”) consists of an antibody that is connected to a drug (the payload) via a linker.

An ADC can be a preferred alternative to systemic chemotherapies, particularly for cancer such as solid tumors, as it can deliver potent antibody-directed payloads directly to the tumor cells.

This targeted approach can limit off-target toxicities of chemotherapy and/or allow for greatly improved potency against cancer.

With these improvements in cancer outcomes, the ADC market with an estimated $11 billion in sales at the end of 2023 is expected to grow to over $50 billion by 2030.

As of the end of 2024, 13 ADCs have been approved by the FDA (mostly first generation;

two have been withdrawn) against multiple cancers, including blood, breast, and lung cancers.

Despite the benefit seen with first generation ADCs, there continues to be significant need for improved ADCs with safer payloads, improved stability and optimized pharmacokinetics.

For example, first generation ADCs often use tubulin inhibitor-based payloads, such as MMAE-based payloads, that have been associated with a class effect of dose-limiting toxicities, like peripheral neuropathy, ocular toxicities and neutropenia.

Next wave ADCs

Recent advances in ADCs have included replacing the tubulin inhibitor-based payloads with Topoisomerase I (“TOPO1”) inhibitor payloads to reduce toxicity, improving linker stability to reduce circulating free payload, and increasing and optimizing the drug-to-antibody ratio (“DAR”) to improve pharmacokinetics and antitumor activity.

In a number of ADC programs, next generation ADCs were shown to have improved ORR by 20-40% over their first-generation precursors.

For example, the ORR for ABBV-011, a calicheamicin-based ADC with a DAR of 2 and a non-cleavable linker, in small cell lung cancer (“SCLC”) was 19%, while the ORR for ABBV-706, a next wave ADC with a TOPO1 inhibitor payload and a DAR of 6, was 61%, representing a 42% higher response rate compared to ABBV-011.

Our Approach:

CPT113-based ADC platform

Each of the ADC Therapies utilizes Hangzhou DAC’s CPT113 platform, which consists of a highly stable yet cleavable linker with proprietary carbon-bridge technology that delivers a TOPO1 inhibitor payload.

We believe that the CPT113 platform’s linker stability and payload has the potential to be highly competitive among the next generation ADC platforms.

Hangzhou DAC selectively designed and synthesized an advanced linker and payload design that supports stability, limits free payload release and improves the pharmacokinetic characteristics for the associated ADCs.

Separately from the ADC Therapies we are licensing, Hangzhou DAC has two internally developed programs utilizing the same platform, DXC006 and DXC1002, that are currently in dose-escalating Phase 1 clinical trials in China.

A critical feature of the CPT113 platform is its stability.

First generation ADCs were challenged by high free payload release in circulation.

Many approved and marketed ADCs have 1 to 20 percent free payload released into the circulation, which limits their therapeutic windows because the high amounts of free payload can generate off-target side effects.

Next generation ADC platforms in development generally seek to lower the amounts of free payload released into circulation.

Based on reported pharmacokinetic results across different ADC programs, as shown in the figure below, the CPT113 platform is likely on par with or better than these latest platforms, demonstrating its highly competitive stability.

Based on highest species reported in publications on file;

note that stability is largely consistent (~1-5X differences) between species for an individual ADC.

Calculated based on molar concentration of free payload and ADC in representative pharmacokinetic studies.

The payload component of CPT113 is a proprietary TOPO1 inhibitor based on a modified form of exatecan.

Exatecan is a semisynthetic, water-soluble derivative of camptothecin, a naturally occurring plant alkaloid that is known for its TOPO1 inhibition and antitumor activity.

TOPO1 are necessary for normal and tumor cell growth, as they are involved in DNA supercoiling and repackaging of DNA during cell division.

Inhibition of TOPO1 prevents DNA from rejoining, thereby causing DNA breaks and leading to cell death.

Although exatecan has shown some antitumor activity, it has been associated with acute toxicity when delivered freely in the circulation, however, has been found to be highly effective as an ADC payload due to its ability to improve the overall efficacy and toxicity of the ADC.

Multiple companies are utilizing pure exatecan or exatecan derivatives in their ADC platforms.

Deruxtecan (“DXd”), for example, has been shown to have potent anti-tumor efficacy with an improved safety profile compared to pure exatecan.

Trastuzumab deruxtecan (“T-DXd”), an ADC consisting of a humanized mAb trastuzumab (Herceptin) covalently linked to DXd, is approved for treatment of breast cancer, gastric cancer and gastroesophageal adenocarcinoma and sold by Daiichi Sankyo.

Our payload has similar structure, cytotoxicity and preclinical safety profile to DXd.

Our Product Candidates

Our lead product candidate HWK-007 is a next wave ADC with a DAR of 6 targeting PTK7 that we plan to develop for the treatment of non-small cell lung cancer (“NSCLC”) and platinum resistant ovarian cancer (“PROC”), with potential to expand into other indications.

We believe HWK-007 has the potential to be among the first in next wave ADCs with a TOPO1 inhibitor payload to enter the clinic.

With its optimized linker and TOPO1 inhibitor payload, we hope to improve upon the initial ORRs seen with cofetuzumab pelidotin (“Cofe-P”), a first generation MMAE-based ADC with a DAR 4 targeting PTK7.

HWK-007 has shown superior cytotoxic activity compared to a first generation MMAE-based PTK7 ADC in both in vitro and in vivo preclinical models.

We are currently completing IND-enabling studies and expect to submit an IND for the use of HWK-007 in treating solid tumors, including NSCLC and PROC, in the second half of 2025.

Target Overview:

Protein tyrosine kinase 7 (PTK7)

Protein tyrosine kinase 7 (“PTK7”) is an oncofetal pseudokinase also known as colon carcinoma kinase 4 (“CCK-4”).

PTK7 is a transmembrane protein with an extracellular region comprised of 7 Ig domains and an intracellular domain that is non-catalytic.

PTK7 drives embryonic early development by regulating cell polarity, movement and development of hematopoietic and somatic progenitor cells often interacting with ligands, co-receptors and intracellular transducers in the Wnt signaling pathway.

PTK7 is subsequently down-regulated in adult tissues and is known as a catalytically inactive receptor tyrosine kinase (“RTK”).

PTK7 is commonly upregulated across a broad spectrum of cancers, being found in tumors associated with endometrial, prostate, cervical, head and neck, breast, colorectal, esophageal, lung, ovarian and gastric intestinal cancers, as shown in the figure below.

In fact, PTK7 is almost exclusively re-expressed in primary and metastatic tumor cells and cancer associated fibroblasts (“CAFs”) in the tumor microenvironment.

PTK7 is known to promote cancer growth and invasion.

Overexpression of PTK7 is associated with poor prognosis, tumor metastasis, and reduced overall survival.

Whitehawk analysis based on Human Protein Atlas, Gepia, and literature review.

PTK7 is a clinically validated tumor target.

In a Phase 1 trial in patients with advanced solid tumors, including PROC, NSCLC or triple-negative breast cancer (“TNBC”), Cofe-P demonstrated clinical activity with ORR ranging from 16 to 27% in all evaluable patients and 23 to 46% in the subgroup with moderate or high expression of PTK7 (“PTK7 mod-high”), as confirmed by immunohistochemistry (“IHC”) analysis of tumor tissues.

In patients treated every three weeks (“Q3W”) cohort, ORR was up to 46% compared to 27% in patients with PROC compared to patients with PTK7 mod-high PROC, 25% compared to 16% in patients with NSCLC compared to patients with PTK7 mod-high NSCLC and 23% compared to 21% in patients with TNBC compared to patients with PTK7 mod-high TNBC.

This is an important finding as PTK7 is an ADC target where a high proportion of marker-positive patients express PTK7 at moderate to high levels.

Despite these encouraging signals, Cofe-P’s commercial potential was limited by the reduced dose intensity and narrow therapeutic window driven by toxicities consistent with MMAE-associated class effects, including Grade 3 headache and fatigue.

Additionally, 25% (28/112) of the Q3W cohort experienced Grade 3 neutropenia.

Overall, common treatment-related adverse events included nausea, alopecia, fatigue, headache, neutropenia and vomiting.

* Mod-high ORR reflects Whitehawk analysis of the PTK7 protein expression and best overall response data for Q3W cohorts in Figure 2 of Maitland et al.

Clin Cancer Research , 2021:

There were 13, 16, and 13 patients with mod-high PTK 7 expressions in PROC, NSCLC, and TNBC, respectively.

Emerging Therapies and their Limitations

Although there are currently no approved ADCs targeting PTK7, there are multiple PTK7 programs currently in, or about to begin, clinical development, some of which are described here:

• PRO1107, being developed by Genmab following its acquisition of ProfoundBio, is currently in Phase 1/2 with the first patient dosed in February 2024.

PRO1107 uses an MMAE payload, which is a tubulin inhibitor similar to the payload in Cofe-P, connected through a protease-cleavable hydrophilic linker system called LD343, and has a DAR of 8.

• DAY301 (MTX-13), being developed by Day One Biopharmaceuticals after acquiring development and commercialization rights outside of the Greater China area from MabCare Therapeutics, recently initiated a Phase 1 trial.

Unlike Cofe-P and PRO1107, DAY301 has a pure exatecan payload which may be associated with myelosuppression.

LY4175408, being developed by Eli Lilly, also has a pure exatecan payload.

We expect Eli Lilly will submit its IND in 2025.

• SKB518, being developed by Kelun Biotech, is currently in Phase 1 in China.

We expect multiple external PTK7 ADC programs are projected to present clinical data in 2025 to 2027, which will further validate our target and TOPO1 inhibitor payload approach.

Additionally, there are multiple preclinical PTK7 bispecific ADCs in development, including the PTK7 x B7-H3 ADC recently acquired by IDEAYA Biosciences.

There are a number of other ADC programs in development for NSCLC targeting other tumor-associated antigens.

Our Product Candidate:

HWK-007, as a differentiated next wave PTK7-directed ADC, is poised to be among the first in next wave ADCs with an alternate TOPO1 inhibitor payload to enter the clinic.

With its optimized linker and TOPO1 inhibitor payload switch, we are targeting to build on the initial ORRs seen with Cofe-P and potentially deliver superior outcomes for patients.

HWK-007 has already demonstrated superior tumor reduction compared to Cofe-P in both in vitro and in vivo preclinical models.

HWK-007 shows superior tumor reduction in a lung cancer cell lines compared to similar doses of Cofe-P.

The in vivo antitumor studies were conducted with human tumor xenografts with moderate to high PTK7 expression in nude mice (n=8 per xenograft).

As shown in the figure below, in human SCLC xenograft models NCI-H446 (PTK7-mod), both HWK-007 and Cofe-P showed clear dose response in antitumor activity but HWK-007 demonstrated increased antitumor activity compared to Cofe-P at each corresponding dose with tumor regression achieved by HWK-007 at higher doses.

Similar results were also observed in xenograft models from other tumor types.

Clinical Development Plan

We plan to complete IND-enabling studies, linker-payload process development, and CMC and submit an IND for the treatment of solid tumors, including NSCLC and PROC, in the second half of 2025.

Subject to FDA acceptance, we plan to initiate a Phase 1 trial by the end of 2025.

Our product candidate HWK-016 is a next wave ADC targeting the membrane-bound portion of MUC16, a glycoprotein often overexpressed in cancers of female origin, such as ovarian cancer, endometrial cancer, cervical cancer, or breast cancer.

MUC16 has been previously a challenging target because a large part of its extracellular portion is often cleaved and released or “shed” into the bloodstream, often called cancer antigen 125 (“CA125”).

HWK-016 is specifically designed to bind to the membrane-bound portion, which we believe can enable greater therapeutic effect at lower doses.

We plan to develop HWK-016 initially for the treatment of PROC, with potential expansion to other ovarian cancers, endometrial cancer, and/or cervical cancer, aiming to deliver a potential best-in-class treatment for these large patient populations.

Our in vitro and in vivo studies show consistent cytotoxic activity by HWK-016, including in the presence of CA125, suggesting that our product candidate does bind to the right epitope.

Our product candidate also has an optimized linker and improved TOPO1 inhibitor payload, which we expect can improve response rate and reduce toxicity.

We plan to complete IND-enabling studies and submit an IND for the treatment of ovarian cancer by the end of 2025.

Target Overview:

Mucin 16 (MUC16) is a heavily glycosylated type 1 transmembrane protein with a low level of expression in normal bronchial, endometrial, ovarian and corneal epithelial cells.

MUC16 is upregulated in a number of cancers, including ovarian cancer, endometrial cancer, cervical cancer, or breast cancer, as well as NSCLC, pancreatic and gastric cancers.

Overexpression of MUC16 promotes cancer cell proliferation and chemoresistance, while also inhibiting anti-cancer immune responses.

Knockdown of MUC16 has been shown to reduce tumor growth, motility, and invasiveness, while overexpression enhances these properties.

MUC16 interacts with various signaling pathways and proteins, such as the JAK2/STAT3/GR axis, PI3k, EGFR and Src family kinases.

Whitehawk analysis based on Human Protein Atlas, Gepia, and literature review.

MUC16 consists of an O-glycosylated N-terminal domain, a tandem repeat domain, approximately 56 SEA (sperm protein, enterokinase and agrin) domains, a transmembrane domain and a cytoplasmic tail.

MUC16 is unique in its large number of SEA domains, as other mucins such as MUC1, MUC12, MUC13, and MUC17 only possess a single SEA module.

SEA domains and their functions are not fully understood but MUC16 is speculated to have two proteolytic sites in the SEA domains, at the 55 th and 56 th SEA domains.

It is believed that MUC16 cleavage occurs at these sites, whereby CA125 is released or “shed” into the bloodstream.

The serum levels of CA125 serve as a biomarker for cancer screening and disease monitoring;

CA125 is one of the best-known blood biomarkers for ovarian cancer and elevated levels are strongly associated with poor prognosis.

MUC16 is a clinically validated tumor target, including by DMUC4064A, a first generation MMAE-based ADC targeting the tandem repeat region of MUC16, that demonstrated efficacy in PROC in an open-label Phase 1 trial.

DMUC4064A, which has a protease-cleavable linker with a DAR of 2, demonstrated 42% ORR at the recommended Phase 2 dose.

Despite this promising response rate, DMUC4064A development was discontinued in 2021 due to a limited therapeutic index, toxicities consistent with MMAE class effects and binding to circulating CA125 that may have hindered effectiveness, also known as an “antigen sink.” Patients treated with DMUC4064A experienced toxicities consistent with other MMAE-based therapies, with 40% of patients reporting ocular toxicities, including Grade 3 ocular events in 9%.

Although MUC16 is expressed in certain ocular cell types, we believe the frequency and severity of ocular toxicities were primarily driven by the MMAE payload rather than on-target effects from MUC16 binding.

Overall, 25% experience Grade 3 or higher treatment-related adverse events.

Common adverse events included fatigue, nausea, abdominal pain, constipation, blurred vision, diarrhea, anemia and peripheral neuropathy.

Additionally, lower doses did not produce

objective responses, likely due to a portion of the ADC binding to circulating CA125.

Consequently, higher doses were necessary to first saturate most of the circulating CA125 before achieving therapeutic efficacy and tumor cell killing.

Liu J, et al.

Gynecol Oncol .

2021;163(3):473-480;

Nonhematologic TRAEs

Liu J, et al.

2016;27(11):2124-2130;

Fatigue 20 (59) 1 (3)

Nausea 16 (47) —

Diarrhea 13 (38) —

Weight decreased 13 (38) —

Hyperglycemia a

Chen Y, et al.

2007;67(10):4924-4932.

Hypertriglyceridemia a

ORR, objective response rate.

Emerging Therapies and their Limitations

Currently, there are no approved or actively developing ADCs targeting MUC16.

Regeneron is developing two MUC16 bispecific T cell-engaging antibodies;

a limitation of this approach, however, includes the modest ORRs observed to date.

While several ADCs targeting other antigens in PROC are under development, none offer the combined advantages of high target expression in both depth and frequency, along with the potential for a matched blood-based biomarker like CA125.

Our Product Candidate:

Our product candidate is designed to bind to a different region than the targets of prior MUC16 therapies in development.

HWK-016 targets membrane-bound MUC16 (mMUC16) below the site of cleavage, so that even if MUC16 is cleaved and release of CA125 occurs, the ADC can stay bound to the cell surface permitting internalization of the TOPO1 inhibitor payload.

This allows HWK-016 to bypass the antigen sink of circulating CA125, and directly target the tumor surface.

Preclinical data shows that HWK-016 demonstrates superior tumor growth inhibition in vivo compared to DMUC4064A in a high CA125-shedding model of ovarian cancer.

In vitro and in vivo data suggest that this next wave approach has the potential for improved response rates in ovarian cancer and other gynecological cancers.

For example, our product candidate HWK-016, along with DMUC and mMUC16 antibodies conjugated to DXd and MMAE payloads, were tested in an in vivo OVCAR-3 CDX model.

Nude mice bearing the OVCAR-3 tumor xenograft were treated with a single dose of ADC at 1 mg/kg.

mMUC16 ADCs displayed significantly increased in vivo antitumor activity compared to DMUC ADCs, regardless of the cytotoxic payload.

No obvious weight loss was observed in any group.

Clinical Development Plan

We plan to complete IND-enabling studies and linker-payload process development in 2025 with IND submission by the end of 2025.

Subject to FDA acceptance, we plan to initiate Phase 1 trial in ovarian cancer in 2026, with the potential to expand into other cancers affecting women, such as endometrial and cervical cancer, where we believe HWK-016 can make a meaningful impact.

Our product candidate HWK-206 is a biparatopic ADC targeting to two epitopes on the SEZ6 protein.

There is limited class competition as ABBV-706 is the only clinical-stage SEZ6 ADC currently in development.

Our product candidate is the only biparatopic ADC in development for SCLC and high-grade neuroendocrine tumors (“NET”) patients, and we believe this approach of binding to two independent sites on the target antigen protein will achieve superior outcomes compared to other SCLC ADCs.

In vitro and in vivo assays demonstrate increased binding and internalization compared to the monotopic ABBV-706.

We plan to complete IND-enabling studies and linker-payload process development in 2025 and first half of 2026, with an IND submission planned in mid-2026.

Target Overview:

Seizure-related homolog protein 6 (“SEZ6”) is a transmembrane protein commonly expressed on neurons, particularly neuronal dendrites, but minimally expressed in normal tissues outside the central nervous system (“CNS”).

SEZ6 plays a role in CNS development and maintenance both during childhood development and in adulthood.

SEZ6 is responsible for dendritic branching and synapse formation.

The extracellular portion of the SEZ6 proteins contain three CUB domains and five SCR domains.

The presence of multiple CUB and SCR domains suggests potential adhesive or receptor trafficking functions but their binding partners are not yet known.

SEZ6 is highly expressed in about 80% of SCLC and also overexpressed in extrapulmonary NETs and CNS tumors.

SEZ6 expression is correlated with tumor progression although its role in cancer is not well understood.

Whitehawk analysis based on Human Protein Atlas, Gepia, and literature review.

Emerging Therapies and their Limitations

Currently, ABBV-706 (developed by AbbVie) is the only clinical stage SEZ6 ADC in development.

ABBV-706 is a TOPO1 inhibitor-based ADC (DAR 6) with a cleavable linker.

In a Phase 1 trial in patients with SCLC and neuroendocrine neoplasms (“NEN”), ABBV-706 demonstrated an overall ORR of 44% (21/48, excludes n=5 with glioblastoma multiforme (“GBM”)), with 60.9% ORR in SCLC and 28% ORR in NENs.

ABBV-706 demonstrated a manageable safety profile with no on-target neurotoxicity.

The promising results with ABBV-706 validated SEZ6 as a target and demonstrated clinical improvement by switching to a cleavable TOPO1 inhibitor linker-payload.

Of note, 77% (41/53) of patients experienced Grade 3 or higher treatment-emergent adverse events (“TEAEs”) with cytopenias being the most frequent.

32% of patients experienced severe adverse events (“SAEs”), with pneumonia being the most common.

Anemia (60%) and fatigue (66%) were the most common any-grade hematologic and non-hematologic TEAEs, respectively.

The maximum tolerable dose (“MTD”) was 3.0 mg/kg, with hematological dose limiting toxicities (“DLTs”) occurring in 2 patients:

one Grade 4 leukopenia and neutropenia lasting >7 days and one Grade 4 thrombocytopenia.

All gastrointestinal toxicities were Grade 1 or 2 and no neurotoxicity or GBM was observed suggesting that there is no intracranial penetration.

While ABBV-706 represents important progress for SCLC, we believe there are opportunities to apply novel ADC engineering to provide a path to even greater gains.

Our Product Candidate:

We plan to investigate a biparatopic ADC approach for SEZ6.

Biparatopic antibodies (which bind two different epitopes of the same protein) can allow for clustering of cells surface receptors by way of binding an epitope of SEZ6 and then a different epitope on another SEZ6 protein.

This clustering ultimately results in the formation of large receptor clusters on the cell surface, which can drive receptor internalization and increase payload release for an ADC.

We believe this target specificity, binding, and the internalization can translate into great efficacy and/or safety gains for patients treated with ADCs.

Weisser et al.

2023;14(1):1394.

Hypercholesterolemia a

Decreased appetite 11 (32) —

Headache 10 (29) —

Peripheral edema 9 (26) —

• “a” Indicates groupings of preferred terms defined by standardized queries in the Medical Dictionary for Regulatory Activities.

• Additional G3 TRAEs were 6% hypokalemia, and 3% each of AST/ALT, amylase, hypophosphatemia, insomnia, lipase, lymphocyte, skin infection, vomiting.

No G4 TRAEs were reported.

In December 2017, we received Orphan Drug Designation (“ODD”) for FYARRO for the treatment of PEComa.

In October 2018, the FDA granted Fast Track designation for FYARRO for the treatment of patients with advanced (metastatic or locally advanced) malignant PEComa.

In December 2018, the FDA granted Breakthrough Therapy Designation (“BTD”) for FYARRO for the treatment of patients with advanced (metastatic or locally advanced) malignant PEComa.

The FDA accepted the NDA in July 2021 and granted full approval on November 22, 2021.

In January 2023, the FDA granted us orphan drug exclusivity ("ODE") for FYARRO for the treatment of patients with advanced malignant PEComa.

As a result of ODE for FYARRO in the advanced malignant PEComa indication, the FDA may not approve any other application to market the same drug for the same indication for a period of seven years from NDA approval of FYARRO (November 22, 2028), except in limited circumstances, such as a showing of clinical superiority over the product with orphan exclusivity.

TSC1 and TSC2 Alterations.

An exploratory mutational analysis was conducted on patients treated with FYARRO in the AMPECT study in advanced malignant PEComa.

In 25 patients with available mutational analysis, TSC1 or TSC2 alterations were found in 14 patients (56%).

In this subset of patients with TSC1 or TSC2 alterations, the response rate was 64% (9/14) (Figure 10).

In particular, TSC2 mutations were significantly associated with response (89% of patients) to FYARRO.

Figure 8 – Spider plot demonstrating change in the sum of target tumor measurements over time, based on mutation status based on exploratory mutational analysis conducted on patients treated with FYARRO in the AMPECT study .

* Arrowheads indicate patients who were still on treatment

FYARRO in patients with prior mTOR inhibitors

A post hoc electronic medical record review provided evidence of clinical benefit of nab -sirolimus in patients with malignant PEComa who had progressed or failed prior mTOR inhibitor treatment:

25% achieved a response (duration of response range:

1.3+–25.2+ months, 3 ongoing), and 50% had stable disease as best response as best response.

Of patients with TSC1 or TSC2 inactivating alterations, 44% had a response.

There are several biparatopic molecules that provide precedent for demonstrating increased therapeutic benefit compared to their single epitope counterparts.

For example, zanidatamab, a biparatopic HER2 Ab (Jazz Pharmaceuticals) binds the same epitopes as trastuzumab (Herceptin) and pertuzumab (Perjeta).

Zanidatamab demonstrated approximately 20% increase in ORR compared to monoparatopic trastuzumab while maintaining a tolerable safety profile.

Our biparatopic SEZ6 ADC, HWK-206, is the only biparatopic ADC in development for small cell lung cancer, and shows potential to outperform the available treatment approaches and the single epitope-binding ADCs in development.

Preclinical models suggest the biSEZ6 antibody shows superior binding and internalization compared to single epitope SEZ6 antibody counterparts, including the antibody used in ABBV-706, with increased mean fluorescence intensity (MFI).

Clinical Development Plan

We plan to explore this potential in our planned Phase 1 trial in SCLC and NETs where there is a significant need for new treatment options.

We plan to complete IND-enabling studies, linker-payload process development and submit an IND in mid-2026.

Intellectual Property

We strive to protect the proprietary technologies that we believe are important to our business, including pursuing and maintaining patent protection intended to cover formulations of FYARRO, its methods of use, related technologies, and other inventions that are important to our business.

In addition to patent protection, we also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection, including our proprietary method of manufacturing FYARRO.

Our commercial success depends, in part, upon our ability to obtain and maintain patent and other proprietary protection for FYARRO and other commercially important technologies, inventions, and know-how related to our business, defend and enforce our intellectual property rights, in particular, our patent rights, preserve the confidentiality of our trade secrets, and operate without infringing valid and enforceable intellectual property rights of others.

We strive to protect the proprietary technologies that we believe are important to our business, including pursuing and maintaining patent protection intended to cover the ADC Therapies, their respective anticipated methods of use, related technologies, and other inventions that are important to our business.

In addition to patent protection, we may also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

Our commercial success will depend, in part, upon our ability to obtain and maintain patent and other proprietary protection for the ADC Therapies, if approved, and other commercially important technologies, inventions, and know-how related to our business, defend and enforce our intellectual property rights, in particular, our patent rights, preserve the confidentiality of our trade secrets, and operate without infringing valid and enforceable intellectual property rights of others.

The patent positions for biotechnology and pharmaceutical companies like us are generally uncertain and can involve complex legal, scientific, and factual issues.

1 unchanged sentence

In addition, the coverage claimed in a patent application can be significantly reduced before a patent is issued, and its scope can be reinterpreted and even challenged after issuance.

As a result, we cannot guarantee that FYARRO will be protected or remain protectable by enforceable patents.

As a result, we cannot guarantee that the ADC Therapies will be protected or remain protectable by enforceable patents.

Moreover, any patents that we hold may be challenged, circumvented, or invalidated by third parties.

For more information regarding the risks related to our intellectual property please see “Risk Factors—Risks Related to Our Intellectual Property”.

We own or exclusively license twelve (12) issued patents in the United States as well as issued patents in other countries.

With respect to our licensed patents, we have exclusive, sublicensable rights to certain patents and patent applications relating to FYARRO under our license agreement with BMS .

As of December 31, 2023, we licensed five (5) issued U.S.

patents with composition of matter and method of use claims covering FYARRO.

The first issued U.S.

patent is expected to expire in 2029, and the other four are expected to expire in 2030, 2036, 2036 and 2040, respectively.

In addition, we licensed related patents in Europe, Australia, North America, South America, and Asia that are expected to expire between

2026 and 2037.

We also own or licensed many pending U.S.

applications and related pending applications in Europe, Australia, North America, South America, Africa, and Asia.

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.

4 unchanged sentences

Similar provisions are available in Europe and in certain other jurisdictions to extend the term of a patent that covers an approved dr ug.

In January 2022, we filed an application for patent term extension based on the approval of FYARRO.

We also intend t o seek patent term extensions in any jurisdictions where they are available, however, there is no guarantee that the applicable authorities, including the FDA, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.

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For more information regarding the risks related to our intellectual property please see “Risk Factors—Risks Related to Our Intellectual Property.”

Commercial Operations

We have built a cross-functional commercial organization and infrastructure to support the commercialization of FYARRO for advanced malignant PEComa in the United States and will continue to evaluate potential partners in markets outside the United States.

We have an experienced oncology commercial team including marketing, commercial operations and sales personnel to promote FYARRO to physicians who are prescribers of treatments for advanced malignant PEComa.

We have assembled a network of specialty distributors and a specialty pharmacy to distribute FYARRO across multiple sites of care in the United States.

Additionally, the sales and marketing teams manage relationships with key accounts such as managed care organizations, group purchasing organizations, hospital systems, physician group networks, and government accounts.

For future approvals of FYARRO in other oncology indications, if any, we intend to retain commercialization rights in the United States and leverage our commercial and marketing organization for FYARRO, with appropriate additions or modifications as necessitated by the specific indications pursued, assuming we obtain regulatory approval in the United States, and consider whether to build our own commercial and marketing organization in select markets outside the United States, or selectively establish partnerships.

Accordingly, we will consider entering into relationships with strategic partners that enable the expansion of the ongoing clinical development and/or licenses for development and commercialization or distribution, while retaining significant value for our shareholders.

These partnerships could focus on specific patient populations and their caregivers, on regional development, or on distribution and sales.

The pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary drugs.

While we believe that our technology, development experience, and scientific knowledge provide us with competitive advantages, we face potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies, and public and private research institutions.

Any drug candidates that we successfully develop and commercialize will compete with existing drugs and new drugs that may become available in the future.

We compete in the segments of the pharmaceutical, biotechnology, and other related markets that address inhibition of kinases in cancer and other rare genetic diseases.

There are other companies working to develop therapies in the field of kinase inhibition for cancer and other diseases.

These companies include divisions of large pharmaceutical companies and biotechnology companies of various sizes.

Many of the companies against which we are competing or which we may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved drugs than we do.

Mergers and acquisitions in the pharmaceutical, biotechnology, and diagnostic industries may result in even more resources being concentrated among a smaller number of our competitors.

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

We could see a reduction or elimination in our commercial opportunity if our competitors develop and commercialize drugs that are safer, more effective, have fewer or less severe side effects, are more convenient, or are less expensive than any drugs that we or our collaborators may develop.

Our competitors also may obtain FDA or other regulatory approval for their drugs more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we or our collaborators are able to enter the market.

The key competitive factors affecting the success of FYARRO are likely to be its efficacy, safety, convenience, price, the effectiveness of companion diagnostics, the level of generic competition, and the availability of reimbursement from government and other third-party payors.

Competition for FYARRO in Advanced Malignant PEComa

In advanced malignant PEComa, other than FYARRO, there are no existing FDA approved therapies or drugs that have been studied in prospective clinical trials.

Following FDA approval, the National Comprehensive Cancer Network (“NCCN”) Sarcoma panel included FYARRO as the only preferred regimen for treatment of malignant PEComa.

FYARRO may face competition from available mTOR inhibitors including sirolimus, everolimus, and temsirolimus or other drug candidates in clinical trials.

As of today, we are not aware of any other companies pursuing FDA approval for drugs to treat advanced malignant PEComa.

Competition for FYARRO in TSC1 and TSC2 Inactivating Alterations

For TSC1 or TSC2 inactivating alterations, there are no existing FDA approved drugs.

If FYARRO receives marketing approval, it may face competition from available mTOR inhibitors including sirolimus, everolimus, and temsirolimus or other drug candidates in clinical trials that target the mTOR pathway, such as dual mTORC1/2 inhibitors or other next-generation mTOR inhibitors.

As of March 6, 2025, patent rights held by us relating to our ADC drug candidates include the following:

• With respect to the PTK7 targeting drug candidate, our material patents consist of one People’s Republic of China (PRC) patent application exclusively licensed from WuXi Biologics and directed to the PTK7 ADC drug candidate, which we intend to pursue patent protection for in key jurisdictions.

This application, if issued, is expected to expire in at least 2046, without taking into account any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

• With respect to the SEZ6 targeting drug candidate, our material patents consist of one PRC patent application exclusively licensed from WuXi Biologics and directed to the SEZ6 ADC drug candidate, which we intend to pursue patent protection for in key jurisdictions.

• With respect to the MUC16 targeting drug candidate, our material patents consist of one PRC patent application exclusively licensed from WuXi Biologics and directed to the MUC16 ADC drug candidate, which we intend to pursue patent protection for in key jurisdictions.

Many companies are active in the oncology market and are developing or marketing products for the specific therapeutic markets that we target, including both antibody- and non-antibody-based therapies.

Similarly, we also face competition from other companies and institutions that continue to invest in innovation in the ADC field, including new payload classes, new conjugation approaches and new targeting moieties.

Specifically, we are aware of multiple companies with ADC technologies that may be competitive with our products and product candidates, including, but not limited to, AbbVie, Daiichi Sankyo, Day One Biopharmaceuticals, Eli Lilly, Genmab, GlaxoSmithKline, Gilead, Kelun, Mersana, Sanofi, Roche, Pfizer, and Zymeworks.

There are hundreds of ADCs in development, the vast majority of which are being developed for the treatment of cancer.

Our industry is characterized by rapidly advancing technologies, intense competition, and a strong emphasis on proprietary products.

We face competition with respect to our current products and product candidates and will face competition with respect to any products and product candidates that we may seek to develop or commercialize in the future.

Our competitors include large pharmaceutical and biotechnology companies, academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization.

Many of our competitors have significantly greater financial resources and capabilities in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approval and marketing than we do.

Furthermore, mergers and acquisitions in the biotechnology industry may result in even more resources being concentrated among a smaller number of our competitors.

In addition, we expect changes to the treatment paradigm, including potential new entrants and new approvals across the lines of therapies.

New technologies, procedures or treatments could change the patient population and their eligibility to use our product candidates, raise expectations regarding safety and efficacy results that are necessary for regulatory approval and, if approved, adoption by the medical community, or otherwise render the ADC Therapies and any other product candidates that we may develop obsolete.

Although there are currently no approved ADCs targeting PTK7, there are multiple PTK7 programs currently in, or about to begin, clinical development, including

• PRO1107, being developed by Genmab following its acquisition of ProfoundBio, is currently in Phase 1/2 with the first patient dosed in February 2024.

PRO1107 uses an MMAE payload, which is a tubulin inhibitor similar to the payload in Cofe-P, connected through a protease-cleavable hydrophilic linker system called LD343, and has a DAR of 8.

Unlike Cofe-P and PRO1107, DAY301 has a pure exatecan payload which may be associated with myelosuppression.

LY4175408, being developed by Eli Lilly, also has a pure exatecan payload.

We expect Eli Lilly will submit its IND in 2025.

• SKB518, being developed by Kelun Biotech, is currently in Phase 1 in China.

• Additionally, there are multiple preclinical PTK7 bispecific ADCs in development, including the PTK7 x B7-H3 ADC recently acquired by IDEAYA Biosciences.

In addition, there are multiple PTK7 ADC programs that are projected to present clinical data in 2025 to 2027, which we believe will further validate our target and TOPO1 inhibitor payload approach.

Currently, there are no approved or actively developing ADCs targeting MUC16.

Regeneron is developing two MUC16 bispecific T cell-engaging antibodies;

a limitation of this approach, however, includes the modest ORRs observed to date.

Currently, ABBV-706 (developed by AbbVie) is the only clinical stage SEZ6 ADC in development.

ABBV-706 is a TOPO1 inhibitor-based ADC (DAR 6) with a cleavable linker.

ABBV-706 demonstrated a manageable safety profile with no on-target neurotoxicity.

The promising results with ABBV-706 validated SEZ6 as a target and demonstrated clinical improvement by switching to a cleavable TOPO1 inhibitor linker-payload.

Manufacturing

We do not own or operate, and have no plans to establish, any manufacturing facilities.

We currently rely on third parties to manufacture FYARRO for preclinical and clinical testing, as well as for our commercial supply of FYARRO.

The Amended and Restated License Agreement for FYARRO with BMS, dated November 2019, transferred the responsibility for manufacturing of FYARRO to us.

FYARRO was previously manufactured for us by BMS through their third-party manufacturer, Fresenius-Kabi, USA.

As a result of the amendment to the License Agreement, we now obtain FYARRO directly from Fresenius-Kabi, USA.

To date, we have obtained drug substance and drug product from third-party manufacturers to support pre-clinical and clinical testing of FYARRO.

On January 13, 2022, we entered into a Negotiated Purchase Order Terms and Conditions for Clinical and Commercial Product, as amended effective as of August 1, 2022 (the “Fresenius Agreement”), with Fresenius Kabi, LLC (“Fresenius Kabi”) pursuant to which Fresenius Kabi will manufacture FYARRO for us, and we will purchase FYARRO as a finished drug product from Fresenius Kabi, on a purchase-order basis.

The Fresenius Agreement is effective through March 31, 2024 (or such later date as may be agreed between the parties in writing) and we are currently negotiating an extension to such agreement.

Under the Fresenius Agreement, we may purchase FYARRO for either clinical or commercial purposes for use in the United States and Canada.

We have a fully validated commercial manufacturing process in place for FYARRO at the Fresenius Kabi's Grand Island Manufacturing facility.

We are evaluating options with Fresenius Kabi to create redundant supply of FYARRO.

In addition to manufacturing, Fresenius Kabi will perform specified labeling, packaging and serialization activities in respect of FYARRO for our benefit.

The price of FYARRO is fixed, subject to the ability of Fresenius Kabi to increase pricing under specified circumstances.

We have an obligation to purchase certain minimum quantities of FYARRO.

Failure to purchase those minimum quantities will result in an additional payment from us to Fresenius Kabi.

We have supply agreements in place for key raw materials used in the manufacture of FYARRO such as the drug substance sirolimus and for human albumin, which are key ingredients in the drug product.

We do not currently have arrangements in place for redundant supply of the key raw materials used in the manufacture of FYARRO.

We expect to continue to evaluate options to cost-effectively produce FYARRO at contract manufacturing facilities.

We generally expect to rely on third parties for the manufacture or development of any companion diagnostics if we are required to do so in the future for FYARRO.

Initially, we intend to continue to benefit from the continuity of partnership with WuXi Biologics and Hangzhou DAC for near-term IND-enabling studies and ADC manufacturing.

We will expand our CRDMO network as appropriate as our portfolio advances further in clinical trials.

Government Regulation

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Generally, pivotal studies are also Phase 3 studies but may be Phase 2 studies if the trial design provides a well-controlled and reliable assessment of clinical benefit, particularly in situations where there is an unmet medical need.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.

Post-approval trials,

sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.

These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.

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Following trial completion, trial data are analyzed to assess safety and efficacy.

The results of preclinical studies and clinical trials are then submitted to the FDA as part of a NDA, along with proposed labeling for the drug and information about the manufacturing process and facilities that will be used to ensure drug quality, results of analytical testing conducted on the chemistry of the drug, and other relevant information.

The results of preclinical studies and clinical trials are then submitted to the FDA as part of an NDA, along with proposed labeling for the drug and information about the manufacturing process and facilities that will be used to ensure drug quality, results of analytical testing conducted on the chemistry of the drug, and other relevant information.

The NDA is a request for approval to market the drug and must contain sufficient evidence of drug product quality, safety and efficacy, which is demonstrated by extensive analytical, preclinical and clinical testing.

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Drug approvals may be withdrawn for non-compliance with regulatory standards or if problems occur following initial marketing.

In November 2021, we received approval for the commercial sale of FYARRO from the FDA to treat patients with advanced (metastatic or locally advanced) PEComas.

The NDA submission was based on results from our Phase 2 registrational study, AMPECT, in patients with advanced malignant PEComa, for whom there were no approved therapies in the U.S.

FDA Expedited Development and Review Programs

The FDA has various programs, including fast track designation, priority review, accelerated approval, and breakthrough therapy designation, which are intended to expedite or simplify the process for the development and FDA review of drugs that are intended for the treatment of serious or life-threatening diseases or conditions and demonstrate the potential to address unmet medical needs.

address unmet medical needs.

The purpose of these programs is to provide important new drugs to patients earlier than under standard FDA review procedures.

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Specifically, new drugs are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

With regard to a fast track product, the FDA may consider for review sections of the NDA on a

rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

With regard to a fast track product, the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

Any product submitted to the FDA for approval, including a product with a fast track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

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Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

We may explore some of these opportunities for FYARRO as appropriate.

We may explore some of these opportunities for the ADC Therapies as appropriate.

Post-Marketing Requirements

restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling, limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

Following approval of a new drug, a pharmaceutical company and the approved drug are subject to continuing regulation by the FDA, including, among other things, establishment registration and drug listing, monitoring and recordkeeping activities, reporting to the applicable regulatory authorities of adverse experiences with the drug, providing the regulatory authorities with updated safety and efficacy information, drug sampling and distribution requirements, and complying with promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling, limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

In particular, the FDA closely regulates the marketing, labeling, advertising, and promotion of drug products.

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Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our drugs under development.

As a condition of the approval of the NDA for FYARRO, we are required to conduct certain post-marketing requirements (“PMR”) and post-marketing commitments (“PMC”), which are ongoing.

If we fail to comply with the PMR and PMC, the FDA may take enforcement actions, which may include, among other things, the issuance of a Warning Letter and assessing civil monetary penalties.

The product may also be deemed misbranded.

Orphan Drug Designation

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In addition, if a product receives the first FDA approval for the indication for which it has orphan designation, the product is entitled to orphan drug exclusivity ("ODE"), which means the FDA may not approve any other application to market the same drug for the same indication for a period of seven years, except in limited circumstances, such as a showing of clinical superiority over the product with orphan exclusivity.

In January 2023, the FDA granted us ODE for FYARRO for the treatment of patients with advanced malignant PEComa.

In Catalyst Pharms., Inc.

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It is unclear how future litigation, legislation, agency decisions, and administrative actions will impact the scope of the ODE.

In June 2024, in Loper Bright Enterprises v.

Raimondo , the U.S.

Supreme Court overruled the Chevron doctrine, which gives deference to regulatory agencies’ statutory interpretations in litigation against federal government agencies, such as

the FDA, where the law is ambiguous.

This landmark Supreme Court decision may invite various stakeholders to bring lawsuits against the FDA to challenge longstanding decisions and policies, such as market exclusivities, which could lead to uncertainties in the industry.

Further, changes in the leadership of the FDA and other federal agencies under the Trump administration may lead to new policies, changes in the regulations, or disruptions to the operations of federal agencies, any of which may impact our clinical development plans.

In the European Union, the European Commission, after receiving the opinion of the European Medicines Agency’s (“EMA”) Committee for Orphan Medicinal Products (“COMP”), grants orphan drug designation to also promote the development of products.

The relevant European legislation provides that a product can be designated as an orphan drug by the European Commission if its sponsor can establish:

that the product is intended for the diagnosis, prevention, or

treatment of (1) a life-threatening or chronically debilitating condition affecting not more than 5 in 10,000 persons in the European Union when the application is made, or (2) a life-threatening, seriously debilitating, or serious and chronic condition in the European Union and that without incentives it is unlikely that the marketing of the product in the European Union would generate sufficient return to justify the necessary investment.

that the product is intended for the diagnosis, prevention, or treatment of (1) a life-threatening or chronically debilitating condition affecting not more than 5 in 10,000 persons in the European Union when the application is made, or (2) a life-threatening, seriously debilitating, or serious and chronic condition in the European Union and that without incentives it is unlikely that the marketing of the product in the European Union would generate sufficient return to justify the necessary investment.

For either of these conditions, the applicant must also demonstrate that there exists no satisfactory method of diagnosis, prevention, or treatment of the condition in question that has been authorized in the European Union or, if such method exists, the product has to be of significant benefit compared to products available for the condition.

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Patent Term Restoration and Marketing Exclusivity

Depending upon the timing, duration, and specifics of the FDA approval of our drug candidate, some of our United States patents may be eligible for limited patent term extension under the Hatch-Waxman Act.

Depending upon the timing, duration, and specifics of the FDA approval of our ADC drug candidate, some of our United States patents may be eligible for limited patent term extension under the Hatch-Waxman Act.

The Hatch-Waxman Act permits a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process.

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Regulatory Matters

Manufacturing, sales, promotion, and other activities following drug approval are also subject to regulation by numerous regulatory authorities in addition to the FDA, including, in the United States, the Centers for Medicare & Medicaid

Services (“CMS”), other divisions of the U.S.

Department of Health and Human Services (“HHS”), the Drug Enforcement Administration for controlled substances, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency, and state and local governments.

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Private third-party payors tend to follow Medicare coverage and reimbursement limitations to a substantial degree, but also have their own methods and approval process apart from Medicare determinations.

Accordingly, decisions regarding the extent of coverage and amount of reimbursement to be provided for FYARRO will be made on a payor-by-payor basis.

Accordingly, decisions regarding the extent of coverage and amount of reimbursement to be provided for the ADC

Therapies will be made on a payor-by-payor basis.

As a result, the coverage determination process may be a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.

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government, state legislatures, and foreign governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement, and requirements for substitution of generic drugs.

Adoption of price controls and cost-containment measures, and

adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results.

Decreases in third-party reimbursement for FYARRO or a decision by a third-party payor to not cover FYARRO could reduce physician usage of such drug and have a material adverse effect on our sales, results of operations and financial condition.

Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results.

The Medicaid Drug Rebate Program (“MDRP”) requires pharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the Secretary of the HHS as a condition for states to receive federal matching funds for the manufacturer’s outpatient drugs furnished to Medicaid patients.

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The plan for the research was published in 2012 by the HHS, the Agency for Healthcare Research and Quality and the National Institutes for Health, and periodic reports on the status of the research and related expenditures are made to Congress.

Although the results of the comparative effectiveness studies are not intended to mandate coverage policies for public or private payors, it is not clear what effect, if any, the research will have on the sales of FYARRO, if any such drug or the condition that such drug is intended to treat are the subject of a trial.

It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s drug could adversely affect the sales of our drug candidate.

It is also possible that comparative effectiveness research

demonstrating benefits in a competitor’s drug could adversely affect the sales of our ADC drug candidate.

If third-party payors do not consider our drugs to be cost-effective compared to other available therapies, they may not cover our drugs as a benefit under their plans or, if they do, the level of payment may not be sufficient to allow us to sell our drugs on a profitable basis.

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The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

These laws, and future state and federal healthcare reform measures, as discussed further below, may be adopted in the future, any of which may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any indication of FYARRO for which it may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

As noted above, the marketability of any products for which we receive regulatory approval for commercial sale may suffer if the government and other third-party payors fail to provide adequate coverage and reimbursement.

These laws, and future state and federal healthcare reform measures, as discussed further below, may be adopted in the future, any of which may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any product candidate for which it may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

As noted above, the marketability of any products for wh ich we receive regulatory approval for commercial sale may suffer if the government and other third-party payors fail to provide adequate coverage and reimbursement.

We expect that an increasing emphasis on cost containment measures in the U.S.

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In addition, in order to be eligible to have its products paid for with federal funds under the Medicaid programs and purchased by certain federal grantees and agencies, a manufacturer also must participate in the Department of Veterans Affairs Federal Supply Schedule (“FSS”) pricing program, established by Section 603 of the Veterans Health Care Act of 1992.

Under this program, the manufacturer is obligated to make products available for procurement on an FSS contract and charge a price to four federal agencies—the Department of Veterans Affairs, the Department of Defense, the Public Health Service, and the Coast Guard—that is at least 24% less than the Non-Federal Average Manufacturing Price for the prior fiscal year.

Health Service, and the Coast Guard—that is at least 24% less than the Non-Federal Average Manufacturing Price for the prior fiscal year.

Since the enactment of the ACA, there have been judicial and Congressional challenges to certain aspects of the ACA.

In June 2021, the Supreme Court held that Texas and other challengers had no legal standing to challenge the ACA, upholding the ACA.

In January 2021, President Biden also issued an executive order to initiate a special enrollment period

to allow people to obtain health insurance coverage through the ACA marketplace and instructs certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, among others.

We cannot predict how future litigation, healthcare reform measures of the Biden administration, or what other regulations will ultimately be implemented at the federal or state level, or the effect of any future legislation or regulation may have on our business.

In January 2021, President Biden also issued an executive order to initiate a special enrollment period to allow people to obtain health insurance coverage through the ACA marketplace and instructs certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, among others.

We cannot predict how future litigation, healthcare reform measures of the Trump administration, or what other regulations will ultimately be implemented at the federal or state level, or the effect of any future legislation or regulation may have on our business.

Moreover, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

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In August 2022, Congress passed the Inflation Reduction Act of 2022, which includes prescription drug provisions that have significant implications for the pharmaceutical industry and Medicare beneficiaries, including allowing the federal government to negotiate a maximum fair price for certain high-priced single source Medicare drugs, imposing penalties and excise tax for manufacturers that fail to comply with the drug price negotiation requirements, requiring inflation rebates for all Medicare Part B and Part D drugs, with limited exceptions, if their drug prices increase faster than inflation, and redesigning Medicare Part D to reduce out-of-pocket prescription drug costs for beneficiaries, among other changes.

In June 2024, in Loper Bright Enterprises v.

Raimondo , the U.S.

Supreme Court overruled the Chevron doctrine, which gives deference to regulatory agencies’ statutory interpretations in litigation against federal government agencies, such as the FDA, where the law is ambiguous.

There are important exemptions to Maximum Fair Price including medications that are orphan drug designated and approved, for only one rare disease, and drugs with low Medicare spend as defined by CMS.

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At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures and, in some cases, designed to encourage importation from other countries and bulk purchasing.

For example, the FDA recently authorized the state of Florida to import certain prescription drugs from Canada for a period of two years to help reduce drug costs, provided that Florida’s Agency for Health Care Administration meets the requirements set forth by the FDA.

For example, the FDA has authorized the state of Florida to develop a program to import certain prescription drugs from Canada for a limited period to help reduce drug costs, provided that Florida’s Agency for Health Care Administration meets the requirements set forth by the FDA.

Other states may follow Florida.

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Other Healthcare Laws

For our product and any product candidates that obtain regulatory approval and are marketed in the United States, our arrangements, directly or indirectly, with third-party payors, healthcare providers, and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial

arrangements and relationships through which we market, sell, and distribute any products for which we obtain marketing approval.

Our employees, consultants, and commercial partners may engage in misconduct or other improper activities, including non-compliance with regulatory standards and requirements.

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Bribery Act of 2010, and other local anti-corruption laws that apply to our international activities;

• the federal Physician Payment Sunshine Act (“Open Payments”), and implementing regulations, which require applicable group purchasing organizations and manufacturers of covered drugs, medical devices, biologicals and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program to report annually to the CMS information related to certain payments and other transfers of value made to covered recipients, including licensed physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain non-physician healthcare professionals (such as physician assistants and nurse practitioners, among others), and teaching hospitals, and information regarding ownership and investment interests held by physicians and their immediate family members;

dentists, optometrists, podiatrists and chiropractors), certain non-physician healthcare professionals (such as physician assistants and nurse practitioners, among others), and teaching hospitals, and information regarding ownership and investment interests held by physicians and their immediate family members;

• analogous state and foreign law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers or patients;

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consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm customers;

foreign and state laws, including the EU General Data Protection Regulation

(“GDPR”) and a version of the GDPR adopted in the United Kingdom (“UK GDPR”), and state laws and regulations, including general legislation such as the California Consumer Protection Act (“CCPA”), and sector- or subject matter-specific laws and regulations, governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts;

foreign and state laws, including the EU General Data Protection Regulation (“GDPR”) and a version of the GDPR adopted in the United Kingdom (“UK GDPR”), and state laws and regulations, including general legislation such as the California Consumer Protection Act (“CCPA”), and sector- or subject matter-specific laws and regulations, governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts;

and state laws related to insurance fraud in the case of claims involving private insurers.

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While there is currently an exception in the CCPA for protected health information that is subject to HIPAA and clinical trial regulations, as currently written, numerous other states have enacted legislation similar to the CCPA, and several states have enacted other privacy and security legislation, such as Washington’s My Health, My Data Act, which includes a private right of action.

The CCPA and such other new and evolving legislation may impact our business activities significantly, and these and other applicable state and foreign privacy laws, as well as uncertain changes in future regulation and legislation, could impact our business strategies, increase our potential liability, increase our compliance costs, and adversely affect our business.

The CCPA and such other new and evolving legislation may impact our business activities significantly, and these and other applicable state and foreign

privacy laws, as well as uncertain changes in future regulation and legislation, could impact our business strategies, increase our potential liability, increase our compliance costs, and adversely affect our business.

The collection and use of personal health data in the European Union are governed by the GDPR and applicable member state legislation.

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Failure to comply with the requirements of the GDPR, UK GDPR, or data protection laws of European Union member states may result in fines and other administrative penalties.

The GDPR and UK GDPR may impose additional responsibility and liability in relation to personal data that we process and we may be required to put in place additional mechanisms in an

effort to achieve and maintain compliance with their obligations.

The GDPR and UK GDPR may impose additional responsibility and liability in relation to personal data that we process and we may be required to put in place additional mechanisms in an effort to achieve and maintain compliance with their obligations.

This may be onerous and adversely affect our business, financial condition, results of operations, and prospects.

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This system went into application in first quarter of 2022.

From January 31, 2025, any trials approved under the Clinical Trials Directive that continue running will need to comply with the Clinical Trials Regulation, and their sponsors must enter information on the trials in the Clinical Trials Information System.

The Clinical Trials Regulation seeks to simplify and streamline the approval of clinical trials in the European Union.

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Employees and Human Capital

We have operated by leveraging skilled experts, consultants, contract research organizations, and contractors to manage our clinical operations, manufacturing, research and development, and other functions under the leadership and direction of our management.

We will continue to expand our infrastructure to manage our operations, including commercial with additional full-time employees.

As of December 31, 2024, we had 40 full-time or part-time employees.

Of these employees, 55 employees are engaged in research and development activities and 34 employees are engaged in selling, general and administrative activities.

In February 2024, we reduced our workforce by 12 employees, primarily related to restructuring of our commercial, medical affairs and corporate support functions.

Following the restructuring, as of March 4, 2024, we had 74 full-time or part time employees, with 50 and 24 of these employees engaged in research and development activities and in selling, general and administrative activities, respectively.

Of these employees, 23 employees were engaged in research and development activities and 17 employees were engaged in selling, general and administrative activities.

In connection with the FYARRO Divestiture, 16 employees remained with Aadi Subsidiary, Inc., and 6 employees departed the company.

As a result, following the FYARRO Divestiture, we have 18 full-time or part-time employees.

None of our employees are represented by labor unions or covered by collective bargaining agreements.

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Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees, advisors and consultants, while being committed to a diverse and dynamic workplace.

The principal purposes of our equity incentive plans are to attract, retain and reward personnel through

the granting of equity-based compensation awards in order to increase shareholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

The principal purposes of our equity incentive plans are to attract, retain and reward personnel through the granting of equity-based compensation awards in order to increase shareholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

Our Corporate Information

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In August 2021, we effected a reverse merger pursuant to which a wholly owned subsidiary of ours, merged with and into Aadi Subsidiary, Inc.

(formerly Aadi Bioscience, Inc.) (“Private Aadi”), with Private Aadi surviving as a wholly owned subsidiary of ours (the "Merger").

(formerly known as Aadi Bioscience, Inc.

or "Private Aadi") (“Aadi Subsidiary”), with Aadi Subsidiary surviving as a wholly owned subsidiary of ours (the "Merger").

Upon the closing of the Merger, we changed our name from “Aerpio Pharmaceuticals, Inc.” to “Aadi Bioscience, Inc.” and the name of Private Aadi was changed from “Aadi Bioscience, Inc.” to “Aadi Subsidiary, Inc.”

Our principal executive offices are located at 17383 Sunset Boulevard, Suite A250, Pacific Palisades, California 90272.

We maintain a website at www.aadibio.com, to which we regularly post copies of our press releases as well as additional information about us.

In connection with the FYARRO Divestiture, KAKEN acquired 100% of the outstanding shares of capital stock of Aadi Subsidiary.

On March 18, 2025, in connection with such transaction, we changed our name from "Aadi Bioscience, Inc." to "Whitehawk Therapeutics, Inc."

Since March 2025, our principal executive offices have been located at 2 Headquarters Plaza, East Building, 11 th Floor, Morristown, NJ 07960.

Prior to March 2025, our principal executive offices were located at 17383 Sunset Boulevard, Suite A250, Pacific Palisades, California 90272.

We maintain a website at www.whitehawktx.com, to which we regularly post copies of our press releases as well as additional information about us.

Our filings with the Securities and Exchange Commission (the “SEC”) will be available free of charge through the website as soon as reasonably practicable after being electronically filed with or furnished to the SEC.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business