Prelude Therapeutics Inc - Annual Report: 2020 (Form 10-K)

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2020

OR

Commission File Number 001-39527

PRELUDE THERAPEUTICS INCORPORATED

(Exact name of Registrant as specified in its Charter)

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DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant’s Definitive Proxy Statement (“Proxy Statement”) relating to the 2021 Annual Meeting of Stockholders will be filed with the Commission within 120 days after the end of the Registrant’s 2020 fiscal year pursuant to Regulation 14A and is incorporated by reference into Part III of this Report.

Table of Contents

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PART I

This Annual Report on Form 10-K contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements are based on our management’s beliefs and assumptions and on information currently available to our management. All statements other than statements of historical facts are “forward-looking statements” for purposes of these provisions, including those relating to future events or our future financial performance. In some cases, you can identify forward-looking statements by terminology such as “may,” “might,” “will,” “should,” “expect,” “plan,” “anticipate,” “project,” “believe,” “estimate,” “predict,” “potential,” “intend” or “continue,” the negative of terms like these or other comparable terminology, and other words or terms of similar meaning in connection with any discussion of future operating or financial performance. These statements are only predictions. All forward-looking statements included in this Annual Report on Form 10-K are based on information available to us on the date hereof, and we assume no obligation to update any such forward-looking statements. Any or all of our forward-looking statements in this document may turn out to be wrong. Actual events or results may differ materially. Our forward-looking statements can be affected by inaccurate assumptions we might make or by known or unknown risks, uncertainties and other factors. We discuss many of these risks, uncertainties and other factors in this Annual Report on Form 10-K in greater detail under the heading “Item 1A—Risk Factors.” We caution investors that our business and financial performance are subject to substantial risks and uncertainties.

Item 1. Business.

Overview

We are a clinical-stage precision oncology company focused on discovering and developing small molecule therapies optimized to target the key driver mechanisms in cancers with high unmet need. By leveraging our core competencies in cancer biology and medicinal chemistry, combined with our target class- and technology platform-agnostic approach, we have built an efficient, fully-integrated drug discovery engine to identify compelling biological targets and create new chemical entities, or NCEs, that we rapidly advance into clinical development. We believe our approach could result in better targeted cancer therapies. Our discovery excellence has been validated by our rapid progress in creating a wholly-owned, internally developed pipeline. Since our inception in 2016, we have received clearance from the U.S. Food and Drug Administration, or the FDA, for four investigational new drug applications, or INDs, and successfully advanced three of these programs into clinical development with the fourth expected to begin clinical development in the first half of 2021. In addition, we have three unique programs in various stages of preclinical development that we plan to advance into clinical development beginning in 2021.

By focusing on developing agents using broad mechanisms that have multiple links to oncogenic driver pathways in select patients, we have developed a diverse pipeline consisting of six distinct programs spanning methyltransferases, kinases, protein-protein interactions and targeted protein degraders. Our pipeline is geared towards serving patients with high unmet medical need where there are limited or no treatment options. We are exploring therapies in both solid tumors and hematological malignancies such as adenoid cystic carcinoma, or ACC, homologous recombination deficient positive, or HRD+, cancers, myelofibrosis, or MF, and glioblastoma multiforme, or GBM, amongst others. We believe we can best address these diseases by developing therapies that target primary and secondary resistance mechanisms.

Our lead product candidates are designed to be oral, potent and selective inhibitors of protein arginine methyltransferase 5, or PRMT5. The potency and selectivity of our product candidates is supported by preclinical data demonstrating nanomolar inhibition of PRMT5 and no inhibition of related enzymes at 1,000 times higher concentration of our product candidates. We are currently advancing our first clinical candidate, PRT543, in a Phase 1 clinical trial in select solid tumors and myeloid malignancies in patients who are refractory to or intolerant of established therapies. Interim Phase 1 results indicate dose-dependent increases in exposure and target engagement, and we have observed early signs of clinical activity, including an ongoing, confirmed complete response, or CR, in a patient with HRD+ high grade serous ovarian cancer through nine months of therapy. A complete response is defined as the disappearance of all target lesions. While we will need to enroll and demonstrate objective responses in additional patients to support further development and potential approval by the FDA or other regulatory authorities, and while such approval is not guaranteed, we are encouraged by the clinical activity as of the date of this Annual Report on Form 10-K. We recently completed the dose escalation portion of the trial. The dose expansion portion of the Phase 1 trial is open for the patient cohort with adenoid cystic carcinoma and we now expect to begin patient enrollment into additional solid tumor and myeloid malignancies expansion cohorts early in the

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second quarter of 2021. We anticipate presenting initial clinical data from the trial at medical meetings in the second half of 2021.

We are also advancing PRT811, a second PRMT5 inhibitor that we have optimized for high brain exposure, in a Phase 1 clinical trial in solid tumors, including GBM. As of the date of this Annual Report on Form 10-K, the trial has demonstrated early signs of clinical activity and tolerability. The previously disclosed refractory GBM patient whose tumor had demonstrated a 66% reduction on monotherapy PRT811 subsequently underwent a follow-up MRI at week 18 and the regression has improved to 77% from baseline, confirming a partial response, or PR, per RANO (response assessment in neuro-oncology) criteria. We expect to begin enrolling patients in the expansion portion of the Phase 1 clinical trial by mid-2021 and anticipate obtaining initial clinical data from this trial by the end of 2021.

PRT1419, our third clinical candidate, is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1. The potency and selectivity of PRT1419 is supported by preclinical data demonstrating nanomolar inhibition of MCL1 and no inhibition of related enzymes at 200 times higher concentration of our product candidate. We have begun enrolling patients with hematologic malignancies, including patients with myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM, into the Phase 1 clinical trial for the oral formulation of PRT1419. We expect to add dose expansion and combination cohorts to this Phase 1 clinical trial in the second half of 2021. Additionally, the FDA recently cleared our IND for an intravenous (IV) formulation of PRT1419. A Phase 1 trial of the IV formulation, which leverages the optimized physicochemical properties of PRT1419, is expected to commence in the first half of 2021 in patients with solid tumors.

Our pipeline is summarized in the figure below:

Prelude Discovery and Development Approach

We carefully evaluate and select our targets based on three key pillars, which provide a framework for optimizing our drug discovery and development efforts.

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Once we have identified optimal targets using the three pillars above, we engage our unique discovery engine to rapidly and efficiently invent and develop molecules. We believe our expertise, capabilities and experience to select high value biological targets and invent molecules with an optimized balance of biological and chemical properties differentiates us from others in the precision oncology space. We believe our unique discovery engine will enable us to continue delivering a new IND every 12 to 18 months.

We design our clinical trials to leverage the broad utility of our compounds with a focus on efficient regulatory pathways to enable our potentially transformative medicines to quickly reach patients with high unmet medical need. By focusing on validated cancer signaling pathways and early clinical proof-of-concept, we seek to advance our programs through expedited approval processes.

Our Product Candidates

Our first two candidates, PRT543 and PRT811, are designed to be potent, selective and oral inhibitors of PRMT5. We believe targeting PRMT5 has broad applicability and a strong scientific rationale for the treatment of cancer as it regulates transcription, translation and messenger ribonucleic acid, or mRNA, as well as the splicing of cancer related genes. Inhibition of PRMT5 has been observed to suppress tumor growth and produce synthetic lethality preclinically.

PRT543, our first clinical candidate, is currently in a Phase 1 clinical trial in advanced solid tumors and select myeloid malignancies. We have been encouraged by both the clinical activity and tolerability data that have been seen in 61 patients (42 with advanced solid tumors, one with NHL, 11 with MF and seven with MDS) that have enrolled into the study as of December 16, 2020. We have observed early signs of clinical activity, including a durable confirmed CR per RECIST v1.1, in a patient with HRD+ high grade serous ovarian cancer, in the 35 mg 5x/week (once a day, for five days, with two days off) cohort. This patient has received nine months of study therapy as of December 16, 2020 and remains in CR. We will need to enroll and demonstrate objective responses in additional patients to support further development and potential approval by FDA or other regulatory authorities, and such approval is not guaranteed. In addition, extended duration of therapy and improvements in symptoms have been observed in several patients with MF, with one patient demonstrating a response of clinical improvement and another patient showing an approximately 66% reduction in Total Symptom Score, or TSS, a validated clinical endpoint in MF. Clinical improvement means an achievement in anemia, spleen, or symptom response without progressive disease or increase in the severity of anemia, thrombocytopenia or neutropenia. We have begun enrolling patients into the expansion portion of the Phase 1 clinical trial in select tumor types that are potentially driven by PRMT5 dysregulation. These tumor types include ACC, MF, genomically selected MDS and HRD+ tumors. We have recently completed the dose escalation portion of the ongoing Phase 1 trial for PRT543. The dose expansion portion of the trial is open for the patient cohort with adenoid cystic carcinoma and we now expect to begin patient enrollment into additional solid tumor and myeloid malignancies expansion cohorts early in the second quarter. We anticipate presenting initial clinical data from the trial at medical meetings in the second half of 2021.

PRT811, our second clinical candidate, is currently advancing in the dose escalation portion of a Phase 1 clinical trial in solid tumors, including GBM and primary central nervous system lymphomas, or PCNSL. PRT811 has been optimized for high brain exposure and hence we believe is uniquely positioned to treat PRMT5 sensitive CNS cancers. We have been encouraged by both the clinical activity and tolerability data that have been seen in 24 patients (eight with GBM, 16 with various advanced solid tumors) that have enrolled into the dose escalation portion of the study as of December 16, 2020. We have observed early signs of clinical activity in a refractory GBM patient whose tumor initially demonstrated a 66% reduction on monotherapy PRT811 at week 6, and subsequently underwent a follow-up MRI at week 18, and the regression has improved to 77% from baseline, confirming a PR per RANO (response assessment in neuro-oncology) criteria. This patient has received five months of study therapy as of December 16, 2020 and remains in PR and is clinically stable. We will need to enroll and demonstrate objective responses in additional patients to support further development and potential approval by FDA or other regulatory authorities, and such approval is not guaranteed. We plan to initially enroll patients in the expansion portion of the clinical trial with GBM, PCNSL and solid tumors with metastatic disease to the CNS once we

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have established an expansion dose. We expect these expansions to begin by mid-2021 and anticipate initial clinical results from this trial by the end of 2021.

PRT1419, our third clinical candidate, is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1. We believe hematological malignancies are particularly sensitive to MCL1 inhibitors. MCL1 upregulation has been noted as a mechanism of acquired resistance to venetoclax and tyrosine kinase inhibitors, or TKIs. In addition, certain solid tumors are responsive to MCL1 inhibition, informing a potential patient selection strategy. We have enrolled four patients into the Phase 1 clinical trial investigating oral PRT1419 in high risk MDS, AML, NHL and MM. Additionally, the FDA recently cleared our IND for an intravenous (IV) formulation of PRT1419. A Phase 1 trial of the IV formulation, which leverages the optimized physicochemical properties of PRT1419, is expected to commence in the first half of 2021 in patients with solid tumors. We believe that the physicochemical and pharmacological properties of PRT1419 allow the optionality of administering PRT1419 by either oral or IV routes.

In addition to our three clinical stage candidates, our two most advanced preclinical programs target cyclin- dependent kinase 9, or CDK9, and Brahma homologue, or BRM, otherwise known as SMARCA2, respectively. PRT2527, designed to be a potent and selective CDK9 inhibitor, has entered IND-enabling studies with an IND submission expected in 2021. We have also identified SMARCA2 protein degraders that appear to be potent based on preclinical data demonstrating degradation of SMARCA2 at sub-nanomolar concentration. Optimization of the lead compound, PRT-SCA2, is progressing, and we expect to initiate IND-enabling studies in 2021. Our sixth program is exploring a kinase target for solid tumors. We are optimizing our lead compound, PRT-K4, and expect to begin IND-enabling studies in 2021.

Our Team

We were founded in 2016 by Kris Vaddi, Ph.D., a founding scientist at Incyte, and have assembled an experienced management team and board of directors with deep expertise in oncology and drug development. We have built from the “ground up” our internal discovery team, led by scientific and medical teams with deep expertise and proven capabilities in inventing and rapidly advancing small molecule medicines that address important gaps in the current precision oncology ecosystem. Members of our management team have successfully developed and commercialized numerous drugs such as Jakafi, Olumiant, Velcade, VITRAKVI, Retevmo, Tabrecta and Pemazyre.

Our Strategy

We aim to create better targeted and more effective cancer therapies. Our goal is to transform the lives of patients with cancer by leveraging the core competencies of our experienced team in medicinal chemistry, cancer biology and clinical development to bring novel drugs to market. We intend to become a fully integrated patient- focused precision oncology company by pursuing the following objectives:

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Our Pipeline

Consistent with our target class agnostic approach, our current pipeline includes six distinct programs spanning methyltransferases, kinases, protein-protein interactions and targeted protein degraders. Since our inception in 2016, we have received clearance for four INDs and advanced three of these programs into clinical development, with the fourth program expected to initiate clinical development in the first half of 2021. In addition, we have three unique programs in various stages of preclinical development that we plan to advance into clinical development beginning in 2021. We have structured and resourced our research and development, or R&D, organization with the goal and expectation of continuing to deliver a new IND every 12 to 18 months.

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Cancer Background and Treatment

Cancer is the second-leading cause of death in the United States. The American Cancer Society estimates that approximately 1.8 million new cancer cases will be diagnosed and more than 600,000 people are expected to die of the disease in the United States in 2020. Cancer is a disease of the genome caused by changes in DNA that alter cell behavior, growth and division. These changes can cause cells to produce abnormal amounts of certain proteins and/or to make aberrant proteins that do not function properly. It is widely understood that cancer cells can eventually evade therapies through mutations or other resistance mechanisms, limiting the long-term success of drug therapies.

Historically, cancer has been treated with surgery, radiation and drug therapy with patients often receiving a combination of these treatment modalities. While surgery and radiation can be effective in patients with localized disease, drug therapies are often required when the cancer has spread beyond the primary site or is not amenable to resection.

Drug therapy is intended to kill or damage malignant cells by interfering with the biological processes that control development, growth and survival of cancer cells. This treatment modality has evolved over time from the use of non-specific cytotoxic therapies to precision oncology medicines targeting molecular pathways or oncogenic drivers. These precision medicines are broadly known as targeted therapies.

Era of Precision Oncology

The first-generation of approved targeted therapies were largely directed at receptor tyrosine kinases (e.g., BCR-ABL, VEGF, EGFR), a superfamily of cell-surface receptors that activate growth factors. Many of these agents that were initially approved in refractory and resistant populations have now become front-line treatments in cancers for which they are indicated. While these targeted therapies have improved the treatment of certain cancers, many fail to address the underlying genomic alterations that drive oncogenesis, leading to limited responses or inadequate therapeutic durability. Since normal cells can rely on these same signaling pathways, there are often toxicities associated with pathway inhibition. In addition, many of these first-generation targeted therapies are multi-kinase inhibitors that interfere with off-target adjacent pathways, resulting in significant toxicities.

A second-generation of targeted cancer therapies has evolved from the nexus of rapid advances in the understanding of tumor biology and increasingly sophisticated diagnostic platforms that enable identification of subsets of tumors based on

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genomic alterations. These therapies often require genomic testing of tumor tissue or blood to identify potentially targetable alterations in a patient’s individual cancer. Increasingly, these precision medicines are agnostic to tumor site of origin and instead target specific oncogenic drivers that can occur broadly across tumor types. In 2018, VITRAKVI (larotrectinib) was approved by the FDA for neurotrophic receptor tyrosine kinase-driven cancers, making it the first new drug to be developed and approved to treat a specific genomic alteration in a tissue-agnostic fashion. This emerging trend for tumor-agnostic indications represents a significant advancement in drug development, clinical trial designs, drug approval patterns and speed to market. Targeted therapies generated approximately $20.1 billion of worldwide sales in 2019 and have remained a mainstay of oncology drug development and treatment.

Next Generation Precision Oncology

First and second-generation precision oncology medicines dramatically changed the landscape of available treatment options for patients with cancer and created a paradigm shift in oncology drug development. However, there are still significant gaps that require further advances to optimize treatment options. For example, oncology drug development has been primarily focused on readily druggable genomic alterations that confer new or enhanced protein activity, known as gain-of-function targets, which represent only a subset of targets in oncology. Additionally, malignant cells may possess or acquire intrinsic resistance by using alternative signaling pathways, enabling them to survive and proliferate and contributing to a lack of response and/or short durability of response to these types of precision medicines. The nearly universal nature of this primary or secondary resistance highlights the urgent need to address resistance using a cellular level understanding of the mechanisms that drive treatment failure.

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By specifically targeting additional pathways of resistance, next generation precision oncology medicines can address the needs of patients whose tumors do not harbor targetable genomic alterations as well as patients who progress on current therapies. These medicines leverage scientific and technological breakthroughs to target new intervention points in oncogenic signaling pathways, including transcriptional regulation of oncogenes and tumor suppressor genes, DNA damage repair pathways and protein structure. These approaches address primary and secondary resistance mechanisms not targetable by earlier generations of precision oncology medicines. Examples of these mechanisms are shown in the figure below.

We believe highly selective and potent molecules that target specific oncogenic mechanisms, regardless of target class, can be an effective strategy to address cancers not amenable to earlier and current treatment modalities. These next-generation precision therapies should possess pharmacological, pharmacokinetic, or PK, and pharmaceutical properties that provide optimized inhibition of the target mechanism, with a safety profile and therapeutic window that allows use in all stages of cancer either as a monotherapy or in combination.

Prelude Discovery and Development Approach

We are guided by our core expertise in cancer biology and medicinal chemistry to create next generation precision oncology medicines. We endeavor to discover, develop and commercialize small molecule drugs that selectively target signaling pathways driving primary or adaptive resistance.

Our approach is target class- and technology platform-agnostic meaning, we do not limit our selection of programs to a defined target class (e.g., kinases) or a technology platform (e.g., protein degradation). We have built from the “ground up” our internal discovery team, led by scientific and medical teams with deep expertise and proven capabilities in inventing and rapidly advancing small molecule product candidates that have the potential to address important gaps in the current precision oncology ecosystem. We design our discovery programs around targets with compelling preclinical and clinical data that have the potential to address cancers of high unmet medical need. We evaluate existing clinical or preclinical biological rationale and chemical space that provide important “proof-of-concept” validation but present significant opportunities for improvement on current therapies. This process has enabled us to rapidly create a wholly-owned, internally developed pipeline of differentiated product candidates for patient populations with cancers that show limited therapeutic durability or do not respond to current treatments.

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As shown in the diagram below, our approach is divided into two related processes—target selection and our unique discovery engine.

Target Selection

We identify vulnerable intervention points in cancers with high unmet need, and then we seek to design solutions that can be precisely tailored to address these in a target class agnostic fashion. Applying our deep expertise in cancer biology and medicinal chemistry, as well as our in-depth understanding of the current landscape of oncology treatments, we interrogate targetable intervention points in the signaling pathways amenable to small molecule-based treatments. We then design, synthesize and optimize molecules that we believe best meet the needs of the patients we strive to serve. Consistent with our patient-centric focus, we take into account a number of patient attributes, including the type of cancer, current standard of care, causes of treatment failure, comorbidities, potential for drug-drug interactions and propensity for CNS disease to be able to develop more effective therapies.

We carefully evaluate and select our targets based on the three key pillars described below which provide a framework for optimizing our drug discovery and development efforts. Our discovery programs are built upon these three pillars:

1) Identify target mechanisms with compelling biological rationale

We focus on target classes that have either yielded successful drugs or are emerging as validated, druggable approaches with compelling driver pathway-based data, as opposed to approaches driven by disease association or novelty of target class. We believe our internal capabilities are best suited to rationally design and develop molecules that can address these mechanisms in a target class agnostic manner. We may expand our focus on other target mechanisms as new biology emerges and is validated.

Our current target mechanisms of focus include:

PRMT5 is a prime example of a target with strong scientific rationale that we are well-suited to address. We believe the target can be exploited to address underserved cancers such as ACC with an undruggable oncogenic driver (such as myeloblastosis, or MYB), as well as to address resistance to several existing, approved targeted agents, including ruxolitinib, venetoclax and CDK4/6 inhibitors. Also, PRMT5 is a potential driver mechanism in GBM, for which a differentiated product with high brain exposure is required.

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2) Leverage our advanced medicinal chemistry capabilities to create better product candidates

We deploy our integrated medicinal and process chemistry expertise to rationally design and synthesize complex chemical entities and rapidly advance through various stages of development. We view all target classes, including enzyme inhibitors (PRMT5, CDK9), protein-protein interactions (MCL1), targeted protein degradation (SMARCA2) and those that require high levels of brain exposure, with equal interest and strive to invent clinical candidates that meet our desired target product profiles.

Our ability to design and develop molecules with potential high brain exposures allows us to target validated mechanisms in cancers with CNS metastasis, as many current treatments do not have adequate brain exposure. Our discovery programs are not only driven by potency, selectivity and PK, but also incorporate optimized physicochemical properties to provide well-balanced clinical candidates.

3) Pursue targets that drive cancers with high unmet need

We believe taking a patient-centric approach to target selection provides opportunities to generate proof-of- concept early in clinical development, can form the basis for the design of pivotal studies with potential for accelerated approval in the most relevant patient population and rapidly advance into earlier lines of treatment.

We focus on targets that allow us to select patients and cancers with high medical unmet need with no approved therapies, or patient populations underserved by approved treatments. We plan to utilize multiple approaches to patient selection, which include biomarker-based enrichment. For example, one cancer of interest with no approved or effective treatments is ACC, which is predominantly driven by a specific oncogenic mechanism such as MYB, where a biomarker selection strategy may not be needed. Alternatively, SMARCA4 mutated cancers are more amenable to a biomarker-based selection strategy.

Lastly, we interrogate targets in pathways that drive resistance to approved treatments in clearly defined patient populations. Specific examples include: AML patients who progress on venetoclax in which MCL1 is a known resistance driver; and patients progressing on ruxolitinib in whom inhibiting PRMT5 can potentially block alternative pathways of resistance such as the transcription factor E2F1.

Our Discovery Engine

Once we have identified optimal targets using the three pillars above, we engage our unique discovery engine to rapidly and efficiently invent and develop molecules with optimized properties. Central to our internal discovery capability is the interplay between our highly experienced biologists and chemists who collaborate in an iterative fashion to rapidly design, synthesize and test novel chemical entities. By coupling our synthetic organic chemistry expertise and analytical technologies, our medicinal chemistry team has rapidly and efficiently synthesized thousands of rationally-designed novel compounds since inception.

Our deep understanding of cancer biology enables a rigorous drug selection process that has allowed us to optimize our lead molecules to interrogate validated cancer pathways with high translational success. We focus on stereochemically-rich molecules with a high degree of 3-dimensional character, which has been shown to correlate with success as compounds transition from discovery, through clinical testing, to drug. Our unique ability to leverage medicinal chemistry to look beyond classic drug-like spaces, such as those involved in protein-protein interaction and targeted protein degradation and to incorporate critical elements of drug-like properties into our candidate compounds is a key aspect of our unique discovery engine. Our internal and external teams utilize a suite of capabilities in crystallography; absorption, distribution, metabolism and excretion, or ADME; PK and pharmacodynamic, or PD, analysis; preclinical efficacy models using cell line xenograft and patient-derived xenograft, or PDX, models; and process scale synthesis and toxicology to evaluate and optimize the lead molecules we invent until they meet rigorous and pre-specified criteria.

Finally, we design our clinical trials to leverage the broad utility of our compounds with a focus on efficient regulatory pathways that enable potentially transformative medicines to quickly reach cancer patients with high unmet medical need. By focusing on validated cancer signaling pathways and early clinical proof-of-concept, we seek to advance our programs through expedited approval processes.

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We believe our rapid progress in creating a wholly-owned, internally developed pipeline with three differentiated clinical-development-stage compounds, a fourth program expected to enter clinical development in the first half of 2021, and multiple additional molecules in various stages of preclinical development across a range of target classes validates our discovery excellence. We have structured and resourced our R&D organization with the goal and expectation of continuing to deliver a new IND every 12 to 18 months. We believe our expertise, capabilities and experience to select high value biological targets and invent molecules with an optimized balance of biological and chemical properties differentiates us from others in the precision oncology space.

Our Product Candidates

PRMT5 Inhibitors: PRT543 & PRT811

Rationale for targeting the PRMT5 pathway in cancer

Cancer is a disease of the genome and all cancers have genomic lesions that must be addressed to develop effective treatments. These genomic changes are important at all stages of cancer progression, including initial formation, growth, and metastasis, and result in the upregulation of genes that promote cell growth and survival together with the downregulation of genes that suppress tumor growth.

PRMT5 controls a number of the biological processes that drive cancer including transcription, translation, DNA repair and cell signaling. Overexpression and increased enzymatic activity of PRMT5 are associated with poor outcome and decreased survival in multiple human cancer settings, as outlined in the table below.

This information is based on published data in peer-reviewed journals and reflects standard therapeutic intervention.

PRMT5 Regulates Transcription and Translation of Cancer-related Genes

The oncogenic process controlled by PRMT5 is mediated through the symmetric dimethylation of arginines on its substrate proteins (Figure 1). PRMT5, an intracellular enzyme, transfers two methyl groups from a co- factor S-adenosyl methionine, or SAM, and deposits them on its substrate proteins resulting in the formation of a symmetric dimethylarginine, or sDMA, mark. This post-translational modification alters the protein structure, impacts interactions with DNA, and also generates docking sites for effector molecules that can promote tumor cell growth and survival. PRMT5 substrate proteins include:

RNA

RNA

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Figure 1. PRMT5 Regulates Oncogenesis and Resistance

Through arginine methylation of histones, transcription factors and the spliceosome complex, PRMT5 regulates the expression of genes involved in promoting cancer cell growth and survival. These include cell cycle genes, tumor suppressors, oncogenes, and genes involved in proliferation and signaling.

PRMT5-regulated transcription factors, including cyclin D1 and MYC, have a well-established role in a number of cancers. Conversely, PRMT5-mediated methylation of histones such as H3 and H4 represses a number of tumor suppressor genes including retinoblastoma, or RB, family members, contributing to unchecked proliferation of malignant cells. In addition, PRMT5 symmetrically dimethylates ribosomal binding proteins and modulates mRNA translation of internal ribosome entry site-containing mRNAs, further promoting the generation of oncogenic proteins. Consistent with its role in promoting cancer, PRMT5 inhibition has been shown to decrease tumor growth in preclinical models. Therefore, PRMT5 is believed to serve as an important mediator of cancer progression and can be targeted to treat a range of solid tumors and hematological malignancies. These attributes make PRMT5 an ideal therapeutic target for cancer.

The role of PRMT5 in regulating gene transcription and translation may be particularly relevant in cancers such as ACC where up to 86% of patients harbor the gene fusion of the MYB family members MYB or MYBL1 with the Nuclear Factor 1B, or NFIB, gene. MYB or MYBL1 gene fusions lead to overexpression of the MYB/ MYBL1 protein. Published data demonstrate that MYB overexpression is important for driving cell proliferation and tumor growth in preclinical ACC models. In addition, our internal data illustrate that PRMT5 inhibition decreased MYB expression levels in MYB-dependent preclinical models and inhibited tumor growth in PDX models of ACC. Recent evidence of clinical activity with a third party PRMT5 inhibitor in patients with ACC further validates PRMT5 as a potential target mechanism in this highly underserved cancer.

PRMT5 Regulates mRNA Splicing in Cancer Cells

In addition to regulating transcription, PRMT5 also modulates gene expression by controlling mRNA splicing. Splicing is a fundamental cellular process that involves the removal of noncoding sequences from the precursor mRNA to produce the mature form that encodes for protein. In the absence of correct mRNA splicing, mutated or unstable proteins are produced, ultimately leading to cell cycle defects, senescence and apoptosis. The splicing reaction is carried out by a multi-protein/RNA complex called the spliceosome. PRMT5 plays an important role in the splicing of mRNA through methylation of spliceosome protein, which is critical for the assembly of the spliceosome complex and its function. In preclinical models, tumors with high degrees of proliferation, such as MYC-driven tumors, were associated with increased activity of PRMT5 to maintain the fidelity of the spliceosome, demonstrating the importance of PRMT5 in this process.

The role of PRMT5 in regulating mRNA splicing may be most relevant in cancers with spliceosomal mutations or those that are dependent on high splicing fidelity, such as GBM. Spliceosomal mutations also occur in more than 50% of MDS patients and at lower frequencies in other tumor types including MF, chronic myelomonocytic leukemia, AML, NHL, MM, chronic lymphocytic leukemia, or CLL, and uveal melanoma. These spliceosomal alterations are often correlated with higher mutational burden and/or poor prognosis. In models of AML, preclinical data demonstrated that PRMT5 inhibition resulted in higher levels of suppression of the growth of cancer cells containing mutated spliceosome proteins compared to those containing unmutated spliceosome proteins.

Synthetic lethality from PRMT5 inhibition in certain settings

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Synthetic lethality applies to specific pairs of genes. A synthetic lethal interaction occurs when a deficiency in either gene alone is viable whereas a deficiency in both genes simultaneously results in cell death. In cancer, synthetic lethality can be exploited to selectively kill cancer cells in which one gene in the pair is mutated or deleted in the tumor cell and the remaining second gene is therapeutically inhibited. This leads to death of the cancer cells whereas normal cells, which lack the specific genetic alteration, are spared the effect of the drug. In the case of PRMT5, it has been demonstrated that certain genomic alterations confer a selective dependence on PRMT5 so that PRMT5 inhibition can be utilized to produce a synthetic lethal effect. For example, PRMT5 inhibition shows a modest preferential impairment of cell viability in methylthioadenosine phosphorylase, or MTAP, -null cancer cells compared to normal cells, suggesting that PRMT5 inhibitors could produce a synthetic lethal effect in GBM, in which nearly half of the patients carry the MTAP deletion.

The synthetic lethal effect of pharmacological inhibitors of DNA repair mechanisms such as poly ADP- ribose polymerases, or PARPs, have been successfully utilized in the treatment of HRD+ cancers. HRD+ can occur as a result of genetic or epigenetic mechanisms that result in loss of genes such as breast cancer genes, or BRCA1 and BRCA2, that are required for efficient DNA repair. More recent data support the potential synthetic lethality of PRMT5 inhibition in tumors that are HRD+ due to the role of PRMT5 in DNA repair (Figure 2). PRMT5 upregulates the transcription of genes involved in HR repair to regulate the DNA damage repair response. PRMT5 inhibition has been shown preclinically to decrease expression of these genes to induce cell death, supporting the potential of PRMT5 inhibitors in HRD+ tumors.

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Figure 2. PRMT5 Inhibition in HRD+ Tumors

PRMT5 upregulates the expression of DNA repair genes including BRCA1, BRCA2, RAD51, RAD51D and Ku80. Inhibition of PRMT5 reduces expression of these genes and prevents DNA repair, inducing a state of “BRCAness” and leading to tumor cell death as well as synergy in combination with PARP inhibitors.

Together, these data support the development of PRMT5 inhibitors in select solid tumors and hematologic malignancies.

Our Approach to Designing Optimized PRMT5 Inhibitors

PRMT5 has strong scientific rationale for its targeting in the treatment of cancer, as its inhibition has been shown to suppress tumor growth and produce synthetic lethality preclinically. PRMT5 contains two binding sites, a substrate and a cofactor (SAM), providing two distinct modes-of-inhibition of PRMT5 (Figure 3). We utilized X-ray crystal structures of PRMT5 to rapidly design and synthesize SAM cofactor mimetic inhibitors that are highly selective for PRMT5, distinct from a substrate competitive inhibitor approach. Given that SAM contributes the methyl group to all of the PRMT5 substrates, we believe this approach gives us an opportunity to more broadly modulate the activity of PRMT5 compared to a substrate competitive inhibitor.

Figure 3. Binding Mode of Prelude PRMT5 Inhibitors

We rationally designed and synthesized more than 600 compounds during the optimization of our lead product candidates to not only improve potency, but also to simultaneously build in ADME and pharmaceutical properties. These efforts led to selection of our first compound, PRT543, a novel SAM mimetic, that is designed to be a highly potent and selective PRMT5 inhibitor. In addition, to create a PRMT5 inhibitor with the potential for high brain exposure, we optimized the molecular and physicochemical properties of our SAM competitive leads using in vitro assays to screen

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for compounds with low efflux potential followed by confirmatory brain exposure studies in vivo. Our second compound, PRT811, is a novel brain penetrant PRMT5 inhibitor. These molecules are differentiated by their mode of inhibition and their potency, which compare favorably to the most advanced PRMT5 inhibitor in development, GSK3326595. PRT543 and PRT811 were selected to advance into clinical development because they have well balanced properties, which we believe will lead to an increase in the probability of clinical activity.

PRT543

Overview

We are currently advancing our first clinical candidate PRT543, an oral inhibitor of PRMT5 in a Phase 1 clinical trial in advanced solid tumors and select myeloid malignancies. Upon establishing a recommended expansion dose, we plan to begin enrolling patients in the expansion portion of the Phase 1 program in select tumor types that are potentially driven by PRMT5 dysregulation. These tumor types include ACC, MF, genomically selected MDS, and genomically selected HRD+ tumors. We have recently completed the dose escalation portion of the trial. The dose expansion portion of the Phase 1 trial is open for the patient cohort with adenoid cystic carcinoma and we now expect to begin patient enrollment into additional solid tumor and myeloid malignancies expansion cohorts early in the second quarter of 2021. We anticipate presenting initial clinical data from the trial at medical meetings in the second half of

2021.

Preclinical Results—Summary

In vitro, we observed that PRT543 is potent and highly selective in biochemical assays. In cellular assays PRT543 treatment resulted in a dose-dependent reduction in symmetric dimethylation of arginine, or sDMA, levels, a direct readout of PRMT5 activity, in tumor cell lines. PRT543 inhibited the proliferation of a panel of cell lines representative of both hematologic and solid tumor types both as monotherapy and in combination with other targeted therapies. PRT543 was active in cell lines that are resistant to other targeted agents.

In vivo, PRT543 demonstrated high oral bioavailability (F%>100% in rats; 65%, in dogs) and a long half- life (~5-10h in rats and ~20h dogs). PRT543 exhibited activity in a range of xenograft and PDX models of solid tumors and hematologic malignancies, including ACC, AML and MF. In these tumor models, PRT543 demonstrated a clear dose-response relationship between suppression of sDMA levels and tumor growth inhibition, or TGI, establishing a link between target engagement and preclinical activity. These data define the target plasma drug concentration and sDMA inhibition goals in the dose escalation portion of human clinical trials.

In Vitro Potency and Selectivity

We investigated the in vitro potency of PRT543 to inhibit the methyltransferase activity of human recombinant PRMT5 by measuring its IC50. IC50 is a quantitative measure of how much of a compound is needed to inhibit a biological process by 50%. In this assay, we observed the IC50 of PRT543 to be 10.8 nM. We also investigated the in vitro selectivity of PRT543 for PRMT5 as compared to a panel of 36 other human methyltransferases. When tested at a concentration 1,000 times above its IC50 for PRMT5, we observed that PRT543 exhibited minimal inhibition of CARM1 (36.5% at 10 μM) and no inhibition of any other human methyltransferase tested.

PRT543 potently reduced sDMA levels, a direct readout of PRMT5 activity, in cells

We determined the potency of PRT543 to inhibit PRMT5 in cells by measuring levels of sDMA, a direct measure of PRMT5 activity. Tumor cell lines were treated in vitro with various concentrations of PRT543 for three days and the PRT543 IC50 value to inhibit sDMA determined. We observed that PRT543 potently and dose-dependently reduced sDMA levels in tumor cell lines in vitro with nanomolar IC50 values (Figure 4). These data demonstrate on-target effects of PRT543 in cells.

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Figure 4. PRT543 Dose-Dependently Reduced sDMA Levels in Tumor Cell Lines In Vitro

Western blot demonstrating concentration-dependent reduction of symmetrically dimethylated SMD3, a known PRMT5 substrate, following

3 days of PRT543 treatment in indicated cell lines. Granta-519 is a MCL cell line and SET-2 is a JAK2 V617F mutant AML cell line.

PRT543 inhibits the proliferation of a broad panel of cell lines in vitro

We investigated the potency of PRT543 to inhibit the proliferation of a panel of cell lines representative of both hematologic malignancies and solid tumors in vitro. Tumor cell lines were treated with various concentrations of PRT543 and the number of viable cells was measured after ten days in culture. We observed that PRT543 inhibited the growth of cell lines representative of both solid tumors and hematologic malignancies with nanomolar potencies, demonstrating its broad anti-tumor effects in vitro (Figure 5).

We also explored whether PRT543 was active in primary cells or cell lines known to be resistant to specific targeted therapies. In vitro, we observed that PRT543 inhibited the growth of primary AML patient samples, including those shown to be resistant to the BCL2 inhibitor, venetoclax, or the FLT3 inhibitor, gilteritinib, two currently approved therapies for AML patients. Additionally, PRT543 demonstrated activity in a cell line rendered insensitive to JAK inhibitors, suggesting that PRMT5 inhibition may overcome resistance to other targeted therapies.

Figure 5: Broad Antiproliferative Activity of PRT543 in a Cancer Cell Line Panel

Profile of the anti-proliferative response to PRT543 in a panel of 85 cell lines following 10 days of treatment. Baseline corresponds to IC50 =

250 nM. Bars below the baseline represent cell lines where PRT543 demonstrates more potent IC50 values and bars above the baseline are less potent.

Given the role of PRMT5 in DNA repair, we investigated the effects of PRT543 to inhibit the growth of HRD+ tumor cell lines. Two HRD+ breast cancer cell lines, MDA-MB-436 and MDA-MB-468, were treated with various concentrations of PRT543 and the number of viable cells was measured after 10 days in culture. We observed that PRT543 demonstrated potent activity in blocking the growth of these cell lines in vitro with IC50 values of 50-150 nM (Figure 6). Consistent with this, PRT543 decreased levels of expression of a number of genes involved in DNA repair, including BRCA1, BRCA2, ATM and ATR, and was synergistic in combination with PARP inhibitors.

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Figure 6. PRT543 Inhibits the Growth of HRD+ Breast Cancer Cell Lines.

Two HRD+ breast cancer cell lines, MDA-MB-436 and MDA-MB-468, were treated for 10 days with PRT543 and effects on cell proliferation determined. Data are plotted relative to DMSO control.

In vivo, PRT543 demonstrated a correlation between sDMA inhibition and efficacy

In vivo, we investigated the ability of PRT543 to reduce sDMA levels in tumor tissues and in plasma in several models, including the SET2 model of AML. PRT543 doses of 5 mg/kg, 15 mg/kg or 30 mg/kg were administered orally to tumor-bearing mice, once daily, for 28 days. As shown in Figure 7, we observed that PRT543 dose-dependently reduced sDMA levels in the tumor, indicating it inhibited cellular PRMT5 activity in vivo. PRT543 demonstrated approximately 90% inhibition of sDMA levels in the tumor at the 30 mg/kg and 15 mg/kg once-a-day, or q.d., doses. It should be noted that at doses that result in a 90% reduction in tumor sDMA, approximately 50% reduction in plasma sDMA levels was observed, suggesting that tumor sDMA may be a more sensitive readout. PRT543 at both dose levels demonstrated significant anti-tumor activity (Figure 7). Collectively, results from these preclinical models support targeting 50% inhibition of plasma or serum sDMA in Phase 1 dose escalation to establish a pharmacologically active dose.

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Figure 7. PRT543 PD/Efficacy Relationship in Preclinical Models

Oral administration of PRT543 leads to dose-dependent decreases in tumor sDMA and TGI in the SET-2 AML model, Western blot showing sDMA reduction in SET-2 tumor tissue collected 4 hours after the last dose, at the end of a 28-day study. Efficacy data represent mean ± SEM with 8 mice/group. * P < 0.05, ** P < 0.01 vs. vehicle by Mann-Whitney U test.

PRT543 is active in models of ACC and MF in vivo

In vitro, we observed that PRT543 decreased the expression of the MYB oncogene as well as MYB-regulated genes in head and neck cancer cell lines. Because the activity of the MYB oncogene may be important in ACC, where approximately 90% of patients have MYB alterations, we investigated whether PRT543 was active in a PDX model of ACC, ACCx9. PRT543 doses of 25 mg/kg and 35 mg/kg were administered orally to tumor- bearing mice, twice daily, for 28 days. We observed that both doses of PRT543 inhibited tumor growth in this PDX model of ACC (Figure 8). These data support the clinical development of PRT543 in ACC.

Figure 8. PRT543 Demonstrated Activity in PDX Models of ACC In Vivo

PRT543 oral administration decreased tumor growth in the ACCX9 PDX model of ACC. Data represent mean ± SEM with 8 mice/group.

In addition to studies in ACC models, we observed that PRT543 was active in vivo in solid tumor models representative of bladder cancer and small cell lung cancer at well-tolerated doses. PRT543 was also active in vivo in models of hematological malignancies, including AML and mantle cell lymphoma. In the Granta-519 model of mantle cell lymphoma, PRT543 demonstrated single agent activity and was synergistic in combination with the approved BCL2 inhibitor, venetoclax (Figure 9).

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Figure 9. PRT543 is Active as Monotherapy and in Combination In Vivo

Oral administration of PRT543 led to dose-dependent TGI in the Granta-519 MCL xenograft model. Combination of PRT543 and venetoclax resulted in significant TGI at doses that did not show activity as monotherapy for both agents in the Granta-519 xenograft model. The doses tested in the combination arm of the study were 20 mg/kg QD of PRT543 and 30 mg/kg QD of venetoclax. Data represent mean ± SEM.

** P < 0.01 vs. Vehicle by Mann-Whitney U test.

Finally, we investigated the activity of PRT543 in a model of JAK2V617F mutant myeloproliferative neoplasms, or MPN. In this model, we observed that PRT543 led to a reduction in spleen size and normalization of white blood cells and reticulocytes counts, key phenotypic effects of JAK2 dyrsegulation through the JAK2V617F mutation, both as monotherapy and in combination with the approved JAK inhibitor, ruxolitinib. Importantly, the observed level of suppression of disease specific effects following treatment with PRT543 were similar to those achieved with the approved therapy, ruxolitinib (Figure 10).

Figure 10. PRT543 Was Active in a Model of JAK2V617F Mutant MPN.

Oral administration of PRT543 as monotherapy and in combination with ruxolitinib led to significant decrease in spleen size in the JAK2VF

bone marrow transplant model of MF. Data represent mean ± SEM. Dotted line indicates mean spleen weight of WT transplanted mice.

* P < 0.05, ** P < 0.01, *** P < 0.001 vs. vehicle by Mann-Whitney U test.

Together, these data provide strong rationale for advancing PRT543 into patients with solid tumors such as ACC and HRD+ tumors as well as myeloid malignancies including MF and MDS, and provide opportunities for patient selection (ruxolitinib failures in MF, patients with spliceosomal mutations, HRD+ tumors, MYB+ ACC) and combination strategies (with ruxolitinib in MF, venetoclax in MDS/AML, PARP inhibitors in HRD+ tumors).

Clinical Experience

All data are reflective of a data cutoff of September 1, 2020 unless otherwise stated.

We are currently enrolling a Phase 1, open-label, multicenter, dose expansion clinical trial of monotherapy PRT543 in patients with advanced solid tumors, MF or MDS. We have been encouraged by both the clinical activity and tolerability data that has been observed in 41 patients (29 with advanced solid tumors, one with NHL, nine with MF and two with MDS) that

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have enrolled into the dose escalation portion of the study as of our data cutoff date of September 1, 2020. We have observed early signs of clinical activity, including a confirmed CR per RECIST v1.1, in a patient with HRD+ high grade serous ovarian cancer, at the 35 mg 5x/week dose level. In addition, one MF patient at the 20 mg twice a week, or b.i.w., dose level has demonstrated a best response of clinical improvement per International Working Group, or IWG, criteria as of September 1, 2020. This patient has exceeded one year on study. A second MF patient at the 40 mg three times a week, or t.i.w., dose level demonstrated an approximately 66% reduction in TSS. Improvement in isolated symptoms and extended duration of therapy have been seen in other MF patients. The safety profile has consisted predominantly of Grade 1-2 adverse events and was similar across both solid tumor and myeloid malignancies patients. As of September 1, 2020, the dose-limiting toxicity experienced at the highest dose level evaluated in both groups has been thrombocytopenia, which in all cases has been reversible without sequalae after a one to two week drug holiday. There have been no deaths or study discontinuation attributed to PRT543. PK/PD analysis reveals dose-dependent increases in drug exposure across doses and schedules with associated decreases in serum sDMA levels. We have recently completed the dose escalation portion of the trial. The dose expansion portion of the Phase 1 trial is open for the patient cohort with adenoid cystic carcinoma and we now expect to begin patient enrollment into additional solid tumor and myeloid malignancies expansion cohorts early in the second quarter of 2021. While early in development and there is no guarantee of approval by the FDA or other regulatory authorities, we are encouraged by the clinical activity of PRT543.

Clinical Trial Design and Schema

Our PRT543 Phase 1 clinical trial design seeks to leverage PRT543’s broad potential therapeutic utility to rapidly generate proof-of-concept across multiple solid tumors and myeloid malignancies. Trial enrollment of patients with relapsed/refractory, or R/R, advanced solid tumors, NHL (Group A) or R/R MF or MDS (Group B) commenced in February 2019 and is being conducted at approximately 25 sites throughout the United States. This clinical trial consists of two parts, a dose escalation portion followed by dose expansion into separate tumor-specific cohorts. Enrollment into the additional dose expansion cohorts is expected to begin early in the second quarter of 2021. Total expected enrollment is anticipated to be approximately 160 patients. The schema is shown below in Figure 11.

Figure 11. PRT543 Clinical Trial Schema

Interim and Preliminary Clinical Results

Interim and Preliminary Safety Data: Group A & Group B

The safety profiles of the 41 patients enrolled have been similar between Group A (solid tumor; 30 patients) and Group B (MF and MDS; 11 patients) treated at doses and schedules ranging from 5 mg b.i.w to 50 mg once a day, or q.d,. Nine patient deaths were reported, none of which were related to PRT543. There were no patients that discontinued study

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therapy due to an adverse event. A total of 18 SAEs have been reported amongst six patients and of those, only one event (grade 4 thrombocytopenia) in one patient was deemed related to PRT543.

Adverse events were similar between patient groups with the majority of these adverse events (84.6%) being Grades 1-2. The most common adverse events were diarrhea, nausea and fatigue, ranging from 30% to 50% in both groups and were manageable with standard treatment routine amongst patients with cancer.

Dose limiting toxicity of grade 4 thrombocytopenia has been observed in two out of three Group A patients at the 50 mg q.d. dose level and one out of six Group B patients at the 40 mg t.i.w. dose level, one of which was deemed to be a serious adverse event, or SAE. However, in all of these patients, platelets recovered to baseline levels after a one to two week drug holiday and they remained on the study and restarted at a lower dose. At the 35 mg q.d. dose level, three of the four patients have experienced grade 3 thrombocytopenia. Patients had their doses reduced and remained on study. Among the eight patients who either started or were dose reduced to the 35 mg 5x/week dose level, only one experienced any thrombocytopenia (grade 3).

Group A (Solid Tumors)

Pharmacokinetic Data; Group A (Solid Tumors)

Preliminary PK data were available for 30 solid tumor patients administered various regimens of oral doses of PRT543 (mean values are shown in Table 2). We observed that PRT543 demonstrated rapid absorption with the Tmax generally occurring between one to three hours with dose-proportional increases in exposure. Half-life values for different doses ranged from approximately 7-18 hours, consistent with the long half-life predicted by preclinical data. Exposures were generally similar between Day 1 (first dose of cycle) and Day 25 at doses up to 35 mg. However, the 50 mg q.d. dose demonstrated significant accumulation of PRT543, which was likely associated with dose-limiting exposure. The calculated weekly exposure of the 50 mg q.d. dose was >2-fold higher than the 35 mg dose administered 5x/week, with a weekly AUC of 243 µM h versus 96 µM h. Our preliminary PK data showed plasma levels at doses of 22.5 mg and above achieved the concentrations required to inhibit PRMT5 in our preclinical in vitro and in vivo models, and hence support continued clinical development. We believe our optimal dose will be between 22.5 mg and 50 mg.

Table 2. Preliminary Day 1 Pharmacokinetics in Solid Tumor Cohort

Cmax means the observed maximum plasma concentration after dosing. Tmax means the time to reach the Cmax. AUC0-t means the area under the plasma concentration time curve from time 0 to the last measurable time point.

Pharmacodynamic Data: Group A (Solid Tumors)

Serum sDMA levels, a PD measurement of PRMT5 target engagement, were assessed at baseline and on Day 15 of the treatment cycle. Dose-dependent inhibition of PRMT5 as demonstrated by serum sDMA reduction was observed across groups in the solid tumor cohort. The mean reduction in sDMA level was approximately 75% at both the 35 mg q.d. and 50 mg q.d. doses, which are the highest dose groups evaluated as of September 1, 2020, demonstrating maximum inhibition of PRMT5 activity. In the other cohorts where the dosing was intermittent (b.i.w. and 5x/week doses), serum for sDMA analyses was collected at least 72 hours after the last dose of PRT543 was administered. Therefore, the extent of PRMT5 inhibition was likely underestimated due to rebound in sDMA when the compound is no longer present. In preclinical models, 50% inhibition of sDMA was associated with anti-tumor activity in vivo.

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Figure 12. PRT543 PD in Solid Tumors

Serum was obtained from patients at various times following administration of PRT543 and analyzed for sDMA levels by LC/MS. The data are shown as % relative to pre-dose levels.

Interim and Preliminary Efficacy Data: Group A (Solid Tumors/NHL)

Thirty patients have been enrolled into Group A (solid tumors/NHL). Thirteen patients have received doses ≥ 35 mg 5x/week and are response evaluable per RECIST 1.1. Of these patients, one patient demonstrated confirmed CR (HRD+ high grade serous ovarian cancer), four patients demonstrated stable disease (including an additional patient with HRD+ ovarian cancer) and four patients showed progressive disease. Seven patients remain on study, of whom four are awaiting their first response assessment. No objective responses were observed in patients that received doses below 35 mg 5x/week. Given that we are still in the dose escalation portion of a Phase 1 clinical trial in a refractory patient population, with the primary objective of evaluating safety and pharmacokinetic properties, and that a majority of patients are likely to be at subtherapeutic doses, we are encouraged by the confirmed CR in the first enrolled biomarker positive patient. The patient, diagnosed in 2014, and subsequently treated with seven prior lines of therapy for metastatic disease, including standards of care such as a PARP inhibitor, as well as experimental therapies, enrolled in the dose escalation portion of the trial at a dose/schedule of 35 mg, 5x/week. Genomic analysis demonstrated mutations in the DNA repair enzymes, RAD51D, ATR and BRCA1. At baseline, the patient was noted to have one target lesion lymph node, per RECIST, measuring 19mm across the shortest axis. Baseline CA-125 tumor marker levels measured 37.8 U/mL. At the first follow up response assessment, occurring eight weeks after enrollment, the patient’s target lesion demonstrated regression to 8mm with an associated drop in CA-125 levels to 2.6 U/mL. At the second follow up scan performed 16 weeks after enrollment, the target lesion regressed in size to 5 mm, confirming the CR. CA-125 levels measured 4.6 U/mL. At the third response assessment, performed 24 weeks after enrollment, the patient’s target lesion remained at 5 mm, further supporting the durability of the CR, and CA-125 levels measured 3.3 U/mL. The patient remains on study. Images from the patient’s computer tomography scans from baseline and 8 weeks, with highlighted target lesions, are shown below in Figure 13.

Figure 13. Baseline and 8 Week Tumor Assessment CT Scans

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Group B (MF and MDS)

Pharmacokinetic and Pharmacodynamic Data: Group B (MF and MDS)

As of the data cutoff, preliminary PK data were available for 11 participants in this cohort (mean values shown in Table 3). As of September 1, 2020, the PRT543 PK profiles have been similar between solid tumor and MF and MDS patients demonstrating rapid absorption and dose-proportional increases in exposure. Exposures were generally similar between Day 1 (first dose of cycle) and Day 25 (last dose of cycle). Our preliminary PK data showed plasma levels at doses of 20 mg and above that achieved the concentrations required to inhibit PRMT5 in our preclinical in vitro and in vivo models, and hence support continued clinical development.

Table 3. Preliminary Day 1 Pharmacokinetics in Myeloid Malignancies Cohort

Similar to the data in the solid tumor cohort, dose-dependent inhibition in sDMA levels was observed in the heme cohort. A maximum inhibition of approximately 40% was observed at the 40 mg doses, but since only intermittent dosing was tested in this cohort, this reduction may be underestimated due to the sample collection 72 hours after the compound was administered.

In addition to changes in sDMA, changes in cytokine levels and other markers of inflammation were measured in the patients in this cohort. Patients with MF have been shown to demonstrate elevated levels of inflammatory markers such as C-reactive protein, serum amyloid A, interleukin-6, tumor necrosis factor, and interleukin-12. PRT543 treatment was associated with reductions in these markers.

Based on the PK and PD data, we anticipate that an additional two to three dose levels, as originally planned, will be required in order to establish a recommended expansion dose in this cohort.

Interim and Preliminary Efficacy Data: Group B (MF and MDS)

Among the 11 patients enrolled into Group B (nine MF and two MDS), all are evaluable for response assessments as per IWG criteria. One MF patient at the 20 mg b.i.w. dose level has demonstrated an objective response of clinical improvement and continues to receive therapy beyond one year to date. A second MF patient at the 40 mg t.i.w. dose level demonstrated an approximately 66% decrease in TSS. Several other MF patients have demonstrated reductions in individual symptoms, notably pruritis, night sweats and fever. Eight patients achieved a best response of SD. We are encouraged by the extended duration of therapy in two additional patients who remained on study for approximately one year.

Clinical Update as of December 16, 2020

As of December 16, 2020, the Phase 1 clinical trial of PRT543 has currently enrolled 61 patients (42 with advanced solid tumors, one with NHL, 11 with MF and seven with MDS). The overall safety profile is unchanged from the September 1, 2020 data cutoff and consistent between both Groups A and B. The majority of drug related adverse events continue to be grade 1-2 with anemia and thrombocytopenia being the most common grade 3-4 adverse events. Thrombocytopenia is the only dose-limiting toxicity. There have been no patients that have discontinued due to adverse events. Amongst the 61 patients, 24 SAEs have been reported amongst 11 patients, with 3 individual SAEs deemed drug related. No drug-related SAEs occurred more than once throughout the study.

We have initiated the ACC expansion cohort of the trial at a dose/schedule of 35mg 5x weekly with the opportunity for intra-patient dose adjustment. Additionally, we have explored both 25mg q.d. and 45mg 5x weekly doses/schedules in the escalation phase, which may enable a dose titration algorithm in expansion. Enrollment into additional solid tumor and myeloid malignancies cohorts is expected to begin early in the second quarter of 2021.

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Addressable Oncology Market for PRT543

Our clinical development strategy is to focus first on indications where there is a patient selection strategy along with a high unmet medical need, no approved therapies and opportunity to utilize early clinical data to design registrational trials. Based on these criteria, the following are examples of indications where we believe we have significant opportunity. In addition to the indications outlined below, we believe there may be opportunity in additional indications in patients with genomically defined tumors.

Adenoid Cystic Carcinoma (ACC)

Adenoid cystic carcinoma is a malignant tumor of the secretory glands often presenting in the oral cavity and pharynx (e.g., salivary glands), with approximately 1,200 patients diagnosed in the United States each year and 10-15,000 patients living with this cancer in the United States. ACC is characterized by indolent, locally invasive growth with a high propensity for recurrence and distant metastasis. The disease typically follows a slow course, with five-, ten-, and 15-year survival rates after surgical resection of 77.3%, 59.6%, and 44.9%, respectively. However, once ACC becomes metastatic, the prognosis worsens and most patients ultimately die from the disease. ACC affects a relatively young patient population, with a median age at diagnosis of 50-60 years.

The vast majority of patients are initially treated with surgical resection, if possible, followed by radiation. Approximately 40-50% of patients progress to develop advanced or metastatic disease. Chemotherapy and tyrosine kinase inhibitor therapies are the most common systemic therapies for advanced/metastatic disease, yet have shown low response rates and limited durability of disease control in clinical trials. There are currently no approved therapies for the treatment of ACC.

Homologous Recombinant Deficient Tumors (HRD+)

Homologous recombination deficient positive tumors were described for the first time in cancers with germline mutations of the tumor suppressors BRCA1/2. Other genetic and epigenetic events can also result in inactivation of various homologous recombination repair components, leading to HRD+ in non-BRCA1/2 mutated cancers.

Germline BRCA1/2 mutations resulting in HRD+ occur in 13% and 15% of ovarian and triple negative breast cancers. Furthermore, 50% and 40% of ovarian and TNBC, respectively, are characterized by harboring HRD+ in the absence of germline BRCA1/2 mutations. Additionally, 10–12% of advanced prostate cancer harbor germline or somatic BRCA2 inactivation and up to 25% contain a DNA repair defect.

BRCA1/2-mutant cancers are sensitive to PARP inhibitors, a class of drugs that block single-strand break DNA repair, favoring accumulation of double-strand breaks that tumors harboring HRD+ cannot repair. Several PARP inhibitors have been approved for the treatment of HRD+ ovarian, breast, prostate, and pancreatic cancers and generated over $1.6 billion of revenue in 2019. There are currently no approved therapies for patients who progress on PARP inhibitors.

Myelofibrosis (MF)

Myelofibrosis is part of a group of progressive blood cancers known as MPN. Approximately two-thirds of the 16,000-18,500 MF patients in the United States are classified as intermediate / high risk and are therefore eligible for systemic treatment. MF is associated with significantly reduced quality of life and shortened survival. As the disease progresses and the bone marrow produces fewer red blood cells, patients experience thrombocytopenia (low platelet counts) and anemia (low red blood cell counts) requiring increasing blood transfusions. Patients with MF suffer from multiple physical symptoms including splenic enlargement, excessive sweating, shortness of breath, bone pain, and fatigue. Demonstrated improvement in the Myelofibrosis Symptom Assessment Form TSS, which is comprised of six specific symptoms associated with MF (abdominal discomfort, pain under the left ribs, an early feeling of fullness, night sweats, bone and muscle pain and itching), has served as a key clinical endpoint in MF trials.

The current standard of care therapy for intermediate- and high-risk MF patients is ruxolitinib, a JAK1/JAK2 inhibitor that inhibits dysregulated JAK. Ruxolitinib revenues in MF were $1.6 billion in 2019. However, patients with anemia and/or thrombocytopenia are ineligible to receive ruxolitinib. Additionally, most patients will experience disease progression on ruxolitinib within three to five years.

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Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes are a group of blood disorders in which bone marrow becomes dysplastic or defective. The affected bone marrow produces aberrant blood cells, resulting in cytopenias (low healthy blood cell counts) that require transfusions. Bone marrow failure is progressive, and in advanced stages of the disease, blasts (immature blood cells) leave the bone marrow and enter the blood stream, leading to AML in approximately one-third of patients.

The American Cancer Society estimates the annual incidence of MDS to be more than 10,000 cases, and studies suggest the prevalence of MDS to be more than 60,000 cases in the United States. Various risk criteria are used to stratify MDS patients, including the French-American-British classifications and the Revised International Prognostic Scoring System, with higher risk MDS patients having a median survival of less than two years. Approximately one-third of MDS patients in the United States are classified as higher risk.

The standard of care treatment for higher risk MDS includes hypomethylating drugs azacitidine and/or decitabine. A significant number of higher risk MDS patients fail or cannot tolerate treatment with azacitidine or decitabine, and almost all patients who initially respond to therapy eventually relapse. Median survival time of MDS patients who have progressed on hypomethylating drugs is less than six months.

Uveal Melanoma (UM)

Uveal melanoma, or UM, is the most common primary intraocular malignancy in adults and comprises 5% of all melanomas. UM is an orphan disease with an estimated annual incidence in the United States and Europe of 6 per million population per year.

Localized treatment for UM, including radiotherapy, phototherapy, and local tumor resection, aims to preserve the eye and vision while preventing metastases. However, surgical removal of the eye can be indicated depending on the tumor size, position, and risk of metastasis. Almost 50% of patients with uveal melanoma will develop distant metastasis. The liver is the most common site of metastasis and is involved in 90% of patients who develop metastatic disease. The median survival of uveal melanoma patients with liver metastases is reported to be five to six months, with a one-year survival of 10% to 15%.

While there have been numerous recent therapeutic advancements and approvals for patients with metastatic cutaneous melanoma, the situation for patients with metastatic uveal melanoma is quite different. Several targeted therapies and immunotherapies have been studied in patients with uveal melanoma; however, response rates have been low (<10%) with median overall survival ranging from 4 to 15 months.

PRT811

Overview

Our second PRMT5 inhibitor, PRT811 is currently advancing in the dose escalation portion of a Phase 1 clinical trial in solid tumors, including GBM and PCNSL. PRT811 is designed to be a highly potent, selective and orally bioavailable molecule optimized for high brain exposure and hence we believe is uniquely positioned to treat PRMT5-sensitive CNS cancers. Upon characterizing PK, PD and safety profile and selecting a recommended dose, we plan to begin enrolling patients, including patients with GBM and other CNS cancers determined to be sensitive to PRMT5 inhibition, in the expansion portion of the clinical trial. We expect these expansions to initiate by mid-2021 and anticipate initial clinical results from this trial by the end of 2021.

Preclinical

In vitro potency and selectivity

We investigated the in vitro potency of PRT811 to inhibit the methyltransferase activity of human recombinant PRMT5 by measuring its IC50. In this assay, we observed the IC50 of PRT811 to be 3.9 nM. We also investigated the in vitro selectivity of PRT811 for PRMT5 as compared to a panel of 36 other human methyltransferases. When tested at a concentration >1,000 times above its IC50 for PRMT5, we observed that PRT811 exhibited minimal inhibition of PRMT7 (53.9% at 10 µM) and no inhibition of any other human methyltransferase tested.

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We determined the potency of PRT811 to inhibit PRMT5 in cells by measuring levels sDMA, a direct measure of PRMT5 activity. Tumor cell lines were treated in vitro with various concentrations of PRT811 for three days and the PRT811 IC50 value to inhibit sDMA determined. We observed that PRT811 potently and dose-dependently reduced sDMA levels in the U87 glioblastoma cell line with an IC50 value of 17 nM (Figure 14). The potency of PRT811 in blocking sDMA levels was confirmed in 11 additional cell lines, with IC50 values in the range of 7-40 nM. These data demonstrate on-target effects of PRT811 in cells.

Figure 14. PRT811 is Highly Selective and Demonstrated Potent Inhibition of sDMA in Cells

Concentration-dependent inhibition of cellular sDMA by PRT811 in U-87 MG cells following three days of treatment in culture. sDMA IC50=17 ± 1 nM (n=12).

We investigated the potency of PRT811 to inhibit the proliferation of a panel of cell lines representative of brain cancers as well as cancers known to have a high rate of brain metastasis (breast, lung, melanoma and hematological malignancies including lymphoma). Tumor cell lines were treated with various concentrations of PRT811 and the number of viable cells was measured after ten days in culture. Consistent with its effects in blocking sDMA levels, PRT811 inhibited the growth of the majority of cell lines in the panel with nanomolar potencies, demonstrating its broad anti-tumor effects in vitro (Figure 15).

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Figure 15. Broad Antiproliferative Activity of PRT811 in a Cancer Cell Line Panel

Waterfall plot showing anti-proliferative activity of PRT811 against a panel of 87 cell lines. Cell panel consists of brain cancer cell lines, as well as breast, lung, and melanoma cells lines, the predominant cancer types that metastasize to the brain.

Preclinical pharmacokinetic profile

The PK profile of PRT811 was characterized in vitro and in vivo in multiple preclinical species including rat, dog and monkey. PRT811 was observed to have good oral bioavailability and high permeability and was not a substrate for P-glycoprotein, or P-gp, and other efflux mechanisms that typically result in low brain exposure. These data suggest PRT811 is not likely to have high efflux out of the brain due to transporters such as P-gp, an important feature of brain penetrant compounds. Accordingly, we observed that the brain exposure of PRT811 in rats after an IV infusion was high with an approximate brain/plasma ratio of two (Table 4). Although both compounds have equivalent potency to inhibit GBM cell line U87 proliferation, the brain:plasma ratio was approximately 100x higher for PRT811 compared to the GSK PRMT5 inhibitor currently in development, providing a clear differentiation for PRT811.

Table 4. Comparison of Cellular Potency and Brain to Plasma Ratio of PRT811 vs. GSK3326595

Concentration-dependent inhibition of U87 glioblastoma tumor cell proliferation in vitro following 10 days of treatment with PRT811 or GSK3326595. Concentration (total) of PRT811 and GSK3326595 in rat plasma and brain following a 4-h IV infusion at 5 mL/h/kg. Data are expressed as mean concentration (±SD) in naïve male animals (n = 3 per time point).

The ability of a compound to effectively achieve high brain exposures has been highlighted most recently by the significantly improved activity of brain penetrant kinase inhibitors compared to their non-brain penetrant counterparts in patients with CNS cancers or with CNS metastasis. In addition, a clear role for PRMT5 inhibition in CNS cancers such as glioblastoma has been demonstrated in preclinical models. Glioblastoma has been shown to be highly dependent on correct mRNA splicing for growth and to have alterations in MTAP and cyclin D1, all markers of enhanced sensitivity to PRMT5

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inhibition. High PRMT5 expression has been shown to reduce GBM median survival from over 700 days to approximately 100 days. Together, these data provide a clear rationale for selecting PRT811 for development in CNS cancers.

PRT811 activity in models for GBM

In vivo, we investigated the ability of PRT811 to reduce sDMA levels in tumor tissues in the U-87MG GBM xenograft tumor model. Tumor-bearing mice were dosed orally once daily for 25 days with either 20 or 30 mg/kg of PRT811. PRT811 at both dose levels demonstrated significant anti-tumor activity in the U-87MG model with 91% inhibition at the 20 mg/kg dose and 100% inhibition at the 30 mg/kg dose (Figure 16). At the 20 mg/kg dose, the plasma concentrations of PRT811 were above the protein binding adjusted in vitro IC50 value observed in the sDMA cellular assay for approximately six hours, suggesting that continual enzyme inhibition is not required for activity in the model.

Figure 16. PRT811 Inhibited Tumor Growth in the U-87MG Subcutaneous Xenograft Model

Nude rats bearing subcutaneously implanted U-87 MG tumors were dosed orally with 20 or 30 mg/kg PRT811 q.d.. Significant antitumor activities were observed at both doses (tumor regression for 30 mg/kg). *: P< 0.05; **: P< 0.01. Student’s t test, 2 tailed. N=8/arm mg/kg, milligrams/kilogram; PO, oral; q.d., once daily; SEM, standard error of the mean.

Since PRT811 was shown to have brain penetration, the effects of PRT811 treatment on sDMA levels in an orthotopic U-87MG model were also assessed. In this model, the U87 glioblastoma cells were implanted directly in the brain. This model requires compound penetration into the brain in order for the compound to inhibit tumor growth. PRT811 was dosed orally once daily for seven days at 80 mg/kg and sDMA levels measured by immunohistochemistry in the brain tumor tissues. We observed that PRT811 reduced sDMA levels in brain tumor tissues by approximately 50% (Figure 17), indicating that it effectively penetrated the brain tumor tissue and inhibited cellular PRMT5 activity in the brain tumor.

Figure 17. PRT811 Decreased sDMA Levels in the U87 Orthotopic Model

Mice bearing orthotopic U-87 MG tumors were treated with vehicle or PRT811 (80 mg/kg, BID) for one week. Whole brain sections (FFPE) were stained with H&E or sDMA antibody.

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In summary, PRT811 was shown to have high brain exposure, to inhibit PRMT5 activity in a brain tumor model and to demonstrate significant anti-tumor activity in vivo. No evidence of CNS toxicity was observed in preclinical toxicology studies. Together, these data support the exploration of PRT811 in cancers, including in GBM, PCNSL and other CNS cancers.

Clinical Experience

All data are reflective of a data cutoff of September 1, 2020 unless otherwise stated.

Data is available from 17 patients (ten with solid tumors, six with glioma, one with diagnosis pending) from the dose escalation portion of the ongoing Phase 1 clinical trial of monotherapy PRT811. The safety profile consists predominantly of Grades 1-2 adverse events and was similar across both solid tumor and glioma patients. As of September 1, 2020, no dose limiting toxicities have been seen. PK/PD analysis reveals dose-dependent increases in drug exposure across doses and schedules with associated decreases in sDMA levels. The dose escalation portion is ongoing. The dose expansion portion of the study is expected to begin in the second half of the year.

Clinical Trial Design and Schema

This is a multicenter, open-label, dose-escalation, dose-expansion Phase 1 clinical trial of PRT811. Enrollment into the dose escalation portion of the clinical trial includes patients with R/R solid tumors, PCNSL, and /or high-grade gliomas. Enrollment initiated in November 2019 and is being conducted across seven sites in the United States. We anticipate initiating enrollment of the dose expansion portion of the clinical trial in two patient cohorts consisting of patients with GBM and R/R PCNSL, respectively, by mid-2021. The total expected enrollment is approximately 60 patients.

Figure 18. PRT811 Clinical Trial Schema

Interim and Preliminary Clinical Data

Interim and Preliminary Results: Dose Escalation

As of September 1, 2020, the safety profile among 17 patients demonstrated that PRT811 has been well tolerated at the doses and schedule ranging from 15 mg to 200 mg (q.d. two weeks on/one week off). There were no deaths or study discontinuations related to PRT811. A total of five SAEs have been reported amongst five patients and of those, none were deemed related to PRT811.

The most commonly reported adverse events, regardless of causality, include constipation (29.4%), nausea (23.5%), vomiting (11.8%) and hyponatremia (11.8%). When examining drug-related adverse events, nausea (17.6%) was most reported. It should be noted that the vast majority, 91.8%, of these adverse events were Grades 1-2 and adverse effects of this type and grade are routine amongst cancer patients and can be medically managed with relative ease.

No dose limiting toxicities have been observed as of September 1, 2020.

Of the 17 patients including six GBM patients evaluated as of September 1, 2020, one patient has demonstrated evidence of tumor size reduction by MRI evaluation. This patient with recurrent GBM, who was originally diagnosed and treated with surgery and chemoradiation with Temodar in July 2019, presented with progressive disease in June 2020. The

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patient initiated study therapy with PRT811 in July 2020 and was placed into the 200 mg (q.d. two weeks on/one week off) dose cohort. The patient’s tumor is positive for IDH1(R132H) mutation and negative for methylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter. Baseline MRI scans revealed a single target lesion, per response assessment in neuro-oncology (RANO) criteria, measuring 23 mm by 10 mm. In September 2020, we were notified that at the patient’s first follow-up scan performed on week seven, the lesion measured 13 mm by 6 mm, representing a 66% decrease from baseline. T2/FLAIR (fluid-attenuated inversion recovery) sequence, measured as a standard part of GBM MRI evaluation, was stable. The patient has not been treated with steroids or Avastin and their clinical status is stable. The patient remains on study with follow-up MRI evaluations to be conducted approximately every eight weeks. Figure 18.1 below shows baseline and the first follow up MRI images of the patient’s lesion.

Figure 18.1

Pharmacokinetic and Pharmacodynamic Data

As of the data cutoff, preliminary PK data were available for 17 patients administered PRT811 at one schedule (q.d. two weeks on/one week off). Mean data are shown in Table 5.

We observed that PRT811 demonstrated rapid absorption with dose-proportional increases in exposure. Half-life values for different doses are similar, ranging from two to four hours, as predicted by preclinical data. The maximum plasma concentration, or Cmax, at the 120 and 200 mg doses reached the estimated IC50 for PRMT5 inhibition. Consistent with the PK, the maximum sDMA inhibition observed, as an indicator of target engagement, was approximately 50% at the 120 and 200 mg dose levels. Based on the current PK and PD, two to three additional cohorts are anticipated, as originally planned, to reach the recommended expansion dose. Our preliminary PK data showed plasma levels at doses of 120 mg and above achieved the concentrations required to inhibit PRMT5 in our preclinical in vitro and in vivo models, and hence support continued clinical development.

Table 5. Preliminary Day 1 PRT811 Pharmacokinetics

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Clinical Update as of December 16, 2020

As of December 16, 2020, the Phase 1 clinical trial of PRT811 has enrolled 24 patients (eight with GBM, and 16 with advanced solid tumors). The overall safety profile is unchanged from the September 1, 2020 data cutoff. Four patients have each experienced one SAE, none of which were attributed to study therapy. No dose limiting toxicities have been observed as of December 16, 2020. There has been one patient that has discontinued study therapy due to transient Grade 2 nausea occurring immediately after ingestion of study therapy.

The 300mg q.d. dose cohort is currently ongoing. We expect to initiate the expansion portion of the trial in cancers including GBM, PCNSL, and CNS metastatic solid tumors by mid-2021.

Addressable Oncology Market for PRT811

Our clinical development strategy for PRT811 is to initially focus on CNS indications where there is a patient selection strategy along with a high unmet need, no approved therapies and opportunity to utilize early clinical data to design registrational trials. Based on these criteria, the following are examples of indications where we believe we have significant opportunity. Additionally, we may explore the activity of PRT811 in CNS metastatic disease, which impacts approximately 200,000 patients annually in the United States.

Glioblastoma multiforme (GBM)

Glioblastoma multiforme is the most common malignant primary brain tumor making up 54% of all gliomas and 16% of all primary brain tumors. It is the most aggressive diffuse glioma tumor of astrocytic lineage and under WHO classification is considered a grade IV glioma. Each year, there are approximately 10,000 patients diagnosed with GBM in the United States. GBM remains an incurable tumor with a median survival of only 15 months. Fewer than five percent of GBM patients live beyond five years.

GBMs can be classified into primary and secondary GBMs. Primary GBM occurs de novo without evidence of a less malignant precursor, whereas secondary GBM develops from initially low-grade diffuse astrocytoma (WHO grade II diffuse astrocytoma) or anaplastic astrocytoma (Grade III). The majority of GBMs (90%) are primary and patients with primary GBM tend to be older (mean age = 55 years) than those with secondary GBM (mean age = 40 years).

Treatment is mainly palliative, initially consisting of surgical resection followed by radiation therapy and concurrent chemotherapy. Current therapies include GLIADEL Wafers (carmustine implant), TEMODAR (temozolomide) and AVASTIN (bevacizumab), which show virtually no overall survival benefit for recurrent tumors.

Primary CNS Lymphoma (PCNSL)

Primary central nervous system lymphoma is a type of NHL in which malignant lymphatic cells form in the brain and/or spinal cord. PCNSL can also start in the eye (ocular lymphoma) and/or can involve the cerebrospinal fluid (leptomeningeal lymphoma).

PCNSL is a rare malignancy with an annual incidence rate of seven cases per 1,000,000 people in the United States. PCNSL is relatively more common in immunosuppressed populations, particularly among people with human immunodeficiency virus, or HIV, infection or in solid organ transplant recipients. The median age of diagnosis is 55; the median age of HIV-infected patients with PCNSL is 35.

From 1998 through 2011, survival was poor for PCNSL cases, with just 15.8% of HIV-infected cases and 28.9% of HIV-uninfected cases alive five years after diagnosis. There is no standard treatment for PCNSL, however patients often receive a combination of Rituxan (rituximab), temozolomide, and high-dose methotrexate.

MCL1 Inhibitor: PRT1419

Overview

PRT1419 is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1. PRT1419 has been optimized to have the PK properties to allow for either oral or IV administration, providing maximal coverage of the target while maintaining an adequate tolerability window. We believe that the physicochemical and pharmacological properties of PRT1419 allow the optionality of administering PRT1419 by either oral or IV route. Based on our preclinical data, as well as

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published third-party data, we believe that hematological malignancies are particularly sensitive to MCL1 inhibitors. MCL1 upregulation has been noted as a mechanism of acquired resistance to venetoclax and TKIs. In addition, certain solid tumors are responsive to MCL1 inhibition, informing a potential patient selection strategy. Based on data demonstrating that MCL1 is a primary resistance mechanism to BCL2 inhibitors like venetoclax, a combination study with azacitidine or venetoclax in MDS/AML is planned. We have begun enrolling patients with hematologic malignancies, including patients with myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM, into a Phase 1 clinical trial for the oral formulation of PRT1419. We expect to add dose expansion and combination cohorts to this Phase 1 clinical trial in the second half of 2021. Additionally, the FDA recently cleared our IND for an intravenous (IV) formulation of PRT1419. A Phase 1 trial of the IV formulation, which leverages the optimized physicochemical properties of PRT1419, is expected to commence in the first half of 2021 in patients with solid tumors.

Background

The ability to evade cell death is a hallmark of cancer because it is one of the unique acquired abilities that allows malignant transformation of a normal cell. MCL1 and BCL2 are both members of a family of proteins that regulate cell survival versus cell death. Under normal circumstances, MCL1 and BCL2 exert their pro-survival function by binding to and sequestering the pro-death proteins, BAK and BAX, and prevent the activation of a downstream cascade leading to apoptosis (Figure 19). In normal cells, cellular stressors such as DNA damage disrupt this interaction and result in cell death. Cancer cells, however, frequently upregulate pro-survival proteins to prevent activation of the apoptotic pathway, thus evading death. MCL1 has been shown to have a critical role in promoting cancer cell survival and is frequently found to be amplified or overexpressed in both solid tumors and hematologic cancers.

Figure 19. MCL1 Promotes Tumor Cell Survival by Inhibiting Apoptosis

Members of the BCL2 protein family control cell survival and cell death. MCL1, a member of the family, acts to suppress cell death and has emerged as a target for anti-cancer therapy and as a resistance mechanism to the BCL2 inhibitor, venetoclax.

Inhibition of MCL1 expression and/or function is therefore of considerable therapeutic interest in cancer. The importance of blocking the protein-protein interaction between pro-survival and pro-death proteins as a therapy to promote tumor cell death has been clinically validated with the BCL2 inhibitor, venetoclax. Venetoclax was approved in 2016 for R/R patients with CLL and in 2018 for patients with AML. MCL1 is upregulated in response to BCL2 inhibition and has been implicated in mediating resistance to venetoclax, as well as to chemotherapeutic agents and other targeted therapies including TKIs. These studies have demonstrated the potentially broad clinical benefits of targeting cell survival through MCL1 inhibition in cancer.

Small molecule MCL1 inhibitors have been shown to be remarkably efficacious as monotherapy in preclinical models of MM, AML and lymphoma. Treatment with these inhibitors leads to robust activation of apoptosis markers including cleaved caspase-3 and cleaved PARP in vivo and in vitro. Objective clinical responses were demonstrated in a Phase 1

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multiple myeloma clinical trial with AMG176, a third-party MCL1 inhibitor, providing clinical validation of the pathway. MCL1 inhibitors have also demonstrated potent synergistic activity in combination with approved standard of care therapies, including venetoclax, in preclinical models of AML. Although these inhibitors show limited efficacy as monotherapy in solid tumor models, combination with TKIs has resulted in potent anti-tumor effects in triple negative breast cancer, melanoma and non-small cell lung cancer.

Although the data on the importance of MCL1 in driving tumor growth and survival are compelling, complete ablation of Mcl1 has been shown to result in cardiomyocyte apoptosis in mice. Mice with heterozygous deletion of Mcl1 resulting in a 50% reduction in MCL1 protein did not demonstrate cardiac abnormalities. These results suggest that an optimized profile for a pharmacological inhibitor of MCL1 should allow for maximal but limited duration of target engagement rather than prolonged coverage to maximize the therapeutic window of MCL1 inhibition in clinical development.

Our Approach to Designing Optimized MCL1 Inhibitors

We used structure-based design to identify PRT1419 as an inhibitor of human MCL1 that is designed to induce tumor cell death by apoptosis. It has been optimized to have high permeability and adequate solubility to provide suitable PK that allows for oral and IV dosing. We believe these features have the potential to maximize the therapeutic window and overcome some of the limitations of current MCL1 inhibitors, as well as provide the convenience and flexibility associated with oral dosing both as monotherapy and potentially in combination with other oral therapies.

PRT1419

In Vitro Potency and Selectivity

We investigated the in vitro potency of PRT1419 to inhibit the protein-protein interaction of human recombinant MCL1 with the pro-death protein, BIM, by measuring its IC50. In this assay, we observed the IC50 of PRT1419 to be 6.6 nM. We also investigated the in vitro selectivity of PRT1419 for MCL1 as compared to related family members, BCL-2 and BCLXL. We observed that PRT1419 showed >200 times weaker inhibition of BCL-2 and BCLXL compared to MCL1.

Tumor cells undergo apoptosis in response to MCL1 inhibition. Therefore, we investigated the potency of PRT1419 to inhibit the proliferation of cell lines representing both solid tumors and hematologic malignancies. Tumor cell lines were treated with various concentrations of PRT1419 and the number of viable cells was measured after two days in culture. We observed that cell lines representing multiple myeloma, lymphomas and leukemias were particularly sensitive to PRT1419 with IC50 values in the nanomolar range.

Since most MCL1 inhibitors have been shown to be highly bound to proteins in the blood, which reduces their effective concentration, PRT1419 was tested in an assay in the presence of human whole blood and shown to retain its potency to activate markers of apoptosis. In this human whole blood assay, we observed that PRT1419 was significantly more potent (9 times) than other MCL1 inhibitors such as AMG176. Consistent with its improved potency, PRT1419 demonstrated anti-tumor activity in vivo at lower doses than those required for activity with AMG176. These data are summarized in Table 6.

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Table 6. In Vitro Properties of PRT1419 Compared to Other MCL1 Inhibitors

Inhibition of cell proliferation was determined in the OPM2 cell line. Whole blood IC50 represents the half maximal concentration required to induce markers of apoptosis in OPM2 cells cultured in human blood. Permeability was assessed in Caco-2 cells. Intrinsic clearance was determined in human hepatocytes. All competitor compounds were obtained from commercial sources.

Pharmacokinetics

In preclinical assays, PRT1419 demonstrated favorable ADME and PK properties. PRT1419 had high oral bioavailability in mice and dogs, adequate solubility, high permeability, and high intrinsic clearance in human hepatocytes which taken together should favor an optimized PK profile for an oral MCL1 inhibitor in patients.

Anti-tumor Activity in Preclinical Models

In vivo, the pharmacological activity of PRT1419 to induce apoptosis in tumor tissue from the subcutaneous multiple myeloma xenograft tumor model (OPM2) was evaluated. Oral administration of a single dose of PRT1419 led to a dose-dependent activation of apoptosis markers including cleaved caspase-3 and cleaved-PARP in tumor tissue. Consistent with these effects, once weekly administration of PRT1419 demonstrated potent and dose-dependent anti-tumor activity in this model (Figure 20), resulting in tumor regressions. Similar activity was also observed with once weekly dosing of PRT1419 in subcutaneous cell line derived xenograft mouse models of AML (MV4-11) and DLBCL (OCI-Ly7).

Figure 20. Anti-Tumor Activity in Preclinical Models of Hematologic Malignancies

PRT1419 was administered orally to tumor-bearing mice (n=8 animals/group). Data represents mean ± SEM (standard error of the means), QW – once weekly, p.o – oral administration, *** P value<0.001 vs. Vehicle by Mann-Whitney U test

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Since MCL1 is known to be a resistance mechanism in patients treated with the BCL2 inhibitor venetoclax, PRT1419 was studied in combination with venetoclax in the MV411 model of AML. As shown in Figure 22, PRT1419 demonstrated enhanced inhibition in combination with venetoclax, resulting in tumor regression in mice.

Figure 21. PRT1419 Demonstrates Enhanced Activity in Combination with Venetoclax

PRT1419 and venetoclax were administered orally as single agents and in combination to tumor-bearing mice (n=8/group). Data represents mean ± SEM (standard error of the means), Venetoclax was dosed at 50 mg/kg; PRT1419 was dosed at 15 mg/kg; *** P value<0.001 vs. Vehicle by Mann-Whitney U test

In summary, PRT1419 demonstrated potent and selective inhibition of MCL1 in vitro and in vivo that resulted in tumor regressions in preclinical models following once weekly oral dosing. PRT1419 was well-tolerated in 28-day toxicology studies in rats and dogs and showed no evidence of cardiac toxicity. Taken together, these studies support the advancement of PRT1419 into clinical trials in patients with hematologic malignancies.

Clinical Trial Design and Study Schema – Oral Formulation

We have begun enrolling patients with hematologic malignancies, including patients with myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM, into a Phase 1 clinical trial for the oral formulation of PRT1419. We expect to add dose expansion and combination cohorts to this Phase 1 clinical trial in the second half of 2021.

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Figure 22. PRT1419 Clinical Trial Schema

Clinical Update as of December 16, 2020 – Oral Formulation

As of December 16, 2020, the Phase 1 clinical trial of PRT1419 has enrolled four patients with various hematological malignancies. No adverse events above Grades 1 or 2 and no serious adverse events have been observed.

We are currently enrolling AML and high-risk MDS patients into the second dose escalation cohort (200mg 1x weekly).

PRT1419 – IV Formulation

The FDA recently cleared our IND for an intravenous (IV) formulation of PRT1419. A Phase 1 trial of the IV formulation, which leverages the optimized physicochemical properties of PRT1419, is expected to commence in the first half of 2021 in patients with solid tumors.

Addressable Oncology Market for PRT1419

Acute Myeloid Leukemia (AML)

AML is a blood cancer wherein myeloid stem cells proliferate and fail to properly differentiate into mature myeloid cells. AML is the second most common leukemia in adults, with the American Cancer Society estimating an annual incidence of nearly 20,000 patients in the United States.

AML is particularly difficult to treat in adults older than 60 years, who account for more than 60% of patients; thus, fewer than 29% of AML patients live beyond five years. There are significant differences in the treatment of AML based on age and fitness. For younger, fit patients current first-line AML treatment typically involves aggressive chemotherapy followed by stem cell transplantation if possible. For older, unfit patients first- line AML treatment typically involves low dose cytarabine or azacytidine, potentially in combination with VENCLEXTA (venetoclax) or other agents.